Amylyx Pharmaceuticals Inc

Previous wording

Our lead asset, AMX0035, is a specially formulated oral fixed-dose combination of sodium phenylbutyrate, or PB, and taurursodiol, or TURSO, developed to target a broad range of neurodegenerative diseases. AMX0035 is designed to mitigate neurodegeneration by simultaneously targeting endoplasmic reticulum, or ER, stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. We have shown in multiple models that AMX0035 can keep neurons alive under a variety of different conditions and stresses. These conditions includein vitro models of neurodegeneration, ER stress, mitochondrial dysfunction, oxidative stress and various other disease-specific models, as well asin vivo models of amyotrophic lateral sclerosis, or ALS, Wolfram syndrome, or WS, Alzheimer’s disease, or AD, and multiple sclerosis, or MS. Trials of AMX0035 in AD and ALS have shown the ability to reduce markers associated with neurodegenerative diseases in clinical trials, including a reduction of tau, a key protein aggregate shared across several neurodegenerative diseases, and YKL-40, a marker of neuroinflammation.

Current wording

AMX0035 is a specially formulated oral fixed-dose combination of sodium phenylbutyrate, or PB, and taurursodiol, or TURSO, developed to target a broad range of neurodegenerative diseases. AMX0035 was developed by Amylyx and is designed to mitigate neurodegeneration by simultaneously targeting endoplasmic reticulum, or ER, stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. We have shown in multiple models that AMX0035 can keep neurons alive under a variety of different conditions and stresses. These conditions includein vitro models of neurodegeneration, ER stress, mitochondrial dysfunction, oxidative stress and various other disease-specific models, as well asin vivo models of ALS, Wolfram syndrome, Alzheimer’s disease, or AD, and multiple sclerosis, or MS. Trials of AMX0035 in AD and ALS have shown the ability to reduce markers associated with neurodegenerative diseases in clinical trials, including a reduction of tau, a key protein aggregate shared across several neurodegenerative diseases, and YKL-40, a marker of neuroinflammation, respectively.

Previous wording

The safety profile of AMX0035 has been well established in clinical trials and postmarketing surveillance. Thousands of adults have been treated with AMX0035 whether through clinical trials across several neurodegenerative conditions and in post-approval settings. AMX0035 has been generally well-tolerated and the most common adverse reactions were gastrointestinal disorders (e.g. diarrhea, nausea, constipation, decreased appetite, abdominal pain, flatulence), occurring more often in the first 3 weeks of treatment and were generally nonserious. The benefit-risk balance of AMX0035 remains favorable for ongoing clinical development programs.

Current wording

The safety profile of AMX0035 has been well established in clinical trials and post-marketing surveillance. Thousands of adults have been treated with AMX0035 whether through clinical trials across several neurodegenerative conditions and in post-approval settings. AMX0035 has been generally well-tolerated and the most common adverse reactions were gastrointestinal side effects (e.g. diarrhea, nausea, constipation, decreased appetite, abdominal pain, flatulence), occurring more often in the first 3 weeks of treatment and were generally nonserious. The benefit-risk balance of AMX0035 remains favorable for ongoing clinical development programs.

Previous wording

We are investigating AMX0035 in neurodegenerative diseases where ER stress and mitochondrial dysfunction are implicated, including WS and progressive supranuclear palsy, or PSP.

Current wording

We are investigating AMX0035 in neurodegenerative and neuroendocrine diseases where ER stress and mitochondrial dysfunction are implicated, including PSP and Wolfram syndrome.

Previous wording

WS is a rare, progressive genetic disease caused by mutations in WFS1 that cause ER stress and mitochondrial dysfunction, leading to multi-organ cell dysfunction and death. We believe WS impacts approximately 3,000 people in the U.S. Researchers from the Washington University School of Medicine in St. Louis, in collaboration with Amylyx, published preclinical data exploring the potential of AMX0035 as a novel therapeutic approach for WS in the peer-reviewed Journal of Clinical Investigation Insight. These data showed that AMX0035 had the ability to dampen the impact of ER stress and mitochondrial dysfunction across patient-derived beta cells and neurons impacted by WFS1 mutations, and thereby potentially stabilizing and in some cases improving cellular functioning and viability. Amylyx announced that the FDA granted orphan drug designation to AMX0035 for the treatment of WS in November 2020.

Current wording

Wolfram syndrome is a rare, progressive genetic disease caused by mutations in the WFS1 gene that cause ER stress and mitochondrial dysfunction, leading to multi-organ cell dysfunction and death. We believe Wolfram syndrome impacts approximately 3,000 people in the U.S. Researchers from the Washington University School of Medicine in St. Louis, in collaboration with Amylyx, published preclinical data exploring the potential of AMX0035 as a novel therapeutic approach for Wolfram syndrome in the peer-reviewed Journal of Clinical Investigation Insight. These data showed that AMX0035 had the ability to dampen the impact of ER stress and mitochondrial dysfunction across patient-derived beta cells and neurons impacted by WFS1 mutations, and thereby potentially stabilizing and in some cases improving cellular functioning and viability. Amylyx announced that the FDA granted orphan drug designation to AMX0035 for the treatment of Wolfram syndrome in November 2020.

