What changed in this filing

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Item 1. Business

2024-02-22 compared with 2023-03-13 · 528 added, 488 removed, 681 unchanged (60% of the section changed)

Our mission is to one day end the suffering caused by neurodegenerative diseases.

We are committed to supporting and creating more moments for the neurodegenerative disease community through the discovery and development of innovative new treatments.

Our first product, RELYVRIO® (sodium phenylbutyrate and taurursodiol), previously known as AMX0035 in the U.S., is approved in the U.S.

for the treatment of ALS in adults.

AMX0035 is also approved with conditions by Health Canada and marketed as ALBRIOZA for the treatment of ALS in Canada.

Unlike most other cells in the body that regularly die and are replaced as part of healthy function, mature neurons are normally resistant to cell death and generally cannot regenerate.

We believe AMX0035 is the first drug candidate to show both a functional and survival benefit in a large-scale clinical trial of patients with ALS.

The results of our Phase 2 clinical trial of AMX0035, known as the CENTAUR trial, were published in the New England Journal of Medicine , in two publications in Muscle & Nerve , and in the Journal of Neurology , Neurosurgery , and Psychiatry .

AMX0035 is a dual UPR-Bax apoptosis inhibitor composed of PB and TURSO (also known as TUDCA).

Through the resolution of the UPR and by inhibiting translocation of the Bax to the outer mitochondrial membrane, we have shown in multiple models that AMX0035 can keep neurons alive under a variety of different conditions and stresses, including in in vitro models of neurodegeneration, endoplasmic reticulum, or ER, stress, mitochondrial dysfunction, oxidative stress and disease-specific models of a variety of other conditions, as well as in vivo models of ALS, Alzheimer’s disease, or AD, and multiple sclerosis, or MS.

We believe AMX0035 has the potential to be a foundational therapy, meaning that it could be used alone or in conjunction with other therapies to change the treatment paradigm across a broad range of neurodegenerative diseases.

We are pursuing ALS as our first indication as it is a disease of rapid and profound neurodegeneration, and we are focused on the development and potential commercialization of AMX0035 for ALS globally.

We have received marketing authorization with conditions by Health Canada for ALBRIOZA for the treatment of ALS.

We announced commercial availability of the product in July 2022.

We have submitted to and received from the national reimbursement authorities, known as the Canadian Agency for Drugs and Technologies in Health, or CADTH, and l’Institut national d’excellence en santé

et en services sociaux, or INESSS, recommendations regarding reimbursement for ALBRIOZA by the Canadian provincial governments, and are negotiating with both public and private payers to obtain reimbursement coverage.

We received approval by the FDA for RELYVRIO in September 2022, and commercial product was first available in October 2022.

This decision represented Amylyx’

first regulatory approval of AMX0035 in the U.S.

and its second worldwide.

We are also actively pursuing regulatory approval of AMX0035 for the treatment of ALS in Europe.

Our MAA remains under review by the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA.

We submitted a Marketing Authorization Application, or MAA, to the EMA in Europe in the first quarter of 2022, which was validated in the same quarter.

We completed the Scientific Advisory Group meeting.

Certain major objections remain, and the CHMP has adopted another round of questions as part of the regulatory process.

We are now in possession of those questions.

In order to respond in accordance with the updated timelines, we now expect an opinion from CHMP mid-year and a decision in the third quarter of 2023 at the earliest.

In November 2021, we initiated a Phase 3 clinical trial of AMX0035 for the treatment of ALS, known as PHOENIX trial, at clinical trial sites in the U.S.

On February 2, 2023, we announced completion of enrollment in PHOENIX, which enrolled 664 participants.

We anticipate topline results from the PHOENIX trial in mid-2024.

This trial is designed to provide further data evaluating the safety and efficacy of AMX0035 over 48 weeks for the treatment of ALS to further support our global regulatory efforts.

European participants completing the 48-week trial have the option to enroll in an open label extension (OLE) phase.

During this phase, all participants receive AMX0035, and continued safety and efficacy measures will be assessed.

We are also developing AMX0035 for other neurodegenerative diseases by leveraging our deep knowledge of and relationships in the neurodegenerative space.

We believe the approach of a dual UPR-Bax apoptosis inhibitor designed to help keep neurons alive could be clinically meaningful for the treatment of other neurodegenerative disease indications in

addition to ALS.

Many common and rare neurodegenerative diseases are characterized by substantial neuronal cellular loss, including AD and Wolfram syndrome, as well as Parkinson’s Disease, Huntington’s Disease, Progressive Supranuclear Palsy, Multi-System Atrophy, and others.

We conducted a Phase 2 clinical trial in AD, known as the PEGASUS trial, to obtain safety data along with initial efficacy and biomarker data which could help us prioritize additional indications to pursue with AMX0035.

We believe the topline results from the PEGASUS trial, reported in November 2021, provide further biological knowledge about AMX0035 which will help inform future clinical development of AMX0035 for the treatment of AD and in other potential indications.

Based on these topline results, AMX0035 met the PEGASUS trial’s primary endpoint of safety and tolerability.

The 6-month trial was not powered to evaluate differences between groups in efficacy outcomes and no differences were seen in a newly developed composite outcome of cognitive, functional, and imaging measures, or secondary efficacy endpoints of cognition, function, and imaging.

In this trial, AMX0035 showed significant effects on biomarkers including neurogranin, YKL-40 or Chitinase 3-like 1 (CHI3L1), and fatty acid binding protein 3 (FABP3).

These results build on previously reported findings that AMX0035 exhibited significant effects on the tau protein, tau phosphorylated at threonine 181, and the amyloid beta 42 to 40 (amyloid-ß1-42, amyloid-ß1-40) ratio in cerebrospinal fluid.

We will continue to evaluate these data and discuss the results of the PEGASUS trial with scientific advisors as we consider potential next steps for the development of AMX0035 for the treatment of AD within our clinical development strategy.

In March 2023, we completed site activation for a Phase 2 clinical trial of AMX0035 for the treatment of Wolfram syndrome, and expect to enroll the first participant in the near term.

We also intend to prioritize our development efforts around neurodegenerative diseases that result in substantial disability, and ultimately death, and where unmet medical needs are greatest.

For example, we recently presented initial in vitro data from our new, internally developed compound, AMX0114, targeting Calpain-2, a critical effector of axonal degeneration.

Since our founding in 2013, our goal has been to improve the quality of, and extend, life for patients suffering from neurodegenerative diseases.

One of our key strategies towards achieving this goal has been to form direct relationships with patients, their families, advocacy groups, and healthcare professionals to bring much needed innovation to patients.

Throughout the development of AMX0035, we have partnered with members of the disease communities we serve, including the ALS Association, the Northeast ALS Consortium, or NEALS, ALS Finding a Cure, the Healey Center at Massachusetts General Hospital, the Cure Alzheimer’s Fund, the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation, to ensure our goals are aligned with patient needs.

In addition, many of the key opinion leaders in the ALS community were and are investigators in our recent and ongoing trials.

These relationships are a cornerstone of our culture and corporate strategy.

Our current pipeline, including the stage of development and approvals of AMX0035 in our target indications, is represented in the table below.

AMX0035 is a proprietary oral fixed-dose combination of two small molecules:

PB, which is a small molecular chaperone that reduces the UPR, preventing cell death resulting from the UPR, and TURSO, (also known as

tauroursodeoxycholic acid, or TUDCA), which is a Bax inhibitor that reduces cell death through apoptosis.

While the PB and TURSO molecules individually are not proprietary to us, we own patents and patent applications covering AMX0035, including the fixed-dose combination of AMX0035 itself.

We believe that our proprietary combination of these two mechanisms of action will allow us to target abnormal cell death to better prevent neurodegeneration than treatment with either mechanism of action alone.

The results of our CENTAUR trial were published in September 2020 in the New England Journal of Medicine and in October 2020 in the Journal of Muscle and Nerve .

Trial results showed that patients receiving AMX0035 experienced statistically significant benefit in retention of function, as measured by the Revised ALS Functional Rating Scale, or ALSFRS-R, as well as nominally significant improvement in overall survival, or OS, when analyzing the full randomized population through the OLE trial in a post hoc analysis (July 20, 2020 and March 1, 2021 data cutoffs).

Results of long-term effect of AMX0035 on tracheostomy/ventilation-free survival and hospitalization were published in May 2022 in the Journal of Neurology Neurosurgery Psychiatry .

AMX0035 was shown to be generally well-tolerated with the prevalence of adverse events comparable across placebo and treatment groups.

We believe AMX0035 is the first drug candidate in ALS to demonstrate a statistically significant benefit in function as measured by a prespecified mean rate change in ALSFRS-R and a nominally significant benefit in a longer-term post hoc analysis of OS, which are both important outcomes for people with ALS.

Amylyx Pharmaceuticals, Inc.

(also referred to as Amylyx, we, our or us) is a commercial-stage biotechnology company with a mission to end the suffering caused by neurodegenerative diseases.

We have been working in amyotrophic lateral sclerosis, or ALS, and neurodegenerative diseases for over a decade and have been making significant progress in transforming the treatment of these diseases.

Since our founding in 2013, we have transformed from a research-stage company focused on addressing the needs of patients suffering from neurodegenerative diseases to a commercial enterprise with development programs across several indications.

Our first commercial product, AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO], also known as RELYVRIO in the U.S.

and ALBRIOZA in Canada) is the first and only ALS therapy of which we are aware that has been shown to slow disease progression, help maintain functional independence, and extend overall survival in the same clinical trial, with a generally well-tolerated side effect profile and oral administration.

AMX0035 was commercially launched as RELYVRIO in the U.S.

in October 2022 and commercially launched as ALBRIOZA in Canada in July 2022.

Since the launch of RELYVRIO and ALBRIOZA through December 31, 2023, we have generated net product revenue of $403.0 million.

We believe AMX0035 has the potential to become a widely-used ALS medication and provides an opportunity to transform ALS from a disease for which symptom management is the standard of care to a disease with meaningful interventions.

In addition, we believe AMX0035 has the potential to be a foundational therapy for neurodegenerative diseases, meaning that it could be used alone or in conjunction with other therapies to change the treatment paradigm across a broad range of neurodegenerative diseases.

We are committed to bringing the benefits of AMX0035 to the more than 200,000 people living with ALS worldwide.

We are building a global infrastructure to commercialize AMX0035 in additional jurisdictions where it may be approved and engaging with key stakeholders around the world to explore opportunities for access including in the EU and Japan.

We continue to focus on the global PHOENIX Phase 3 clinical trial of AMX0035 for the treatment of ALS, a 48-week, randomized, double-blind, placebo-controlled trial at clinical sites in the U.S.

and Europe, and expect to report topline results during or before the second quarter of 2024.

If the data from PHOENIX are supportive, it will be the first time that two clinical trials have demonstrated a benefit in ALS.

We believe that supportive PHOENIX data will further accelerate the commercial launch of AMX0035 and the transformation of the treatment of ALS.

In addition to ALS, we believe there is strong scientific rationale to use AMX0035 to treat other neurodegenerative diseases.

AMX0035 was designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum, or ER, stress and mitochondrial dysfunction, two connected central pathways that lead to neurodegeneration.

We believe that our proprietary combination of PB and TURSO and their respective mechanisms of action will allow us to synergistically target abnormal cell death to better prevent neurodegeneration than treatment targeted at either mechanism of action alone.

We are actively advancing clinical trials to evaluate AMX0035 in progressive supranuclear palsy, or PSP, and Wolfram syndrome, or WS.

Consistent with our commitment to ongoing research to identify additional potential treatments for ALS and other neurodegenerative diseases, we also are developing AMX0114, an antisense oligonucleotide, for the treatment of people living with ALS.

Our current pipeline is represented in the table below.

Our Company and Team

Amylyx was founded with the ambitious goal of improving the quality and length of life for patients suffering from neurodegenerative diseases.

From a dorm room at Brown University in 2013, our Co-CEOs and Co-Founders, Josh Cohen and Justin Klee set out to determine why neurons die, and have ever since been working to develop AMX0035, which we believe is the first drug candidate to show function and survival benefits in patients with ALS, and other novel therapies.

To help realize our goal, we have assembled a team with deep scientific, clinical, business and leadership experience, bolstered by expertise in biotechnology.

Amylyx was founded on one simple, unanswered question:

What causes neurons to die?

Co-CEOs Josh Cohen and Justin Klee began their journey of uncovering the answer, building a world-class company dedicated to ending the suffering caused by relentless progressive neurodegenerative diseases, 11 years ago in 2013.

We have assembled a team with deep scientific, clinical, business and leadership experience, bolstered by expertise in biotechnology to help realize our goal.

Our Chief Financial Officer, James Frates, brings over 20 years of experience as the Chief Financial Officer of Alkermes.

