CalciMedica, Inc.

We are a clinical-stage biopharmaceutical company focused on developing therapeutics for serious illnesses driven by inflammatory and immunologic processes and direct cellular damage. Our product candidates target calcium release-activated calcium (“CRAC”) channels and, if approved, would represent a new class of therapeutics.

Clinical and preclinical data suggest that inhibition of CRAC channels may have therapeutic potential through a dual mechanism involving modulation of inflammatory signaling and protection of tissue cells from calcium-mediated injury. Dysregulated CRAC channel signaling has been implicated in a range of acute and chronic diseases characterized by immune activation, inflammation, and cellular injury. We seek to leverage our CRAC channel inhibitor platform to develop therapies for indications in which these pathways are clinically relevant.

Our lead product candidate is Auxora, a potent and selective, intravenously formulated small-molecule CRAC channel inhibitor containing the active compound zegocractin (formerly CM4620). Auxora has been evaluated in multiple Phase 2 clinical trials across acute critical care settings, including acute pancreatitis (“AP”), severe COVID-19 pneumonia, and pediatric asparaginase-induced pancreatic toxicity (“AIPT”), and acute kidney injury (“AKI”) with associated acute hypoxemic respiratory failure (“AHRF”). Results from these studies have informed our understanding of the pharmacologic profile of CRAC channel inhibition in acute inflammatory conditions.

We are continuing development activities in AP and have engaged with the U.S. Food and Drug Administration (“FDA”) regarding the design of a potential pivotal program in AP. We expect to finalize the pivotal program design in the first half of 2026.

In January 2026, following a recommendation from the Independent Data Monitoring Committee (“IDMC”), we discontinued the KOURAGE Phase 2 clinical trial evaluating Auxora in patients with AKI and AHRF due to a safety concern relating to a mortality imbalance that warranted reevaluation of study design. The IDMC did not identify evidence of drug-related toxicity, and our comprehensive review, performed in conjunction with external experts, reached the same conclusion. Imbalances in the patients’ severity of disease at baseline may have contributed to the observed safety concern. We plan to discuss the KOURAGE data and potential future development in AKI with the FDA in the second quarter of 2026.

In parallel, we have generated preclinical data supporting the potential application of CRAC channel inhibition in both chronic and acute inflammatory and immunologic diseases. These efforts include animal model data suggesting potential relevance in pulmonary arterial hypertension (“PAH”), chronic pancreatitis, rheumatoid arthritis, ulcerative colitis, allergic asthma, and traumatic brain injury. Our current nonclinical development efforts are focused on CM5480, a CRAC channel inhibitor being advanced for the treatment of PAH, with submission of an Investigational New Drug application (“IND”) currently anticipated in 2027. Depending on financing we also expect to continue selective research activities to further evaluate CRAC channel inhibition across other inflammatory and immunologic indications.

Our Pipeline

Our product candidates are summarized in the table below, including their current stage of development and primary indications:

Clinical Experience with Auxora

We have studied Auxora in multiple clinical trials, including several Phase 2 trials conducted in the United States and internationally across different acute care settings. These studies have evaluated Auxora in diverse patient populations characterized by significant inflammation and organ dysfunction and have provided clinical data regarding the pharmacologic effects of CRAC channel inhibition.

In the CARDEA trial, a randomized, double-blind, placebo-controlled Phase 2 study in patients hospitalized with severe COVID-19 pneumonia with acute respiratory distress syndrome (“ARDS”), treatment with Auxora was associated with a statistically significant 56% relative reduction in all-cause mortality at 30 days compared to placebo (p=0.016). In a post-hoc analysis of 38 patients enrolled in CARDEA who had AKI, defined as an estimated glomerular filtration rate (“eGFR”) ≤ 60 ml/min/1.73 m², and moderate or severe respiratory failure at baseline, treatment with Auxora was associated with a 62.7% relative reduction in mortality at day 30 compared to placebo, which persisted through day 60. Post-hoc analyses are exploratory in nature and are not powered for definitive conclusions.

In CARPO, an international, randomized, double-blind, placebo-controlled Phase 2b trial in patients with AP and accompanying systemic inflammatory response syndrome (“SIRS”), the medium- and high-dose Auxora groups demonstrated a reduction in new-onset severe respiratory failure compared to placebo. Specifically, both dose groups showed a 100% relative risk reduction in new-onset severe respiratory failure versus placebo, with statistical significance observed for each dose group individually (p<0.05) and for the combined medium- and high-dose groups compared to the combined placebo and low-dose groups (p=0.0027).

We also conducted KOURAGE, a randomized, double-blind, placebo-controlled Phase 2 trial evaluating Auxora in patients with AKI and AHRF. In January 2026, following a recommendation from the IDMC, we discontinued the trial due to a safety concern relating to a mortality imbalance that warranted reevaluation of study design. The IDMC did not identify evidence of drug-related toxicity, and our comprehensive review, performed in conjunction with external experts, reached the same conclusion. Imbalances in the patients’ severity of disease at baseline may have contributed to the observed safety concern.

Results from several Auxora clinical trials have been published in peer-reviewed journals or presented at medical meetings. These include results from CARPO, a randomized Phase 2b trial in AP; the open-label Phase 2a trial in AP; the first cohort of patients treated in the investigator-initiated Phase 1/2 CRSPA trial in pediatric AIPT; and both the open-label Part 1 and the blinded, randomized, placebo-controlled Part 2 components of the Phase 2 CARDEA trial in patients with severe COVID-19 pneumonia.

Auxora for the Treatment of Acute Pancreatitis

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Completed Phase 2b clinical trial: We completed CARPO, an international, randomized, double-blind placebo-controlled Phase 2b clinical trial evaluating Auxora in 216 patients with AP and accompanying SIRS. In October 2024, we presented late-breaking and previously announced data from CARPO during a plenary session at the American College of Gastroenterology annual meeting. The trial met its primary objective by demonstrating a statistically significant dose response in median time to solid food tolerance in a prespecified subgroup of patients with hyper-inflamed AP. In addition, the medium- and high-dose Auxora groups showed a reduction in severe organ failure and a 100% relative risk reduction in new-onset severe respiratory failure compared to placebo. This effect was statistically significant for each dose group individually (p<0.05) and for the combined medium- and high-dose groups compared to the combined placebo and low-dose groups (p=0.0027). Patients in the high-dose group also demonstrated an approximately 20% relative risk reduction in new-onset necrotizing pancreatitis compared to placebo and a median time to medically indicated discharge that was 15 hours shorter than placebo. A stratified win-ratio analysis of key clinical endpoints demonstrated a win-ratio of 1.640 in favor of the high-dose Auxora group compared to placebo (p=0.0372).

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Completed open-label Phase 2a clinical trial: We also completed a randomized, open-label Phase 2a clinical trial evaluating Auxora in 21 patients with AP and accompanying SIRS who presented with hypoxemia. Patients treated with Auxora in addition to standard of care (“SOC”) demonstrated improved clinical outcomes compared to patients receiving SOC alone, including a reduced need for mechanical ventilation among patients with severe respiratory failure at enrollment. Results from this trial were published in March 2021 in the peer-reviewed journal Pancreas.

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Ongoing planning for a potential pivotal program: Based on the results of CARPO and prior clinical experience, we expect to finalize the design for a pivotal program in AP in the first half of 2026 and, subject to funding, be in a position to initiate that program later in 2026. Auxora has received Fast Track designation from the FDA and orphan drug designation in the European Union (“EU”) from the European Medicines Agency (“EMA”) for the treatment of AP. However, there is no guarantee that Fast Track designation will result in a faster regulatory review or regulatory approval, if at all.

Auxora for the Treatment of Acute Kidney Injury with associated Acute Hypoxemic Respiratory Failure

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Phase 2 clinical trial. In July 2024, we announced the enrollment of the first patient in KOURAGE, a Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating Auxora for the treatment of patients with Stage 2 or Stage 3 AKI and AHRF receiving oxygen by non-invasive mechanical ventilation, high flow nasal cannula, or invasive mechanical ventilation. In January 2026, following a recommendation from the IDMC, we discontinued the trial due to a safety concern relating to a mortality imbalance that warranted reevaluation of study design. The IDMC did not identify evidence of drug-related toxicity, and our comprehensive review, performed in conjunction with external experts, reached the same conclusion. Imbalances in the patients’ severity of disease at baseline may have contributed to the observed safety concern. We plan to discuss the KOURAGE data and potential future development in AKI with the FDA in the second quarter of 2026.

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Clinical observations supporting development in AKI. Clinical observations from our prior Auxora studies provide supportive evidence for the evaluation of Auxora in AKI. In the CARDEA trial, a Phase 2 study in patients hospitalized with severe and critical COVID-19 pneumonia with ARDS, treatment with Auxora was associated with a 40% reduction in newly reported AKI (a common consequence of COVID-19 pneumonia) compared to placebo. In a post-hoc analysis of 38 patients who enrolled in CARDEA with AKI, defined as an estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73 m², in addition to moderate or severe respiratory failure, which was an inclusion criterion, Auxora treatment was associated with a 62.7% relative reduction in mortality at day 30 compared to placebo, which persisted through day 60. In addition, biomarker analysis from blood samples obtained from more than 190 CARDEA patients demonstrated changes compared to placebo that have been associated with improved endothelial function in prior studies, including increases in angiopoietin-1 and decreases in angiopoietin-2 and D-dimer levels. In CARDEA, changes in these biomarkers were correlated with improved clinical outcomes.

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Preclinical studies supporting development in AKI. Preclinical studies evaluating Auxora in a rat ischemia/reperfusion injury model of AKI demonstrated improvements in kidney function following injury. Animals treated with Auxora showed greater recovery of glomerular filtration rate (“GFR”) compared to placebo-treated animals. In the setting of severe kidney injury, Auxora-treated animals survived, whereas placebo-treated animals did not, supporting the potential role of CRAC channel inhibition in mitigating kidney injury and improving survival in severe AKI.

Auxora for the Treatment of AIPT: Pancreatitis as a Side Effect of Treatment for Pediatric ALL

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Ongoing Phase 1/2 investigator-led clinical trial. CRSPA is an investigator-initiated, open-label Phase 1/2 clinical trial evaluating Auxora in up to 24 pediatric patients in the United States who develop AIPT during treatment for acute lymphoblastic leukemia (“ALL”). The trial is designed to assess the safety and tolerability of Auxora in this setting and to generate additional information regarding its use in critically ill pediatric patients.

The first cohort of nine patients has been completed, and data from this cohort were presented at the American Society of Hematology (“ASH”) annual meeting in December 2023. In this cohort, patients who received a full course of Auxora treatment experienced a more rapid resolution of symptoms compared to matched historical controls. These patients also spent fewer days in the hospital and intensive care unit, and blinded central review of pancreatic imaging showed reductions in the development of significant pancreatic necrosis and overall disease severity compared to historical controls. Specifically, none of the Auxora-treated patients developed greater than 30% pancreatic necrosis at 30 days, compared to 27% of patients in the historical control group. In addition, none of the Auxora-treated patients required total parenteral nutrition (“TPN”), whereas more than 50% of patients in the historical control group required TPN for several weeks on average.

Enrollment is ongoing across an expanded network of trial sites, and we expect to provide a study update in 2026.

Auxora for the Treatment of Acute Respiratory Failure

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Completed Phase 2 clinical trial in hospitalized COVID-19 pneumonia patients. We completed CARDEA, a randomized, double-blind, placebo-controlled Phase 2 clinical trial evaluating Auxora in 284 patients hospitalized in the United States with severe COVID-19 pneumonia with ARDS who were receiving supplemental oxygen but not mechanical ventilation. The primary efficacy analysis included 261 patients with moderate to severe respiratory failure. In this trial, treatment with Auxora was associated with a reduction in time to recovery and a statistically significant 56% relative reduction in all-cause mortality at 30 days compared to placebo (p=0.0165), as well as a 33% relative reduction in mortality at 60 days (p=0.1449). Median time to recovery was seven days for Auxora-treated patients compared to ten days for placebo-treated patients (p=0.098). Results from this study were published in April 2022 in the peer-reviewed journal Critical Care.

CM5480 for the Treatment of Pulmonary Arterial Hypertension

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Preclinical observations for CM5480 in PAH. A preclinical study published in JCI Insightin 2025 has demonstrated that inhibition of Orai1-mediated CRAC channel activity may have therapeutic relevance in PAH. In published studies, CRAC channel inhibition was associated with improvements in pulmonary hemodynamics, attenuation of pulmonary vascular remodeling, and improvements in right ventricular function in established animal models of PAH. These effects are consistent with the known role of CRAC channel signaling in pulmonary vascular smooth muscle cell proliferation, endothelial dysfunction, inflammation, and maladaptive vascular remodeling, all of which are central features of PAH pathophysiology. We believe these findings support further evaluation of CM5480 as a potential therapeutic candidate for PAH.