Previous wording

In April 2024, we announced interim data from the HELIOS trial, an ongoing, open-label Phase 2 study designed to evaluate if AMX0035 slows progression of diabetic, visual, and other measures in people living with WS and to evaluate safety and tolerability. The interim analysis performed was based on a data cutoff as of March 5, 2024 and included all participants who completed their Week 24 assessments as of the cutoff (n=8). The primary efficacy endpoint of the trial measures change from baseline in C-peptide, an established, objective laboratory measure of pancreatic beta cell function and glycemic control, assessed using a Mixed Meal Tolerance Test (MMTT). Secondary and exploratory outcomes include the measurement of other diabetic responses and other domains affected by the disease. The interim data from eight participants who received 24 weeks of treatment demonstrated that AMX0035 had a clinically meaningful effect on key outcomes including preliminary overall improvement in glucose control measures, visual acuity measures and disease burden in adult participants living with WS, where disease progression was expected. The safety profile of AMX0035 was consistent with that observed in other populations in which the drug has been extensively studied. We anticipate topline data for all 12 participants at Week 24 in the fall of 2024.

Current wording

In April 2024, we announced interim data from the HELIOS trial, an ongoing, open-label Phase 2 study designed to evaluate if AMX0035 slows progression of diabetic, visual, and other measures in people living with Wolfram syndrome and to evaluate safety and tolerability. The interim analysis performed was based on a data cutoff as of March 5, 2024 and included all participants who completed their Week 24 assessments as of the cutoff (n=8). The primary efficacy endpoint of the trial measures change from baseline in C-peptide, an established, objective laboratory measure of pancreatic beta cell function and glycemic control, assessed using a Mixed Meal Tolerance Test (MMTT). Secondary and exploratory outcomes include the measurement of other diabetic responses and other domains affected by the disease. The interim data from eight participants who received 24 weeks of treatment demonstrated that AMX0035 had a clinically meaningful effect on key outcomes including preliminary overall improvement in glucose control measures, visual acuity measures and disease burden in adult participants living with Wolfram syndrome, where disease progression was expected. The safety profile of AMX0035 was consistent with that observed in other populations in which the drug has been extensively studied. We plan to present the HELIOS topline data from the HELIOS trial for all 12 participants at Week 24, including all of the longer-term data available for participants who have reached their Week 36 or Week 48 visit at that time, at a medical meeting this fall. We are engaging with stakeholders, including the FDA, and planning for a single Phase 3 clinical trial and will share additional details on the clinical trial design once finalized.

Previous wording

PSP is a rare neurological disorder that affects body movements, walking, balance and eye movement and is characterized by widespread neurodegeneration associated with tau protein deposition in subcortical regions of the brain. Based on in vitro, in vivo and clinical data, AMX0035 may influence tau pathology, a key hallmark in people living with PSP. Genetic evidence indicates that a risk factor for PSP may be the unfolded protein response activated in disease-affected regions of the brain. PB has been shown to upregulate and recruit chaperone proteins, stabilize protein folding, and reduce ER stress and the unfolded protein response, while TURSO has been shown to inhibit tau phosphorylation induced by metabolic stress. In addition to preclinical data on PB and TURSO individually, PB and TURSO combined have shown a synergistic effect in targeting the hallmark pathways of neurodegeneration to simultaneously prevent or slow neuronal cell death. There are currently no approved therapies for the treatment of PSP, and the disease is reported to affect seven in 100,000 people worldwide. We are pursuing this indication based on AMX0035’s mechanism, preclinical data, and the tau reduction seen in the Phase 2 PEGASUS trial of AMX0035 in AD.

Current wording

PSP is a rare neurodegenerative disorder that affects body movements, walking, balance and eye movement and is characterized by widespread neurodegeneration associated with tau protein deposition in subcortical regions of the brain. Based on in vitro, in vivo and clinical data, AMX0035 may influence tau pathology, a key hallmark in people living with PSP. Genetic evidence indicates that a risk factor for PSP may be the unfolded protein response activated in disease-affected regions of the brain. PB has been shown to upregulate and recruit chaperone proteins, stabilize protein folding, and reduce ER stress and the unfolded protein response, while TURSO has been shown to inhibit tau phosphorylation induced by metabolic stress. In addition to preclinical data on PB and TURSO individually, PB and TURSO combined have shown a synergistic effect in targeting the hallmark pathways of neurodegeneration to simultaneously prevent or slow neuronal cell death. There are currently no approved therapies for the treatment of PSP, and the disease is reported to affect seven in 100,000 people worldwide. We are pursuing this indication based on AMX0035’s mechanism, preclinical data, and the tau reduction seen in the Phase 2 PEGASUS trial of AMX0035 in AD.

