MIRA PHARMACEUTICALS, INC.

Overview

MIRA Pharmaceuticals, Inc. (NASDAQ: MIRA) is a clinical-stage pharmaceutical development company advancing two neuroscience programs targeting neurologic and neuropsychiatric disorders. The company holds exclusive rights in the U.S., Canada, and Mexico for Ketamir-2 and MIRA-55, two novel drug candidates designed to address unmet medical needs in pain management, depression, PTSD and cognitive function.

Ketamir-2: A Novel Oral Ketamine Analog

Ketamir-2 is a patent-pending, oral ketamine analog currently being evaluated for the treatment of diabetic neuropathy and is in an ongoing Phase I clinical trial. The compound is designed to overcome the limitations of existing ketamine-based treatments, offering the potential for enhanced safety, improved tolerability, and better oral bioavailability. If approved, Ketamir-2 could provide a safer, more effective option for patients suffering from neuropathic pain, treatment-resistant depression (TRD), major depressive disorder with suicidal ideation (MDD-SI), and post-traumatic stress disorder (PTSD), with the possibility of additional Phase I studies exploring these indications.

Neuropathic pain is a complex, chronic condition resulting from damage or dysfunction in the nervous system, leading to abnormal sensations or pain responses. Common symptoms include burning, coldness, “pins and needles” sensations, numbness, itching, and sudden electric shock-like pain. Neuropathic pain can arise from metabolic disorders (such as diabetic neuropathy), viral infections (like post-herpetic neuralgia), autoimmune diseases, chemotherapy-induced neuropathy, traumatic nerve injury, stroke, or spinal cord injury.

Existing treatment options include antidepressants (tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors), anticonvulsants (gabapentin and pregabalin), topical agents (lidocaine patches and capsaicin), and opioids. However, these therapies often provide incomplete relief, have significant side effects, and, in the case of opioids, carry a high risk of addiction. Ketamine has demonstrated efficacy for neuropathic pain, but its poor oral bioavailability and high risk of side effects have limited its widespread use. Ketamir-2 aims to address these challenges, offering a treatment with fewer side effects, lower abuse potential, and more convenient oral dosing.

MIRA-55: A Novel Oral Pharmaceutical Marijuana Analog

MIRA-55 is a preclinical-stage investigational drug designed to support cognitive function and enhance memory. It is currently being evaluated in preclinical studies for its potential benefits in neuropsychiatric, inflammatory, and neurologic disorders. If approved, MIRA-55 could provide a breakthrough treatment for patients experiencing cognitive decline, including those with early neurodegenerative conditions.

Regulatory and DEA Classification

The U.S. Drug Enforcement Administration (DEA) has completed its scientific review of both Ketamir-2 and MIRA-55, determining that neither compound will be classified as a controlled substance or listed chemical under the Controlled Substances Act and its governing regulations. This regulatory distinction significantly enhances their commercial and clinical viability, removing potential barriers associated with controlled substances and positioning both compounds for streamlined clinical development and commercialization.

MIRA Pharmaceuticals remains committed to advancing Ketamir-2 and MIRA-55 through clinical development with a focus on addressing major unmet medical needs and improving patient outcomes.

Preclinical Studies and Pharmacology of Ketamir-2

MIRA has conducted extensive preclinical studies to characterize the pharmacological profile, safety, and therapeutic potential of Ketamir-2, an investigational compound targeting neuropathic pain, treatment-resistant depression (TRD), major depressive disorder with suicidal ideation (MDD-SI), and post-traumatic stress disorder (PTSD). These studies, performed in accordance with ICH and FDA regulatory guidelines, include in vitro and in vivo assessments to evaluate receptor binding, efficacy, selectivity, pharmacokinetics, metabolism, general pharmacology and toxicology.

Mechanism of Action and Receptor Selectivity

Ketamir-2 has been identified as a low-affinity NMDA receptor antagonist, selectively binding to the PCP-site with an IC50 of approximately 100 µM. Its primary metabolite, Nor-Ketamir, also binds to the PCP-site and also does not exhibit affinity for NMDA site, with an IC50 of approximately 300 µM. This targeted receptor interaction differentiates Ketamir-2 from ketamine, which exhibits broader receptor binding, including opioid and monoaminergic receptors, and binds to NMDA receptors with significantly higher affinity (0.5–1 µM).

Efficacy in Animal Models

The therapeutic potential of Ketamir-2 was evaluated in preclinical neuropathic pain and depression models, demonstrating significant effects:

Recent Developments

Executive Incentive Compensation Program

On March 26, 2025, the compensation committee (the “Committee”) of MIRA Pharmaceuticals, Inc. (the “Company”) adopted the Company’s Executive Incentive Compensation Plan (the “EICP”) for Erez Aminov, its Chairman and Chief Executive Officer. The EICP was approved by the Committee following greater presentation of the EICP to the board of directors of the Company (the “Board”). The specific terms of the EICP were prepared by the Board’s independent compensation consultant.

Under the EICP, Mr. Aminov is eligible to receive an annual target bonus of $242,500, with a maximum bonus of up to $485,000 (the “Annual Target Bonus”). The Annual Target Bonus is equally weighted (though as adjusted as appropriate) based on the following three components: (i) achievement of clinical milestones for the Company’s drug candidates, (ii) entering into certain strategic partnerships, and (iii) achieving capital raise milestones. Each component under the 2025 Program may be achieved and a corresponding payout made independent of the other components, but only after such component meets the minimum threshold of $40,017 is reached before any bonus payments will be made.