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Ongoing preclinical development. We are conducting additional preclinical activities to support the advancement of CM5480 toward clinical development for PAH, including studies to further characterize its pharmacology, pharmacokinetic profile, and safety. These activities are intended to support IND-enabling development, with submission of an IND currently anticipated in 2027.

Potential Additional Indications

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Oral CRAC channel inhibitors for chronic inflammatory and immunologic diseases. We have conducted exploratory preclinical research evaluating orally available CRAC channel inhibitors in models of chronic inflammatory and immunologic diseases. These studies suggest that CRAC channel inhibition may have potential relevance in indications such as chronic pancreatitis, rheumatoid arthritis, ulcerative colitis, and allergic asthma. We expect to continue selective research activities to further evaluate CRAC channel inhibition as a potential mechanism in additional inflammatory and immunologic diseases.

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Auxora in preclinical models of ulcerative colitis. Preclinical studies have suggested that CRAC channel inhibition by zegocractin, the active ingredient in Auxora, may have relevance in inflammatory bowel disease. In a mouse model of ulcerative colitis, oral administration of zegocractin every other day for 30 days was associated with a significant reduction in intestinal inflammation. This work was conducted in collaboration with investigators at Charité – University Medicine Berlin and New York University Grossman School of Medicine and was published in EMBO Molecular Medicine in August 2022.

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Auxora in preclinical models of allergic asthma. Zegocractin has been evaluated in mouse models of allergic airway inflammation and influenza A virus infection to assess whether CRAC channel inhibition could reduce asthmatic inflammation without impairing antiviral immune responses. In these studies, oral administration of zegocractin was associated with reductions in peribronchiolar inflammation and lung mucus production in the asthma model, without affecting viral responses in the influenza A model. These findings were published in Science Advances in October 2022.

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CRAC channel inhibition in preclinical models of traumatic brain injury. In a preclinical study using a mouse model of traumatic brain injury induced by controlled cortical impact, inhibition of Orai1-mediated CRAC channel signaling using an Orai1-selective compound was associated with reduced brain damage. These effects were attributed to suppression of microglial activation, a key contributor to neuroinflammation. This work was published in the Journal of Neurotrauma in 2019 and supports the broader role of CRAC channel signaling in inflammatory injury responses within the central nervous system.

Our Strategy

We are a clinical-stage biopharmaceutical company focused on the discovery and development of CRAC channel inhibitors. Our strategy is centered on advancing therapies for acute critical illnesses with high unmet medical need, while selectively expanding our platform into chronic inflammatory and immunologic diseases. We seek to leverage the broad biological relevance of CRAC channel signaling, our differentiated small-molecule chemistry, and our clinical experience to build a focused and scalable pipeline.

Our strategy includes the following key elements:

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Advance Auxora toward potential pivotal development in AP. AP is a serious inflammatory condition with no approved disease-modifying therapies. Based on results from our completed Phase 2a and Phase 2b clinical trials, we expect to finalize the design for a potential pivotal program in AP in the first half of 2026 and, subject to funding, be in a position to initiate that program later in 2026.

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Evaluate potential future development of Auxora in AKI with associated AHRF following the discontinuation of KOURAGE. We are conducting KOURAGE, a Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating Auxora in patients with Stage 2 or Stage 3 AKI and associated AHRF. In January 2026, following a recommendation from the IDMC, we discontinued the trial due to a safety concern relating to a mortality imbalance that warranted reevaluation of study design. The IDMC did not identify evidence of drug-related toxicity, and our comprehensive review, performed in conjunction with external experts, reached the same conclusion. Imbalances in the patients’ severity of disease at baseline may have contributed to the observed safety concern. We plan to discuss the KOURAGE data and potential future development in AKI with the FDA in the second quarter of 2026.

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Advance CM5480 for PAH. We are advancing CM5480, a small-molecule CRAC channel inhibitor, as a potential treatment for PAH. We are currently conducting IND-enabling activities, with submission of an IND application currently anticipated in 2027.

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Generate additional clinical experience with Auxora in pediatric AIPT. We are supporting CRSPA, an investigator-initiated Phase 1/2 clinical trial evaluating Auxora in pediatric patients with asparaginase-induced pancreatic toxicity (“AIPT”). This study is designed to assess safety and tolerability and to generate additional information regarding the use of Auxora in critically ill pediatric patients, with an update expected in 2026.

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Leverage completed respiratory failure studies to inform future development. We have completed Phase 2 clinical trials evaluating Auxora in patients with acute respiratory failure associated with COVID-19 pneumonia, including both non-mechanically ventilated and mechanically ventilated patients. We believe these studies provide clinically relevant insights into the role of CRAC channel inhibition in acute respiratory failure and may inform future development strategies.

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Leverage our CRAC channel inhibition platform across additional indications. CRAC channels play a central role in inflammatory signaling and calcium-mediated tissue injury across multiple cell types. We believe this biology supports the potential application of CRAC channel inhibition in a range of acute and chronic inflammatory and immunologic diseases. While our current development efforts are focused on Auxora and CM5480, we continue selective research activities to evaluate additional indications and compounds within our portfolio.

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Pursue strategic partnerships and licensing opportunities. We believe that development and potential commercialization of Auxora and other product candidates, particularly in acute care settings and international markets, may benefit from strategic partnerships. We are evaluating collaboration and licensing opportunities to support development, commercialization, or geographic expansion of our programs.

Our Team

Our executive team is led by A. Rachel Leheny, Ph.D., our Chief Executive Officer, who has more than 30 years of experience in the life sciences industry as a scientist, venture capital investor, and investment banking research analyst. Kenneth Stauderman, Ph.D., a co-founder and our Chief Scientific Officer, has more than 30 years of experience in drug discovery and development and is a leading expert in CRAC channel biology, having contributed to foundational work in the field. Sudarshan Hebbar, M.D., our Chief Medical Officer, has more than 15 years of clinical development and product development and was previously a practicing nephrologist and critical care physician. Raven Jaeger, MS, our Chief Regulatory Officer, has over 20 years of regulatory affairs experience, including involvement in multiple marketing approvals in serious diseases with high unmet medical need.

Our Science

Essential Roles of Calcium Signaling

Calcium serves as an essential intracellular messenger and plays a critical role in a wide range of biological processes. Within cells, calcium is primarily stored in the endoplasmic reticulum (“ER”), where concentrations are approximately 1,000 to 5,000 times higher than in the cytoplasm. In response to specific extracellular signals, calcium is released from the ER into the cytoplasm, triggering signaling cascades that regulate key cellular functions, including gene transcription, protein kinase signaling, cell growth, differentiation, and division. Under conditions of significant cellular stress, excessive release of calcium from intracellular stores can contribute to cellular injury or cell death.

CRAC Channels

Calcium release-activated calcium (“CRAC”) channels play a central role in replenishing calcium stores within the ER and sustaining calcium-dependent cellular signaling. CRAC channels are composed of two principal proteins: stromal interaction molecule

1 (“STIM1”), an ER-resident calcium sensor, and Orai1, a calcium channel located in the plasma membrane. When calcium levels in the ER decline, STIM1 undergoes a conformational change and activates Orai1, allowing extracellular calcium to enter the cell.

In certain pathological conditions, CRAC channels may become activated in non-physiological ways, such as through toxin-induced or stress-related depletion of ER calcium stores. This can lead to sustained calcium influx and overactivation of downstream signaling pathways.

CRAC channels serve to replenish calcium levels in the ER and to provide calcium for cellular signaling events.

CRAC Channel Signaling in Inflammation and Cellular Injury

The biological consequences of CRAC channel activation depend on the cell type and the magnitude and duration of calcium entry. In immune cells, such as T lymphocytes, CRAC channel-mediated calcium influx is essential for initiating adaptive immune responses and driving the production of inflammatory cytokines. In non-immune tissue cells, excessive calcium entry through CRAC channels can activate pathways associated with cellular injury and death, thereby exacerbating inflammation.

Substantial evidence from in vitro and in vivo studies, including animal genetic models and human genetics, supports the role of STIM1 and Orai1 in calcium homeostasis and immune function. At the phenotypic level, individuals with homozygous loss-of-function mutations in STIM1 or Orai1 develop severe combined immunodeficiency, reflecting the critical role of CRAC channel signaling in immune competence. In contrast, individuals with heterozygous mutations typically do not exhibit overt clinical abnormalities, despite partial reductions in CRAC channel activity.

In lymphocytes, CRAC channels play a critical role in regulating calcium entry that initiates both rapid and sustained immune responses. Within minutes of CRAC channel activation, changes in intracellular calcium levels can inhibit lymphocyte migration while simultaneously promoting immune cell activation. With prolonged calcium signaling, supported by both calcium release from the endoplasmic reticulum and CRAC channel–mediated calcium entry, additional downstream effects occur, including immune cell proliferation, differentiation, and the expression of immune-activated genes, as well as the production of cytokines and chemokines.

Many of these longer-duration effects are mediated through calcium-dependent signaling pathways involving calcineurin and nuclear factor of activated T cells (“NFAT”), which together link elevations in intracellular calcium to transcriptional activation. Calcineurin is a calcium-activated phosphatase that enables NFAT to translocate to the nucleus, where NFAT drives the expression of numerous pro-inflammatory cytokines, including interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), and tumor necrosis factor alpha (“TNFα”). The calcineurin–NFAT pathway is a well-validated immunoregulatory mechanism and is the target of established immunosuppressive therapies such as cyclosporine and tacrolimus.

Increased levels of intracellular calcium mediated by CRAC channels activate a number of inflammatory pathways.

Inflammatory and injury-related diseases, including AP, AKI, acute respiratory failure, and traumatic brain injury, have been associated with activation or overactivation of CRAC channel signaling. Preclinical studies suggest that inhibition of CRAC channels may reduce inflammatory signaling and limit tissue injury in these disease settings. While multiple CRAC channel inhibitors have been described in the scientific literature, relatively few have advanced into clinical development due to challenges related to selectivity, pharmacokinetics, or formulation.

Advantages to Our Approach

We believe CRAC channels represent attractive therapeutic targets because they are expressed on both immune cells, such as T lymphocytes, and critical organ tissue cells, including endothelial cells. Overactivation of CRAC channels can contribute to cellular injury and cytokine-mediated pro-inflammatory processes. In immune cells, CRAC channel signaling serves as a proximal step in the production of pro-inflammatory cytokines, while in tissue cells, excessive calcium influx can drive endothelial instability and cellular damage. We believe the key advantages of CRAC channel inhibition include the following:

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Dual mechanism of action. Our CRAC channel inhibitors are designed to address disease through both direct tissue protection and modulation of inflammatory signaling pathways.

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Upstream modulation of inflammatory pathways. CRAC channel inhibition acts upstream of multiple inflammatory mediators and signaling pathways, including those targeted by established immunosuppressive agents such as cyclosporine. This upstream positioning may allow for coordinated down-regulation of multiple pro-inflammatory cytokines, in contrast to therapies that target a single cytokine.

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Rapid and reversible immunomodulation. Our CRAC channel inhibitors are small-molecule drugs that can provide rapid onset of immunomodulatory activity with the potential for relatively rapid offset, which can allow for rapid recovery of immune function following treatment.

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Relevance across acute critical illnesses. We believe that common biological mechanisms involving inflammation and calcium-mediated tissue injury underlie multiple acute critical illnesses, creating the potential for a single therapeutic approach to be applicable across different disease settings.

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Differentiated formulation capabilities. Our proprietary intravenous lipid nanoemulsion formulation used in Auxora is designed to enhance drug delivery to lipophilic organs, such as the pancreas, lungs, and kidneys, which are commonly affected in acute critical illnesses.

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Potential for chronic disease applications. Certain of our proprietary CRAC channel inhibitors are orally bioavailable, enabling potential use in chronic inflammatory and immunologic conditions.

Auxora, a Selective CRAC Channel Inhibitor

We are developing Auxora, an intravenous formulated small molecule CRAC channel inhibitor, for the treatment of acute inflammatory diseases, including AP, AKI with AHRF and AIPT. We hold worldwide rights to the active ingredient in Auxora, zegocractin. Zegocractin inhibits calcium entry into cells by selectively inhibiting the Orai1-containing CRAC channels. In anin vitro selectivity panel, zegocractin demonstrated high selectivity relative to other ion channels, receptors, and transporters, consistent with the structural distinctiveness of CRAC channels.