Previous wording

The ORION trial, a Phase 3 trial of AMX0035 for the treatment of PSP, remains ongoing. The primary efficacy endpoint of the ORION trial evaluates disease progression as measured by the rate of change on the 28-item Progressive Supranuclear Palsy Rating Scale (PSPRS), total score at Week 52, an established and validated endpoint in PSP clinical trials. Secondary efficacy endpoints are disease progression as measured by a modified 10-item PSPRS score and motor aspects of activities of daily life as measured by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 2 (MDS-UPDRS Part II). Exploratory outcomes include changes in activities of daily living, cognitive function, quality of life, overall survival, brain regional volumes, fluid biomarkers of neuronal injury/inflammation, and caregiver burden. Safety and tolerability will be evaluated by assessing the frequency of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs). Data from an interim analysis of the ORION study of AMX0035 in PSP are expected in mid-2025.

Current wording

The ORION trial, a Phase 2b/3 global trial of AMX0035 for the treatment of PSP, remains ongoing. The primary efficacy endpoint of the ORION trial evaluates disease progression as measured by the rate of change on the 28-item Progressive Supranuclear Palsy Rating Scale (PSPRS), total score at Week 52, an established and validated endpoint in PSP clinical trials. Secondary efficacy endpoints are disease progression as measured by a modified 10-item PSPRS score and motor aspects of activities of daily life as measured by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 2 (MDS-UPDRS Part II). Exploratory outcomes include changes in activities of daily living, cognitive function, quality of life, overall survival, brain regional volumes, fluid biomarkers of neuronal injury/inflammation, and caregiver burden. Safety and tolerability will be evaluated by assessing the frequency of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs). Data from an interim analysis of the ORION study of AMX0035 in PSP are expected in mid-2025.

Previous wording

To that end, we have completed the IND-enabling studies of AMX0114, a potent antisense oligonucleotide targeting inhibition of Calpain-2, a key contributor to the axonal (also known as Wallerian) degeneration pathway. Axonal degeneration has been recognized as an important early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases. Calpain-2 is considered an essential protein in the process of axonal degeneration and has been repeatedly linked to neurofilament biology in published studies. Preclinical studies completed to date have shown that AMX0114 can achieve potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and Calpain-2 protein levels in human motor neurons. Moreover, in preclinical efficacy studies, treatment with AMX0114 reduced extracellular neurofilament light chain levels following neurotoxic insult in induced pluripotent stem cell (iPSC)-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. Neurofilament is a broadly researched biomarker in ALS. We plan to file an IND application, then initiate a multiple ascending dose clinical trial of AMX0114 in people living with ALS in the second half of 2024.

Current wording

To that end, we have completed the IND-enabling studies of AMX0114, a potent antisense oligonucleotide targeting inhibition of Calpain-2, a key contributor to the axonal (also known as Wallerian) degeneration pathway. Axonal degeneration has been recognized as an important early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases. Calpain-2 is considered an essential protein in the process of axonal degeneration and has been repeatedly linked to neurofilament biology in published studies. Preclinical studies completed to date have shown that AMX0114 can achieve potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and Calpain-2 protein levels in human motor neurons. Moreover, in preclinical efficacy studies, treatment with AMX0114 reduced extracellular neurofilament light chain levels following neurotoxic insult in induced pluripotent stem cell (iPSC)-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. Neurofilament is a broadly researched biomarker in ALS. We are moving forward with our plans and are preparing to initiate a multiple ascending dose clinical trial of AMX0114 in people living with ALS in the second half of 2024.

Previous wording

On April 4, 2024, we announced that we have started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ (sodium phenylbutyrate and taurursodiol [also known as ursodoxicoltaurine]; also known as AMX0035) for the treatment of ALS and remove the product from the market in the U.S. and Canada. This decision was informed by topline results from the global Phase 3 PHOENIX trial, which failed to meet its prespecified primary and secondary endpoints, engagement with regulatory authorities, and discussions with the ALS community. As of April 4, 2024, RELYVRIO/ALBRIOZA is no longer available for new patients. Patients currently on therapy in the U.S. and Canada who, in consultation with their physician, wish to stay on treatment can be transitioned to a free drug program.

Current wording

On April 4, 2024, we announced we had started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ (sodium phenylbutyrate and taurursodiol [also known as ursodoxicoltaurine]; also known as AMX0035) for the treatment of ALS and remove the product from the market in the U.S. and Canada. This decision was informed by topline results from the global Phase 3 PHOENIX trial, which failed to meet its prespecified primary and secondary endpoints, engagement with regulatory authorities, and discussions with the ALS community. As of April 4, 2024, RELYVRIO/ALBRIOZA was no longer available for new patients. Patients who were currently on therapy in the U.S. and Canada who, in consultation with their physician, wished to stay on treatment had the option to be transitioned to a free drug program. We will continue to collect available data on survival and to share learnings from PHOENIX to help inform future ALS research. We are planning to wind down the Open Label Extension by the end of 2024. Separately, the PHOENIX survival data collection efforts will continue at the encouragement of ALS specialists.