Under the EICP, Mr. Aminov will be eligible for certain long-term awards of up to 500,000 performance-based units of the Company’s common stock, par value $0.001 upon the Company achieving specified milestones based upon the Company reaching certain market capitalization values and the progress of the Company’s drug candidates.

Mr. Aminov will also be entitled to an amount equal to 3% of the total value of any mergers and acquisition or strategic transaction completed by the Company.

All awards under the EICP are subject to the approval of the Board and the Committee. Furthermore, the Board and the Committee, each in its sole discretion, generally retain the right to amend, supplement, supersede or cancel any awards under the EICP for any reason, and reserve the right to determine whether and when to pay out any bonus amounts pursuant to or outside of the EICP, regardless of the achievement of the performance targets.

In addition, the Committee approved an increase of Mr. Aminov’s salary to $485,000 effective April 1 st.

Binding Letter of Intent with SKNY Pharmaceuticals Inc.

On March 19, 2025, the Company entered into a binding letter of intent (the “LOI”) with SKNY Pharmaceuticals, Inc. (“SKNY”), a privately held Delaware corporation, to acquire SKNY through a stock exchange transaction (the “SKNY Acquisition”). The acquisition will bring SKNY-1, a novel oral drug candidate targeting weight loss and smoking cessation—two of the leading causes of preventable death—into MIRA’s development pipeline. As part of the agreement, SKNY will provide a $5 million capital infusion in cash or cash equivalents, further strengthening MIRA’s financial position and supporting future growth initiatives.

SKNY holds exclusive rights to its compounds in the United States, Canada, and Mexico. Under the terms of the LOI, SKNY will merge into the Company through a stock exchange, with each outstanding share of SKNY’s common stock being exchanged for shares of MIRA’s common stock. The exact exchange ratio will be determined by an independent third-party valuation firm (the “Independent Valuator”) based on the relative values of both companies. The completion of the SKNY Acquisition is contingent upon the Independent Valuator determining that SKNY’s valuation is at least equal to or greater than that of the Company. The SKNY Acquisition will be subject to shareholder approval of both companies.

Safety and Toxicology Studies

Cardiovascular, CNS, and Respiratory Safety

A GLP-compliant safety pharmacology program evaluated the effects of Ketamir-2 on the cardiovascular, central nervous system (CNS), and respiratory function using standard nonclinical models.

Toxicology and Dose Tolerability

Comprehensive toxicology studies were conducted in Sprague Dawley rats and Beagle dogs to assess systemic exposure, metabolism, and dose tolerability.

Pharmacokinetics and Metabolism

A series of in vivo pharmacokinetics (PK) and toxicokinetic (TK) studies assessed the absorption, metabolism, and systemic exposure of Ketamir-2.

Ketamir-2 Clinical Development Program

The clinical development program for Ketamir-2 follows a structured, multi-phase approach, beginning with IND-enabling studies and progressing through Phase I and Phase IIa clinical trials. The objective is to evaluate the safety, efficacy, and optimal use of Ketamir-2 for the treatment of diabetic neuropathy, with a focus on patient safety and regulatory compliance. If successful, Ketamir-2 could provide a novel treatment option that addresses the limitations of existing therapies for neuropathic pain management.

IND-Enabling Studies and Regulatory Progress

The development pathway began with the completion of IND-enabling studies, including pharmacokinetics, pharmacodynamics, toxicology, and safety pharmacology assessments in compliance with FDA regulatory standards. Following the submission of an Investigational New Drug (IND) application for diabetic neuropathy to the FDA in December 2024, the agency provided feedback requiring the completion of a neurotoxicity study before proceeding with human dosing in the United States. This study is currently ongoing, and we expect it to be completed by May 2025.

While awaiting the completion of the neurotoxicity study, we have received approval from the Israeli Ministry of Health and Institutional Review Board (IRB) to initiate our Phase I studies. The study will be conducted at the Clinical Pharmacology Unit, Hadassah Medical Center in Jerusalem, Israel. We plan to begin Phase I clinical trials in Israel in the first quarter of 2025, followed by Phase IIa studies in diabetic neuropathy patients to be initiated in the fourth quarter of 2025.

Phase I: Safety and Dosage Determination in Healthy Volunteers

Study Design

Participant Selection

Dosing and Administration

Outcome Measures

Phase IIa: Dose, Tolerability, and Early Efficacy in Diabetic Neuropathy

Following the completion of Phase I, Phase IIa clinical trials will focus on diabetic neuropathy patients. This phase will evaluate the optimal dose and tolerability while also collecting preliminary efficacy data.

Study Design

Participant Selection

Dosing Regimen

Outcome Measures

Clinical Manufacturing and Drug Supply

Recipharm Israel Ltd., a leading global contract development and manufacturing organization (CDMO), has successfully completed the upscaling, development, and GMP manufacturing for clinical and preclinical supplies of Ketamir-2.