Auxora is formulated as an IV lipid nanoemulsion designed to facilitate rapid delivery to lipophilic organ tissues, including the pancreas, lungs, and kidneys, which are commonly affected in acute critical illnesses. The formulation consists of nanometer-sized lipid droplets suspended in an aqueous solution, into which zegocractin is incorporated. Following intravenous administration, the lipid-based formulation enables rapid tissue distribution, which we believe may be important in acute settings where timely inhibition of CRAC channel activity could limit further tissue injury. Auxora was well tolerated in single-dose and multiple-dose Phase 1 clinical trials in healthy adults, as well as in Phase 2 clinical trials in patients with COVID-19 pneumonia and in Phase 2a and Phase 2b clinical trials in AP.

Preclinical Evidence for Anti-Inflammatory Activity of Zegocractin

In vitro studies using activated human peripheral blood mononuclear cells (“PBMCs”), which are predominantly lymphocytes, demonstrated that zegocractin produced concentration-dependent inhibition of the release of multiple pro-inflammatory cytokines, including interleukin-2 (“IL-2”) and interleukin-17 (“IL-17”), when measured at 48 hours. The range of cytokines affected is consistent with the central role of calcium signaling and CRAC channel activation in inflammatory responses.

Zegocractin inhibited the release of broad set of cytokines from activated human PBMCs.

Beyond immune cells, dysregulated calcium signaling has been implicated in cellular injury across multiple organ systems. Excess intracellular calcium in tissues such as the kidney, pancreas, lungs, and nervous system can activate pathways leading to cell damage or cell death, contributing to tissue dysfunction and organ failure. These injury processes can further amplify inflammatory immune responses, exacerbating disease severity.

CRAC channel overactivation drives intracellular calcium excess, immune cell activation, and tissue cell injury across multiple organ systems.

Pharmacodynamic Profile of Auxora

Auxora is a proprietary intravenous lipid nanoemulsion formulation of the small-molecule CRAC channel inhibitor zegocractin. To assess the pharmacodynamic (“PD”) activity of Auxora, we developed an ex vivo assay using blood samples in which IL-2 release is stimulated as a surrogate marker of immune cell activation. This assay is intended to evaluate the immunomodulatory effects of CRAC channel inhibition.

Following administration, Auxora rapidly redistributes from the plasma into lipophilic tissues and is predominantly eliminated through the biliary system. Residual drug in lipophilic tissues is gradually cleared over the course of a few months, resulting in trace plasma concentrations that have not been associated with biological or clinical activity to date. Additional nonclinical and clinical safety assessments are expected to be conducted as part of later-stage development.

Using the IL-2 release assay, Auxora demonstrated a rapid onset of immunomodulatory activity, with inhibition observed within approximately 30 minutes following dosing in blood samples obtained from patients with AP treated with Auxora. Recovery of IL-2 release was observed within approximately 24 to 48 hours after completion of dosing, indicating offset of immunomodulatory activity following cessation of drug infusion.

Auxora has a rapid on-off effect as demonstrated by the onset of immunomodulation after dosing and the recovery of the immune system after the drug infusion is stopped.

We believe that this rapid onset and offset of pharmacodynamic activity may be relevant in acute clinical settings, where transient modulation of immune signaling may be desirable. In a rat pharmacokinetic study, administration of Auxora resulted in high drug exposure in the pancreas, lungs, kidneys, and plasma at two and four hours following initiation of a four-hour infusion. By eight hours, tissue and plasma drug levels declined, consistent with rapid redistribution and clearance.

Administration of Auxora to rats led to rapid increase in drug levels in the pancreas, lung, kidney and plasma.

Potency and Selectivity of Auxora

Zegocractin, the active molecule in Auxora, has demonstrated high potency and selectivity as a CRAC channel inhibitor in in vitro electrophysiological studies conducted in our laboratories, including studies published in the peer-reviewed journal Cell Calcium. As illustrated in the table below, zegocractin potently inhibits Orai1-containing CRAC channels, with 50% inhibition of channel activity observed at nanomolar (“nM”) concentrations.

In contrast, zegocractin demonstrated limited activity against other ion channels, including channels important for cardiac function. For example, zegocractin produced less than 10% inhibition of human voltage-gated calcium channels and human hERG potassium channels at micromolar (“µM”) concentrations, corresponding to a greater than 100-fold selectivity for Orai1-containing CRAC channels. These findings are consistent with the structural and functional distinctiveness of CRAC channels compared to other ion channels.

We believe that the potency and selectivity profile observed for zegocractin supports its further evaluation as a therapeutic candidate. Other compounds within our proprietary CRAC channel inhibitor portfolio have demonstrated broadly similar potency and selectivity characteristics in preclinical assays.

IC50 = concentration producing 50% inhibition of channel activity. Activity of each channel was assessed by electrophysiological (electrical) measurements of either calcium ion (Ca2+) or potassium ion (K+) flow through the indicated channel. The maximum soluble concentration of compound (10 µM) was tested on the cardiac channels.

Auxora for the Treatment of AP

We have evaluated Auxora in two Phase 2 clinical trials in patients with AP and accompanying SIRS, a population at increased risk for severe disease and organ failure. In both studies, treatment with Auxora was associated with improvements in clinically meaningful outcomes related to inflammation, organ function, and recovery.

We have completed CARPO, a randomized, double-blind, placebo-controlled Phase 2b clinical trial in patients with AP and SIRS, which was designed to evaluate dose response and inform the design of a potential pivotal program. We have received Fast Track designation from the U.S. Food and Drug Administration (“FDA”) and orphan drug designation in the European Union from the European Medicines Agency (“EMA”) for Auxora for the treatment of AP. There can be no assurance that Fast Track designation will result in expedited regulatory review or approval.

Based on the results of CARPO and prior clinical experience, we expect to finalize the design for a pivotal program in AP in the first half of 2026 and, subject to funding, be in a position to initiate that program later in 2026.

Acute Pancreatitis Background

AP is an acute inflammatory process of the pancreas that presents as severe upper abdominal pain, often accompanied by nausea and vomiting. The disease is characterized by premature activation of digestive enzymes within pancreatic acinar cells, leading to pancreatic tissue injury, necrosis, and a local inflammatory response that can progress to systemic inflammation.

While many cases of AP are mild and resolve with supportive care, a substantial subset of patients develop moderate to severe disease. In these patients, the inflammatory response can trigger SIRS, resulting in dysfunction of distant organs, most commonly the lungs. Approximately one-third of patients with severe AP develop acute lung injury or acute respiratory distress syndrome (“ARDS”), and respiratory failure accounts for an estimated 60% of AP-related deaths in developed countries.

There are an estimated 300,000 hospitalizations for AP annually in the United States. Mortality in mild AP is less than 1% but increases to approximately 20% to 30% in patients with persistent severe disease. Approximately 50-60% of hospitalized patients with AP present with SIRS and are predicted to have moderate or severe disease, and approximately 30-40% of this group ultimately develop moderate or severe AP. Based on these estimates, we believe that approximately 60,000 patients per year in the United States progress to moderate or severe AP.

AP can progress from mild disease to systemic inflammation and moderate or severe illness, with interrelated complications that include pancreatic necrosis, organ failure, prolonged hospitalization, and increased mortality.

Currently, there are no approved therapies for AP. Standard of care consists of supportive measures, including intravenous fluids, pain control, nutritional support, and close monitoring for the development of organ failure. Patients who develop severe disease remain at risk for prolonged hospitalization, organ failure, long-term complications, and death.

AP has multiple underlying etiologies, most commonly gallstones and alcohol-related injury, which together account for approximately 60% to 80% of cases, with additional causes including hypertriglyceridemia, metabolic disorders, trauma, procedures, medications, genetic factors, and autoimmune disease. Despite these diverse triggers, AP appears to converge on a shared pathological mechanism characterized by dysregulated intracellular calcium signaling within pancreatic acinar cells, leading to cellular injury, enzyme activation, and inflammation.

Excessive signaling through calcium-dependent pathways plays a central role in the pathogenesis of AP. Under normal physiological conditions, pancreatic acinar cells rely on tightly regulated, transient intracellular calcium release to control digestive enzyme secretion. In AP, pathological stimuli lead to sustained elevations of intracellular calcium, resulting in mitochondrial dysfunction, premature intracellular activation of digestive enzymes, and subsequent acinar cell injury and death.

In addition to driving local pancreatic damage, dysregulated calcium signaling contributes to a robust inflammatory response. Injured pancreatic tissue releases inflammatory mediators that activate immune cells and amplify cytokine production, which in some patients progresses to SIRS. This systemic inflammation can result in distal organ dysfunction, most commonly affecting the lungs.

Respiratory complications are a major driver of morbidity and mortality in AP. In patients with severe disease, inflammatory cytokines and endothelial injury increase vascular permeability within the lungs, leading to hypoxemia, acute lung injury, and acute respiratory distress syndrome (“ARDS”). These processes are believed to be mediated, at least in part, by CRAC channel–dependent calcium influx in both immune cells and endothelial cells. As a result, inhibition of CRAC channels has the potential to attenuate both direct pancreatic injury and the downstream inflammatory and endothelial processes that contribute to respiratory failure and other organ dysfunction in AP.

Inhibition of CRAC channels has the potential to impact multiple pathologies associated with AP.

Completed Phase 2a Clinical Trial in Acute Pancreatitis

We completed a randomized, open-label Phase 2a clinical trial of Auxora in 21 patients with AP and predicted moderate or severe disease, as defined by the presence of SIRS and hypoxemia. Fourteen patients received Auxora plus standard of care (“SOC”), and seven patients received SOC alone. Auxora was administered intravenously once daily for up to four days.

Trial design for Auxora AP Phase 2a clinical trial.

Patients with AP are typically unable to tolerate solid food until pancreatic inflammation resolves. At study entry, only one patient in each treatment group was tolerating solid food. After 72 hours, seven of 14 patients treated with Auxora were able to tolerate solid food compared to one of seven patients receiving SOC alone. At hospital discharge, 13 of 14 Auxora-treated patients were tolerating solid food compared to three of seven SOC-treated patients.

AP patients treated with Auxora were able to tolerate food sooner than matched controls.

Auxora was generally well tolerated in the trial. Treatment-emergent adverse events (“TEAEs”) were reported in 12 patients (86%) receiving Auxora and four patients (43%) receiving SOC alone, with most adverse events reported in Auxora-treated patients being mild and resolving or resolved by the end of the study. SAEs occurred in three Auxora-treated patients (21%) and two SOC-treated patients (29%). One death occurred in the Auxora group and was attributed to abdominal compartment syndrome and multi-organ failure. None of the adverse events or SAEs were deemed to be related to Auxora by the principal investigators.

CARPO: Completed Phase 2b Clinical Trial in Acute Pancreatitis

CARPO was a randomized, double-blind, placebo-controlled Phase 2b clinical trial evaluating Auxora in patients with AP and accompanying SIRS. A total of 216 patients were enrolled across 37 clinical centers and randomized 1:1:1:1 to receive high-dose (2.0 mg/kg), medium-dose (1.0 mg/kg), or low-dose (0.5 mg/kg) Auxora, or matching placebo. Study drug was administered intravenously over four hours once daily for three consecutive days. Baseline demographic and disease characteristics were balanced across treatment groups.

The primary objective of CARPO was to evaluate dose response and inform selection of an optimal dosing regimen for future clinical development. The primary endpoint for dose response was time to solid food tolerance, with secondary and exploratory endpoints evaluating organ failure, recovery, and safety. Additional endpoints were assessed to support the construction of a composite endpoint for a potential Phase 3 trial, including mortality, new-onset severe respiratory failure, necrotizing pancreatitis, and time to medically indicated discharge. A stratified win-ratio analysis incorporating these endpoints was also performed.

Trial design for CARPO, Phase 2b clinical trial in AP.

CARPO met its primary objective by demonstrating a dose-dependent improvement in time to solid food tolerance in a pre-specified subgroup of patients with hyper-inflammatory AP. In this subgroup, placebo-treated patients required a median of 4.7 days to tolerate solid food, while patients treated with Auxora demonstrated earlier recovery, with improvements of 1.9 days (41.0% relative reduction) in the high-dose group, 2.1 days (43.6% relative reduction) in the medium-dose group, and 1.5 days (31.0% relative reduction) in the low-dose group. In patients without hyper-inflammatory AP, median time to solid food tolerance was rapid across all treatment groups, limiting the ability to detect a treatment effect.

Auxora treatment was also associated with clinically meaningful reductions in severe organ failure, particularly respiratory failure. New-onset severe respiratory failure was reduced by 100% in the combined medium- and high-dose Auxora groups compared to the combined placebo and low-dose groups (p<0.01). This reduction was also statistically significant when the high- and medium-dose groups were analyzed individually versus placebo (p<0.05). In addition, new-onset persistent respiratory failure was reduced by 64.2% in the combined medium- and high-dose Auxora groups compared to the combined placebo and low-dose groups (p<0.05).