Previous wording

As of March 31, 2024, we had cash, cash equivalents and short-term investments of $373.3 million. In April 2024, we announced a restructuring to focus our financial resources on upcoming clinical milestones. Under the restructuring, we will reduce our workforce by approximately 70% and decrease external financial commitments outside of our priority areas. We believe that with these changes, our existing cash, cash equivalents and short-term investments as of March 31, 2024, will be sufficient to meet our anticipated operating and capital expenditure requirements for at least one year from the issuance of this Quarterly Report. We have based this estimate on assumptions that may prove to be wrong, and we could exhaust our available capital resources sooner than we expect. See “Liquidity and Capital Resources” below.

Current wording

As of June 30, 2024, we had cash, cash equivalents and short-term investments of $309.8 million. In April 2024, we announced a restructuring to focus our financial resources on upcoming clinical milestones. Under the restructuring, we started the process to reduce our workforce by approximately 70% and decreased external financial commitments outside of our priority areas. We believe that with these changes, our existing cash, cash equivalents and short-term investments as of June 30, 2024, will be sufficient to meet our anticipated operating and capital expenditure requirements for at least one year from the issuance of this Quarterly Report. We have based this estimate on assumptions that may prove to be wrong, and we could exhaust our available capital resources sooner than we expect. See “Liquidity and Capital Resources” below.

Previous wording

We will continue to incur significant expenses as we advance AMX0035, AMX0114 and advance or acquire any future product candidates through preclinical and clinical development, setup and initiate additional trials, hire additional clinical, scientific, management and administrative personnel, seek regulatory approval and pursue commercialization of any approved product candidates. We may also incur expenses related to business development activities, such as in-licensing of product candidates.

Current wording

We will continue to incur significant expenses as we advance avexitide, AMX0035, AMX0114 and advance or acquire any future product candidates through preclinical and clinical development, setup and initiate additional trials, hire additional clinical, scientific, management and administrative personnel, seek regulatory approval and pursue commercialization of any approved product candidates. We may also incur expenses related to business development activities, such as in-licensing of product candidates.

Previous wording

We expect to finance our near-term operations through our existing cash, cash equivalents and short-term investments and if needed, the sale of equity, debt financings or other capital sources, including potential collaborations with other companies, royalty financings, or other strategic transactions. Our inability to raise capital as and when needed could have a negative impact on our financial condition and ability to pursue our business strategies. There can be no assurances that our current operating plan will be achieved or that additional funding, if required, will be available on terms acceptable to us, or at all.

Current wording

We expect to finance our near-term operations through our existing cash, cash equivalents and short-term investments and if needed, the sale of equity, debt financings or other capital sources, including potential collaborations with other companies, royalty financings, or other strategic transactions. Our inability to raise capital or secure other funding as and when needed could have a negative impact on our financial condition and ability to pursue our business strategies. There can be no assurances that our current operating plan will be achieved or that additional funding, if required, will be available on terms acceptable to us, or at all.

Previous wording

Product revenue, net recognized during the three months ended March 31, 2024 and 2023 primarily relates to units of ALBRIOZA and RELYVRIO sold in Canada and the U.S., respectively. In April, 2024, we announced that we started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™and remove the product from the market in the U.S. and Canada based on topline results from the global Phase 3 PHOENIX trial. As a result, we will not generate revenue from the sale of RELYVRIO®/ALBRIOZA™ in future periods.

Current wording

Product revenue, net recognized during the three and six months ended June 30, 2024 and 2023 primarily relates to units of ALBRIOZA and RELYVRIO sold in Canada and the U.S., respectively. In April, 2024, we announced we had started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™and remove the product from the market in the U.S. and Canada based on topline results from the global Phase 3 PHOENIX trial. As a result, we will not generate revenue from the sale of RELYVRIO®/ALBRIOZA™ in future periods.

Previous wording

Cost of sales consists primarily of costs associated with the manufacturing of RELYVRIO, ALBRIOZA and certain period costs, which include:

Current wording

Cost of sales consists primarily of costs associated with the manufacturing of RELYVRIO, ALBRIOZA, certain period costs and losses on purchase commitments with contract manufacturing organizations. Following our announcement of a process to discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ and remove the product from the market in the U.S. and Canada, we will not report product cost of sales in future periods.