Our Chief Commercial Officer, Margaret Olinger, brings three decades of expertise in commercial launches and operations, most recently at Alexion.

Our Chief Medical Officer, Camille L.

Bedrosian, brings nearly 30 years of experience in building successful clinical development and translation research programs in the pharmaceutical industry, including as Chief Medical Officer at Ultragenyx, Alexion, and ARIAD Pharmaceuticals.

Our Chief Technical Operations Officer, Tom Holmes, brings more than 25 years of leadership experience at Biogen in supply chain, pharmaceutical manufacturing and program management.

Our Head of Regulatory Affairs, Tammy Sarnelli, brings more than 30 years of experience from Biogen and other companies in early and late-stage neurology and rare disease development.

Our Global Head of Human Resources, Debra Canner, brings over 20 years of experience, having served as the Chief of Human Resources Officer at Akamai and as part of Genzyme.

Our Chief Legal Officer and General Counsel, Gina M.

Mazzariello, brings more than 20 years of corporate and commercial legal experience in the healthcare industry, including holding leadership positions at Boehringer Ingelheim USA, Inc.

Our Global Head of Clinical Research & Development and Chief Medical Officer, Patrick D.

Yeramian, brings over 30 years of medical and pharmaceutical industry experience.

This team brings a diverse set of skills uniquely suited to drive successful commercialization of AMX0035 in ALS while continuing to advance AMX0035 in other indications.

Effective December 1, 2022, Dr.

Yeramian shifted to a part-time role and we expect he will ultimately transition out of his role into retirement, although no definitive date has been set for such transition.

We have engaged in a search to identify a full-time successor as part of our management succession process.

We recently appointed Karen Firestone to our Board of Directors, effective as of March 16, 2023.

Prior to founding her current fund, Aureus, Karen spent 22 years with Fidelity where, among other responsibilities, she managed the Biotechnology sector fund.

She has a demonstrated track record of applying her strategic acumen and commercial mindset to drive progress in the space and look forward to her counsel as we continue working toward our mission.

Our Chief Human Resources Officer, Linda Arsenault, brings over 30 years of people leadership and strategic business acumen including most recently from Sunovion where she was the Chief Human Resources Officer.

This team brings a diverse set of skills uniquely suited to drive successful commercialization of AMX0035 in ALS while continuing to advance our pipeline, including studying AMX0035 in other indications, and to explore new approaches and compounds in-house and in partnership with leading clinicians and researchers.

Our mission is to one day end the suffering caused by neurodegenerative diseases.

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• Effectively and efficiently commercializing RELYVRIO for ALS in adults in the U.S.

and ALBRIOZA for ALS in Canada, obtaining additional regulatory approvals of AMX0035, and commercializing AMX0035 in other key territories, if approved.

In 2022, AMX0035 was approved by the FDA and commercially launched in the U.S.

as RELYVRIO and approved with conditions and commercially launched as ALBRIOZA in Canada.

We believe our commercial capabilities, coupled with our understanding of the ALS patient and medical community, enabled us to successfully commercialize, to date, RELYVRIO for ALS in the U.S.

and ALBRIOZA for ALS in Canada.

We received FDA approval in the U.S.

for AMX0035 as RELYVRIO for the treatment of ALS in adults in September 2022 and launched RELYVRIO commercially in the U.S.

in October 2022.

We received marketing authorization with conditions in Canada for ALBRIOZA for the treatment of ALS in June 2022 and launched ALBRIOZA commercially in Canada in July 2022.

We believe our commercial capabilities, coupled with our understanding of the ALS patient and medical community, will enable us to successfully commercialize

RELYVRIO for ALS in the U.S.

and ALBRIOZA for ALS in Canada and to launch AMX0035 for the treatment of ALS successfully in other key territories, if approved.

Obtaining additional regulatory approvals of AMX0035 for ALS, with an initial focus on Europe.

In June 2022, AMX0035 received marketing authorization with conditions as ALBRIOZA in Canada for the treatment of ALS and in September 2022, AMX0035 received approval in the U.S.

as RELYVRIO for the treatment of ALS in adults.

Based on the results from our CENTAUR trial, we have been exploring pathways towards regulatory approval in several additional territories, including Europe.

We believe that the CENTAUR trial may also be able to support marketing authorization in Europe and other jurisdictions.

We submitted an MAA in Europe in the first quarter of 2022, and we now expect an opinion from CHMP mid-year and a decision in the third quarter of 2023 at the earliest.

Effectively and efficiently commercializing AMX0035 in other key territories, if approved.

We are continuing to build our sales team, internal capabilities and outside vendor network to support commercialization in the U.S.

We will continue to build our capabilities in Europe and other jurisdictions to support commercialization of AMX0035, if approved.

For example, in January 2023, we entered into a distribution agreement with Neopharm to commercialize AMX0035 in Israel, Gaza, West Bank and Palestinian Authority, subject to regulatory review and approval.

We anticipate that our commercial infrastructure will be scalable for subsequent launches in other key markets if we receive marketing approval in these territories as well.

We remain committed to bringing the benefits of AMX0035 to the more than 200,000 people living with ALS worldwide.

Assuming the data from the PHOENIX trial are supportive, we plan to seek approval for AMX0035 for the treatment of ALS in the EU and the United Kingdom, or UK, as quickly as possible.

In addition, we continue to interact with key stakeholders around the world, including Japan, to explore opportunities for access.

• Maximizing the therapeutic potential of AMX0035 by expanding into additional neurodegenerative diseases.

We believe the data from the CENTAUR trial showing functional and survival benefits for ALS patients treated with AMX0035 support its potential mechanism of targeting ER stress and mitochondrial dysfunction.

Based on our extensive understanding of disease pathways, we believe AMX0035 may provide benefit across multiple diseases characterized by neurodegeneration.

As we select the next indications for AMX0035 we will prioritize those indications which we believe, if successful, will most rapidly lead to marketed products and to patient benefit.

We conducted our Phase 2 PEGASUS clinical trial in AD to obtain safety data along with initial efficacy and biomarker data, which will help us evaluate the development of AMX0035 for the treatment of AD within our clinical development strategy.

In March 2023, we completed site activation for a Phase 2 clinical trial of AMX0035 for the treatment of Wolfram syndrome, and expect to enroll the first participant in the near term.

Continuing to cultivate a network of patient advocacy groups, key opinion leaders, research institutions, and healthcare professionals to inform our patient-centric approach.

We have cultivated a network of key constituents, which we believe will continue to help us to develop therapies in an efficient and impactful manner.

Integrating the experiences and insights from these parties, which include patients, their families, and organizations such as the ALS Association, NEALS, ALS Finding a Cure, the Healey Center at Massachusetts General Hospital, the Cure Alzheimer’s Fund, the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation, continues to inform our approach to developing therapies that can potentially transform the lives of patients and their families.

We intend to continue to engage with each of these constituents through conferences, clinical trials and informal communications as we further develop and pursue commercialization of AMX0035.

We believe our preclinical data and clinical data from the CENTAUR trial showing functional and survival benefits for ALS patients treated with AMX0035 support its potential mechanism of targeting ER stress and mitochondrial dysfunction.

Based on our extensive understanding of neurodegenerative disease pathways, we believe AMX0035 may provide benefit across multiple diseases characterized by neurodegeneration.

We conducted our Phase 2 PEGASUS clinical trial in AD to obtain safety data along with initial efficacy and biomarker data, which is helping us evaluate the development of AMX0035 for the treatment of AD within our clinical development strategy.

We are also pursuing development of AMX0035 for the treatment of PSP with our Phase 3 ORION clinical trial and WS with our Phase 2 HELIOS clinical trial.

As we select additional indications for AMX0035, we will prioritize those indications which we believe, if successful, will most rapidly lead to marketed products and to patient benefit, if approval is received.

• Continuing to collaborate with a network of patient advocacy organizations, key opinion leaders, research institutions, and healthcare professionals to inform our patient-centric approach.

We have partnered with a network of key constituents, which we believe will continue to help us to develop therapies in an efficient and impactful manner.

What we learn from the experiences and insights from these groups, which include people living with neurodegenerative diseases, their families, and organizations continues to inform our approach to discovering and developing treatments for people living with ALS and advancing research that addresses unmet needs in additional neurodegenerative diseases.

It is a standard practice for Amylyx to partner and consistently engage with these key constituents throughout the pre-clinical to commercialization continuum as we continue to advance our pipeline to better serve and benefit the patients and clinicians.

• Deploying a strategic approach to design, acquire and develop new therapies.

We follow a scientifically rigorous approach to evaluating new opportunities to broaden our portfolio.

We plan to target assets that allow us to leverage our experience with neurodegenerative pathways and AMX0035’s mechanism of action, focusing primarily on preventing neuron death.

We plan to target assets that allow us to leverage our experience with neurodegenerative pathways and AMX0035’s mechanism of action, focusing

primarily on preventing neuron death.

When evaluating assets, we consider not only our ability to apply our experience with AMX0035, but also a variety of factors, including unmet medical need, biological rationale, feasibility of clinical development, potential for regulatory approval, costs of development, competitive landscape and commercial potential.

For example, in July 2022, we announced that we entered into a two-year sponsored research agreement with Sunnybrook Research Institute to expedite the identification of novel drug candidates that inhibit Bax and Bak for the development of therapeutics for neurodegenerative diseases, specifically ALS.

We are also developing AMX0114, an antisense oligonucleotide, for people living with ALS.

Neurodegenerative Disease

The prevention of neurodegeneration represents one of today’s most significant unmet medical needs.

The development of therapies that preserve neuron health has historically presented unique challenges, including an imperfect understanding of underlying biology and a lack of translation of activity observed in preclinical studies to results in clinical trials.

Currently approved therapies for many neurodegenerative diseases are generally only symptom modifying and have demonstrated limited efficacy.

There remains an urgent need for novel approaches to address most neurodegenerative diseases, especially for progressive and severe conditions such as ALS.

The Role of the Endoplasmic Reticulum and Mitochondria in Neurodegenerative Disease

The prevention of neurodegeneration represents one of today’s most significant unmet medical needs.

The development of therapies that preserve neuron health has historically been limited by unique challenges, including an imperfect understanding of underlying biology and a lack of translation of activity observed in preclinical studies to results in clinical trials.

Many neurodegenerative diseases only have symptom-modifying treatment options, with no approved therapies that meaningfully alter the disease course.

Others that have approved disease altering therapies still have an unmet need for additional options to further slow disease progression and/or improve survival outcomes.

There remains an urgent need for novel approaches to address most neurodegenerative diseases, especially for progressive and severe conditions such as ALS, PSP, WS and AD.

Background and Rationale for AMX0035 in Neurodegenerative Disease

Unlike most other cells in the body that regularly die and are replaced as part of healthy function, mature neurons are normally resistant to cell death and generally cannot regenerate.

Neuron death is only triggered when multiple stress factors are activated beyond the neuron’s recovery capacity, a circumstance commonly seen in neurodegenerative disorders.

Most neurodegenerative disorders have complex pathophysiology, with multiple pathways contributing and converging to eventually cause neuron death.

A large fraction of these pathological changes in neurons can be linked to dysfunction in the ER and mitochondria that affect metabolism and secretion of lipids and proteins, calcium homeostasis, and energy production.

Dysfunction in these two essential cellular structures is implicated across many neurodegenerative disorders, highlighting the central role they play in maintaining neuron health and survival and providing the rationale for our focus, which is to rescue ER and mitochondrial function, and to protect and preserve neurons.

The ER is responsible for protein and lipid synthesis, folding and quality control of proteins, and storing calcium for cellular energy production by the mitochondria.

The ER is also a primary sensor of stressful intracellular conditions, activating a wide number of molecular pathways that belong to a specific process, referred to as the ER stress response, that controls protein homeostasis.

ER stress, or dysfunction associated with protein misfolding and aggregation, has been implicated in the pathogenesis of neurodegenerative disease.

In neurodegenerative disorders, misfolded proteins and accumulations of protein aggregates can cause oxidative stress and a feedback loop resulting in ER stress.

When the ER stress response is activated due to misfolded and aggregated proteins, the UPR, is engaged as a regulatory mechanism to reduce the load of misfolded proteins and restore a healthy cellular state.

Molecular chaperones are the critical regulators of protein homeostasis under ER stress.

Pathological conditions such as neurodegenerative diseases that disturb protein folding and maturation can trigger ER stress and engage the UPR.

When the natural protein homeostasis in the cell cannot be achieved, the UPR triggers cellular death, or apoptosis.

The Role of the ER in Neurodegenerative Disease

Mitochondrial Dysfunction

The mitochondria are a central regulatory point for the control of cell death.

When mitochondria detect sufficient cell damage, they signal for the cell to initiate a cell death cascade.