Auxora treatment in CARPO was associated with a dose-dependent reduction in severe organ failure and a complete elimination of new-onset severe respiratory failure at the medium and high doses compared with placebo.

Patients in the high-dose Auxora group also experienced an approximately 20% relative reduction in the incidence of new-onset necrotizing pancreatitis compared to placebo and had a median time to medically indicated discharge that was approximately 15 hours shorter than placebo-treated patients.

Auxora treatment in CARPO was associated with reductions in new-onset necrotizing pancreatitis, faster time to medically indicated discharge, and fewer patients remaining hospitalized over time, consistent with improved resolution of disease severity and accelerated clinical recovery in AP.

A stratified win-ratio analysis incorporating mortality, new-onset severe respiratory failure, necrotizing pancreatitis, and time to medically indicated discharge demonstrated a statistically significant benefit for the high-dose Auxora group compared to placebo, with a win ratio of 1.640 (p=0.0372).

Stratified win-ratio analysis in CARPO demonstrated a statistically significant overall clinical benefit for high-dose Auxora versus placebo, driven by favorable outcomes across key hierarchical endpoints including new severe respiratory failure, necrotizing pancreatitis, and time to medically indicated discharge.

Auxora was generally well tolerated in CARPO. Treatment-emergent serious adverse event rates trended lower with increasing dose, and no drug-related serious adverse events or deaths were observed in patients receiving the high-dose Auxora regimen.

In February 2026, results from CARPO were published ineClinicalMedicine (The Lancet Discovery Science suite).

Implications for Pivotal Program Design in AP

The results of CARPO provide important insights to inform the design of a potential pivotal clinical trial in AP. The observed dose-dependent improvements in time to solid food tolerance in patients with hyper-inflammatory AP, together with reductions in severe and persistent respiratory failure and supportive win-ratio findings, suggest that a future pivotal program may focus on patients at highest risk for severe disease and organ failure. In addition, the consistency of treatment effects observed across multiple clinically meaningful endpoints supports the use of a hierarchical composite endpoint incorporating mortality, respiratory failure, and recovery measures, such as time to medically indicated discharge. The safety and tolerability profile observed in CARPO, including the absence of drug-related serious adverse events at the high dose, further supports evaluation of this dosing regimen in a future pivotal program. We expect to finalize the design for a pivotal program in AP in the first half of 2026 and, subject to funding, be in a position to initiate that program later in 2026.

CRSPA: Ongoing Open-Label Phase 1/2 Clinical Trial in AIPT (Pancreatitis as a Side Effect of Pediatric ALL Treatment)

CRSPA is an ongoing investigator-sponsored, open-label Phase 1/2 clinical trial evaluating Auxora in up to 24 pediatric patients who develop AIPT treatment for acute lymphoblastic leukemia (“ALL”). The study is being conducted by St. Jude Children’s Research Hospital and is designed to assess the safety and tolerability of Auxora in this pediatric population, while also exploring its potential to reduce complications of AP.

AIPT shares key pathological features with AP more broadly, including pancreatic inflammation, acinar cell injury, and systemic inflammatory responses. As a result, we believe findings from CRSPA may provide supportive evidence for the activity of CRAC channel inhibition in pancreatitis across different patient populations.

Preliminary results from the first cohort of nine pediatric patients were presented at the American Society of Hematology meeting in December 2023. In this cohort, Auxora was generally well tolerated, and no drug-related safety concerns were identified. Compared to a matched historical control group, Auxora-treated patients experienced shorter hospital stays, reduced need for intensive care, and no requirement for total parenteral nutrition. Blinded central review of pancreatic imaging also showed reduced severity of pancreatitis and a lower incidence of significant pancreatic necrosis in Auxora-treated patients.

*One patient in matched T16 cohort was unable to be evaluated for pancreatic necrosis or a CTSI score.

CTSI score definitions:

0-3 mild AP

4-6 moderately severe AP

≥7 severe AP

Based on these results, investigators selected the dose used in the initial cohort as the recommended Phase 2 dose. Enrollment is ongoing across an expanded network of trial sites, and we expect to provide a study update in 2026.

Preclinical Studies with Auxora in AP

In preclinical studies, Auxora demonstrated anti-inflammatory and tissue-protective effects in multiple animal models of AP. In a cerulein-induced rat model of AP, administration of Auxora following disease induction reduced pancreatic acinar cell injury and significantly decreased inflammatory markers in both the pancreas and the lung. Specifically, Auxora treatment reduced histopathologic evidence of acinar cell damage by approximately 50% and lowered expression of inflammatory biomarkers, including myeloperoxidase (“MPO”) and the cytokines TNFα and IL-6, by approximately 80–90% in pancreatic tissue. Consistent with the systemic nature of AP, inflammatory markers that were elevated in lung tissue following disease induction were also significantly reduced by Auxora treatment. Results from this study were published in The Journal of Physiology.

Auxora inhibited the expression of MPO, TNFα and IL-6 in the cerulein-induced AP model in both the pancreas and lung.

Consistent with these findings, the active ingredient in Auxora, zegocractin, reduced pancreatic inflammation, edema, and acinar cell necrosis in additional mouse models of AP induced by bile acids (gallstone model) and by fatty acid and ethanol exposure (alcohol model). In both models, zegocractin administered after disease onset reduced histopathologic measures of pancreatic injury by approximately 50%, supporting the role of CRAC channel inhibition across multiple etiologies of AP

Zegocractin decreases pancreatic damage in two models of AP in mice. Shown are histology photomicrographs of the pancreas. The top panels are examples from control animals in both the gallstone (left) and alcohol (right) models showing the presence of inflammatory cells (small dark dots), edema (white areas) and acinar cell necrosis (light red). Bottom panels are from animals treated with Zegocractin, showing reduced inflammation, edema and necrosis. White bars = 50 m.

In addition to reducing pancreatic injury, CRAC channel inhibition preserved pancreatic ductal cell function in animal models of AP. In cerulein-induced, gallstone, and alcohol models of AP, post-insult administration of a CRAC channel inhibitor preserved pancreatic ductal fluid secretion, which is required for normal digestive enzyme and bicarbonate release. Restoration of ductal secretion is considered an important component of disease resolution in AP and may contribute to improved ability to tolerate oral nutrition, a clinically meaningful recovery endpoint evaluated in our clinical trials.

CM5480 (CM-C) treatment led to the preservation of pancreatic ductal secretion in a cerulein-induced AP model.

Auxora for the Treatment of Acute Kidney Injury

Preclinical studies reported in the scientific literature have demonstrated that CRAC channel inhibition can reduce tissue injury in animal models of AKI. We also conducted preclinical studies of Auxora in a rat model of AKI and evaluated clinical outcomes related to kidney function across our studies in acute critical illness.

In July 2024, we announced enrollment of the first patient in KOURAGE, a Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating Auxora for the treatment of patients with Stage 2 or Stage 3 AKI and associated AHRF. In January 2026, the trial was discontinued following a recommendation from the Independent Data Monitoring Committee due to a safety concern. We plan to discuss the KOURAGE data and potential future development in AKI with the FDA in the second quarter of 2026.

Acute Kidney Injury Background

AKI is characterized by an initial injury phase, followed by a recovery phase, and, in some patients, progression to long-term kidney damage. Patients who do not fully recover from the initial injury are at increased risk of developing chronic kidney disease, end-stage renal failure, dialysis dependence, or increased mortality. AKI is classified into Stage 1, Stage 2, and Stage 3 based on changes in serum creatinine and urine output, with Stage 2 and Stage 3 representing more severe disease and higher morbidity and mortality.

AKI commonly occurs in the setting of critical illness, including infection, trauma, and myocardial infarction. In the United States, there are approximately five million ICU admissions annually, and approximately half of these patients develop AKI. Of these, an estimated 1.25 million patients develop Stage 2 or Stage 3 AKI, and approximately 800,000 patients have Stage 2 or Stage 3 AKI with associated AHRF. There are currently no approved disease-modifying therapies for AKI, and standard of care remains supportive.

KOURAGE: Phase 2 Clinical Trial in AKI with Associated AHRF

KOURAGE was a randomized, double-blind, placebo-controlled Phase 2 clinical trial designed to evaluate Auxora in patients with severe AKI and associated AHRF. Patients were stratified by AKI stage and by use of invasive mechanical ventilation at randomization. Auxora or placebo was administered as a four-hour intravenous infusion at a dose of 2.0 mg/kg as an initial dose, followed by additional infusions of 1.6 mg/kg at approximately 24, 48, 72, and 96 hours.

The primary endpoint of KOURAGE was a hierarchical composite analyzed using a win-ratio method that first compares all-cause mortality through Day 30 and then, among surviving patients, compares the number of days alive and free from mechanical ventilation and renal replacement therapy through Day 30. Secondary endpoints included individual assessments of all-cause mortality, ventilator use, dialysis use, and kidney function as measured by estimated glomerular filtration rate (“eGFR”) through Day 90, as well as major adverse kidney events at 90 days (“MAKE-90”).

In January 2026, following a recommendation from the IDMC, we discontinued the trial due to a safety concern relating to a mortality imbalance that warranted reevaluation of study design. The IDMC did not identify evidence of drug-related toxicity, and our comprehensive review, performed in conjunction with external experts, reached the same conclusion. Imbalances in the patients’ severity of disease at baseline may have contributed to the observed safety concern. We plan to discuss the KOURAGE data and potential future development in AKI with the FDA in the second quarter of 2026.

Clinical Observations Supporting the Potential Use of Auxora in AKI

Although the CARDEA trial was designed to evaluate Auxora in patients hospitalized with severe COVID-19 pneumonia, AKI was reported in a number of patients, consistent with the known association between critical respiratory illness and kidney injury. In CARDEA, we observed an approximately 40% reduction in the frequency of newly reported AKI in patients treated with Auxora compared to placebo.

In a post-hoc analysis of 38 CARDEA patients who enrolled with AKI, defined as an eGFR ≤ 60 mL/min/1.73 m², and who also had moderate or severe respiratory failure (an inclusion criterion for the study), Auxora-treated patients experienced a 62.7% relative reduction in mortality at Day 30 compared to placebo, with this difference persisting through Day 60. These analyses were exploratory and not prespecified, and they were not powered for definitive conclusions.

CARDEA Phase 2 COVID-19 pneumonia trial results demonstrating reduced mortality and kidney injury with Auxora, including in a subgroup that enrolled with AKI.

Biomarker Evidence Supporting a Role in Endothelial and Inflammatory Pathways

Biomarker analysis from blood samples obtained from over 190 CARDEA patients further support the potential relevance of CRAC channel inhibition in AKI. Angiopoietin-1, angiopoietin-2, and D-dimer are biomarkers associated with endothelial cell function and vascular integrity. Angiopoietin-1 is associated with maintenance of endothelial stability, whereas angiopoietin-2 and D-dimer are associated with endothelial activation, dysfunction, and thrombosis.

Compared to placebo, patients treated with Auxora demonstrated statistically significant increases in angiopoietin-1 levels and statistically significant decreases in angiopoietin-2 and D-dimer levels. These biomarker changes are consistent with improved endothelial function and reduced endothelial injury, processes believed to play a central role in the pathophysiology of AKI in critically ill patients.

Angiopoietin-1 levels show a statistically significant greater increase in Auxora-treated patients compared to placebo patients while Angiopoietin-2 and D-dimer levels show a statistically greater decrease.

In addition, independent work by others has shown that elevated serum levels of interleukin-17 (“IL-17”), a cytokine regulated by CRAC channel signaling, are disproportionately increased in patients with Stage 2 and Stage 3 AKI and that the degree of elevation is independently associated with both in-hospital mortality and adverse long-term outcomes. These findings provide additional mechanistic support for targeting CRAC channel–mediated inflammatory pathways in severe AKI.

Preclinical Studies with Auxora in AKI

In collaboration with researchers at Indiana University, we conducted preclinical studies evaluating Auxora in a rat ischemia-reperfusion model of AKI. In these studies, Auxora-treated animals demonstrated improvements in glomerular filtration rate (“GFR”) compared to placebo-treated animals. In more severe injury settings, survival outcomes differed between treated and placebo groups. Auxora treatment was also associated with reductions in IL-17 producing immune cells in kidney and lung tissue.

While these findings provided mechanistic rationale for clinical evaluation, preclinical results may not be predictive of clinical outcomes in humans.