Previous wording

Research and development expenses consist primarily of costs incurred in connection with the research and development of AMX0035, AMX0114 and other potential future product candidates. We expense research and development costs as incurred. These expenses include:

Current wording

Research and development expenses consist primarily of costs incurred in connection with the research and development of AMX0035, avexitide, AMX0114 and other potential future product candidates. We expense research and development costs as incurred. These expenses include:

Previous wording

Research and development activities are central to our business model. Product candidates such as AMX0035 in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, such as AMX0114, primarily due to the increased size and duration of later-stage clinical trials and related product manufacturing expenses. We expect that our research and development expenses will continue to increase in connection with our planned clinical development activities in the near term and in the future. At this time, we cannot accurately estimate or know the nature, timing and costs of the efforts that will be necessary to complete the clinical development of AMX0035 and any future product candidates. Our clinical development costs may vary significantly based on factors such as:

Current wording

Research and development activities are central to our business model. Product candidates such as AMX0035 in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, such as AMX0114, primarily due to the increased size and duration of later-stage clinical trials and related product manufacturing expenses. We expect that our research and development expenses will continue to increase in connection with our planned clinical development activities in the near term and in the future. At this time, we cannot accurately estimate or know the nature, timing and costs of the efforts that will be necessary to complete the clinical development of AMX0035, avexitide and any future product candidates. Our clinical development costs may vary significantly based on factors such as:

Previous wording

The successful development and commercialization of AMX0035 and any other current or future product candidates is highly uncertain, due to the numerous risks and uncertainties associated with product development and commercialization, including the following:

Current wording

The successful development and commercialization of AMX0035, avexitide and any other current or future product candidates is highly uncertain, due to the numerous risks and uncertainties associated with product development and commercialization, including the following:

Previous wording

the availability of drug substance and drug product for use in production of AMX0035;

Current wording

the availability of drug substance and drug product for use in production of AMX0035 or other product candidates;

Previous wording

A change in the outcome of any of these variables with respect to the development of AMX0035 or any future product candidates could have a significant impact on the cost and timing associated with the development of our product candidates. We may never succeed in obtaining or maintaining, as applicable, regulatory approval for AMX0035 or any future product candidates.

Current wording

A change in the outcome of any of these variables with respect to the development of AMX0035, avexitide or any other current or future product candidates could have a significant impact on the cost and timing associated with the development of our product candidates. We may never succeed in obtaining or maintaining, as applicable, regulatory approval for AMX0035, avexitide or any other current or future product candidates.

Previous wording

Selling, general and administrative expenses consist primarily of salaries and related costs for personnel in executive, finance, sales, marketing, as well as administrative functions. Selling, general and administrative expenses also include legal fees relating to patent and corporate matters; professional fees for accounting, auditing, tax, compliance with Section 404 of the Sarbanes-Oxley Act and administrative consulting services; corporate insurance costs; administrative travel expenses; sales and marketing expenses; information technology; charitable donations to independent charitable foundations; facility-related and other operating costs. In April 2024, we announced a restructuring plan designed to focus our resources on key clinical and preclinical programs. The restructuring includes a reduction in force which is expected to reduce our workforce by approximately 70% and a decrease in external financial commitments outside our priority areas. As a result, we anticipate that our selling, general and administrative expenses will decrease in 2024 as compared to 2023.

Current wording

Selling, general and administrative expenses consist primarily of salaries and related costs for personnel in executive, finance, sales, marketing, as well as administrative functions. Selling, general and administrative expenses also include legal fees relating to patent and corporate matters; professional fees for accounting, auditing, tax, compliance with Section 404 of the Sarbanes-Oxley Act, or Section 404, and administrative consulting services; corporate insurance costs; administrative travel expenses; sales and marketing expenses; information technology; charitable donations to independent charitable foundations; facility-related and other operating costs. In April 2024, we announced the Restructuring Plan designed to focus our resources on key clinical and preclinical programs. The restructuring includes a reduction in force which is expected to reduce our workforce by approximately 70% and a decrease in external financial commitments outside our priority areas. As a result, we anticipate that our selling, general and administrative expenses will decrease in 2024 as compared to 2023.

Previous wording

Income taxes are determined using the asset and liability approach. Deferred tax assets and liabilities represent future tax consequences of temporary differences between the financial statement carrying amounts and the tax basis of assets and liabilities and for tax attribute carryforwards using enacted tax rates expected to be in effect in the years in which the differences reverse. Realization of our deferred tax assets is dependent upon the generation of future taxable income, the amount and timing of which are uncertain. Valuation allowances are provided, if, based upon the weight of available evidence, it is more likely than not that some or all of the deferred tax assets will not be realized. We continue to maintain a full valuation allowance against all of our deferred tax assets based on management’s evaluation of all available evidence, including our history of incurring significant losses from operations.

Current wording

Income taxes are determined using the asset and liability approach. Deferred tax assets and liabilities represent future tax consequences of temporary differences between the financial statement carrying amounts and the tax basis of assets and liabilities and for tax attribute carryforwards using enacted tax rates expected to be in effect in the years in which the differences reverse. Realization of our deferred tax assets is dependent upon the generation of future taxable income, the amount and timing of which are uncertain.