MIRA-55: A Novel Oral THC Analog

Our objective is to develop and commercialize new treatment options for neuropsychiatric, inflammatory, and neurologic diseases and disorders. Cannabinoids are a class of chemical compounds that are naturally occurring and are primarily found in cannabis plant extracts. The two major cannabinoids found in cannabis plant extracts include tetrahydrocannabinol, a compound that is the main psychoactive ingredient of cannabis (or THC) and cannabidiol, the second most prevalent active ingredient in cannabis which does not have psychoactive properties (or CBD). These compounds bind to CB1 and CB2 cannabinoid receptors, which are found throughout the body. Specifically, CB1 receptors are concentrated in the central nervous system (or CNS), while CB2 receptors are found mostly in peripheral organs and are associated with the immune system. When the chemical compounds bind to these cannabinoid receptors, the process elicits certain physiological responses. Physiological responses to cannabinoids may vary among individuals. Some of the effects of cannabinoids have been shown to impact nervous system functions, immune responses, muscular motor functions, gastrointestinal maintenance, blood sugar management, and the integrity of ocular functions. Based on pre-clinical testing, our product candidate, MIRA-55, appears to have a strong selectivity for CB2 versus CB1, and is designed to minimize the risk of psychoactive adverse events associated with CB1 activation.

Mechanism of Action of MIRA-55

We believe that the effects of MIRA-55 at the cannabinoid receptors CB1 and CB2 is predicted to account for most of its potential therapeutic effects, especially as it relates to its anti-inflammatory properties. For example, the difference in the dose-response effects of MIRA-55 compared with THC on CB1 receptors appears to coincide with its improved therapeutic profile. If approved by the FDA, MIRA-55 may potentially provide therapeutic effects and enhanced cognition and memory.

THC has been demonstrated to have biphasic physiological effects (meaning effects in two phases), which have been described for over 40 years: at low levels THC has positive effects while high doses cause the opposite, undesirable symptoms. Examples of biphasic effects at low versus high levels of THC include the anti-anxiety versus pro-anxiety effects, respectively. Through pre-clinical test, we obtained the following dose-response effects for MIRA-55 and THC at the CB1 receptor (see below). In contrast to THC, which displays an initial maximally stimulatory and then inhibitory response at CB1, MIRA-55 appears to act as a monophasic partial agonist (meaning it has a lower intrinsic activity than full agonists) in that it creates a stimulation throughout its dose range, achieving a moderate activation of the CB1 even at high doses. We believe that this accounts for the potential broad therapeutic efficacy of MIRA-55 and the observed absence of negative symptoms even at maximal doses of the drug.

**Figure 1:**Compound activity with the selected GPCR Biosensor Assays: THC vs MIRA-55 agonist activity at the CB1 Receptor.

In pharmacology, “efficacy” or “Emax” refers to the maximum response that can be achieved with a drug or agent. It represents the extent or magnitude of the response produced by the drug once it has bound to its target, typically referred to as a receptor. The binding between a drug and its receptor is characterized by affinity, which quantifies the strength of their interaction. Efficacy, however, assesses the action or effect of the drug following binding to the receptor.

The dose-response curve is a commonly used graph in pharmacology that depicts the relationship between the effect of a drug and its dosage. The X-axis represents the increasing doses of the drug, while the Y-axis represents the response produced by the drug. In the case of the figure above, the term “% Efficacy” on the Y-axis refers to the maximum response that can be achieved with the agonist (MIRA-55 or THC) in relation to its ability to activate GPCR receptors (specifically CB1 receptors). GPCRs are G-protein-coupled receptors that form a large group of proteins which are expressed on the cell surface of eukaryotic cells to detect molecules outside the cell and activate cellular response.

The data presented in the figure above has been normalized to the maximal and minimal responses observed in the presence of a control compound and vehicle, respectively. This normalization allows for a standardized comparison of the agonist’s efficacy.

MIRA-55 Preclinical Developments and Studies

As of the date of this report, we have completed several preclinical studies of MIRA-55, including, but not limited to, radio-ligand binding assays, the elevated plus maze (EPM) model of anxiety, and hot plate model thermal sensitivity testing.

We have studied the effects of acute administration of MIRA-55 on anxiety-related phenotypes in mice to model human conditions. An intraperitoneal injection of placebo (e.g., saline) or MIRA-55 (50 mg/kg treatment) was administered to C57Bl/6 mice (n=5/group) that were 8-12 weeks old. Thirty minutes following injection, mice were tested in anxiety-related measures using the Elevated Plus Maze (EPM). The EPM is a widely used preclinical behavioral assay for rodents and has been validated to assess the anti-anxiety effects of pharmacological agents. If determined and approved by the FDA or other regulatory agencies, MIRA-55 appears to have anti-anxiety effects at doses that lacked side effects of sedation or intoxication in mice. The EPM measures anxiety in rodents as a screening test for putative anxiolytic compounds and as a general research tool in neurobiological anxiety research, such as Generalized Anxiety Disorder (GAD) or Post-Traumatic Stress Disorder (PTSD). The model is based on the animal’s aversion to open spaces, which are present in the open arms of the maze. Anti-anxiety effects of test agents are demonstrated by an increase in the percentage of time spent in the open arms with treatment compared to placebo. The total distance traveled is a measure of the overall level of arousal and mobility of the mice undergoing testing on the EPM and is used to rule out any sedating or intoxicating effects of the test agent.

Preclinical studies have also shown the potential of MIRA-55 for relieving pain. Several clinically approved pharmacological agents used to treat pain, including opioids, have been demonstrated to delay or ameliorate the onset of heat sensitivity upon paw exposure of mice to heat. Thirty minutes after treatment with either a placebo (control) or MIRA-55, mice were placed on a heated plate to measure the time it took for each mouse to lift its paw in response to the mild pain they felt from the heat. Mice treated with pain-alleviating drugs took significantly longer to become bothered by the heat and to lift their paws. Similarly, mice treated with MIRA-55 statistically took significantly more time to lift their legs, indicating MIRA-55’s potential effectiveness as a possible treatment for pain in this model. If approved by the FDA, MIRA-55 may potentially provide therapeutic effects for pain control.