Auxora for the Treatment of Acute Respiratory Failure (Supportive Clinical Evidence)

Respiratory failure is a major driver of morbidity and mortality in acute inflammatory diseases, including AP and AKI with associated AHRF. Lung injury in these conditions is characterized by cytokine-mediated inflammation, endothelial dysfunction, and increased vascular permeability—processes in which CRAC channel–mediated calcium signaling plays a central role. We believe that clinical and biomarker findings from our completed COVID-19 pneumonia with ARDS studies provide important supportive evidence for the role of CRAC channel inhibition in reducing respiratory failure across acute inflammatory settings.

Observations from our clinical studies in AP informed our exploration of Auxora in severe COVID-19 pneumonia with ARDS. In our Phase 2a AP trial, patients presenting with markedly elevated interleukin-6 (“IL-6”) levels experienced reductions in IL-6 over the course of treatment when treated with Auxora compared to standard of care alone. IL-6 is a central mediator of systemic inflammation and lung injury and has been strongly associated with disease severity, respiratory failure, and mortality in COVID-19 and other causes of acute lung injury. These findings, together with the role of CRAC channels in regulating cytokine production and endothelial permeability, provided the rationale to evaluate Auxora in severe COVID-19 pneumonia with ARDS as a model of inflammatory respiratory failure.

Completed Phase 2 Clinical Trial in Severe COVID-19 Pneumonia (CARDEA)

CARDEA was a Phase 2, randomized, double-blind, placebo-controlled trial evaluating Auxora in hospitalized adults with severe COVID-19 pneumonia with ARDS requiring supplemental oxygen but not invasive mechanical ventilation. All patients received corticosteroids and nearly all received anticoagulation as part of standard of care. A total of 284 patients were enrolled, including a pre-specified 261-patient efficacy population with moderate to severe hypoxemia (PaO₂/FiO₂ ≤200). The primary clinical findings from the CARDEA Phase 2 trial were reported in April 2022 in the peer-reviewed journal Critical Care.

Trial design for double-blind Phase 2 clinical trial in hospitalized COVID-19 pneumonia patients on oxygen (Part 2).

In the efficacy population, Auxora treatment was associated with clinically meaningful improvements across multiple endpoints related to respiratory recovery and survival. Day-30 all-cause mortality was 7.7% in Auxora-treated patients compared to 17.6% in placebo-treated patients, representing a 56% relative reduction in mortality (p=0.0165). At Day-60, mortality was 13.8% with Auxora compared to 20.6% with placebo, representing a 33% relative reduction. Auxora-treated patients also demonstrated a trend toward faster recovery, with a median time to recovery of seven days compared to ten days with placebo.

Auxora plus SOC demonstrated a significant decrease in mortality compared to placebo plus SOC. (N=261)

Consistent with these clinical findings, Auxora treatment was associated with improvements in oxygenation, reduced progression to ventilatory support, and favorable effects on biomarkers of inflammation and endothelial dysfunction, including reductions in C-reactive protein, ferritin, D-dimer, and CD25 levels. Serious adverse events occurred less frequently in Auxora-treated patients than in placebo-treated patients, and Auxora was generally well tolerated.

Relevance to AP and AKI with associated AHRF Programs

We believe the CARDEA results provide important clinical validation of CRAC channel inhibition as a strategy to mitigate inflammatory lung injury, preserve endothelial function, and reduce progression to severe respiratory failure. Respiratory failure is a leading cause of death in severe AP and in patients with AKI complicated by hypoxemic respiratory failure. Accordingly, the observed reductions in ventilator use, inflammatory biomarkers, and mortality in CARDEA support the mechanistic and clinical rationale for Auxora in these indications, even though we are not currently pursuing standalone development in COVID-19 or ARDS.

CM5480 for the Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (“PAH”) is a progressive and life-threatening disease characterized by elevated pulmonary vascular resistance resulting from pathological remodeling of the pulmonary vasculature, endothelial dysfunction, inflammation, and maladaptive right ventricular hypertrophy and failure. Despite the availability of multiple approved therapies that target vasodilation pathways, PAH remains associated with significant morbidity and mortality, and there remains a need for therapies that address the underlying disease biology.

CRAC channel signaling mediated by Orai1 plays an important role in several cellular processes central to PAH pathophysiology, including pulmonary vascular smooth muscle cell proliferation, endothelial dysfunction, inflammatory signaling, and right ventricular remodeling. Dysregulated calcium influx through CRAC channels has been implicated in pathological vascular remodeling and inflammatory activation that contribute to disease progression in PAH.

A preclinical study in the peer-reviewed journal JCI Insight demonstrated that inhibition of Orai1-mediated CRAC channel activity was associated with improvements in pulmonary hemodynamics, attenuation of pulmonary vascular remodeling, and preservation of right ventricular structure and function in established animal models of PAH. In these studies, CRAC channel inhibition reduced pathological changes in the pulmonary vasculature and improved measures of right heart function, supporting the hypothesis that targeting CRAC channel signaling may have disease-modifying potential in PAH. These findings are consistent with the known role of calcium-dependent signaling in vascular smooth muscle cell proliferation, endothelial activation, and inflammatory responses that drive pulmonary vascular remodeling.

In a monocrotaline (MCT) rat model of established PAH, CM5480 improved cardiac output and reduced right ventricular remodeling both as monotherapy and in combination with standard-of-care therapies, supporting its potential disease-modifying activity in PAH.

CM5480 is an Orai1-selective CRAC channel inhibitor that we are advancing as a potential therapeutic candidate for the treatment of PAH. Based on its pharmacologic profile and the preclinical data supporting CRAC channel inhibition in PAH, we believe CM5480 has the potential to address key biological processes underlying disease progression rather than solely providing symptomatic vasodilation.

We are conducting additional preclinical development activities to support the advancement of CM5480 toward clinical development for PAH, including studies to further characterize its pharmacology, pharmacokinetics, and safety profile. These efforts are intended to support IND-enabling development, and we currently anticipate submitting an IND for CM5480 in 2027.

Preclinical studies for Chronic Inflammatory and Immunological Diseases

In addition to our programs in acute critical illnesses and pulmonary arterial hypertension, we have generated and evaluated preclinical data supporting the potential applicability of CRAC channel inhibition across a range of chronic inflammatory and immunologic diseases. These efforts are intended to demonstrate the breadth of our CRAC channel inhibitor platform rather than to indicate active clinical development programs beyond our current priorities.

We are developing orally bioavailable CRAC channel inhibitors for use in chronic disease settings where intravenous administration would not be practical. In multiple preclinical models, CRAC channel inhibition has demonstrated anti-inflammatory, tissue-protective, and immunomodulatory effects in diseases characterized by dysregulated calcium signaling, immune activation, and tissue injury.

Chronic Pancreatitis

In a mouse model of chronic pancreatitis, CRAC channel inhibition reduced pancreatic fibrosis, preserved acinar and ductal cell function, and improved pancreatic ductal secretion. These findings suggest a potential role for CRAC channel inhibition in chronic pancreatitis, a debilitating disease associated with pain, fibrosis, progressive loss of pancreatic function, and increased cancer risk. We are evaluating chronic pancreatitis as a potential future indication for orally administered CRAC channel inhibitors.

CRAC channel inhibitor reduced acinar cell necrosis (top panels), prevented the formation of fibrosis (bottom left) and restored pancreatic ductal secretion (bottom right) in a mouse model of chronic pancreatitis.

Autoimmune and Inflammatory Diseases

Preclinical studies conducted by others have established a role for CRAC channel inhibition in autoimmune disease. In collagen-induced arthritis (“CIA”) models, both pharmacologic inhibition and genetic modulation of Orai1 have been shown to reduce disease severity (British Journal of Pharmacology, 2015; Journal of Pharmacological Sciences, 2017).

Consistent with these prior findings, we have demonstrated in our own preclinical studies that several of our Orai1-selective CRAC channel inhibitors reduce disease severity in a rat model of CIA. In these studies, oral administration of three of our portfolio compounds resulted in significant reductions in knee joint histopathology compared to vehicle-treated controls. Reductions in histopathologic scores averaged approximately 60-75% across compounds following once-daily oral dosing. In addition, these histopathologic improvements were accompanied by reductions in a pharmacodynamic marker of immune activation, as measured by decreased stimulated interleukin-2 (“IL-2”) release in an ex vivo blood assay.

CM6325 produced significant and dose-related reductions in summed knee histopathology scores (composed of measures of inflammation, pannus formation, cartilage damage and bone resorption) in rat model of collagen-induced arthritis. Blood samples taken at the end of the study showed that a pharmacodynamic (PD) readout, stimulated IL-2 release, was also decreased by CM6325 in a significant and dose-related manner. *p < 0.05.

In models of inflammatory bowel disease, oral administration of a CRAC channel inhibitor reduced intestinal inflammation and inflammatory CD4⁺ T-cell responses; these findings were reported in EMBO Molecular Medicine (2022).

Systemic administration of CM4620 (zegocractin) alleviates colon inflammation in mice. Histological sections of distal and proximal colon were scored for the presence of inflammatory cells (Colitis Score). CD4+ T cells were isolated from animals after treatment with vehicle or CM4620 and stimulated ex vivo with a phorbol ester (PMA) + ionomycin for 4 hours. Frequencies (%) of IFN-g, TNFα and IL-2 T cells were then determined.

In models of allergic asthma, CRAC channel inhibition reduced airway inflammation and mucus production without impairing antiviral immune responses to influenza A virus, as reported in Science Advances (2022).

CM4620 (zegocractin) reduces lung inflammation in a mouse model of allergic asthma but does not compromise adaptive immunity to influenza A virus infection. Lung sections from control and CM4620 treated asthmatic mice were stained with hematoxylin and eosin (H&E) or periodic acid- Schiff (PAS) to detect inflammation and mucus production, respectively. Influenza A virus (IAV) expression was quantified in lung by quantitative RT-PCR of RNA for nuclear segment 5 of IAV (a specific probe for IAV), and is presented as expression relative to the housekeeping gene Rpl32.

Central Nervous System Injury

CRAC channel inhibition has also demonstrated tissue-protective effects in a preclinical model of traumatic brain injury, where treatment reduced lesion size, hemorrhage, and neuroinflammatory responses. These findings were reported in The Journal of Neurotrauma (2019) and further support the role of CRAC channel–mediated calcium signaling in inflammatory tissue injury across organ systems.

CM5480 reduced injury in a traumatic brain injury model in mice.

Summary

Taken together, these preclinical findings reinforce our view that CRAC channel inhibition represents a broadly applicable therapeutic approach across acute and chronic inflammatory diseases. While we are not currently pursuing clinical development in most of these indications, we believe these data highlight the potential versatility of our platform and may inform future research, partnering, or development opportunities.

P-Values and Confidence Intervals

The conventional method for measuring the statistical significance of a result is known as the “p-value,” which represents the probability of obtaining results at least as extreme as those observed assuming the null hypothesis (e.g., no treatment effect) is true. Generally, a p-value less than 0.05 is considered statistically significant and may be supportive of a finding of efficacy by regulatory authorities. However, regulatory authorities, including the FDA, do not rely on strict statistical significance thresholds as criteria for marketing approval and maintain the flexibility to evaluate the overall risks and benefits of a treatment. A confidence interval (“CI”) is a range of values estimated from observed data. It is conventional to present 95% CIs, meaning that, under repeated sampling, the confidence interval procedure would be expected to contain the true value 95% of the time. For measures expressed as differences, the null value is typically 0; for measures expressed as ratios (such as hazard ratios or relative risks), the null value is typically 1.0. If a CI excludes the applicable null value, the result is often considered statistically significant at the corresponding level.

Sales and Marketing

Given our stage of development, we have not yet established a commercial organization or distribution capabilities. We intend to build a commercial infrastructure to support sales of our product candidates. We expect to manage sales, marketing and distribution through internal resources and third-party relationships. While we may commit significant financial and management resources to commercial activities, we will also consider collaborating with one or more pharmaceutical companies to enhance our commercial capabilities. As our future product candidates progress through our pipeline, our commercial plans may change. Clinical data, the size of the development programs, the size of our target markets, the size of a commercial infrastructure and manufacturing needs may all influence our commercialization strategies.

Manufacturing

We do not own or operate manufacturing facilities for the production of any of our product candidates and potential future products, nor do we have plans to develop our own manufacturing operations in the foreseeable future. We currently rely, and expect to continue to rely for the foreseeable future, on contract manufacturing organizations (“CMOs”) for all our required raw materials, drug substance and drug product needs for preclinical research, clinical trials and initial commercialization. We do not have long-term agreements with any of these third parties. We also do not have any current contractual relationships for the manufacture of commercial supplies of any of our product candidates and potential future products and do not plan to enter into any until we are further into clinical development. If any of our products are approved by any regulatory agency, we intend to enter into agreements with a CMO and one or more back-up manufacturers for the commercial production of those products. Development and commercial quantities of any products that we develop will need to be manufactured in facilities, and by processes, that comply with the requirements of the FDA and the regulatory agencies of other jurisdictions in which we are conducting clinical research or seeking marketing approval.