Among other steps, this cascade includes the recruitment

of a series of apoptotic proteins including Bcl-2-associated X protein, or BAX, the release of cytochrome c from a pore in the mitochondrial membrane called the mitochondrial permeability transition pore, and finally the activation of caspase 3, an executioner protein for apoptosis.

In neurodegenerative diseases, triggers such as altered calcium homeostasis, glutamate excitation of the cell, damage to the mitochondria or mitochondrial DNA and detection of aberrant double-stranded DNA and accumulation of unfolded proteins at the mitochondria all lead to mitochondrially mediated cell death.

Inhibition of proteins such as BAX could result in a greater threshold for cell death and longer survival of key neurons implicated in the progression of neurodegenerative disease.

Linkage Between Mitochondria and ER

The mitochondria and the ER are often physically linked by a membrane called the mitochondrial associated ER membrane, or MAM.

Through this linkage, calcium and molecules are shuttled between the two organelles.

It is our belief that this connection, or crosstalk, allows the cell to integrate responses between the two organelles and that activation of mitochondrial damage pathways will activate the UPR and vice versa .

Both the mitochondria and the UPR in the ER can trigger cell death.

As such, we believe both pathways are crucial to the pathogenesis of neurodegenerative diseases and both need to be addressed simultaneously to effect a substantial change in survival of neurons undergoing neurodegenerative processes.

The Role of the ER and Mitochondria in Neuron Death

Background and Rationale for AMX0035

We have designed AMX0035 to reduce neuron death through simultaneous mitigation of ER stress and mitochondrial dysfunction.

AMX0035 is a coformulation of two small molecules, PB and TURSO.

Dysfunction in these two essential cellular structures is implicated across many neurodegenerative disorders, highlighting the central role they play in maintaining neuron health and survival and providing the rationale for AMX0035, which was designed to rescue ER and mitochondrial function, and to protect and preserve neurons.

AMX0035, a dual unfolded protein response, or UPR, -Bax apoptosis inhibitor, is a proprietary oral fixed-dose combination of two small molecules:

PB, which is a small molecular chaperone that reduces the UPR, preventing cell death resulting from the UPR, and TURSO, which is a Bax inhibitor that reduces cell death through apoptosis.

Through the resolution of the UPR and by inhibiting translocation of the Bax to the outer mitochondrial membrane, we have shown in multiple models that AMX0035 can keep neurons alive under a variety of different conditions and stresses, including in in vitro models of neurodegeneration, ER stress, mitochondrial dysfunction, oxidative stress and disease-specific models of a variety of other conditions, as well as in vivo models of ALS, AD and multiple sclerosis, or MS.

We designed AMX0035 to reduce neuron cell death through simultaneous mitigation of ER stress and mitochondrial dysfunction.

PB has been shown to reduce ER stress through upregulation of a protein known as DJ-1 that is a master chaperone regulator, recruitment of other chaperone proteins, and as a small molecular chaperone.

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Through our research, we identified the specific ratios at which the combination of PB and TURSO target these critical, connected pathways and show synergistic activity in improving neuronal cell viability in vitro .

In 2022, preclinical data showing the combined potential synergistic effect of PB and TURSO, compared to the individual compounds, were published in the peer-reviewed medical journal Annals of Clinical and Translational Neurology .

These data on the transcriptomic and metabolomic profiles of primary skin fibroblasts from adults with sporadic ALS and adults without ALS showed that combined PB and TURSO had a greater and more distinct effect on genes and metabolites involved in ALS-relevant pathways compared to either sodium phenylbutyrate or taurursodiol (also known as ursodoxicoltaurine) alone.

We then developed AMX0035 as an optimized oral formulation to be tested in vivo and clinically.

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The results of this in vitro model are shown in the graphic below.

Additionally, we have observed benefit from the administration of particular ratios of PB and TURSO across in vitro models of ER stress, mitochondrial dysfunction, oxidative stress, and disease specific models of ALS, AD, Parkinson’s disease, MS, Friedreich’s Ataxia, primary mitochondrial myopathies and a variety of other conditions.

We have also conducted in vivo models of PB and TURSO, in combination, including models of ALS, AD and MS.

Additionally, academic groups have conducted studies with monotherapy treatment with TURSO and/or PB in models of ALS, AD, MS, Parkinson’s Disease, Huntington’s Disease, Progressive Supranuclear Palsy, Multi-System Atrophy, X-linked adrenoleukodystrophy, and a variety of other models.

We believe this body of evidence collectively supports the use of this combination to treat neurodegenerative indications and led us to pursue the development of our proprietary drug candidate, AMX0035.

Additionally, academic groups have conducted studies with monotherapy treatment with TURSO and/or PB in models of ALS, AD, MS, Parkinson’s Disease, Huntington’s Disease, PSP, Multi-System Atrophy, X-linked adrenoleukodystrophy, and a variety of other models.

We believe this body of evidence collectively supports the use of this combination to treat neurodegenerative indications and led us to pursue the development of AMX0035 in other disease indications.

AMX0035 for the Treatment of ALS

Overview of ALS

We are initially developing AMX0035 for the treatment of ALS, an adult-onset, progressive, and fatal neurodegenerative disorder of the neuromuscular system resulting in muscle weakness and paralysis leading to death.

ALS involves the progressive degeneration of motor neurons in the spinal cord and brain that are responsible for controlling voluntary muscle movement.

This progressive loss of motor neurons leads to muscle weakness, loss of muscle mass, and inability to control movement.

ALS remains universally fatal with a median survival of less than three years from symptom onset and less than two years from diagnosis.

Despite being classified as a rare disease by the FDA and the EMA, ALS is considered one of the more common adult-onset neuromuscular diseases worldwide.

We initially developed AMX0035 for the treatment of ALS, a relentlessly progressive and fatal neurodegenerative disease.

ALS is caused by motor neuron death in the brain and spinal cord, leading to deteriorating muscle function, the inability to move, speak, swallow, and eat, respiratory paralysis, and, eventually, death.

In the later stages of the disease, a person might require constant care, a wheelchair to enable mobility, and mechanical support to communicate, eat and breathe.

ALS remains universally fatal with approximately half of patients passing away less than a median of 3 years from symptom onset.

Despite being classified as a rare disease by the U.S.

Food and Drug Administration, or the FDA, and the European Medicines Agency, or the EMA, ALS is considered one of the more common adult-onset neuromuscular diseases worldwide.

At least 200,000 people worldwide are diagnosed with ALS.

We estimate, based on public sources, that there are approximately 30,000 ALS patients in the U.S.

More than 30,000 ALS patients are estimated to be located in the EU and the United Kingdom, or UK, and about 3,000 ALS patients are located in Canada.

Over 90% of patients have no family history of ALS, known as “sporadic”

More than 30,000 ALS patients are estimated to be located in the EU and the UK, and an estimated 3,000 ALS patients are located in Canada.

Over 90% of patients have no family history of ALS, known as “sporadic” ALS.

While other development approaches seek to address genetic instances of ALS, AMX0035 is designed to target all instances of ALS, regardless of whether it is sporadic or genetic.

Due to the two-year median survival of patients diagnosed with ALS, a high proportion of the patient population has been recently diagnosed and a therapy that is able to improve the survival of patients with ALS has the potential to increase the number of patients who are able to continue living with their disease.

Most people who develop ALS are between the ages of 40 and 70, with a median age of 55 at the time of diagnosis.

However, cases of the disease do occur in people in their twenties and thirties.

Medical costs for patients newly diagnosed with ALS in the U.S.

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Caregivers are often forced to miss work or give up employment opportunities to provide care, leading to increased financial strain.

The disease also impacts the patient’s family, who generally provide the bulk of caregiving, which often entails the provision of 24-hour care.

The constant adaptation of caregivers to the demands of the ALS disease progression requires significant physical effort and mental exhaustion particularly during the advanced stages of the disease.

Given half of the patients diagnosed with ALS pass away less than a median of 3 years from symptom onset, a high proportion of the patient population has been recently diagnosed.

A therapy that is able to extend independence and slow the loss of physical function of people living with ALS has the potential to increase the number of people who are able to continue living with their disease.

Significant Unmet Need in ALS

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There is a significant unmet need for ALS therapies that target multiple pathogenic pathways, are disease-modifying, and can provide both functional and survival benefit to patients.

Only two FDA-approved therapeutic agents for ALS, riluzole, an anti-glutamatergic agent, and edaravone, a free-radical scavenger, have been shown to modulate the course of ALS.

AMX0035 treatment by itself and coupled with two other FDA-approved therapeutic agents for ALS, riluzole, an anti-glutamatergic agent, and edaravone, a free-radical scavenger, have been shown to modulate the course of ALS.

In pivotal clinical trials, riluzole demonstrated longer time to tracheostomy or death compared to placebo and edaravone demonstrated longer retention of function compared to placebo.

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Due to the multi-pathway pathophysiology of ALS, experts agree that successful treatment will likely require concurrent targeting of multiple key neuronal death pathways.

There is a strong rationale for treatments that target identified convergence points of these critical pathways, including in the ER and mitochondria, and we believe that a therapy that targets multiple pathways at once, like AMX0035, aligns with the emerging ALS treatment paradigm.

There is a strong rationale for treatments that target identified convergence points of these critical pathways, including in the ER and mitochondria, and we believe that a therapy that targets multiple pathways simultaneously, like AMX0035, aligns with the emerging ALS treatment paradigm.

Clinical Development of AMX0035 for ALS

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The FDA granted orphan drug designation for AMX0035 for the treatment of patients with ALS in September 2017.

The EMA granted orphan designation to AMX0035 for the treatment of patients with ALS in April 2020.

In December 2019, we announced positive topline results from our CENTAUR trial.

The trial met its primary endpoint, and we published detailed trial data in the New England Journal of Medicine in September 2020 and in the Journal of Muscle and Nerve in October 2020.

We submitted a New Drug Submission, or NDS, in Canada in the second quarter of 2021, an NDA in the U.S.

in the fourth quarter of 2021 and an MAA in Europe in the first quarter of 2022.

The EMA granted orphan designation to AMX0035 for the treatment of patients with ALS in April 2020.

We submitted a New Drug Submission, or NDS, in Canada in the second quarter of 2021, a New Drug Application, or NDA, in the U.S.

in the fourth quarter of 2021 and a MAA in Europe in the first quarter of 2022.

In June 2022, AMX0035 received marketing authorization with conditions as ALBRIOZA by Health Canada for the treatment of ALS, and we launched ALBRIOZA commercially in Canada in July 2022.

In September 2022, AMX0035 received approval as RELYVRIO by the FDA for the treatment of ALS in adults following the second virtual meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, or the Advisory Committee, held on September 7, 2022.

As a result of the FDA’s approval of AMX0035, we launched RELYVRIO commercially in the U.S.

In September 2022, AMX0035 received approval as RELYVRIO by the FDA for the treatment of ALS in adults, and we launched RELYVRIO commercially in the U.S.

in October 2022.

In Europe, our MAA also remains under review by CHMP.

We completed the Scientific Advisory Group meeting.

Certain major objections remain, and the CHMP has adopted another round of questions as part of the regulatory process.

We are now in possession of those questions.

In order to respond in accordance with the updated timelines, we now expect an opinion from CHMP mid-year and a decision in the third quarter of 2023 at the earliest.

In October 2023, the Committee for Medicinal Products for Human Use, or CHMP, of the EMA confirmed its initial negative opinion on the MAA for AMX0035, for the treatment of adults with ALS in the EU.

The decision followed the conclusion of the CHMP’s formal re-examination procedure of an initial negative opinion adopted in June 2023.

In January 2024, the European Commission confirmed the adoption of the CHMP’s negative opinion.

We continue to focus on the completion of the global PHOENIX Phase 3 clinical trial of AMX0035 for the treatment of ALS, which was initiated prior to our MAA submission in November 2021.

If PHOENIX is supportive, we plan to seek approval in the EU again as quickly as possible.

CENTAUR, Our Phase 2 Trial of AMX0035 in ALS

In September 2020, we published detailed results from the Phase 2, randomized, double-blind, placebo-controlled CENTAUR trial.

The CENTAUR trial was conducted at 25 centers of the NEALS, and evaluated adult patients with ALS.

In September and October 2020, we published detailed results from the Phase 2, randomized, double-blind, placebo-controlled CENTAUR trial.

The CENTAUR trial was conducted at 25 NEALS centers and evaluated adult patients with ALS.

Key inclusion criteria were definite ALS defined by the revised El Escorial criteria, which entails having various clinical signs and symptoms, defined as upper and lower motor neuron signs, in at least three defined body regions, less than 18 months from symptom onset and slow vital capacity, or SVC, greater than 60%.