MIRA-55 is a CB2 agonist, which may also be an optimal treatment for neurodegenerative diseases associated with neuroinflammation caused by microglial activation. CB2 agonism has been shown in preclinical studies to regulate neuroinflammatory processes, reducing the neuronal damage characteristic of degeneration. We believe there may be a strong rationale for CB2 agonism in neurodegenerative diseases, given increased CB2 expression in patients with these diseases as well as preliminary results from animal models. We see potential for a potent CB2 agonist to treat a range of neurodegenerative diseases. MIRA-55, through its robust activity at CB2 compared to CB1, was designed to minimize the risk of psychotropic adverse events associated with CB1 activation. If approved by the FDA, MIRA-55 may potentially provide therapeutic effects for neurodegenerative and neuroinflammatory illnesses.

Our preclinical development program for MIRA-55 has included a variety of testing. Summarized below are the tests we have completed. Our interpretation of results derived from preclinical data, or our conclusions based on preclinical data, may prove inaccurate and are not necessarily predictive indicators of future results. See the section below titled “Research and Testing to Date - MIRA-55” for more information.

In addition to the studies completed, we have ongoing preclinical studies evaluating the effects of MIRA-55 on memory and cognition in animal models. These studies aim to further assess MIRA-55’s potential for enhancing cognitive function and addressing deficits associated with neurodegenerative and neuropsychiatric disorders.

Our MIRA-55 Clinical Development Program

Following the preclinical development plan outlined above, we intend to advance MIRA-55 toward an Investigational New Drug (IND) application submission to the FDA for the treatment of cognitive decline in elderly patients. This patient population represents a significant unmet medical need, and we believe MIRA-55 has the potential to provide therapeutic benefits in this area.

The timing of our IND submission will be based on the completion of ongoing preclinical studies, regulatory discussions, and overall development progress. If the FDA allows the program to proceed, a Phase I trial would be expected to begin following the standard regulatory review period post-IND submission.

All development plans are subject to FDA review and acceptance. As discussions with the FDA progress, we may refine our timeline for clinical trials and regulatory submissions as appropriate. Given the inherent uncertainties in drug development, there is no guarantee that our clinical development activities will align with anticipated timelines.

Market Opportunity and Competitive Advantage of Ketamir-2 in Neuropathic Pain Treatment

Market Opportunity

Neuropathic pain is a significant and growing health concern in the United States, affecting approximately 10% of adults (PMC5677393). The North American neuropathic pain market was valued at approximately $2.60 billion in 2022 and is projected to reach $5.20 billion by 2030, growing at a 9.0% compound annual growth rate (CAGR) during this period (Data Bridge Market Research). This growth is driven by an aging population, increasing prevalence of diabetes, chemotherapy-induced neuropathy, and post-surgical nerve injuries.

Despite the high prevalence and economic burden, current treatment options remain limited, often ineffective, or associated with significant side effects and safety concerns. Standard treatments include antidepressants (tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), anticonvulsants (gabapentin, pregabalin), opioids, and topical agents. However, these medications often provide incomplete pain relief, require long-term use, and come with risks such as sedation, cognitive impairment, addiction, and withdrawal symptoms.

The strong demand for innovative, effective, and safer neuropathic pain treatments presents a major market opportunity for Ketamir-2, a novel investigational therapy designed to address these critical treatment gaps.

Competitive Advantage of Ketamir-2

Ketamir-2 has the potential to transform neuropathic pain management by offering a more effective, safer, and accessible treatment compared to existing therapies, including currently approved medications.

By offering oral bioavailability, improved safety, reduced abuse potential, and a potential advantage over currently approved neuropathic pain treatments, Ketamir-2 is positioned to become a leading treatment option in the rapidly growing neuropathic pain market, addressing an urgent need for more effective and accessible pain management solutions.

Ketamir-2 Development Strategy

The goal is to advance the development of Ketamir-2 as an orally administered medication with the potential for fewer side effects and greater accessibility, free from the restrictions imposed by ketamine’s REMS. Ketamir-2 aims to address the urgent clinical need for a rapid-acting treatment for diabetic neuropathy and treatment-resistant depression (TRD) in patients who can take the medication at home.

The strategic focus is to establish proof of concept in human patients, demonstrating Ketamir-2’s safety, efficacy, and differentiation from existing therapies. In parallel, the company will actively explore effective exit strategies, including strategic partnerships, licensing opportunities, or potential acquisition pathways to maximize value and commercial potential.

MIRA-55 Development strategy

Our goal is to develop therapeutics targeting well-characterized CB1 and CB2 receptors with optimized pharmacological properties to transform the lives of patients with neurological diseases. Key elements of our strategy to achieve this goal include:

Ketamir-2

Preclinical Research Findings

In Silico Analysis of Targets of Ketamir-2 vs Ketamine

In silico analysis, referring to computer-based techniques, has become an integral part of pharmaceutical research and development.7 This approach utilizes computational methods to analyze and predict the properties and behaviors of pharmaceutical compounds. The use of in silico analysis is especially crucial in the early stages of drug development, as it aids in identifying potential drug targets and elucidating differences between a new drug and its parent compound. By analyzing large datasets, such as genomic, proteomic, and metabolomic data, researchers can predict how different compounds might interact with various biological targets. This approach helps in understanding the mechanism of action of new drugs and can significantly reduce the time and cost associated with experimental screening. InSilico Trials was contracted to provide a comparison between targets of Ketamir-2 vs ketamine employing their target identification protocol. The following characterize some of the unique targets that are predicted to interact with either Ketamir-2 or ketamine, thereby differentiating one drug from the next.