Previous wording

Product revenue, net was $88.6 million for the three months ended March 31, 2024, compared to $71.4 million for the three months ended March 31, 2023. During these periods, product revenue, net was primarily related to units of RELYVRIO and ALBRIOZA sold in the U.S. and Canada, respectively. In April 2024, we announced we started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™and remove the product from the market in the U.S. and Canada based on topline results from the Phase 3 PHOENIX trial.

Current wording

Product revenue, net was $87.6 million for the six months ended June 30, 2024, compared to $169.6 million for the six months ended June 30, 2023. During these periods, product revenue, net was primarily related to units of RELYVRIO and ALBRIOZA sold in the U.S. and Canada, respectively. On April 4, 2024, we announced we had started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ and remove the product from the market in the U.S. and Canada based on topline results from the Phase 3 PHOENIX trial. As a result, we did not generate significant revenue from product sales in the second quarter of 2024.

Previous wording

Cost of sales were $116.4 million for the three months ended March 31, 2024, compared to $5.3 million for the three months ended March 31, 2023. During these periods, cost of sales consisted of costs to procure, manufacture and distribute our marketed products, RELYVRIO and ALBRIOZA. On April 4, 2024, we announced we started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ and remove the product from the market in the U.S. and Canada based on topline results from the Phase 3 PHOENIX trial. As a result, the Company recorded approximately $110.5 million of charges associated with the write-down of inventory and loss on firm purchase commitments for the three months ended March 31, 2024.

Current wording

Cost of sales were $123.8 million for the six months ended June 30, 2024, compared to $10.9 million for the six months ended June 30, 2023. During these periods, cost of sales consisted of costs to procure, manufacture and distribute our marketed products, RELYVRIO and ALBRIOZA. On April 4, 2024, we announced we had started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ and remove the product from the market in the U.S. and Canada based on topline results from the Phase 3 PHOENIX trial. As a result, the Company recorded approximately $117.9 million of charges associated with the write-down of inventory and losses on firm purchase commitments for the six months ended June 30, 2024.

Previous wording

Research and development expenses were $36.6 million for the three months ended March 31, 2024, compared to $24.2 million for the three months ended March 31, 2023. During these periods, most of our research and development expenses were related to the development and clinical trials of AMX0035. The increase was primarily due to a $5.9 million increase in payroll and personnel-related costs, a $4.2 million increase in spending on AMX0035 for the treatment of PSP and a $2.2 million increase in other costs. The increase in payroll and personnel-related costs was primarily due to an increase in the number of employees supporting research and development efforts. The increase in spending on AMX0035 for the treatment of PSP was primarily related to costs to support the initiation and continuation of the ORION Phase 3 trial, and the increase in other costs were primarily due to an increase in preclinical development activities.

Current wording

Research and development expenses were $60.0 million for the six months ended June 30, 2024, compared to $53.2 million for the six months ended June 30, 2023. During these periods, most of our research and development expenses were related to the development and clinical trials of AMX0035. The increase was primarily due to a $6.1 million increase in spending on AMX0035 for the treatment of PSP, a $3.5 million increase in payroll and personnel-related costs and a $4.0 million increase in other costs. The increase in spending on AMX0035 for the treatment of PSP was primarily related to costs to support the continuation of the ORION Phase 2b/3 global clinical trial. The increase in payroll and personnel-related costs was primarily due to an increase in the number of employees supporting research and development efforts and the increase in other costs were primarily due to an increase in preclinical development activities. This increase was offset by a $6.8 million decrease in spending on AMX0035 for the treatment of ALS due to the completion of the Phase 3 PHOENIX trial, which failed to meet its prespecified primary and secondary endpoints.

Previous wording

Selling, general and administrative expenses were $57.8 million for the three months ended March 31, 2024 compared to $44.0 million for the three months ended March 31, 2023. The increase was primarily due to increases of $3.5 million in payroll and personnel-related costs, including stock-based compensation, $2.5 million in consulting and professional services, and $7.7 million in other expenses. The increase in payroll and personnel-related costs was primarily due to hiring additional personnel in commercial and general and administrative functions to support our growth, as well as commercialization preparation initiatives in the EU. The increases in consulting and professional services and other expenses were primarily due to an increase in spending for commercial activities, operations as a public company, and other expenses.

Current wording

Selling, general and administrative expenses were $79.4 million for the six months ended June 30, 2024 compared to $87.4 million for the six months ended June 30, 2023. The decrease was primarily due to a decrease of $8.6 million in payroll and personnel-related costs and a decrease of $4.2 million in consulting and professional services, offset by an increase of $4.8 million in other expenses. The decrease in payroll and personnel-related costs was primarily related to a decrease in the number of employees as a result of the Restructuring Plan. The decrease in consulting and professional services is primarily due to a decrease in commercial sales and marketing activity as a result of removing RELYVRIO®/ALBRIOZA™ from the market in the U.S. and Canada based on topline results from the global Phase 3 PHOENIX trial. The increase in other expenses is primarily due to an increase in spending for operations as a public company and other expenses.