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Participants were allowed to continue on their selected standard of care, including treatment with riluzole and/or edaravone.

Eligible participants (n=137) were randomized two-to-one to treatment with AMX0035, one sachet (each containing one

gram of TURSO and three grams of PB) given once daily for the first three weeks, and if tolerated, the dose was then increased to twice-daily for the remainder of a 24 week treatment period, or matching placebo.

Eligible participants (n=137) were randomized two-to-one to treatment with AMX0035, one sachet (each containing one gram of TURSO and three grams of PB) given once daily for the first three weeks, and if tolerated, the dose was then increased to twice-daily for the remainder of a 24 week treatment period, or matching placebo.

Two participants did not have follow-up efficacy assessments and were not included in the efficacy population (modified intention to treat, or mITT, n=135).

These two participants were included in the safety population (intention to treat, or ITT, n=137).

Upon completion of the 24-week, parallel group phase of the trial, participants were eligible to enroll in the OLE trial in which all participants were followed up to 35 months while participants and physicians remained blinded to the original treatment group.

Upon completion of the 24-week, parallel group phase of the trial, participants were eligible to enroll in the Open Label Extension, or OLE, trial in which all participants were followed up to 35 months while participants and physicians remained blinded to the original treatment group.

Of participants completing the CENTAUR trial randomization phase, 92% elected to enroll in the OLE.

The first protocol of the OLE was completed in March 2021.

first protocol of the OLE was completed in March 2021.

Actual duration of patient treatments across the randomization phase and the OLE, both with the PB-TURSO combination and via placebo, are shown in the graphic below:

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The ALSFRS-R scale is the most widely used ALS rating scale in ALS clinical practice and in ALS clinical trials.

It measures patient’s functional ability and is broken down into four domains:

It measures patients' functional ability and is broken down into four domains:

bulbar (which includes speech, salivation and swallowing), fine motor (which includes handwriting, cutting food/handling utensils, dressing and hygiene), gross motor (which includes turning in bed, walking, and climbing stairs) and breathing (which includes dyspnea, orthopnea and respiratory insufficiency).

A decrease of one point on the ALSFRS-R scale can reflect severe limitations in a patient’s independence, and a two-point increase on the ALSFRS-R scale would be associated with:

• eating successfully with some difficulty instead of needing a feeding tube;

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These results showed that patients receiving AMX0035 scored an average of 2.32 points higher on the ALSFRS-R as compared to patients receiving placebo after 24 weeks, a difference of 25%, as shown in the graph below.

In a survey of ALS clinicians and researchers conducted and sponsored by NEALS, with the objective of determining what percentage reduction in ALSFRS-R would be considered clinically meaningful, a difference of greater than or equal to 20% in ALSFRS-R total score was considered clinically meaningful by a majority of clinicians and researchers surveyed.

considered clinically meaningful by a majority of clinicians and researchers surveyed.

More recent publications by ALS experts have shared the viewpoint that a single point difference can be considered clinically meaningful.

Two participants did not have follow-up efficacy assessments and were not included in the efficacy population (modified intention to treat n=135).

Secondary efficacy outcomes measuring disease free progression were the decline in muscle strength as measured by Accurate Test of Limb Isometric Strength, or ATLIS, testing and lung function measured by SVC, both expressed as percent of predicted values and key study events including death, permanent ventilation and hospitalization.

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In addition, a time-to-event analysis was conducted on key study events including death, permanent ventilation and hospitalization events over the 24-week randomized phase of the trial.

Because enrollment of patients in the CENTAUR trial was limited to patients who, in the investigator’s opinion, would be able to complete 6-month follow up, few events of this nature were expected during the initial, 24-week randomized phase of the trial.

As a result, we observed a positive, but not statistically significant, difference between the trial’s treatment and control groups during the 24-week randomized phase of

There was no statistically significant difference between the rate of decline in plasma levels of the neurofilament observed in the trial’s treatment and control groups during the 24-week randomized phase of the study.

Because enrollment of patients in the CENTAUR trial was limited to patients who, in the investigator’s opinion, would be able to complete a 6-month follow up, few events of this nature were expected during the initial, 24-week randomized phase of the trial.

As a result, we observed a positive, but not statistically significant, difference between the trial’s treatment and control groups during the 24-week randomized phase of

Phosphorylated neurofilament heavy chain was measured in plasma in the CENTAUR trial.

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Pre-specified analyses were conducted to determine if the use of concomitant medications impacted results.

These analyses found that AMX0035’s effect on the primary outcome was consistent regardless of baseline use of concomitant medications (riluzole and/or edaravone).

OS was analyzed for all subjects randomized in the CENTAUR trial (ITT analysis) and compared patients originally randomized to AMX0035 (n=89) with those randomized to placebo (n=48).

These analyses found that AMX0035’s effect on the primary outcome was consistent regardless of baseline use of concomitant medications (riluzole and/or edaravone).

Overall survival, or OS, was analyzed for all subjects randomized in the CENTAUR trial (ITT analysis) and compared patients originally randomized to AMX0035 (n=89) with those randomized to placebo (n=48).

In this post hoc analysis, the vital status of each participant was measured by a participant locating service which used sources such as the U.S.

social security death index up to July 20, 2020 even if he or she did not continue into the OLE, stopped study drug, dropped out of the study or was lost to follow-up.

social security death index up to March 1, 2021 even if he or she did not continue into the OLE, stopped study drug, dropped out of the study or was lost to follow-up.

Over the duration of follow up, the risk of death was 36% lower among those originally randomized to AMX0035 compared with those originally randomized to placebo (hazard ratio, or HR, of 0.64;

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and a p-value of 0.048).

Median survival duration was 25.0 months (95% CI of 19.0 to 33.6 months) in the group previously randomized to AMX0035 and 18.5 months (95% CI of 13.5 to 23.2 months) in the group previously randomized to placebo as seen in the graph below.

As reflected in the data tables below, participants originally randomized to AMX0035 showed a longer median survival of 6.5 months (data cutoff July 20, 2020) and 4.8 months (data cutoff March 1, 2021) than those originally randomized to placebo.

The FDA considers that the survival data available for

RELYVRIO are exploratory and should be interpreted cautiously given the limitations of data collected outside of a controlled study.

Post Hoc Survival Analysis (July 20, 2020 Data Cutoff)

Post Hoc Survival Analysis (March 1, 2021 Data Cutoff)

We also conducted three additional post hoc analyses of AMX0035 survival data which we provided as confirmatory evidence of our findings in the CENTAUR trial and which were provided to the FDA in support of our marketing application for AMX0035.

Median survival duration was 23.5

months (IQR of 14.6 to 39.3 months) in the group previously randomized to AMX0035 and 18.7 months (IQR of 11.7 to 31.3 months) in the group previously randomized to placebo as seen in the graph below.

We also conducted three additional post hoc analyses of AMX0035 survival data and one additional post hoc biomarker analysis.

These analyses consisted of the following:

a new analysis utilizing a statistical method to adjust for the effect of treatment crossover;

a new analysis comparing observed survival in the CENTAUR trial to predicted survival using the European Network for the Cure of ALS survival prediction model derived from an ALS natural history database;

and a new analysis comparing observed survival from the CENTAUR treatment group to survival of matched treatment naïve participants from historical clinical trials of ALS.

an analysis utilizing a statistical method, known as the rank-preserving structural failure time model (RPSFTM), to adjust for the effect of treatment crossover;

an analysis comparing observed survival in the CENTAUR trial to predicted survival using the European Network for the Cure of ALS survival prediction model derived from an ALS natural history database;

an analysis comparing observed survival from the CENTAUR treatment group to survival of matched treatment naïve participants from historical clinical trials of ALS;

and finally an analysis performed on neuroinflammatory biomarkers using plasma samples from participants in CENTAUR.

In May 2022, the post hoc analysis using RPSFTM, a method frequently employed in oncology to account for placebo crossover, estimated a 9.7-month longer median survival duration for participants originally randomized to AMX0035 than participants originally randomized to placebo.

In addition, participants randomized to receive AMX0035 and who continued into the OLE phase showed an 15-month longer median survival duration than participants who never received AMX0035 in a subgroup analysis.

The European Network to Cure ALS, or ENCALS, has collected data on more than 10,000 people living with ALS and used this data to create a prognostic model based on baseline factors to predict patient survival time.

Amylyx collaborated with the originators of this model to predict treatment naïve overall survival time for each individual participant in CENTAUR.

The predicted (treatment naïve) survival data generated using this model were compared against the actual observed survival data in the CENTUR study.

In this post hoc analysis, participants randomized to AMX0035 had a 9.9-month longer median survival compared to the prediction arm.

In October 2023, the post hoc analyses comparing the long term survival of participants in the CENTAUR study versus a propensity score-matched, AMX0035 naïve propensity score-matched, AMX0035 were published in the peer-reviewed medical journal, Annals of Clinical and Translational Neurology .

In this analysis, we observed a median overall survival of 10.4 months longer in the AMX0035 group.

Participants treated with AMX0035 at the start of the clinical trial, which means that they both started AMX0035 six months earlier and were on it for longer than participants starting on placebo, saw a greater survival benefit.

In December of 2023, post hoc analyses performed on neuroinflammatory biomarkers using plasma samples from CENTAUR trial participants were published in Journal of Neurology, Neurosurgery and Psychiatry .

demonstrated a significant reduction in plasma concentrations of YKL-40 (also known as chitinase-3-like protein 1) and the systemic inflammatory biomarker C-reactive protein (CRP), two plasma neuroinflammatory biomarkers in ALS, over 24 weeks, with reductions observed as early as Week 12 in participants from the CENTAUR trial.

We also performed sensitivity analyses on the CENTAUR trial data, including a joint rank test, which showed no bias in the estimate of the primary functional outcome by loss of data due to participant death.

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The observed AEs from the CENTAUR trial are summarized in the chart below.

Adverse Events (AEs) (1) Occurring in ≥5% of Patients in either Treatment Group

(Safety Population, n=137)

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One patient in the placebo group (2% of patients) and none in the AMX0035 group experienced a death equivalent event (i.e., tracheostomy/PAV) during the 24-week study.

In March 2022, we announced the launch of a U.S.

EAP that the FDA authorized for people with ALS who meet certain eligibility criteria for participation.

The EAP was discontinued alongside the commercial launch of RELYVRIO in the U.S.

We believe AMX0035 is the first drug candidate in ALS to demonstrate a statistically significant benefit both in function as measured by a prespecified mean rate change in ALSFRS-R and in a longer-term analysis of OS, both important outcomes for people with ALS.

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Clinical Development Plan of AMX0035 in ALS

We submitted an NDA to the FDA in the fourth quarter of 2021 and, in September 2022, the FDA approved AMX0035 as RELYVRIO for the treatment of ALS in adults.

We submitted an NDS for AMX0035 for the treatment of ALS to Health Canada in the second quarter of 2021, and in June 2022, AMX0035 received marketing authorization with conditions as ALBRIOZA in Canada.

We also submitted an MAA for approval of AMX0035 for the treatment of ALS to the EMA CHMP in the first quarter of 2022, and we expect an opinion from CHMP mid-year and a decision in the third quarter of 2023 at the earliest.

In November 2021, we initiated our global 48-week PHOENIX, randomized, double-blind, placebo-controlled trial at clinical sites in the U.S.

The PHOENIX trial is designed to provide further data evaluating the safety and efficacy of AMX0035 for the treatment of ALS to further support our global regulatory efforts.

Our global PHOENIX Phase 3 clinical trial of AMX0035 for the treatment of ALS, a 48-week, randomized, double-blind, placebo-controlled trial at clinical sites in the U.S.

and Europe, is designed to provide further data evaluating the safety and efficacy of AMX0035 for the treatment of ALS.

Enrollment in this trial was completed in March 2022 in the U.S.

and in February 2023 in Europe.

We anticipate topline results from the PHOENIX trial in mid-2024.

We announced the completion of enrollment in the PHOENIX trial, which enrolled 664 participants, in February 2023.

We expect to report topline results from the PHOENIX trial during or before the second quarter of 2024.

The primary endpoints in our PHOENIX trial will be a composite measure of survival and ALSFRS-R total score progression over 48 weeks and safety and tolerability over 48 weeks.

The secondary endpoints of our PHOENIX trial will be SVC, ALSAQ-40 (a questionnaire which provides a subjective health measure to specifically assess quality of life for patients with ALS), EQ5D-5L (a standard qualify of life measure), decline in King’s (a staging measurement in ALS based on the number of central nervous system, or CNS, regions involved and requirement for gastrostomy or noninvasive ventilation) and MiToS stages (a functional staging measure that can be derived prospectively from the ALSFRS-R subscore

using standard methods), ventilation free survival, and long-term survival.