Studies evaluating the mechanism of action of the investigational product indicate that Ketamir-2 exhibits a highly selective receptor binding profile. Specifically, Ketamir-2 was found to be a low affinity NMDA receptor antagonist, that selectively binds to the phencyclidine (PCP)-site with an IC 50 on this receptor site of ~100 µM. In contrast, ketamine primarily works as an NMDA receptor antagonist with affinities in the range of 0.5-1 µM.

Ketamir-2 selective target:

Additionally, while ketamine has a broader receptor binding profile which includes opioid receptors and receptors associated with monoaminergic systems, the receptor binding profile of Ketamir-2 and the primary metabolite of Ketamir-2 is specific to the NMDA receptor PCP-site.

Pharmacology:

Primary pharmacology studies (in vitro and in vivo) conducted to support the advancement of Ketamir-2 are summarized in the table below. In vivo pharmacology assessments include evaluation of Ketamir-2 using endpoint assessments post-dose administration that are traditionally utilized to evaluate behavioral indices such as spontaneous horizontal locomotor activity, anxiety, and depression in addition to evaluation of the therapeutic efficacy in a rodent model of neuropathic pain. While endpoint assessments pertaining to depression, anxiety, and general locomotion are not direct evidence of an improvement in indices of neuropathic pain, discordant neuropharmacological signaling through the NMDA receptor is a commonality within neuropsychiatric disorders such as depression and anxiety. Specifically, overactivation of the NMDA receptor has been suggested to play a role in major depressive disorders for which anxiety is comorbid. Moreover, signaling through the NMDA receptor plays a role in the pain transmission pathway and is thus associated with neuropathic pain. Thus, data derived from assessments traditionally used in the evaluation of potential antidepressant therapeutics such as the forced swim test, elevated plus maze, and open field test are directly linked to the mechanism of action of Ketamir-2.

MIRA Pharmaceuticals has completed a series of nonclinical pharmacology studies characterizing Ketamir-2 efficacyin vitro andin vivo in animal models. Results ofin vitro assessments which evaluated the pharmacological activity of Ketamir-2 indicate that Ketamir is a low affinity NMDA receptor antagonist that selectively binds to the PCP-site with an IC 50 of ~100 µM on this receptor site. Nor-Ketamir, the primary metabolite of Ketamir-2, selectively binds to the PCP-site with no affinity for NMDA. The IC 50 is ~300 µM. Evaluation of therapeutic efficacy of Ketamir-2 in animal models of depression, anxiety and neuropathic pain (i.e., Chung model) indicate that treatment with Ketamir-2 results in anti-anxiolytic and anti-depressive behavior in behavioral assessments such as the open-field test, elevated plus maze, and the forced swim test. Moreover, animals administered 30 – 300 mg/kg Ketamir-2 exhibited significant increases in mean withdrawal threshold on Day 15 and 22 (100 and 300 mg/kg only) when compared to Day 14 post-surgery values. These ameliorative effects are observed in the absence of off-target binding/signaling from both Ketamir-2 and the primary metabolite Nor-Ketamir.

Figure 2: Effect of Ketamir-2 on neuropathic pain in male rats. Study represents the sensitivity to von-Frey filaments at 15 (blue) and 22 days (purple) after induction of neuropathy.

Bioavailability:

MIRA has conducted a series of informational ADME assessments typical for a novel therapeutic classified as a small molecule. The data indicate that Ketamir-2 is permeable at a dose of 10 µM (A-B and B-A) and is not highly bound to plasma proteins in mouse, rat, dog, cynomolgus monkey, or human plasma. Substrate interaction and metabolism studies indicate that Ketamir-2 is not a substrate of P-glycoprotein and is metabolized in mice, rats, dogs, cynomolgus monkey, and human hepatocytes with half-lives between 3.26 – 18.3 min. This biotransformation, as evaluated in human hepatic microsomes, is primarily the result of N-demethylation with metabolism being mediated primarily by CYP2B6 and CYP3A4

In addition to these data, the pharmacokinetics of Ketamir-2 have been characterized in a series of in vivo PK/TK studies conducted in Sprague Dawley rats and Beagle dogs. General PK data indicate that Ketamir-2 does cross the blood brain barrier with longer exposure times and greater levels of nor-Ketamir present in the brain. Moreover, the PK profile of Ketamir-2 following oral administration is characterized by rapid absorption, a short half-life, high clearance, and lower oral bioavailability.

Within the definitive toxicology studies, in general, females had higher systemic exposure than males of both Ketamir-2 and nor-Ketamir at 100 and 300 mg/kg/day (Days 1 and 14) and at 1000 mg/kg/day (Day 1) in rats and at 100 mg/kg/day (Days 1 and 14) and at 50 mg/kg/day (Day 1) in canines. Within rats, systemic exposure increased dose proportionally in females on Day 1 and in both sexes on Day 14 but increased more than dose proportionally in males on Day 1. In contrast, systemic exposure in canines increased in a more than dose proportional manner in both sexes on Days 1 and 14. The metabolite to parent (nor-Ketamir/Ketamir-2) ratios in AUC 0-24h ranged from 2.2 – 22 and 4.5 – 44 in rats and canines, respectively.