Competition

The pharmaceutical and biotechnology industries are characterized by intense competition and rapid innovation. While we believe that our product candidates, as well as our development experience and scientific knowledge may provide significant advantages relative to current approaches and therapies in the treatment of acute critical illnesses and chronic inflammatory and immunologic diseases, our competitors may be able to develop other compounds or drugs that are able to achieve similar or better results. We face potential competition from many different sources, including large multinational pharmaceutical companies, established biotechnology companies and specialty pharmaceutical companies, and universities and other research institutions. Many of these groups have materially greater financial, manufacturing, marketing, research and drug development resources than we do. Large pharmaceutical companies in particular have extensive expertise in preclinical and clinical testing and in obtaining regulatory approvals for drugs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large, established companies.

We are a clinical-stage biopharmaceutical company focused on developing therapeutics that treat serious acute inflammatory illnesses driven by hyperinflammation processes and direct cellular damage. The molecular targets we are addressing are CRAC channels, and our most advanced clinical candidate, Auxora, is in clinical development for AP, AIPT, and AKI with AHRF. Other companies, including Rhizen Pharmaceuticals AG, Vivreon Biosciences, LLC, Medshine Discovery, Inc., Eldec Pharmaceuticals, and ChemiCare srl, have CRAC channel inhibitors (including both small molecules, peptides, and monoclonal antibodies) in clinical or preclinical development for various indications. Several of these have reached Phase 1 or Phase 2 clinical trials in indications we are not currently pursuing. Any of these companies could elect to re-direct their efforts and compounds to indications we are pursuing.

With respect to AP, we are developing Auxora as a disease-modifying therapy intended to reduce inflammatory injury and organ dysfunction during the acute episode, whereas most other drug treatments and approaches in clinical development focus on addressing symptoms or sequelae (e.g., analgesia, supportive care regimens, antibiotics in selected settings, anticoagulation strategies, nutritional approaches, and other anti-inflammatory or supportive interventions). In addition, certain companies are developing therapies intended to reduce the risk of recurrent pancreatitis in defined metabolic subpopulations, rather than treat AP directly. For example, therapies that lower triglycerides by targeting apolipoprotein C-III (“ApoC-III”) have been approved in the United States for familial chylomicronemia syndrome (“FCS”), a rare genetic disorder associated with markedly elevated triglycerides and risk of pancreatitis, including Ionis’s Tryngolza (olezarsen). Arrowhead also received FDA approval for Redemplo (plozasiran) for FCS, and reported reductions in pancreatitis risk in its clinical program. While such triglyceride-lowering approaches may reduce pancreatitis risk in FCS and certain severe hypertriglyceridemia populations, these patients represent a small subset of the overall AP population, and these strategies are generally focused on prevention of attacks associated with specific etiologies rather than treatment of AP across heterogeneous causes. Other approaches to treat acute pancreatitis include RABI-767, a pancreatic lipase inhibitor from Panafina Inc., currently in a Phase 2 trial, and SCM-AGH, a mesenchymal stem cell treatment from SCM Lifsciences, completing a Phase 1/2 trial.

With respect to AIPT, there is currently no disease modifying treatment for patients who develop pancreatic toxicity as a result of asparaginase treatment for ALL. The current SOC addresses symptoms like pain, the inability to eat, and infection, and withdraws asparaginase, a key component of the ALL treatment regimen.

With respect to AKI with associated AHRF, there are currently no approved disease-modifying therapies. In the area of AKI, most companies in the space are pursuing strategies to prevent AKI in high risk populations. There are two ongoing Phase 2 clinical trials to treat AKI in the setting of sepsis, i.e., sepsis-associated AKI or SA-AKI, one from Novartis (TIN816, a recombinant CD39) and a second from AstraZeneca (AZD-4144, a NLRP-3 inhibitor). Other than these drug candidates, to our knowledge, there are no other novel compounds currently in clinical development in the US that are intended to treat rather than prevent AKI. If, however, a strategy to prevent AKI were to be effective, the number of patients we are targeting for Auxora could decrease.

Our commercial opportunity could be substantially limited in the event that our competitors develop and commercialize products that are more effective, safer, more convenient or cheaper than our product candidates. In geographies that are critical to our commercial success, competitors may also obtain regulatory approvals before us, resulting in our competitors building a strong market position in advance of our product’s entry. We believe the competitive factors that will determine the success of our programs will be the efficacy, safety, pricing and reimbursement, and convenience of our future product candidates.

Intellectual Property

We have developed and continue to expand our patent portfolio for Auxora. As of December 31, 2025, we have issued patents and pending patent applications in the United States and other countries throughout the world directed to compositions of matter, various methods of use, formulations, and synthetic processes. For patents directed to compositions covering Auxora, we own four issued U.S. patents and over 60 issued patents world-wide. We also have one pending U.S. patent application and five pending patent applications in Japan, China and India directed to compositions covering Auxora. Composition of matter patents for Auxora have expirations ranging from 2031 and 2036 with Auxora and other pre-clinical drugs having world-wide composition of matter patents to 2036, not including any patent term adjustment or any patent term extension.

For patents and patent applications directed to methods of using Auxora for the treatment of AP, as of December 31, 2025, we own two issued U.S. patents and over 30 issued patents world-wide. We also own one issued U.S. patent, one U.S. provisional patent application, two U.S. patent applications, and 21 pending patent applications in the following jurisdictions: Argentina, Australia, Canada, China, Europe, Hong Kong, India and Japan for AP and other indications. These issued patents and any patents issuing from pending U.S. and ex-U.S. applications are expected to expire between 2031-2046, not including any patent term adjustment or any patent term extension. We have also filed one U.S. patent application, and applications in Australia, Canada, China, Europe and Japan directed to using a subject’s P/F ratio (the ratio of arterial oxygen pressure to fractional inspired oxygen) as a biomarker when treating acute lung injury and acute respiratory distress syndrome with Auxora. Any patents ultimately issuing from these applications are expected to expire around 2043, not including any patent term adjustment or patent term extension. We jointly own U.S. patent application direct to treatment of pediatric pancreatitis. Any patents ultimately issuing from this application are expected to expire around 2046.

Additionally, we jointly own one issued U.S. patent and, 14 issued patents world-wide directed to treatment for stroke and traumatic brain injury. These patents are expected to expire around 2036, not including any patent term adjustment or patent term extension. Also, we have filed one U.S patent application directed to treatment of non-alcoholic fatty liver disease using Auxora. Any patents ultimately issuing from this application are expected to expire around 2047, not including any patent term adjustment or patent term extension.

Moreover, for patent protection directed to formulations and crystalline forms of Auxora, we have one pending U.S. patent application, one granted in each Australia, China, Mexico, Canada, South Korea, and Japan and three pending applications in the following jurisdictions: Australia, Brazil and Europe. Any patents that ultimately issue from these patent applications are expected to expire around 2038, not including any patent term adjustment or patent term extension.

With respect to the synthetic of Auxora, we have one issued U.S. patent, one pending U.S. patent application, one pending U.S. provisional application, one issued patent in Japan, and pending applications in Canada, China, Europe, India, and South Korea. Any patents ultimately issuing from these applications are expected to expire around 2040, not including any patent term adjustment or any patent term extension.

Beyond patent coverage for Auxora, we have 18 issued U.S. patents, six issued patents world-wide, and a pending PCT application and one U.S. provisional application directed to CRAC channel inhibitors and their uses.

In addition to patent protection, we rely on trade secret protection and know-how to expand our proprietary position around our chemistry, technology, and other discoveries and inventions that we consider important to our business.

Government Regulation and Product Approval

As a pharmaceutical company that operates in the United States, we are subject to extensive regulation. Government authorities in the United States (at the federal, state and local level) and in other countries extensively regulate, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug products such as those we are developing. Product candidates that we develop must be approved by the FDA, before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in a foreign country. Generally, our activities in other countries will be subject to regulation that is similar in nature and scope as that imposed in the United States, although there can be important differences. Additionally, some significant aspects of regulation in Europe are addressed in a centralized way, but country-specific regulation remains essential in many respects.

U.S. Drug Development Process

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”), and its implementing regulations. A new drug must be approved by the FDA pursuant to a new drug application (“NDA”) before it may be legally marketed in the United States. Drugs are also subject to other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, and local statutes and regulations require the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial sanctions. Sanctions brought by the FDA and the Department of Justice (“DOJ”), or other governmental entities, could include, among other actions, refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.

The process required by the FDA before a drug may be marketed in the United States generally involves the following:

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completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practice (“GLP”) regulations and other applicable regulations;

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submission to the FDA of an IND, which must become effective before human clinical trials may begin;

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approval by an independent institutional review board (“IRB”) at each clinical site before each trial may be initiated;

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preparation of clinical trial material in accordance with current Good Manufacturing Practices (“cGMPs”);

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performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s good clinical practice (“GCP”) regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

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submission to the FDA of an NDA, including payment of application user fees, after completion of all pivotal trials, and which provides substantive evidence of the products’ candidates safety and efficacy from results of nonclinical testing and clinical trials;

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a determination by the FDA within 60 days of its receipt of an NDA that the application is sufficiently complete to permit a substantive review, in which case the NDA is filed for review;

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satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

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potential FDA audit of the preclinical and/or clinical trial sites that generated the data in support of the NDA to assess compliance with GCP regulations and data integrity, among other things;

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satisfactory completion of an FDA advisory committee review, if applicable; and

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FDA review and approval of the NDA, including consideration of the views on the FDA advisory committee, if one was involved, prior to any commercial marketing or sale of the drug in the United States.

Before testing any compound with potential therapeutic value in humans, the drug candidate enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the potential safety and activity of the drug candidate. The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs. The sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. An IND is an exemption from the FDCA that allows an unapproved product to be shipped in interstate commerce for use in an investigational clinical trial and a request for authorization from the FDA to administer an investigational drug product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials. Some preclinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The FDA may also impose complete or partial clinical holds on an IND for a drug candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA. Submission of a study protocol, therefore, may or may not result in FDA authorization to begin a clinical trial.

Clinical trials involve the administration of the drug candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include the requirement that all research participants provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Further, each clinical trial must be reviewed and approved by an independent IRB at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

Information related to the investigational product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the U.S. registration of the clinical trial. Sponsors are also obligated to disclose the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed in some cases for up to two years after the date of completion of the trial. Competitors may use this publicly available information to gain knowledge regarding the progress of development programs. Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Phase 1. The drug candidate is initially introduced into healthy human participants and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion, and the side effects associated with increasing doses and if possible, to gain early evidence of effectiveness. In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

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Phase 2. The drug candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases or conditions and to determine dosage tolerance, optimal dosage and dosing schedule. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

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Phase 3. The drug candidate is administered to an expanded patient population to further evaluate dosage and clinical efficacy at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall benefit/risk ratio of the product and provide an adequate basis for product approval. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

Post-approval studies, or Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development. Sponsors typically use the meetings at the end of the Phase 2 trial to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected AEs or any finding from tests in laboratory animals that suggests a significant risk for human participants. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research participants or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final drug. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

There are also various laws and regulations regarding laboratory practices, the experimental use of animals, and the use and disposal of hazardous or potentially hazardous substances in connection with the research. In each of these areas, the FDA and other regulatory authorities have broad regulatory and enforcement powers, including the ability to levy fines and civil penalties.

U.S. Review and Approval Processes

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug candidate, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product. Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational drug product to the satisfaction of the FDA. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances.

In addition, the PREA requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective. Sponsors are required to submit PSPs to the agency for review within sixty days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 clinical trial. The FDA and the sponsor must reach an agreement on the PSP although a sponsor can submit amendments to an agreed upon PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials or other clinical development programs. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data need to be collected before the pediatric clinical trials begin. Unless otherwise required by regulation, the Pediatric Research Equity Act does not apply to any drug for an indication for which orphan designation has been granted. However, if only one indication for a product has orphan designation, a pediatric assessment may still be required for any applications to market that same product for the non-orphan indication(s).

The FDA reviews all NDAs submitted to determine if they are substantially complete before it accepts them for filing and may request additional information rather than accepting an NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt. The FDA may refuse to file any NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the NDA must be resubmitted with the additional information. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the PDUFA guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted. The current review goal for priority NDAs for new-molecular entities is six months from the filing date, or eight months from the date of receipt in light of the 60-day filing period. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.