Key inclusion criteria for the PHOENIX trial include ALS patients with clinically definite or clinically probable ALS by El Escorial criteria (2-4 body areas with clinical signs consistent with ALS), <24 months from symptom onset, SVC >55%, and riluzole/edaravone use permitted.

In July 2022, we announced a planned OLE for the PHOENIX trial and in March 2022, we announced the launch of a U.S.

expanded access program, or EAP, that the FDA authorized for people with ALS who meet certain eligibility criteria for participation.

The EAP will be wound down alongside the commercial launch of RELYVRIO in the U.S., with a target close of the EAP in the first half of 2023.

On February 2, 2023, we announced the completion of enrollment in the PHOENIX trial, which enrolled 664 participants.

Because marketing approvals we have obtained may be limited, subject to restrictions or post-approval requirements, we may need to provide post-marketing support in those jurisdictions.

Key inclusion criteria for the PHOENIX trial

include ALS patients with clinically definite or clinically probable ALS by El Escorial criteria (2-4 body areas with clinical signs consistent with ALS), <24 months from symptom onset, SVC >55%, and riluzole/edaravone use permitted.

European participants completing the 48-week trial had the option to enroll in an open label extension phase.

During this phase, all participants received AMX0035, and continued safety and efficacy measures were assessed.

Because marketing approvals we have obtained to date may be limited, subject to restrictions or post-approval requirements, we may need to provide post-marketing support in those same jurisdictions.

For example, as part of our approval for RELYVRIO in the U.S., we have post-marketing requirements to conduct carcinogenicity studies in mice and rats, drug-drug interaction studies, and studies in patients with kidney or liver impairment.

In addition, one of the conditions of the marketing authorization in Canada for AMX0035 (ALBRIOZA) for the treatment of ALS is the provision of data from our ongoing PHOENIX trial and other additional planned or ongoing studies.

In addition, one of the conditions of the marketing authorization in Canada for AMX0035 is the provision of data from our ongoing PHOENIX trial and other additional planned or ongoing studies.

The outcomes of the PHOENIX trial could have a material effect on our business.

We anticipate topline results in mid-2024.

Any additional regulatory approvals we may receive may be limited or subject to restrictions or post-approval commitments.

We also have studies planned to further assess the safety and efficacy of AMX0035 in people living with ALS, including in real-world settings.

These collaborative studies include a single center experience and a payer database observational study among others.

Commercialization of AMX0035 in ALS

We believe the global commercial opportunity for AMX0035 in ALS is driven by its being the first and only ALS therapy of which we are aware that helps to slow disease progression, maintains functional independence and extends overall survival in the same trial.

AMX0035 is generally well-tolerated, with a manageable side effect profile and convenient oral administration.

AMX0035 has been shown to have a significant impact on clinically meaningful endpoints, including reducing time to first hospitalization and permanent ventilation in ALS patients.

From launch to December 31, 2023, we generated net product revenue from sales of AMX0035 of $403.0 million.

AMX0035 for the Treatment of Other Potential Indications

Based on our extensive understanding of disease pathways, we believe AMX0035 may provide benefit across multiple diseases, including AD, Wolfram syndrome, Parkinson’s Disease, Huntington’s Disease, Progressive Supranuclear Palsy, Multi-System Atrophy, primary lateral sclerosis, ischemic stroke, MS, Friedreich’s ataxia, Leigh’s syndrome and Leber’s hereditary optic neuropathy.

We are prioritizing these conditions on an indication-by-indication basis, based on the strength of the data supporting AMX0035’s potential, including the data from our recently completed PEGASUS trial;

Based on our extensive understanding of disease pathways, we believe AMX0035 may provide benefit across multiple diseases, including AD, WS, Parkinson’s Disease, Huntington’s Disease, PSP, Multi-System Atrophy, primary lateral sclerosis, ischemic stroke, MS, Friedreich’s ataxia, Leigh’s syndrome and Leber’s hereditary optic neuropathy.

We are prioritizing these conditions on an indication-by-indication basis, based on the strength of the data supporting AMX0035’s potential;

the urgency of the unmet need;

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We will prioritize those indications which we believe have the greatest chance of providing patients with benefit and the most rapid pathway to market.

In March 2023, we completed site activation for a Phase 2 clinical trial of AMX0035 for the treatment of Wolfram syndrome, and expect to enroll the first participant in the near term.

Clinical Development of AMX0035 for Progressive Supranuclear Palsy

We initiated the ORION trial, a global, pivotal Phase 3 trial of AMX0035 for the treatment of PSP in December 2023.

ORION is a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to assess the efficacy and safety of AMX0035 compared to placebo.

Approximately 600 participants will be enrolled in approximately 100 sites across the United States, Canada, the EU, the United Kingdom, and Japan, making what we expect to be this the largest PSP clinical trial to date.

The primary efficacy endpoint will evaluate change in disease progression from baseline to Week 52 as measured by total score on the 28-item Progressive Supranuclear Palsy Rating Scale (PSPRS), 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).

Topline results are anticipated in either 2025 or 2026.

Participants completing the

52-week randomized, placebo-controlled phase of the trial will have the option to enroll in an Open Label Extension where all participants will receive AMX0035 for up to an additional year.

ORION was designed and planned in collaboration with key global academic leaders, people living with PSP and their caregivers, and industry advocacy organizations.

PSP is a sporadic, rare and adult-onset neurodegenerative disorder that affects walking and balance, eye movement, swallowing, and speech.

The disease is reported to affect seven in 100,000 people worldwide.

People living with PSP have a life expectancy of six to eight years after initial diagnosis, and PSP typically begins in late-middle age and rapidly progresses over time.

There are currently no approved therapies for the treatment of PSP.

Preclinical data support the potential of both sodium phenylbutyrate, PB, and taurursodiol, TURSO, the two small molecules in the fixed-dose combination of AMX0035, for the potential treatment of PSP.

In a variety of in vitro experiments, sodium phenylbutyrate upregulated and recruited chaperone proteins, stabilized protein folding, and reduced ER stress and the unfolded protein response, which can lead to apoptosis if the stress is overwhelming.

It has been shown in PSP that the unfolded protein response is activated in disease-affected regions in PSP and genetic evidence indicates this activation is not a protective response but a risk factor for the development of PSP.

TURSO stabilized the mitochondrial membrane by reducing the translocation of cell death regulator Bax, leading to improved mitochondrial function and energy production, and an increased cell apoptotic threshold.

In PSP, impairment of mitochondrial function has been shown in cybrid cell lines from patients with PSP as well as neurons derived from patients with PSP.

PSP is characterized by abnormal tau inclusions and is consequently also known as a tauopathy.

Similar to other neurodegenerative diseases, pathophysiologic changes underlying PSP are multifactorial with several genetic and environmental factors likely contributing to tau dysfunction and aggregation.

Multiple pathways, including genetic mutations, endoplasmic reticulum stress and the activation of unfolded protein response, mitochondrial dysfunction, and neuroinflammation have been implicated as contributors to tau dysfunction and aggregation.

Based on preclinical data and biomarker analyses from the Phase 2 PEGASUS trial of AMX0035 in AD, AMX0035 was shown to significantly lower levels of tau and other markers of neurodegeneration.

Clinical Development of AMX0035 for WS

We announced that the FDA granted orphan drug designation to AMX0035 for the treatment of WS in November 2020.

In March 2023, we completed site activation for a Phase 2 clinical trial of AMX0035 for the treatment of WS and in April 2023, we announced that the first participant was dosed.

The trial is an exploratory open-label proof of biology study assessing the effect of AMX0035 safety and tolerability, and various measures of endocrinological, neurological and ophthalmologic function.

We anticipate topline results from the trial in 2024.

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.

These data were published in the peer-reviewed Journal of Clinical Investigation , characterizing a pathogenic variant in the WFS1 gene (WFS1 c.1672C>T, p.R558C), identifying a platform for further genotype-phenotype analysis, and providing initial proof-of-concept for the therapeutic development of AMX0035 in WS.

The study demonstrated that iPSC-derived WS models can provide a model of genotype-phenotype relationships that correlate with clinical observations.

Study highlights related to AMX0035 included:

• Administration of AMX0035 improved WFS1 protein expression, increased insulin secretion, and inhibited cell death in β cells with the WFS1 c.1672C>T, p.R558C variant.

AMX0035 also prevented cellular death in patient-derived neuronal progenitor cells.

Gene enrichment analysis revealed that treatment with AMX0035 ameliorated organelle dysfunction, mitophagy, ER stress, and apoptosis.

• Furthermore, AMX0035 delayed the onset of the diabetic phenotype in vivo in the Wfs1-knockout mouse model of WS.

WS is an autosomal recessive neurodegenerative disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration.

Common manifestations of WS include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties.

The prognosis of WS

is poor, and many people with the disease die prematurely with severe neurological disabilities.

WS is a rare, pediatric, life-threatening disease thought to be caused by variants in the WS WFS1 gene, or WFS1, and, in a small fraction of patients, pathogenic variants in the CDGSH iron sulfur domain protein 2 CISD2 gene, or CISD2.

There are currently no drugs approved for WS.

WS appears to be a disease of ER stress.

WFS1 encodes and produces the vital wolframin protein, which appears to be involved in ER regulatory processes.

WFS1 deficiency leads to chronic ER stress and the UPR.

WFS1 also negatively regulates activating transcription factor 6 (ATF6), a UPR molecule, resulting in cell death.

Furthermore, a recent study suggested that WFS1 impacts mitochondrial function by transporting Ca2+ from the ER to the mitochondria through the mitochondria-associated ER membrane, or MAM.

AMX0035 targets pathways central to WS, including the UPR, and has shown beneficial effects in a variety of models of WS, including cellular models and patient-derived cell line models.

For example, to test the potential effects of AMX0035 in the modulation of ER stress in the context of WS, the effects of PB, TURSO and AMX0035 were tested in an in vitro model of wild-type and WFS1-deficient pancreatic beta cell lines.

In these cells, when compared with the control group, only AMX0035, but not PB or TURSO alone, was able to significantly prevent tunicamycin-induced cell death in WFS1-deficient pancreatic beta cell lines as measured by caspase 3 / 7 activity (p = 0.017).

Additionally, a combination of PB and TURSO was studied in vitro in human patient-derived neural progenitor cells harboring mutations in WFS1, which cause WS.

Both PB and TURSO, when applied alone, were observed to inhibit cell death in each of three different human cell lines as compared to control conditions, and the application of PB and TURSO in combination was observed to result in significantly lower levels of cell death in three separate patient-derived WS cell lines differentiated to produce patient-derived neural progenitor cells, as compared to either the control or treatment with PB or TURSO alone.

Thus, in relevant models of WS, use of AMX0035 was observed to have synergistic effects lowering cell death as compared to either the control group or treatment with PB or TURSO alone.

For these reasons, we believe AMX0035 is a promising clinical candidate for WS.

Clinical Development of AMX0035 for AD

We designed our multicenter, randomized, double-blind, placebo-controlled Phase 2 PEGASUS trial with AD experts to evaluate the safety, tolerability and activity of AMX0035 in patients with late mild cognitive impairment, or MCI, or early-to-moderate dementia.

The PEGASUS trial was designed to have broad entry criteria to include participants at different stages of AD to allow us to assess the biological effect of AMX0035 across the spectrum of disease and determine if there are any patients who might see a greater benefit from therapy.

Eligible participants (n=95), adults ages 55 to 89 years old, were randomized three-to-two to treatment with AMX0035, one sachet (each containing one gram of TURSO and three grams of PB) given twice-daily over 24 weeks, or matching placebo.

In 2021, we completed and reported the results from our Phase 2 PEGASUS trial evaluating the safety, tolerability and activity of AMX0035 in patients with late mild cognitive impairment, or MCI, or early-to-moderate dementia.

The purpose of this trial was to collect biomarker data relevant to both AD and other neurodegenerative diseases and help inform our decisions on the development of AMX0035 in AD.

The PEGASUS trial was a randomized, placebo-controlled Phase 2 trial in 95 participants in the U.S.

Patients were randomized three-to-two to treatment with AMX0035, one sachet (each containing one gram of TURSO and three grams of PB) given twice-daily over 24 weeks, or matching placebo.

The primary investigator for the PEGASUS trial, Dr.

Steven Arnold, presented topline results from the PEGASUS trial at the Clinical Trials on Alzheimer’s Disease conference, or CTAD, which was held during the fourth quarter of 2021.

Based on these topline results, AMX0035 was generally well-tolerated with approximately 80% of patients completing dosing in the trial in the AMX0035 arm.

Safety results are depicted in the figure below.

As in the CENTAUR trial, a higher

percentage of patients in the AMX0035 arm had gastrointestinal adverse events.

As in the CENTAUR trial, a higher percentage of patients in the AMX0035 arm had gastrointestinal adverse events.