MIRA-55

Eurofins DiscoverX has developed a panel of cell lines stably expressing non-tagged GPCRs that signal through cyclic adenosine monophosphate, a messenger used for intracellular signal transduction in many different organisms (or cAMP). Hit Hunter® cAMP assays are specialized tests that track the activation of a type of cell receptor known as GPCR. GPCRs play a crucial role in how cells respond to external signals, and they are activated through two pathways: Gi and Gs secondary messenger signaling. These pathways are like internal communication systems in cells that relay signals from the outside to trigger specific responses inside the cell. The assay is conducted in a straightforward, uniform manner without the need for image-based analysis. This method uses a technology developed by DiscoverX called Enzyme Fragment Complementation (or EFC). In EFC, fragments of an enzyme, specifically β-galactosidase (β-Gal), are brought together to become functional only when the GPCR is activated. β-Galactosidase, the enzyme used as a functional reporter in this assay, is typically inactive in fragmented form and becomes active when the fragments reassemble, indicating the activation of the GPCR. In this case, the GPCR target was CB1 receptor. Compounds were tested in agonist and antagonist mode with the requested GPCR Biosensor Assays. For agonist assays, data was normalized to the maximal and minimal response observed in the presence of control ligand and vehicle. This Eurofins DiscoverX system was used to test THC vs MIRA-55 agonist activity at the CB1 receptor.

Unlike CB1 receptors that mediate many of the psychotropic effects of cannabinoids on the CNS, CB2 receptors are predominantly present on cells of the immune system. Based on preliminary results of our GPCR biosensor assays, the CB2 receptor agonistic effects of MIRA-55 are 8-fold more potent than THC and 30-fold more potent than CBD.

The study regarding the ability of MIRA-55 vs THC vs CBD to activate CB2Receptors and alter intracellular cAMP levels was performed by the CRO Eurofins DiscoverX.

As can be seen in the table below, the EC50 (i.e. concentration required to induce a half maximal response) for MIRA-55 was 8 times more potent than THC and at least 30 times more potent that CBD-i.e. it only took 1 uM of MIRA-55 to induce the same response that required 8 uM of THC and >30 uM of CBD.

**Table:**The foregoing measurements were performed as follows:

DiscoverX has developed a panel of cell lines that stably express non-tagged GPCRs (G-protein coupled receptors) capable of signaling through cAMP. The Hit Hunter® assay platform is used to investigate the functionality and response of these GPCRs.

In the case of the CB2 receptor, which is a GPCR involved in various physiological processes and has potential therapeutic implications, the Hit Hunter® assay can be employed to study the effects of drug agonists on CB2 receptor activity.

To measure the half maximal response (EC50) of CB2 receptor activation by a drug agonist that leads to a decrease in cAMP levels, an alternative approach may be required. One common method involves using forskolin, an activator of adenylate cyclase, to stimulate cAMP production. Forskolin bypasses the GPCR signaling and directly activates adenylate cyclase, resulting in increased cAMP levels.

In the presence of forskolin, the drug agonist at the CB2 receptor can then be tested at various concentrations to determine its ability to inhibit the forskolin-induced cAMP production. The drug’s concentration that leads to a 50% reduction in forskolin-stimulated cAMP levels can be considered the half maximal response or EC50.

Completed Pre-Clinical Tests

EPM Model of Anxiety Test

EPM is a widely used behavioral test to assess anxiety-like behavior in rodents. Typically, rodents tend to avoid open spaces due to their natural aversion to potentially dangerous areas. Therefore, spending more time in the open arms of the maze indicates decreased anxiety-like behavior. Similarly, the total distance travelled can reflect general locomotor activity and exploratory behavior, which can be influenced by the state of anxiety and the effect of drugs.

The EPM apparatus consists of two open arms and two enclosed arms elevated above the floor. Blue Bars represent the percentage of time spent in the open arms by mice in the placebo and drug-treated groups. Green Bars show the total distance travelled by mice in both groups during the EPM test

The issue of how to test the effect of MIRA-55 on cognition was complicated by the following:1) MIRA-55 has anti-anxiety (i.e. anxiolytic) effects, 2) anxiolytics can potentially improve cognitive assessment outcomes by reducing anxiety levels that may otherwise hinder cognitive functioning. Thus, in commonly performed tests of cognition in mice, such as novel object recognition and Morris water maze, anxiolytic medications can indirectly result in improved performance by decreasing anxiety rather than by directly improving cognition. To separate assessments of the impact of MIRA-55 on cognitive performance from its demonstrated anti-anxiety effects, we employed a model of context fear conditioning wherein we dosed the mice after training. Context fear conditioning in mice is a behavioral paradigm used to measure cognitive processes related to associative learning and memory. Associative learning, where an individual learns to associate specific stimuli or contexts with outcomes, in this case the mice associate being in a specific chamber with receiving a mild foot shock that occurs during training the day before testing. This process of forming associations between stimuli, actions, and consequences is involved in numerous skills and behaviors in everyday life: it underlies learning new skills, developing habits, and acquiring knowledge through experiences and conditioning. The use of associating the chamber with the foot shock on day one, means that when the mice are returned to the chamber on day 2 a measure of how much freezing they do corresponds to a read out of how well they can recall the experiences they had during training on day 1 (i.e. the greater the freezing, the better the recollection of the association between the chamber and food shock). Since the mice are given MIRA-55 AFTER training that takes place on day 1, and only before testing on day 2, there is no concern about the anxiolytic effects of MIRA-55 on learning during training, but rather this model tests MIRA-55’s effects on performance only-which in this case represents memory (i.e. the ability to recognize and recall the chamber where they had previously been shocked) and to translate that into an associated behavior (i.e. freezing). As published in the Journal of Neuropharmacology in 2023, THC and cannabis impair context fear conditioning, both when given prior to training (because of its anti-anxiety effects) and when given prior to testing (because of its cognitive impairing effects). MIRA-55 resulted a dramatic effect on cognitive performance in the context fear conditioning model, the percentage of time spent freezing-that is a demonstration of their memory and association-in the mice who received MIRA-55 at a dose of 75 mg/kg was more than twice that of those who received 0 mg/kg=placebo (i.e. 55% vs 25%, p<0.0001). Thus, MIRA-55 doubled the cognitive performance of the mice compared to placebo. This degree of improvement in cognitive performance in healthy mice dosed just prior to testing and after learning has not been demonstrated with any cannabinoid compound previously.