After the NDA submission is accepted for filing, the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity. The FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes independent clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions and typically follows the advisory committee’s recommendations.

Before approving an NDA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical sites to assure that the clinical trial was conducted in compliance with IND study requirements and GCP requirements by each of the entities involved in the clinical trials, including clinical investigators and any third- party CROs. After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical data and/or (an) additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials. For example, the FDA may require Phase 4 testing, which involves clinical trials designed to further assess a drug safety and effectiveness, and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized; the FDA may prevent or limit further marketing of a product based on the results of post-marketing trials or surveillance programs. The FDA may also determine that a REMS is necessary to ensure that the benefits of the drug outweigh its risks and to ensure the safe use of the drug. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS during the application review process; the FDA will not approve the NDA without an approved REMS, if required. A REMS could include medication guides, physician communication plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. The FDA determines the requirement for a REMS, as well as the specific REMS provisions, on a case-by-case basis.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product. Orphan designation must be requested before submitting an NDA. After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities. The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers. Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity. If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

Expedited Development and Review Programs and Accelerated Approval

The FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria. Specifically, new drugs are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to the combination of the product and the specific indication for which it is being studied. The sponsor of a fast track product has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA is submitted, the product candidate may be eligible for priority review. With regard to a fast track product, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

Any product submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review. A product is eligible for priority review if it is designed to treat a serious condition, and if approved, would provide a significant improvement in the treatment, diagnosis or prevention of a serious condition compared to marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review. The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months of the filing date for review of new molecular entity NDAs under its current PDUFA review goals.

In addition, a product may be eligible for accelerated approval. Drug products intended to treat serious or life- threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials to verify the predicted clinical benefit. Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required clinical trials, or if such trials fail to verify the predicted clinical benefit. In addition, the FDA requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

A sponsor may seek FDA designation of a drug candidate as a “breakthrough therapy” if the drug is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Breakthrough therapy designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance. The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met. The FDA must take certain actions with respect to breakthrough therapies, such as holding timely meetings and providing advice to the product sponsor, intended to expedite the development and review of an application for approval of a breakthrough therapy.

Fast track designation, priority review, accelerated approval, and breakthrough therapy designation do not change the standards for approval but may expedite the development, review, or approval process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened. In addition, such designations or shortened review periods may not provide a material commercial advantage.

Post-Approval Requirements

Any drug products manufactured or distributed pursuant to FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual program fees for any marketed products.

In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements after approval to ensure the long term stability of the drug product. cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. In addition, changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may require prior FDA approval before being implemented.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including AEs of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, imposition of post-market studies or clinical studies to assess new safety risks, or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

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fines, warning letters, or untitled letters;

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clinical holds on clinical studies;

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refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product approvals;

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product seizure or detention, or refusal to permit the import or export of products;

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consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

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mandated modification of promotional materials and labeling and the issuance of corrective information;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or

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injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising and promotion of drug products, including promotional activities involving the internet and industry-sponsored educational activities. A company can make only those claims relating to safety and efficacy that are approved by the FDA and in accordance with the approved labeling. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion by manufacturers of uses or patient populations that are not described in the product’s approved labeling (known as “off label uses”). Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested and approved by the FDA. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion. The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labeling.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”) which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of wholesale drug distributors by the states. Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution. Most recently, the Drug Supply Chain Security Act (“DSCSA”) was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States. The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a 10 year period that is expected to culminate in November 2023.

U.S. Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration and specifics of the FDA approval of the use of our product candidates, some of our U.S. patents, if granted, may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent restoration term of up to five years, as compensation for patent term lost during product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA and the approval of that application. Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.

The U.S. Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we may intend to apply for restoration of patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

In addition, the Hatch-Waxman Amendments to the FDCA authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute and also enacted Section 505(b)(2) of the FDCA. To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application (“ANDA”), to the agency. In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing conducted for a drug product previously approved under an NDA, known as the reference listed drug (“RLD”). Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug. In contrast, Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. A Section 505(b)(2) applicant may eliminate the need to conduct certain preclinical or clinical studies, if it can establish that reliance on studies conducted for a previously-approved product is scientifically appropriate. Unlike the ANDA pathway used by developers of bioequivalent versions of innovator drugs, which does not allow applicants to submit new clinical data other than bioavailability or bioequivalence data, the 505(b)(2) regulatory pathway does not preclude the possibility that a follow-on applicant would need to conduct additional clinical trials or nonclinical studies; for example, they may be seeking approval to market a previously approved drug for new indications or for a new patient population that would require new clinical data to demonstrate safety or effectiveness. The FDA may then approve the new product for all or some of the label indications for which the RLD has been approved, or for any new indication sought by the Section 505(b)(2) applicant, as applicable Market exclusivity provisions under the FDCA can also delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve an ANDA or a 505(b)(2) NDA submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the RLD or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the RLD holder. The FDCA also provides three years of marketing exclusivity for an NDA, or a supplement to an existing NDA, if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the original active agent. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA filed under section 505(b)(1) of the FDCA. However, an applicant submitting a full NDA would be required to either conduct or obtain a right of reference to all of the preclinical studies and adequate and well- controlled clinical trials necessary to demonstrate safety and effectiveness.

Orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances. Pediatric exclusivity is another type of non-patent market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

Federal and State Fraud and Abuse, Data Privacy and Security of Health Information, and Transparency Laws and Regulations

In addition to FDA restrictions on marketing of pharmaceutical products, federal and state healthcare laws and regulations restrict business practices in the biopharmaceutical industry. These laws may impact, among other things, our current and future business operations, including our clinical research activities, and proposed sales, marketing and education programs and may constrain the business or financial arrangements and relationships with healthcare providers and other parties through which we market, sell and distribute our products for which we obtain marketing approval. These laws include anti-kickback and false claims laws and regulations, data privacy and security of health information, and transparency laws and regulations, including, without limitation, those laws described below.

The U.S. federal Anti-Kickback Statute prohibits any person or entity from, among other things, knowingly and willfully offering, paying, soliciting or receiving remuneration to induce or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. The term “remuneration” has been broadly interpreted to include anything of value. The U.S. federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary managers on the other. Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor. Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the statute has been violated. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances. Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.

A person or entity does not need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation. In addition, the government may assert that a claim including items or services resulting from a violation of the U.S. federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil FCA or the civil monetary penalties laws.

Federal civil and criminal false claims laws and civil monetary penalties laws, including the federal civil FCA, prohibit any person or entity from, among other things, knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government. Actions under these laws may be brought by the Attorney General or as a qui tam action by a private individual in the name of the government. A claim includes “any request or demand” for money or property presented to the U.S. government. Pharmaceutical and other healthcare companies have been prosecuted under these laws for, among other things, allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product and for causing false claims to be submitted because of the companies’ marketing of products for unapproved, and thus non-reimbursable, uses.

The federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) also created new federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business. HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”), and their respective implementing regulations, impose specified requirements on certain types of individuals and entities, including covered entities, business associates and their covered subcontractors, relating to the privacy, security and transmission of individually identifiable health information. Among other things, HITECH makes HIPAA’s security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities, which include certain healthcare providers, healthcare clearinghouses and health plans, that create, receive, maintain or transmit individually identifiable health information in connection with providing a service for or on behalf of a covered entity as well as their covered subcontractors. HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions. In addition, state laws govern the privacy and security of health information in certain circumstances, many of which are not pre-empted by HIPAA, differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Additionally, the federal Physician Payments Sunshine Act, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (currently defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

We may also be subject to state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, marketing expenditures or drug pricing, and state and local laws that require the registration of pharmaceutical sales representatives.

In addition, certain states require, the registration of manufacturers and wholesale distributors of pharmaceutical products. All of our activities are also potentially subject to federal and state consumer protection and unfair competition laws.

Because of the breadth of these laws and the narrowness of available statutory exceptions and regulatory safe harbors, it is possible that some of our business activities could be subject to challenge under one or more of such laws. If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to significant penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations. To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti- fraud and abuse laws, implementation of corporate compliance programs, reporting of payments or transfers of value to healthcare professionals, and additional data privacy and security requirements.

Pharmaceutical Coverage, Pricing and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we or our collaborators obtain regulatory approval. In the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend, in part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such drug products.

In the United States, third-party payors include federal and state healthcare programs, government authorities, private managed care providers, private health insurers and other organizations. Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of medical drug products and medical services, in addition to questioning their safety and efficacy. Such payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular indication. We or our collaborators may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals. Nonetheless, our product candidates may not be considered medically necessary or cost-effective. Moreover, the process for determining whether a third-party payor will provide coverage for a drug product may be separate from the process for setting the price of a drug product or for establishing the reimbursement rate that such a payor will pay for the drug product. A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement can differ significantly from payor to payor. As a result, one payor’s determination to provide coverage for a drug product does not ensure that other payors will also provide coverage for the drug product. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

If we elect to participate in certain governmental programs, we may be required to participate in discount and rebate programs, which may result in prices for our future products that will likely be lower than the prices we might otherwise obtain. For example, drug manufacturers participating under the Medicaid Drug Rebate Program must pay rebates on prescription drugs to state Medicaid programs. In addition, the U.S. Department of Health and Human Services (“HHS”) imposes rebates on many Medicare Part B and Medicare Part D products to penalize price increases that outpace inflation on an annual basis. Further, recently HHS has been empowered to negotiate the price to negotiate the price of certain single-source drugs that have been on the market for at least 7 years covered under Medicare as part of the Medicare Drug Price Negotiation Program. Each year up to twenty (20) products will be selected by HHS for the Medicare Drug Price Negotiation Program. Products subject to the Medicare Drug Price Negotiation Program are expected to experience a significant reduction in reimbursement from the Medicare program on a per unit basis.

Different pricing and reimbursement schemes exist in other countries. In the EU, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular drug candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines, but monitor and control company profits. The downward pressure on health care costs in general, particularly prescription drugs, has become very intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country.

The marketability of any product candidates for which we or our collaborators receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care in the United States has increased and we expect will continue to increase the pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we or our collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Healthcare Reform

The FDA’s and other regulatory authorities’ policies may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our product candidates. For example, in December 2016, the 21st Century Cures Act (“Cures Act”) was signed into law. The Cures Act, among other things, was intended to modernize the regulation of drugs and devices and to spur innovation. Legislative proposals continue to be discussed in the U.S. Congress as potentially leading to a future “Cures 2.0” bill that is expected to have bipartisan support. In addition, in August 2017, the FDA Reauthorization Act was signed into law, which reauthorized the FDA’s user fee programs and included additional drug product provisions. The legislative reauthorization was completed in 2022, which reauthorized four of the largest FDA user fee programs for the next five-year cycle. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

In addition, a primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and other third-party payors in the United States have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products and services, implementing reductions in Medicare and other healthcare funding and applying new payment methodologies. For example, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively “Affordable Care Act”), was enacted, which substantially changed the way healthcare is financed by both the government and private insurers, and continues to significantly impact the U.S. pharmaceutical industry.

There have been amendments to and executive, judicial and Congressional challenges to certain aspects of the Affordable Care Act since its enactment, and it is possible that there will be additional challenges and amendments to the Affordable Care Act in the future. For example, on July 4, 2025, the One Big Beautiful Bill Act (the “OBBBA”) was signed into law, which narrowed access to ACA marketplace exchange enrollment and declined to extend the ACA enhanced advanced premium tax credits that expired at the end of 2025, which, among other provisions in the law, are anticipated to reduce the number of Americans with health insurance. The OBBBA also is expected to reduce Medicaid spending and enrollment by implementing work requirements for some beneficiaries, capping state-directed payments, reducing federal funding, and limiting provider taxes used to fund the program. Congress is considering proposed legislation intended to further reduce healthcare costs with alternatives to replace the expired ACA subsidies. It is possible that the Affordable Care Act will be subject to additional challenges in the future. It is unclear how any such challenges and the healthcare reform measures of the current administration will impact the Affordable Care Act, our business, or financial condition.

Other legislative changes have also been proposed and adopted in the United States since the Affordable Care Act was enacted that affect health care expenditures. These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year pursuant to the Budget Control Act of 2011, which began in 2013 and will remain in effect until 2032, unless additional Congressional action is taken.