Previous wording

We recorded an income tax provision of $0.2 million and an income tax benefit of $0.2 million for the three months ended March 31, 2024 and 2023, respectively. The income tax provision for the three months ended March 31, 2024 was driven by discrete income tax expense of $0.2 million. The income tax benefit for the three months ended March 31, 2023 was primarily driven by the estimated effective tax rate for the year, as well as discrete income tax benefit of $0.3 million.

Current wording

We recorded an income tax provision of $0.2 million and an income tax benefit of $1.8 million for the six months ended June 30, 2024 and 2023, respectively. The income tax provision for the six months ended June 30, 2024 was driven by discrete income tax expense of $0.2 million. The income tax benefit for the six months ended June 30, 2023 was primarily driven by the estimated effective tax rate for the year, as well as discrete income tax benefit of $0.3 million.

Previous wording

In the second half of 2022, we began generating revenue from the sale of our approved drug product RELYVRIO, known as ALBRIOZA in Canada. In April 2024, we announced that we have started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ for the treatment of ALS and remove the product from the market in the U.S. and Canada. As of April 4, 2024, RELYVRIO/ALBRIOZA was no longer available for new patients. We also announced a restructuring plan designed to focus our resources on key clinical and preclinical programs (the Restructuring Plan). The Restructuring Plan includes a reduction in force which is expected to reduce our workforce by approximately 70% and a decrease in external financial commitments outside of its priority areas. We expect to substantially complete the Restructuring Plan by the end of the third quarter of 2024. As part of this Restructuring Plan, we expect to incur severance and severance-related charges of approximately $19.1 million. To date, we have financed our operations primarily through revenue from the sale of our approved products, the sale and issuance of common stock, convertible preferred stock and convertible notes. As of March 31, 2024, we had cash, cash equivalents and short-term investments of $373.3 million.

Current wording

In the second half of 2022, we began generating revenue from the sale of our approved drug product RELYVRIO, known as ALBRIOZA in Canada. In April 2024, we announced that we had started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ for the treatment of ALS and remove the product from the market in the U.S. and Canada. As of April 4, 2024, RELYVRIO/ALBRIOZA was no longer available for new patients. We also announced the Restructuring Plan designed to focus our resources on key clinical and preclinical programs. The Restructuring Plan includes a reduction in force which is expected to reduce our workforce by approximately 70% and a decrease in external financial commitments outside of our priority areas. We substantially completed the Restructuring Plan in the second of 2024. To date, we have financed our operations primarily through revenue from the sale of our approved products, the sale and issuance of common stock, convertible preferred stock and convertible notes. As of June 30, 2024, we had cash, cash equivalents and short-term investments of $309.8 million.

Previous wording

From inception through March 31, 2024, we have raised $669.5 million in aggregate proceeds, net of issuance costs, primarily from the issuance of common stock, convertible preferred stock, convertible notes and grant agreements. Based on our current operational plans and assumptions, we believe that our existing cash, cash equivalents, and short-term investments, will be sufficient to meet our anticipated operating and capital expenditure requirements for at least twelve months after the date of the filing of this Quarterly Report. We have based these estimates on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we expect.

Current wording

Based on our current operational plans and assumptions, we believe that our existing cash, cash equivalents, and short-term investments, will be sufficient to meet our anticipated operating and capital expenditure requirements for at least twelve months after the date of the filing of this Quarterly Report. We have based these estimates on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we expect.

Previous wording

We expect to incur significant expenses in connection with our ongoing activities, particularly as we advance the preclinical activities, manufacturing and clinical trials of AMX0035 and any other current or future product candidates or acquire or in-license additional product candidates or products. In addition, we expect to continue to incur costs associated with operating as a public company, including significant legal, accounting, investor relations and other expenses. Because we no longer qualify as an emerging growth company as defined in the JOBS Act and we are currently considered a large accelerated filer, we are no longer currently entitled to rely on exemptions from certain compliance requirements that are applicable to companies that are emerging growth companies including, among other requirements, the auditor attestation requirements of Section 404(b) and reduced reporting requirements. We expect to incur significant expenses as we:

Current wording

We expect to incur significant expenses in connection with our ongoing activities, particularly as we advance the preclinical activities, manufacturing and clinical trials of AMX0035, avexitide and any other current or future product candidates or acquire or in-license additional product candidates or products. In addition, we expect to continue to incur costs associated with operating as a public company, including significant legal, accounting, investor relations and other expenses. Because we no longer qualify as an emerging growth company as defined in the JOBS Act and we are currently considered an accelerated filer, we are no longer currently entitled to rely on exemptions from certain compliance requirements that are applicable to companies that are emerging growth companies including, among other requirements, the auditor attestation requirements of Section 404(b) and reduced reporting requirements. We expect to incur significant expenses as we:

Previous wording

continue our research and development efforts, including our ongoing Phase 3 trial of AMX0035 in PSP and our ongoing Phase 2 trial of AMX0035 for the treatment of WS;