However, no SAEs were attributed to AMX0035 in the PEGASUS trial.

The 6-month trial was not powered to evaluate differences between the AMX0035 and placebo arms in cognition, function or imaging.

The primary endpoint of the trial was to compare the safety and tolerability of a fixed-dose combination of AMX0035 versus placebo in subjects with MCI (high or intermediate likelihood due to AD) or dementia due to AD over a 24-week treatment period.

The secondary endpoints of the trial were to:

determine the effects of AMX0035 treatment on whole brain and regional brain atrophy, as assessed by volumetric MRI;

assess the impact of AMX0035 treatment on clinical symptoms as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, or ADAS-Cog, the Dementia Severity Rating Scale, or DSRS, and the FAQ;

assess the effect of AMX0035 treatment on measures of neuropsychiatric symptoms, as assessed by the Neuropsychiatric Inventory Questionnaire;

measure the effects of AMX0035 treatment on functional MRI measures including connectivity with resting state Blood Oxygenation Level Dependent imaging.

Additionally, the trial evaluated differences between the AMX0035 and placebo arms as measured by GST, a newly developed composite outcome of cognitive, functional, and imaging measures named the Global Statistical Test, or GST, over the 24-week treatment period.

The GST is a combination of three change-from-baseline to end-of-study endpoints:

Cognition (Modified Alzheimer’s Disease Composite Score, or MADCOMS), Function (Functional Activities Questionnaire, or FAQ) and Total Hippocampal Brain Volume (Magnetic Resonance Imaging, or MRI).

The GST is calculated for each subject as a mean score across the above three component endpoints for each subject in the trial.

This mean score was then analyzed as an efficacy variable.

Finally, the exploratory objectives of the trial were to measure the effect of AMX0035 treatment on biochemical markers of amyloid-ß1-42, amyloid-ß1-40, total tau (t-tau), tau phosphorylated at threonine 181 (ptau 181), neuronal injury markers, mitochondrial redox and function markers, and neuroinflammation, as assessed in cerebrospinal fluid, or CSF, from all volunteers.

The exploratory objectives of the trial were to measure the effect of AMX0035 treatment on biochemical markers of amyloid-ß1-42, amyloid-ß1-40, total tau (t-tau), tau phosphorylated at threonine 181 (ptau 181), neuronal injury markers, mitochondrial redox and function markers, and neuroinflammation, as assessed in cerebrospinal fluid, or CSF, from all volunteers.

While functional MRI analyses remain ongoing, no significant differences between dosing groups were observed for any efficacy endpoints in this trial (p>0.05).

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Significant impacts on multiple biomarkers of interest in AD were observed in the trial.

In CSF, the AMX0035-group showed significant reductions of tau protein 181 (p<0.001) and phosphorylated tau protein (p<0.001) compared with the placebo group, modulation of the amyloid beta 42/40 ratio (p<0.05) and increase of 8-hydroxy-2’

-deoxyguanosine, (p<0.01).

These topline results from the PEGASUS trial are still subject to further audit and verification procedures and additional biomarker results are not yet available.

We believe the biomarker and imaging outcomes from the trial have substantially improved and will continue to inform our knowledge of the impact of AMX0035 on the neurodegenerative pathways relevant to the progression of AD, which have been and will be informative as we continue clinical development of AMX0035 in AD and other potential indications.

We believe these insights will help us to examine any effects of AMX0035 on AD’s progression, which could inform future work in AD as well as clinical trial design for other indications.

Clinical Development of AMX0035 for Wolfram Syndrome

In March 2023, we completed site activation for a Phase 2 clinical trial of AMX0035 for the treatment of Wolfram syndrome, and expect to enroll the first participant in the near term.

Amylyx anticipates topline results from the trial in 2024.

Researchers from the Washington University School of Medicine in St.

Louis, in collaboration with Amylyx, recently published preclinical data exploring the potential of AMX0035 as a novel therapeutic approach for Wolfram syndrome.

demonstrated that iPSC-derived Wolfram syndrome models can provide a model of genotype-phenotype relationships that correlate with clinical observations.

Study highlights related to AMX0035 included:

Administration of AMX0035 improved WFS1 protein expression, increased insulin secretion, and inhibited cell death in β

cells with the WFS1 c.1672C>T, p.R558C variant.

AMX0035 also prevented cellular death in patient-derived neuronal progenitor cells.

Gene enrichment analysis revealed that treatment with AMX0035 ameliorated organelle dysfunction, mitophagy, ER stress, and apoptosis.

Furthermore, AMX0035 delayed the onset of the diabetic phenotype in vivo in the Wfs1-knockout mouse model of Wolfram syndrome.

Wolfram syndrome is a rare, pediatric, life-threatening disease thought to be caused by variants in the Wolfram syndrome WFS1 gene, or WFS1, and, in a small fraction of patients, pathogenic variants in the CDGSH iron sulfur domain protein 2 CISD2 gene, or CISD2.

Wolfram syndrome results in deafness, blindness, ataxia, neurodegeneration and ultimately death.

There are currently no drugs approved for Wolfram syndrome.

Wolfram syndrome appears to be a disease of ER stress.

WFS1 encodes and produces the vital wolframin protein, which appears to be involved in ER regulatory processes.

WFS1 deficiency leads to chronic ER stress and the UPR.

WFS1 also negatively regulates activating transcription factor 6 (ATF6), a UPR molecule, resulting in cell death.

Furthermore, a recent study suggested that WFS1 impacts mitochondrial function by transporting Ca2+ from the ER to the mitochondria through the MAM.

AMX0035 targets pathways central to Wolfram syndrome, including the UPR, and has shown beneficial effects in a variety of models of Wolfram syndrome, including cellular models and patient-derived cell line models.

For example, to test the potential effects of AMX0035 in the modulation of ER stress in the context of Wolfram syndrome, the effects of PB, TURSO and AMX0035 were tested in an in vitro model of wild-type and WFS1-deficient pancreatic beta cell lines.

Additionally, a combination of PB and TURSO was studied in vitro in human patient-derived neural progenitor cells harboring mutations in WFS1, which cause Wolfram Syndrome.

Both PB and TURSO, when applied alone, were observed to inhibit cell death in each of three different human cell lines as compared to control conditions, and the application of PB and TURSO in combination was observed to result in significantly lower levels of cell death in three separate patient-derived Wolfram syndrome cell lines differentiated to produce patient-derived neural progenitor cells, as compared to either the control or treatment with PB or TURSO alone.

Thus, in relevant models of Wolfram syndrome, use of AMX0035 was observed to have synergistic effects lowering cell death as compared to either the control group or treatment with PB or TURSO alone.

For these reasons, we believe AMX0035 is a promising clinical candidate for Wolfram syndrome.

We continue to use these results to evaluate and inform our clinical development strategy of AMX0035 in AD and other potential indications.

We are currently evaluating these data and discussing the results of the PEGASUS trial with scientific advisors as we consider potential next steps for the development of AMX0035 for the treatment of AD within our clinical development strategy.

Clinical Development of New Formulation for AMX0035 in ALS

We are working on a new taste-masked formulation of AMX0035.

This formulation may allow for new intellectual property.

Clinical Development of AMX0114 for ALS

We believe that a cure for ALS will require a combination approach, targeting multiple cellular pathways implicated in disease pathogenesis.

As part of this effort, we are investigating AMX0114, an antisense oligonucleotide, designed to target the gene encoding calpain-2, a key contributor to the axonal (Wallerian) degeneration pathway.

Axonal degeneration has been recognized as a key early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases.

Activation of the calcium-dependent protease calpain-2 is proposed as a critical effector of axonal degeneration.

Calpain-2 has been implicated in the pathogenesis of ALS based on findings of elevated levels of calpain-2 and its cleavage products in postmortem ALS tissue, therapeutic benefit of calpain-2 modulation in animal models of ALS, and the role of calpain-2 in cleaving neurofilament, a broadly researched biomarker in ALS.

Preclinical studies completed to date have shown that AMX0114 achieves potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and calpain-2 protein levels in human motor neurons.

Moreover, treatment with AMX0114 reduced extracellular neurofilament light chain (NfL) levels following neurotoxic insult in iPSC-derived human motor neurons, and treatment with AMX0114 improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations.

AMX0114 is being advanced through Investigational New Drug, or IND, -enabling studies and we expect to file an IND and enter the clinic in 2024.

Development of a Composite Diagnostic Biomarker for ALS

People living with ALS spend approximately one-third of their disease course searching for a diagnosis.

One of the key drivers of diagnostic delay in ALS is the lack of reliable, validated biomarkers to aid in diagnosis.

Techniques to support earlier diagnosis are critical to advance care and treatment for ALS and mitigate the significant psychological stress that people living with ALS and their families experience during a lengthy diagnostic process.

We are working to develop a novel composite biomarker with the aim of facilitating earlier diagnosis of ALS.

A pilot study is underway, which will provide information about the performance of putative biomarkers, identify candidate biomarkers, and inform the design of subsequent validation studies.

Patient Advocacy

The patient advocacy landscapes for ALS and other neurodegenerative diseases are large, and encompass groups at the international, multiregional and country-specific level.

We have built strong medical and commercial relationships at the international level, with our current emphasis being on ALS advocacy groups in the U.S., Canada and Europe.

We plan to engage country-specific groups in Europe based on clinical trial results, as well as our medical and commercial priorities.

Working with key advocacy groups is critical to our mission, as patients are at the center of everything we do.

The patient advocacy landscapes for ALS and other neurodegenerative diseases are large and complex integrated networks, and encompass groups at the international, multiregional and country-specific level.

We have built credible and trusted partnerships across these complex networks at the international level, with our current emphasis being on ALS advocacy groups in the U.S., Canada, Europe, and APAC.

Working with key advocacy groups is critical to our mission, as people living with these neurodegenerative diseases and their families are at the center of everything we do.

This starts with transparent communication and awareness about our science, data and development plans.

We seek ensure that these advocacy groups are informed and able to answer questions from their members about PB, TURSO and AMX0035.

We engaged with patient advocacy groups in the U.S.

and Europe for feedback on the design of our ongoing global Phase 3 PHOENIX trial of AMX0035 for the treatment of ALS, which is emblematic of the partnerships we are building with the community.

In addition, we treat patient advocacy groups as important stakeholders as we address access to AMX0035 outside ongoing clinical trials, such as expanded access and compassionate use programs.

We have sought and will continue to seek guidance and insights from as many patient advocacy groups as possible and have plans in place to engage groups on an ongoing basis.

These groups have also reviewed messaging and press releases from the company to ensure they take into account the patient voice.

Commercialization

Since obtaining regulatory approval, we have seen strong interest in AMX0035, and we are encouraged by the early success of our commercial launch.

We believe the global commercial opportunity for AMX0035 in ALS is driven by its being the first and only treatment for ALS of which we are aware that potentially provides a combination of longer retention of function, improved survival, a generally well-tolerated side effect profile and convenient oral administration.

AMX0035 has been shown to have a significant impact on clinically meaningful endpoints, including reducing time to first hospitalization and permanent ventilation in ALS patients.

AMX0035 is also being considered for other neurodegenerative disorders.

ALS is a rare disease, but public sources estimate that ALS affects at least 200,000 people worldwide, and we estimate that there are approximately 29,000 ALS patients in the U.S.

More than 30,000 ALS patients are estimated to be living with ALS in the EU and the UK and about 3,000 ALS patients are estimated to be living with ALS in Canada.

In the U.S., ALS is treated by neurologists at certified ALS Centers or by other neurologists.

In Canada and in Europe, most ALS patients are treated at ALS Centers.

The vast majority of people with ALS (over 90%) have sporadic disease, showing no clear family history.

Most people who develop ALS are between the ages of 40 and 70, with a median age of 55 at the time of diagnosis.

However, cases of the disease do occur in people in their twenties and thirties.

People with ALS spend approximately one-third of their disease course searching for a diagnosis and, once diagnosed, there are few approved therapies available.

ALS is a relentlessly progressive and highly heterogenous disease that arises from multiple mechanistic underpinnings, leading patients to experience variable onset, persistent progression, and shortened survival.

The disease remains universally fatal with median survival of less than three years from symptom onset and less than two years from diagnosis.

We have conducted market research with physicians, patients, caregivers, nurses, and payors in the U.S., Western Europe and Canada to understand the unmet need and potential of AMX0035 in ALS.

Clinicians universally report dissatisfaction with currently approved therapies and state the need for additional options for their ALS patients.

When shown a target product profile for AMX0035, the majority of ALS specialists and neurologists with whom we spoke are open to utilizing it in early-to-mid-stage patients, with some also stating the potential for use in late-stage patients.