There has been heightened governmental scrutiny recently over the manner in which pharmaceutical companies set prices for their marketed products, which has resulted in several Congressional inquiries, presidential executive orders and proposed federal legislation, as well as state efforts, designed to, among other things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

We expect that these and other healthcare reform measures that may be adopted in the future, particularly in light of the recent U.S. Presidential and Congressional elections, may result in more rigorous coverage criteria and lower reimbursement and in additional downward pressure on the price that we receive for any approved product. The current presidential administration is pursuing policies to reduce regulations and expenditures across government including at HHS, the FDA, the Centers for Medicare & Medicaid Services (“CMS”) and related agencies. These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business. For example, the current administration has announced agreements with several pharmaceutical companies that require the drug manufacturers to offer, through a direct to consumer platform, U.S. patients and Medicaid programs prescription drug Most-Favored Nation pricing equal to or lower than those paid in other developed nations, with additional mandates for direct-to-patient discounts and repatriation of foreign revenues. Other recent actions and proposals include, for example, (1) reducing agency workforce and cutting programs; (2) directing HHS and other agencies to lower prescription drug costs for Medicare through a variety of initiatives, including by improving upon the Medicare Drug Price Negotiation Program and establishing Most-Favored-Nation pricing for pharmaceutical products; (3) imposing tariffs on imported pharmaceutical products; and (4) as part of the Make America Healthy Again (“MAHA”) Commission’s Strategy Report released in September 2025, working across government agencies to increase enforcement on direct-to-consumer pharmaceutical advertising. Additionally, the current administration recently called on Congress to enact "The Great Healthcare Plan," to codify and expand Most-Favored Nation pricing, lower government subsidies to private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase, and enact restrictions on pharmacy benefit manager (“PBM”) payment methodologies, among other things. Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors. The implementation of cost-containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our drugs, once marketing approval is obtained.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, designed to encourage importation from other countries and bulk purchasing. Any such approved importation plans, if implemented, may result in lower drug prices for products covered by those programs.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action. We anticipate that such new laws will result in additional downward pressure on coverage and the price that we receive for any approved product, and could seriously harm our business. Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our products. In addition, it is possible that there will be further legislation or regulation that could harm our business, financial condition, and results of operations. Additionally, health reform initiatives may arise in the future.

Privacy and Security Laws

In the United States and in addition to federal laws described above, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts. For instance, the California Consumer Privacy Act (“CCPA”), created individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling certain personal data of consumers or households. The CCPA, among other things, imposes data privacy obligations on covered companies and provides privacy rights to California residents, including the right to access and delete their personal data, opt out of certain personal data sharing, and receive detailed information about how their personal data is used. The CCPA also includes a private right of action with statutory damages for certain data breaches, thereby potentially increasing risks associated with a data breach. Further, the California Privacy Rights Act (“CPRA”) expanded the CCPA’s requirements, including by affording additional rights and protections to California residents and establishing a regulatory agency to implement and enforce the law. Both the CCPA and CPRA have in the past and continue to impact our business activities depending on how they are interpreted and exemplifies the risk to our business of the evolving regulatory environment related to personal data and protected health information. Numerous U.S. states have enacted comprehensive privacy laws that impose obligations on covered businesses which are similar to the CCPA, and we expect more states to pass similar laws in the future.

We also are subject to applicable data protection laws in the jurisdictions in which we are established or in which we sell or market our products or run clinical trials. For example, if we conduct EU-based clinical trials, we will be subject to the EU General Data Protection Regulation (“EU GDPR”) in relation to our collection, control, processing and other use of personal data of data participants within the European Economic Area (“EEA”) (i.e., data relating to an identifiable living individual). The UK has adopted the UK General Data Protection Regulation, which imposes similar requirements for the processing of UK individuals’ personal data (collectively with the EU GDPR, the “GDPR”). The GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing activities and implement policies as part of its mandated privacy governance framework. It also requires data controllers to be transparent and disclose to data participants (in a concise, intelligible and easily accessible form) how their personal data is to be used, imposes limitations on retention of personal data; defines for the first time pseudonymized (i.e., key-coded) data; introduces mandatory data breach notification requirements; and sets higher standards for data controllers to demonstrate that they have obtained valid consent for certain data processing activities. If in the future we conducted clinical trials in the EU or the UK, we would be subject to EU and UK rules with respect to cross-border transfers of personal data out of the EU and UK. We would be subject to the supervision of local data protection authorities in those jurisdictions where we conduct our trials or are otherwise subject to the GDPR. Fines for certain violations of the GDPR are significant: up to the greater of €20 million or 4% of total global annual turnover. In addition to the foregoing, a violation of the GDPR or other applicable privacy and data protection laws and regulations could result in regulatory investigations, reputational damage, orders to cease/change our use of data, enforcement notices, or potential civil claims including class action type litigation.

In addition, the GDPR includes restrictions on cross-border data transfers. Certain aspects of cross-border data transfers under the GDPR are uncertain as the result of legal proceedings in the EU. This may increase the complexity of transferring personal data across borders. The GDPR will increase our responsibility and liability in relation to personal data that we process where such processing is subject to the GDPR, and we may be required to put in place additional mechanisms to ensure compliance with the GDPR, including as implemented by individual countries. Although there are legal mechanisms to allow for the transfer of personal data from the EEA and UK to the United States, they are subject to legal challenges and uncertainty about compliance with EU data protection laws remains and there are similar uncertainties around data transfers to and from the United Kingdom.

Moreover, the U.S. Department of Justice issued a rule entitled the Preventing Access to U.S. Sensitive Personal Data and Government-Related Data by Countries of Concern or Covered Persons, which places additional restriction on certain data transactions involving countries of concern (e.g., China, Russia, Iran) and covered persons that may impact certain business activities such as vendor engagements, sale or sharing of data, employment of certain individuals, and investor agreements. Violations of the rule could lead to significant civil and criminal fines and penalties. The rule applies regardless of whether data is anonymized, key-coded, pseudonymized, de-identified or encrypted, which presents particular challenges for companies like ours and may impact our ability to transfer data in connection with certain transactions or agreements.

In the ordinary course of our business, we and the third parties upon which we rely process personal data or other sensitive information, and, as a result, we and the third parties upon which we rely face a variety of evolving threats, which could cause security incidents. Such incidents may trigger obligations under privacy and security law, regulations, rules, and industry standards as well as policies, contractual obligations, and other obligations related to data privacy and security, in addition to leading to significant interruptions in our operations, ability to provide our products or services, loss of sensitive information and income. We may expend significant resources or modify our business activities (including our clinical trial activities) to try and protect against security incidents. Certain data privacy and security obligations have required us to implement and maintain specific security measures or industry-standard or reasonable security measures to protect our information technology systems and sensitive information.

The U.S. Foreign Corrupt Practices Act

The U.S. Foreign Corrupt Practices Act of 1977 (“FCPA”) prohibits any U.S. individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations. Importantly, United States authorities that enforce the FCPA, including the Department of Justice, deem most healthcare professionals and other employees of foreign hospitals, clinics, research facilities and medical schools in countries with public health care or public education systems to be “foreign officials” under the FCPA. We also may be implicated under the FCPA for activities by our partners, collaborators, contract research organizations, vendors or other agents. If and when we interact with foreign healthcare professionals and researchers in testing and marketing our products abroad, we must have policies and procedures in place sufficient to prevent us and agents acting on our behalf from providing any bribe, gift or gratuity, including excessive or lavish meals, travel or entertainment in connection with marketing our products and services or securing required permits and approvals such as those needed to initiate clinical trials in foreign jurisdictions.

Europe/Rest of World Government Regulation

In addition to regulations in the United States, we will be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of our products. Whether or not we or our potential collaborators obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries. Certain countries outside of the United States have a similar process that requires the submission of an application for a clinical trial authorization (“CTA”) much like the IND prior to the commencement of human clinical trials. In the EU, for example, a CTA must be submitted to each country’s national health authority and an application made to an independent ethics committee, much like the FDA and IRB, respectively. Once the CTA is approved in accordance with a country’s requirements and a favorable ethics committee opinion has been issued, clinical trial development may proceed.

Following the United Kingdom’s departure from the EU on January 31, 2020, the United Kingdom followed the same regulations as the EU until the end of 2020, during the so-called Transition Period. As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”) is the United Kingdom’s standalone medicines and medical devices regulator. As a result of the Northern Ireland protocol, different rules will apply in Northern Ireland than in England, Wales, and Scotland, together, Great Britain (“GB”); broadly, Northern Ireland will continue to follow the EU regulatory regime, but its national competent authority will remain the MHRA. The MHRA has recently published detailed guidance for industry and organizations to follow from January 1, 2021 now that the Transition Period is over, which will be updated as the United Kingdom’s regulatory position on medicinal products evolves over time. The guidance includes clinical trials, marketing authorizations, importing, exporting, and pharmacovigilance and is relevant to any business involved in the research, development, or commercialization of medicines in the United Kingdom.

The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, the clinical trials are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

To obtain regulatory approval of an investigational drug under EU regulatory systems, we must submit a marketing authorization application either under the so-called centralized or national authorization procedures.

Centralized procedure. The centralized procedure provides for the grant of a single marketing authorization by the European Commission following a favorable opinion by the EMA that is valid in all EU member states, as well as Iceland, Liechtenstein and Norway. The centralized procedure is compulsory for medicines produced by specified biotechnological processes, products designated as orphan medicinal products, and products with a new active substance indicated for the treatment of specified diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders or autoimmune diseases, other immune dysfunctions and viral diseases. The centralized procedure is optional for other products that represent a significant therapeutic, scientific or technical innovation, or whose authorization would be in the interest of public health or which contain a new active substance for indications other than those specified to be compulsory.

National authorization procedures. There are also two other possible routes to authorize medicinal products in several EU countries, which are available for investigational medicinal products that fall outside the scope of the centralized procedure:

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Decentralized procedure. Using the decentralized procedure, an applicant may apply for simultaneous authorizations in more than one EU Member State of medicinal products that have not yet been authorized in any EU Member State and that do not fall within the mandatory scope of the centralized procedure.

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Mutual recognition procedure. In the mutual recognition procedure, a medicine is first authorized in one EU Member State, in accordance with the national procedures of that country. Following this, further marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization.

The EMA grants orphan drug designation to promote the development of products for the treatment, prevention or diagnosis of life-threatening or chronically debilitating conditions affecting not more than five in 10,000 people in the EU. In addition, orphan drug designation can be granted if the drug is intended for a life threatening or chronically debilitating condition in the EU and without incentives it is unlikely that sales of the drug in the EU would be sufficient to justify the investment required to develop the drug. Orphan drug designation is only available if there is no other satisfactory method approved in the EU of diagnosing, preventing or treating the condition, or if such a method exists, the proposed orphan drug will be of significant benefit to patients. Orphan drug designation provides opportunities for free or reduced-fee protocol assistance, fee reductions for marketing authorization applications and other post-authorization activities and ten years of market exclusivity following drug approval, which can be extended to 12 years if trials are conducted in accordance with an agreed-upon pediatric investigational plan. The exclusivity period may be reduced to six years if the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

For other countries outside of the EU, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, again, the clinical trials are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If we or our potential collaborators fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Facilities

Our corporate headquarters are located in La Jolla, California, where we lease approximately 2,850 square feet of office and laboratory space pursuant to a lease agreement. We believe that our existing facilities are adequate for the foreseeable future. As we expand, we believe that suitable additional and/or alternative spaces will be available in the future on commercially reasonable terms, if required.

Employees and Human Capital Resources

As of December 31, 2025, we had 16 full-time employees, eight of whom were primarily engaged in research and development activities. A total of five employees have an M.D., Ph.D. or Pharm.D. degree. A significant number of our employees are located in La Jolla, California. None of our employees are represented by a labor union, and we consider our employee relations to be good. We also engage various consultants that are primarily engaged in research and development activities.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees. The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards and cash-based performance bonus awards.

Corporate Information

We originally formed in May 2011 as Graybug, LLC, which was converted into a corporation in February 2015. Our corporate headquarters are located at 505 Coast Boulevard South, Suite 307, La Jolla, CA 92037, and our telephone number is (858) 952-5500. Our corporate website address is https://calcimedica.com/. Information contained on, or accessible through, our website shall not be deemed incorporated into and is not a part of this Annual Report on Form 10-K. Our periodic and current reports are available on our website, free of charge, as soon as reasonably practicable after filing. We may use our website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation Fair Disclosure promulgated by the SEC. These disclosures will be included under the Investor Relations section of our website at ir.calcimedica.com. We have included our website in this Annual Report on Form 10-K solely as an inactive textual reference.

On March 20, 2023, Graybug, now known as CalciMedica, Inc., completed the Merger with Private CalciMedica, in accordance with the terms of the Merger Agreement, whereby Merger Sub merged into Private CalciMedica, with Private CalciMedica surviving as Graybug’s wholly owned subsidiary. Pursuant to the Merger Agreement, Graybug changed its name to CalciMedica, Inc.

On December 31, 2024, Private CalciMedica was dissolved and combined into CalciMedica, Inc.