Because MIRA-55 is an anxiolytic, we decided to test whether it could impair cognitive function. We therefore sought to determine if MIRA-55 could impair attention-a different aspect of cognition than memory, recall and associative learning, and one that is affected negatively by sedating compounds (e.g. THC, Cannabis, benzodiazepine, etc.) and positively by stimulants (e.g. caffeine, nicotine, amphetamine) In order to assess whether MIRA-55 affected attention as compared to THC required a different testing model-Psychomotor Vigilance Test (PVT). The rat Psychomotor Vigilance Test (rPVT) is a widely used method to measure sustained attention in rodents. In the rPVT model, rats are trained to respond to a visual stimulus by pressing a lever, with shorter reaction times indicative of better attentional performance. Mice with longer reaction times or higher variability in response times may be considered to have attention deficits or altered vigilance. Data is shown as percentage accuracy at pressing the lever within the allowed reaction time vs dose of drug used. We have found that at doses of THC that impair attention, MIRA-55 had no negative effects on attention (i.e. their accuracy at pressing a lever at the right amount of time after receiving a trained cue was not impaired at all).

We plan to conduct further neurobehavioral evaluations of orally administered MIRA-55 in rats and mice, along with a respiratory evaluation of orally administered MIRA-55 in rats. Additionally, in vitro testing is planned to assess the effects of MIRA-55 on hERG (the human Ether-à-go-go-Related Gene) channel currents, an early FDA-required assay that helps identify potential cardiac abnormalities before advancing to human dose studies.

hERG encodes a potassium ion channel that plays a critical role in the electrical activity of the heart. The hERG channel mediates the repolarizing current in the cardiac action potential, ensuring proper heart rhythm. If the function of this channel is inhibited—whether by drug interaction or rare genetic mutations—it can lead to long QT syndrome, a potentially life-threatening condition.

In addition to these studies, we are planning a 28-day toxicology analysis in dogs and rats as part of the broader safety evaluation of MIRA-55.

We have also initiated analytical development and manufacturing for MIRA-55. Our suppliers are working toward scaling production under GLP/cGMP conditions, building upon previous non-GMP batches used in initial testing. We are collaborating closely with our suppliers to generate sufficient cGMP-grade MIRA-55 materials for planned preclinical toxicity programs, expanded animal testing, and potential human trials, which will be conducted pending regulatory approval.

Regulation

The FDA and comparable regulatory authorities in state and local jurisdictions impose substantial and burdensome requirements upon companies involved in the clinical development, manufacture, marketing, and distribution of drugs. These agencies and other federal, state, and local entities regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of our drug candidates.

U.S. Government Regulation

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires 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 a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending New Drug Applications (or NDAs), withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

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

Pre-clinical studies

Before testing any drug or biological product candidate in humans, the product candidate must undergo rigorous pre-clinical testing. The pre-clinical developmental stage generally involves laboratory evaluations of drug chemistry, formulation, and stability, as well as studies to evaluate toxicity in animals, to assess the potential for adverse events (“AEs”) and, in some cases, to establish a rationale for therapeutic use. The conduct of pre-clinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies. An IND sponsor must submit the results of the pre-clinical studies, 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 a request for authorization from the FDA to ship an investigation product and then administer it to humans and must be allowed to proceed by the FDA before human clinical trials may begin. Some long-term pre-clinical testing, such as animal tests of reproductive AEs and carcinogenicity, may continue after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions before that time related to one or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

Clinical trials

The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by, or under control of, the trial sponsor, in accordance with GCPs, which include the requirement that all research patients 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. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. Information about most clinical trials must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website. Information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the 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.

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

Post-approval trials, sometimes referred to as Phase IV 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, particularly for long-term safety follow up. In certain instances, the FDA may mandate the performance of Phase IV clinical trials as a condition of approval of an NDA or a Biologics License Application (“BLA”).

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if significant adverse events (“SAEs”) occur. The FDA or the sponsor may suspend or terminate a clinical trial at any time, or the FDA may impose other sanctions on various grounds, including a finding that the research patients are being exposed to an unacceptable health risk. Similarly, an IRB can refuse, 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.

Concurrently with clinical trials, companies usually complete additional pre-clinical studies and must also develop additional information about the physical characteristics of the drug or biological product 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 product candidate and, among other things, the sponsor must develop methods for testing the identity, strength, quality, potency, and purity of the final biological product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the biological product candidate does not undergo unacceptable deterioration over its shelf life.

Marketing Approval

Assuming successful completion of the required clinical testing, the results of the pre-clinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls, and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. In most cases, the submission of an NDA is subject to a substantial application user fee.