Current wording

continue our research and development efforts, including our ongoing Phase 3 trial of AMX0035 in PSP and our ongoing Phase 2 trial of AMX0035 for the treatment of Wolfram syndrome;

Previous wording

the scope, progress, results and costs of drug discovery, laboratory testing, preclinical and clinical development for AMX0035 and any future product candidates;

Current wording

the scope, progress, results and costs of drug discovery, laboratory testing, preclinical and clinical development for AMX0035, avexitide and any future product candidates;

Previous wording

the costs, timing and outcome of regulatory review of AMX0035 and any future product candidates;

Current wording

the costs, timing and outcome of regulatory review of AMX0035, avexitide and any future product candidates;

Previous wording

timing delays with respect to preclinical and clinical development of AMX0035 and any future product candidates, including as result of any future outbreak of any highly infectious or contagious diseases;

Current wording

timing delays with respect to preclinical and clinical development of AMX0035, avexitide and any future product candidates, including as result of any future outbreak of any highly infectious or contagious diseases;

Previous wording

During the three months ended March 31, 2024, operating activities used $0.5 million of cash, primarily resulting from our net loss of $118.8 million and $2.6 million net accretion of discounts on investments, offset by $110.5 million of inventory impairment and loss on firm purchase commitments, $9.9 million of non-cash stock-based compensation expense and $0.2 million of net cash provided by changes in our operating assets and liabilities.

Current wording

During the six months ended June 30, 2024, operating activities used $67.1 million of cash, primarily resulting from our net loss of $191.5 million, $5.8 million net accretion of discounts on investments and $8.5 million of net cash used by changes in our operating assets and liabilities, offset by $117.9 million of inventory impairment and loss on firm purchase commitments and $19.5 million of non-cash stock-based compensation expense.

Previous wording

Net cash provided by our operating assets and liabilities primarily consisted of a $19.7 million decrease in accounts receivable, net, offset by a $9.3 million increase in inventory capitalized during the period, a $2.1 million increase in prepaid expenses and other current assets, a decrease of $7.8 million in accrued expenses and a $0.7 million decrease in accounts payable.

Current wording

Net cash used by changes in our operating assets and liabilities primarily consisted of a $36.0 million decrease in accounts receivable, net, offset by a $9.3 million increase in inventory capitalized during the period, net of inventory written-off, a decrease of $20.3 million in accrued expenses and a $17.1 million decrease in accounts payable.

Previous wording

During the three months ended March 31, 2023, operating activities used $5.1 million of cash, primarily resulting from $11.4 million of net cash used by changes in our operating assets and liabilities and $2.9 million net amortization of premiums and discounts on investments, offset by $7.5 million of non-cash stock-based compensation expense.

Current wording

During the six months ended June 30, 2023, operating activities provided $3.5 million of cash, primarily resulting from our net income of $23.6 million and $17.5 million of non-cash stock-based compensation expense, offset by $4.9 million net accretion of discounts on investments and $33.2 million of net cash used by changes in our operating assets and liabilities.

Previous wording

Net cash used in our operating assets and liabilities primarily consisted of a $13.3 million increase in inventory capitalized during the quarter, a $2.9 million increase in prepaid expenses and other current assets and a $2.2 million increase in accounts receivable, net, offset by a $4.6 million increase in accounts payable and a $2.2 million increase in accrued expenses.

Current wording

Net cash used in our operating assets and liabilities primarily consisted of a $32.6 million increase in inventory capitalized during the period and a $18.2 million increase in accounts receivable, net, offset by a $18.5 million increase in accounts payable.

Previous wording

During the three months ended March 31, 2024, net cash provided by investing activities was $0.8 million, resulting primarily from $74.0 million of investments that matured, partially offset by $73.1 million of purchases of short-term investments during the period.

Current wording

During the six months ended June 30, 2024, net cash used by investing activities was $28.1 million, resulting primarily from $232.0 million of purchases of short-term investments during the period, offset by $204.0 million of investments that matured.

Previous wording

During the three months ended March 31, 2023, net cash provided by investing activities was $56.0 million, resulting primarily from $66.0 million of investments that matured, offset by $9.8 million of purchases of short-term investments during the period.

Current wording

During the six months ended June 30, 2023, net cash provided by investing activities was $179.2 million, resulting primarily from $189.5 million of investments that matured, partially offset by $9.8 million of purchases of short-term investments during the period.

Previous wording

During the three months ended March 31, 2024, net cash provided by financing activities was $0.1 million. This amount consisted primarily of $0.1 million of proceeds from exercises of stock options and vesting of stock awards, net of withholding taxes paid on stock-based awards.

Current wording

During the six months ended June 30, 2024, net cash provided by financing activities was $0.2 million. This amount consisted primarily of $0.2 million of proceeds from exercises of stock options and vesting of stock awards, net of withholding taxes paid on stock-based awards.