We submitted an NDA to the FDA in the fourth quarter of 2021 and, in September 2022, the FDA approved AMX0035 as RELYVRIO for the treatment of ALS in adults.

We submitted an NDS for AMX0035 in ALS with Health Canada in the second quarter of 2021, which received marketing authorization with conditions as ALBRIOZA by Health Canada in June 2022.

We also submitted an MAA in Europe in the first quarter of 2022, and we expect an opinion from CHMP mid-year and a decision in the third quarter of 2023 at the earliest.

We also plan to discuss AMX0035 with other health authorities around the world to determine the most appropriate path forward in their respective territories.

We also initiated our ongoing Phase 3 PHOENIX trial in the fourth quarter of 2021 to further support the safety and efficacy of AMX0035 for the treatment of ALS and our global regulatory efforts, and in February 2023 we announced completion of enrollment in that trial.

Our pre-launch activities in other key jurisdictions include building awareness of and education regarding the disease severity and pathophysiology of ALS, increasing understanding of the clinical impact of a change in a patient’s ALSFRS-R score, and building general awareness of our company through active participation in key neurology conferences, patient meetings, partnerships with patient advocacy groups, targeted omnichannel initiatives and payor education in each of the key territories.

In addition, we intend to continue to pursue an active public relations strategy.

For example, the double-blind results of our CENTAUR trial have already been published in the New England Journal of Medicine , while the long-term survival study results appeared in the Journal of Muscle & Nerve .

Our initial plans are to continue to build out our commercial operations in the U.S.

and Canada and to build commercial operations in Europe to be prepared for potential approval of AMX0035 in the EU.

There are approximately 186 ALS Association certified, recognized, or affiliated centers in the U.S., 17 Canadian ALS Research Network Clinics in Canada, and an established network of ALS Centers of Excellence per country in each of the major EU countries, which we plan to target with a specialty key account management team.

We will continue to evaluate market entry opportunities beyond these geographies either on our own or with a partner.

We seek ensure that these advocacy groups are informed, able to answer questions from their constituents, and advocate appropriately for access and policies to benefit their community.

The biotechnology and pharmaceutical industries are characterized by rapid technological advancement, significant competition and an emphasis on proprietary products.

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These competitors may also vie for a similar pool of qualified scientific and management talent, sites and patient populations for clinical trials, as well as for technologies complementary to, or necessary for, our programs.

AMX0035 for the Treatment of ALS

Prior to AMX0035, in the past 30 years, only two product candidates had been approved for the treatment of ALS in the U.S.

and Canada, and only one product candidate had been approved for the treatment of ALS in Europe.

These two previously approved drugs, riluzole (marketed under the name Rilutek) and edaravone (marketed under name Radicava in the U.S.

and Radicut in Japan), are often used in combination.

We expect that further therapies and drugs which may be approved in the future will also be used in combination with existing drugs, absent incompatibility or other barriers to combination.

For example, in May 2022, Mitsubishi Tanabe Pharma America, Inc.

announced that the FDA approved an oral formulation of intravenous, or IV, administered alternative to Radicava for the treatment of ALS.

We believe there are currently no other approved treatments for ALS which show both a functional and survival benefit for ALS patients.

Patients with ALS in North America are commonly treated with riluzole and edaravone, which are palliative in nature.

However, we are aware of several product candidates in clinical development that may compete with AMX0035 for the treatment of ALS, including product candidates being developed by Biogen, Seelos Therapeutics and Prilenia Therapeutics.

To date, we believe none of the above product candidates has shown statistically significant clinical results on prespecified outcomes in any prior trials.

We anticipate that ALS will continue to be an area of research in the healthcare sector and that drug candidates will continue to be developed and studied for treatment of the disease.

While we anticipate the general practice in ALS will continue to be the use of approved agents as single drug therapy or combination, our commercial potential could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or tolerable or are less expensive than AMX0035 or products that we may develop.

In addition, we are aware of one ongoing clinical study in Europe which is evaluating the effects on ALS of TURSO, one of the two components in AMX0035.

The outcome of this study could have an impact on the commercial potential of AMX0035.

A large number of trials and studies are ongoing in the many additional neurodegenerative diseases which we are evaluating for future clinical work for AMX0035 including AD, Wolfram syndrome, Parkinson’s Disease, Huntington’s Disease, Progressive Supranuclear Palsy, Multi-System Atrophy, primary lateral sclerosis, ischemic stroke, MS, Friedreich’s ataxia, Leigh’s syndrome and Leber’s hereditary optic neuropathy.

Some of these diseases also have therapies approved which impact disease progression.

The competitive landscape in these diseases will affect the potential opportunity for AMX0035.

Supply and Manufacturing

We rely, and expect to continue to rely for the foreseeable future, on third-party contract manufacturing organizations, or CMOs, for the production of AMX0035 in compliance with current Good Manufacturing Process, or

cGMP, requirements, for commercial supply as well as for use in clinical trials under the guidance of members of our organization.

We rely, and expect to continue to rely for the foreseeable future, on third-party contract manufacturing organizations, or CMOs, for the production of AMX0035 and AMX0114 in compliance with current Good Manufacturing Process, or cGMP, requirements, for commercial supply as well as for use in clinical trials under the guidance of members of our organization.

For AMX0035, we utilize two active pharmaceutical ingredients, or APIs, PB and TURSO, which are manufactured and released to us from third-party manufacturers.

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Manufacturing Agreement with Patheon

In November 2019, we entered into a master manufacturing services agreement, or the Manufacturing Agreement, with Patheon, pursuant to which Patheon provides cGMP manufacturing, quality control, quality assurance, stability testing, packaging and related services to us.

In November 2019, we entered into a master manufacturing services agreement, or the Manufacturing Agreement, with Patheon, Inc., or Patheon, pursuant to which Patheon provides cGMP manufacturing, quality control, quality assurance, stability testing, packaging and related services to us.

We have executed an initial product agreement under the Manufacturing Agreement, which covers AMX0035.

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We may terminate the Manufacturing Agreement or any product agreement:

upon 30 days’

prior written notice if any government or regulatory authority permanently prevents us from selling AMX0035 in Canada, the EU or the U.S., if approved, or upon 90 days’

prior written notice, if we no longer intend to order manufacturing services due to AMX035’s discontinuance in the market.

Patheon may terminate any product agreement under the Manufacturing Agreement upon 30 days’

prior written notice, if we project zero volume for twelve successive months during the term of such product agreement.

Additionally, Patheon may terminate the Manufacturing Agreement or any product agreement if payment in full of any overdue, undisputed invoice is not received within 30 days of Patheon’s suspension of manufacturing services for nonpayment or, in certain circumstances, upon nine months’

prior written notice if we assign any rights under the Manufacturing Agreement or a product agreement.

In addition, either party may terminate the Manufacturing Agreement or any product agreement for cause, including the other party’s uncured material breach and upon written notice, in the case of the other party’s insolvency or bankruptcy.

upon 30 days’ prior written notice if any government or regulatory authority permanently prevents us from selling AMX0035 in Canada, the EU or the U.S., if approved, or upon 90 days’ prior written notice, if we no longer intend to order manufacturing services due to AMX035’s discontinuance in the market.

Patheon may terminate any product agreement under the Manufacturing Agreement upon 30 days’ prior written notice, if we project zero volume for twelve successive months during the term of such product agreement.

Supply Agreement with CU Chemie

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The agreement has an initial term of five years and will automatically renew for successive terms of two years, unless earlier terminated.

After the expiration of the initial term, either party may terminate the

agreement for convenience upon three months’

prior written notice.

Additionally, either party may terminate the agreement in the case of the other party’s uncured material breach or upon the insolvency or bankruptcy of the other party.

After the expiration of the initial term, either party may terminate the agreement for convenience upon three months’ prior written notice.

Additionally, either party may terminate the agreement in the case of the other party’s uncured material breach or upon the insolvency or bankruptcy of the other party.

Supply Agreement with ICE

In December 2019, we entered into a supply agreement with Prodotti Chimici e Alimentari S.p.A.

(now ICE S.p.A., or ICE), as amended in July 2021, pursuant to which ICE agreed to supply to us, on a non-exclusive basis, bulk drug substance of TURSO, which we use in the manufacture of AMX0035.

The agreement has an initial term of five years and will automatically renew for successive terms of five years, unless earlier terminated.

ICE may terminate the agreement upon three months written notice.

Additionally, either party may terminate the agreement in the case of the other party’s insolvency or bankruptcy, or in case of the other party’s uncured breach.

In August 2023, we entered into a commercial supply agreement with ICE S.p.A., or ICE (formerly Prodotti Chimici e Alimentari S.p.A.), pursuant to which ICE agreed to supply to us, on an exclusive basis, bulk drug substance of tauroursodeoxycholic acid , which we use in the manufacture of AMX0035.

The agreement contains certain minimum purchase requirements.

The agreement has an initial term ending in December 2028 and can be renewed as determined by a joint steering committee.

Either party may terminate the agreement in the case of the other party’s insolvency or bankruptcy, or in case of the other party’s uncured breach.

Intellectual Property

While the PB and TURSO molecules individually are not proprietary to us, we own patents and patent applications covering AMX0035, including the fixed-dose combination of AMX0035 itself.

Intellectual property is of vital importance in our field and to pharmaceuticals generally.

Our commercial success depends in part on our ability to obtain intellectual property that protects AMX0035 and its uses, and any future product candidates.

Our commercial success depends in part on our ability to obtain intellectual property that protects AMX0035 and its uses, and any future product

We seek to protect and enhance proprietary technology, inventions and improvements that are commercially important to the development of our business and AMX0035, in particular, by seeking, maintaining and defending U.S.

and foreign patent rights.

We are actively building our intellectual property portfolio in our therapeutic area, including around AMX0035.

Our current patent portfolio as of the date of this prospectus includes three patent families.

In those three families, we currently own a total of 100 issued patents and pending patent applications directed to our technologies, including AMX0035.

We are actively building our intellectual property portfolio in our therapeutic area, including around AMX0035 and AMX0114.

Our current patent portfolio includes eight patent families.

In those eight families, we currently own a total of 122 issued patents and pending patent applications directed to our technologies, including AMX0035.

Currently, our patent portfolio includes six issued U.S.

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The foreign jurisdictions in which we have been issued patents include Albania, Austria, Australia, Bosnia and Herzegovina, Belgium, Bulgaria, China, Croatia, Cyprus, Czech Republic, Denmark, Estonia, the EU, Finland, France, Germany, Greece, Hong Kong, Hungary, Ireland, Iceland, Italy, Japan, Lithuania, Latvia, Macao, Macedonia, Malta, Monaco, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, San Marino, Serbia, Slovenia, Slovakia, South Korea, Spain, Sweden, Switzerland, Turkey, and UK.

We also have patent applications pending in Australia, China, the EU, Hong Kong, Japan, South Korea, the U.S.

We also have patent applications pending in Australia, Canada, the EU, Macao, Japan, South Korea, the U.S.

and other jurisdictions.

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Although no patents have yet issued from this family, we expect the term on patents issuing from this family to extend until at least August 2040.

Our fourth patent family is directed to methods of treating Alzheimer’s disease and other tauopathies (including progressive supranuclear palsy) with combinations of a phenylbutyrate compound and a bile acid (including sodium phenylbutyrate and TURSO).

We have patent applications pending in this family in Argentina, Taiwan, as well as a Patent Cooperation Treaty (PCT) application.

Although no patents have yet issued from this family, we expect the term on patents issuing from this family to extend until at least November 2042.

Our fifth patent family is directed to methods of co-administering other therapeutic drugs (including substrates of cytochrome P450, drugs with a narrow therapeutic index, and substrates of Organic Anion Transporter 1 (OAT1)) with combinations of a phenylbutyrate compound and a bile acid (including sodium phenylbutyrate and TURSO).

We have patent applications pending in this family in the U.S., Argentina, Taiwan, as well as a Patent Cooperation Treaty (PCT) application.

Although no patents have yet issued from this family, we expect the term on patents issuing from this family to extend until at least March 2042.

Our sixth patent family is directed to pharmacokinetic characteristics following the administration of TURSO and sodium phenylbutyrate.

We have patent applications pending in this family in the U.S., Argentina, Taiwan, as well as a Patent Cooperation Treaty (PCT) application.

Although no patents have yet issued from this family, we expect the term on patents issuing from this family to extend until at least May 2042.

Our seventh patent family is directed to methods of co-administering other therapeutic drugs (including inhibitors of bile salt efflux pump (BSEP)) with combinations of a phenylbutyrate compound and a bile acid (including sodium phenylbutyrate and TURSO).

We have patent applications pending in this family in the U.S., Argentina, Taiwan, as well as a

Patent Cooperation Treaty (PCT) application.

Although no patents have yet issued from this family, we expect the term on patents issuing from this family to extend until at least May 2042.