The review process typically takes twelve months from the date the NDA is submitted to the FDA. The FDA conducts a preliminary review of all NDAs within the first 60 days after submission to determine whether they are sufficiently complete to permit substantive review before accepting them for “filing.” The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information and may be subject to an additional application user fee. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged, or held meets standards designed to assure the product’s continued safety, quality and purity. Under the current guidelines in effect in the Prescription Drug User Fee Act (PDUFA), the FDA has a goal to review and act on the submission within ten months from the completion of the preliminary review of a standard NDA for a new molecular entity.

The FDA also may require submission of a REMS plan to ensure that the benefits of the drug outweigh its risks. The REMS plan could include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.

The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides 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.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application 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 trial sites to assure compliance with GCP requirements.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a complete response letter. A complete response letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA and may require additional clinical trials or pre-clinical studies in order for FDA to reconsider the application. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

Post-approval requirements

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. 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 user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.

Intellectual Property

KETAMIR-2

We license the U.S., Canadian, and Mexican patent rights for the use of KETAMIR-2 in human applications from MIRALOGX. MIRALOGX filed international application no. PCT/US2024/018594 under the Patent Cooperation Treaty (PCT) on March 6, 2024, titled, ANTIDEPRESSANT COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF TREATING DEPRESSION AND OTHER DISORDERS, and in due course intends to enter the national phase in the United States, Canada and Mexico, among other countries. These applications, if granted and subject to payment of patent maintenance fees, would offer protection extending through at least March 6, 2044. The patent rights for KETAMIR-2 outside of the United States, Canada, and Mexico are not included in our current patent rights.

Our license from MIRALOGX is set forth in the Exclusive License Agreement, dated November 15, 2023, pursuant to which the licensed field of use includes therapeutic treatments and other medical or health uses in humans, and related preclinical studies and activities conducted in furtherance of obtaining regulatory approval for and commercialization of human therapeutic treatments and uses (the “MIRALOGX License Agreement”). “Licensed Product” is defined as a drug product containing as an active agent 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one or a pharmaceutically acceptable salt or ester thereof. We also have the right to grant corresponding sublicenses under the licensed patent rights. The MIRALOGX License Agreement provides for the payment to MIRALOGX of an 8% royalty (payable quarterly) on our net sales of Licensed Products by us or our sublicensees and on non-royalty bearing milestone revenue, with the royalty obligation ceasing upon the later of the expiration of the last-to-expire licensed patent. The agreement also provides for an up-front Cost Reimbursement of $100,000 payable to MIRALOGX to cover the already-incurred costs associated with the patent rights. The Cost Reimbursement is the only payment made to date under the agreement. MIRALOGX may terminate the agreement upon insolvency, an uncured breach including the failure to make any payment owed under the agreement or the failure to use commercially reasonable efforts to develop the licensed product, or upon a default of the November 15, 2023 Promissory Note and Loan Agreement. The MIRALOGX License Agreement provides that MIRALOGX will have sole control over the filing, prosecution, maintenance, and management of the licensed patent rights, provided that we will be responsible for the cost of prosecuting and maintaining the licensed patents. The agreement grants to us the primary right, but not the obligation, to enforce the licensed patent rights.

Besides relying on patents, we also rely on trade secrets, proprietary know-how and continuing innovation to develop and maintain our competitive position, especially when we do not believe that patent protection is appropriate or can be obtained. We seek protection of these trade secrets, proprietary know-how and any continuing innovation, in part, through confidentiality and proprietary information agreements. However, these agreements may not provide meaningful protection for, or adequate remedies to protect, our technology in the event of unauthorized use or disclosure of information. Furthermore, our trade secrets may otherwise become known to, or be independently developed by, our competitors. We intend to seek appropriate patent protection for technology in our research and development programs, where applicable, and their uses by filing patent applications in the United States and other selected countries. We intend for these patent applications to cover, where possible, claims for compositions of matter, medical uses, processes for preparation and formulations.

MIRA-55

We have a pending provisional patent application directed to MIRA-55, a structure that was synthesized and isolated during the research and development of MIRA1a titled “Synthetic Cannabinoid Analogs, Pharmaceutical Compositions and Methods of Treating Anxiety and Other Disorders”. The Company intends to pursue domestic and foreign filings based on the provisional application to seek global patent protection for MIRA-55.

MIRA1a

The U.S. Patent 10,787,675 B2, titled “Purified Synthetic Marijuana and Methods of Treatment by Administering Same,” which covers the MIRA1a compoundper se as a racemic mixture, an isolated R-enantiomer, or an isolated S-enantiomer, as well as pharmaceutical formulations of the compound, was assigned to our Company by SRQ Patent Holdings II, LLC (“SRQ”) in December 2021. This patent also covers MIRA1a in methods of treating Alzheimer’s disease, anxiety, depression, and addictions. Subject to payment of patent maintenance fees, the ‘675 patent offers protection extending through at least February 11, 2039. According to the assignment and royalty agreement, we owe 8% in royalty revenue on net sales price and royalty revenue and 8% of milestone payment revenue to SRQ.

The royalties shall continue, in each country on a product-by-product and country-by-country basis until the later of i) the date of expiration of the last to expire patent included within the Innovation, or ii) the date of expiration of the last strategic partnership/licensing agreement including the Innovation.

We currently have no plans to develop the MIRA1a compound for approval and commercialization in or outside of the United States. See “Risk Factors- Risks Related to Our Intellectual Property- We own the rights associated with our patents in the United States, but we do not own the rights to patents covering MIRA1a in foreign jurisdictions.”