Our eighth patent family is directed to oligonucleotides targeting the Calpain-2 transcript.

We have patent applications pending in this family in the U.S., as well as a Patent Cooperation Treaty (PCT) application.

Although no patents have yet issued from this family, we expect the term on patents issuing from this family to extend until at least May 2043.

We cannot be sure that patents will be granted with respect to any of our pending patent applications nor with respect to any patent applications that may be filed by us in the future.

Further, we cannot be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial

Further, we cannot be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products.

Finally, we cannot be sure that our granted patents, and any future patents granted to us, will be found valid and/or enforceable following a litigation or administrative procedure.

In January 2021, Bruschettini S.r.l.

and Lederer & Keller Patentanwälte Partnerschaft mbB each filed oppositions at the European Patent Office to our issued European Patent, EP2978419.

At a high level, this patent claims various methods of treating neurodegenerative disease (and or the causes or conditions thereof) with a bile acid and a phenylbutyrate compound.

The opponents contended that the patent should be revoked in its entirety on various grounds, including for allegedly having an insufficient disclosure and for lack of inventive step.

The EPO issued a preliminary opinion dated October 13, 2021, and a summons to attend oral proceedings (also dated October 13, 2021) that set a date of June 2, 2022 for the oral proceedings.

At the oral proceedings on June 2, 2022, the Opposition Division maintained European Patent, EP2978419 as granted.

The scope of the issued claims was not limited.

On June 17, 2022, the Opposition Division handed down the written decision providing detailed legal reasoning for the outcome of the oral proceedings.

On August 4, 2022, Bruschettini S.r.l.

filed a notice of appeal.

The other opponent did not file a notice of appeal.

On September 29, 2022, Bruschettini S.r.l filed a request to withdraw the appeal.

As the sole appellant has withdrawn their appeal, the Board of Appeal has closed the appeal proceedings and terminated the opposition proceedings with communication dated October 14, 2022.

The Opposition Division maintained European Patent, EP2978419 as granted in oral proceedings on June 2, 2022.

The decision of the Opposition Division has become final and EP2978419 is maintained as granted.

EP2978419 has been opted-out from the jurisdiction of the Unified Patent Court effective April 26, 2023.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.

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Our commercial success also depends in part on our ability to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary rights.

A comprehensive discussion on risks relating to intellectual property is provided in Item 1A of this Annual Report entitled “Risk Factors—Risks Related to Our Intellectual Property.”

We have conducted searches of the patent landscape at certain points and in certain jurisdictions with respect to AMX0035, and based on these searches and our analyses, we have not identified any issued patents that we believe are valid and could be successfully asserted to block our ability to commercialize AMX0035.

European Patent EP3016654, entitled “Tauroursodeoxycholic acid (TUDCA) for Use in the Treatment of Neurodegenerative Disorders,”

is owned by Bruschettini S.r.l.

European Patent EP3016654, entitled “Tauroursodeoxycholic acid (TUDCA) for Use in the Treatment of Neurodegenerative Disorders,” is owned by Bruschettini S.r.l.

The patent relates to use of TURSO in the treatment of ALS in a mammal.

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Oral proceedings were held before an Opposition Division of the EPO on June 11, 2021.

At the end of the oral proceedings, the Opposition Division announced the decision revoking all claims of EP3016654.

end of the oral proceedings, the Opposition Division announced the decision revoking all claims of EP3016654.

A written decision has been issued;

however Bruschettini has appealed the decision of the Opposition Division to the Board of Appeal.

A response to Bruschettini’s appeal has been filed on June 7, 2022 requesting that the appeal should be dismissed and that the decision of the Opposition Division to revoke all claims of EP3016654 be upheld.

The Board of Appeal has issued summons to attend oral proceedings on May 24, 2023.

The oral proceedings will be held on June 5, 2024.

Government Regulation

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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 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 U.S.

generally involves the following:

Completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations;

Submission to the FDA of an Investigational New Drug application, or IND, which must become effective before human clinical trials may begin;

• Completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations;

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

• Approval by an independent institutional review board, or IRB, at each clinical site before each trial may be initiated;

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• Satisfactory completion of an FDA advisory committee review, if applicable;

Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current Good Manufacturing Practice, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

• Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current Good Manufacturing Practice, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

• Satisfactory completion of FDA audits of clinical trial sites to assure compliance with cGCPs and the integrity of the clinical data;

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Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.

The NIH’s Final Rule on ClinicalTrials.gov registration and reporting requirements became effective in 2017, and both the NIH and FDA recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.

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

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The sponsor also must notify the FDA of any unexpected

fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information.

Phase 1, Phase 2 and Phase 3 trials may not be completed successfully within any specified period, or at all.

Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

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Expanded Access to an Investigational Drug for Treatment Use

Expanded access, sometimes called “compassionate use,”

is the use of investigational products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.

Expanded access, sometimes called “compassionate use,” is the use of investigational products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.

The rules and regulations related to expanded access are intended to improve access to investigational products for patients who may benefit from investigational therapies.

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There is no obligation for a manufacturer to make its investigational products available to eligible patients as a result of the Right to Try Act.

Combination Rule for Fixed-Dose Combination Products

Under the combination rule, the FDA may not file or approve an NDA for a fixed-dose combination product unless each component of a proposed drug product is shown to make a contribution to the claimed effects and the dosage of each

component (amount, frequency, duration) is safe and effective for the intended population.

To satisfy these requirements, the FDA typically requires a clinical factorial study, designed to assess the effects attributable to each drug in the combination product.

This is particularly true when the ingredients are directed at the same sign or symptom of the disease or condition.

The FDA has accepted a variety of approaches to satisfy the combination rule.

In December 2015, the FDA proposed regulations that would allow the agency to waive the requirements of the combination rule for certain drug products under particular circumstances.

The FDA has not, to date, finalized these regulations, but the FDA has stated that factorial studies may be unethical (e.g., omitting a drug known to improve survival) or impractical (there may be too many components to conduct a factorial study, meaning the trial cannot be conducted).

The FDA has also stated that it may be possible to use other types of clinical and nonclinical data and mechanistic information available to demonstrate the contributions of the individual active ingredients to the effect of the combination.

Similar requirements may be imposed on us by the EMA in the EU and comparable regulatory authorities in other jurisdictions.

While no similar combination rule formally exists in Canada, Health Canada may consider the contributions of each component in a combination product in connection with review of the NDS.

NDA Submission and Marketing Approval

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, 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 FDA will initially review an NDA for completeness before it accepts it for “filing.”

Under the FDA’s procedures, the agency has 60 days from its receipt of the NDA to determine whether the application will be accepted for filing based on the agency’s threshold determination that the application is sufficiently complete to permit substantive review.

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing”

of a standard NDA, for a new molecular entity to review and act on the submission, and six months from the filing date of a new molecular entity NDA with priority review.

The FDA will initially review an NDA for completeness before it accepts it for “filing.” Under the FDA’s procedures, the agency has 60 days from its receipt of the NDA to determine whether the application will be accepted for filing based on the agency’s threshold determination that the application is sufficiently complete to permit substantive review.

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA, for a new molecular entity to review and act on the submission, and six months from the filing date of a new molecular entity NDA with priority review.

Accordingly, this review process typically takes 12 months and eight months, respectively from the date the NDA is submitted to the FDA.

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FDA regulations and guidance also allow for greater flexibility and tolerance for uncertainty in the context of rare and fatal diseases.

The FDA also assesses whether the facility in which the product is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

In addition, under the Pediatric Research Equity Act of 2003, or PREA, as amended, certain NDAs or supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before initiation of the Phase 3 or Phase 2/3 study.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The FDA and the sponsor must reach an agreement on the PSP.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before initiation of the Phase 3 or Phase 2/3 study.

The initial Pediatric Study Plan must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The FDA and the sponsor must reach an agreement on the Pediatric Study Plan.

A sponsor can submit amendments to an agreed-upon initial Pediatric Study Plan at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

PREA does not apply to a drug for an indication for which orphan drug designation has been granted.

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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.

In this event, the application must be resubmitted with the additional information.

The resubmitted application is also subject to review before the FDA accepts it for filing.

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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.

specifications.

Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with cGCP requirements.

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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.

Even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.

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Orphan product exclusivity means that the FDA may not approve any other applications to market the same product for the same indication for seven years, except in certain limited circumstances.

drug designated as an orphan drug ultimately receives marketing approval for an indication broader than what it was designated for, it may not be entitled to exclusivity.

If a drug designated as an orphan drug ultimately receives marketing approval for an indication broader than what it was designated for, it may not be entitled to exclusivity.

Orphan exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same active ingredient for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.

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The FDA maintains several programs intended to facilitate and expedite development and review of new drugs to address unmet medical needs in the treatment of serious or life-threatening diseases or conditions.

These programs include Fast Track designation, Breakthrough Therapy designation, Priority Review and accelerated approval, and the purpose of these programs is to either expedite the development or review of important new drugs to get them to patients earlier than under standard FDA development and review procedures.

These programs include Fast Track Designation, Breakthrough Therapy Designation, Priority Review Designation and accelerated approval, and the purpose of these programs is to either expedite the development or review of important new drugs to get them to patients earlier than under standard FDA development and review procedures.

The FDA has a FastTrack program that is intended to expedite or facilitate the process for reviewing new drugs that meet certain criteria.

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The FDA determines at the time that the marketing application is submitted, on a case-by-case basis, whether the proposed drug represents a significant improvement in treatment, prevention or diagnosis of disease when compared with other available therapies.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review and to shorten the FDA’s goal for taking action on an NDA for a new molecular entity from ten months to six months from the date of filing.

A product may also be eligible for accelerated approval if it treats a serious or life-threatening disease or condition, generally provides a meaningful advantage over available therapies and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

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Pediatric exclusivity is another type of regulatory market exclusivity in the U.S.

Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods or listed patents.

This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request”

for such a trial.

Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods for all formulations, dosage forms, and indications of the active moiety and patent terms.

This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.

Post-approval Requirements

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The FDA may impose a number of post-approval requirements as a condition of approval of an NDA.

For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

FDA regulations require that products be manufactured in specific facilities and in accordance with cGMP regulations which require, among other things, quality control and quality assurance, the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs, including those supply products, ingredients and components thereof, are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.

Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the U.S.

Changes to the manufacturing process are strictly

regulated and often require prior FDA approval before being implemented.

In addition, the Drug Supply Chain Security Act, or DSCSA, was enacted in 2013 with the aim of building an electronic system to identify and trace certain prescription drugs and biologics distributed in the United States.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a 10-year period that culminated in November 2023.

The FDA established a one-year stabilization period from November 2023 to November 2024 for trading partners to continue to build and validate interoperable systems and processes to meet certain requirements of the DSCSA.

The law's requirements include the quarantine and prompt investigation of a suspect product, to determine if it is illegitimate, notifying trading partners and the FDA of any illegitimate product, and compliance with product tracking and tracing requirements.

Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented.

FDA regulations also require investigation and correction of any deviations from cGMP requirements and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use.

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imposition of post-market studies or clinical trials to assess new safety risks;

or imposition of distribution or other restrictions under a REMS program.

or imposition of distribution

or other restrictions under a REMS program.

Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products.

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A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Further, courts have found that if “one purpose”

of remuneration is to induce referrals, the AKS is violated.

Further, courts have found that if “one purpose” of remuneration is to induce referrals, the AKS is violated.

In addition, the government may assert that a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the federal False Claims Act, or FCA;

the federal civil and criminal false claims laws, including the FCA, which can be enforced by private citizens through “qui tam”

or “whistleblower”

actions, and civil monetary penalty laws, which impose criminal and civil penalties against individuals or entities for, among other things, knowingly presenting, or causing to be presented, claims for payment or approval from Medicare, Medicaid, or other federal health care programs that are false or

• the federal civil and criminal false claims laws, including the FCA, which can be enforced by private citizens through “qui tam” or “whistleblower” actions, and civil monetary penalty laws, which impose criminal and civil penalties against individuals or entities for, among other things, knowingly presenting, or causing to be presented, claims for payment or approval from Medicare, Medicaid, or other federal health care programs that are false or fraudulent;

knowingly making or causing a false statement material to a false or fraudulent claim or an obligation to pay or transmit money or property to the federal government;

or knowingly concealing or knowingly and improperly avoiding or decreasing such an obligation.

Pharmaceutical and other healthcare companies have been, and continue to be, prosecuted under these laws, among other things, for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product and for causing false claims to be submitted because of the companies’

marketing of the product for unapproved, off-label, and thus generally non-reimbursable, uses.

Manufacturers can be held liable under the federal False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

Similar to the AKS, a person or entity does not need to have actual knowledge of these statutes or specific intent to violate them in order to have committed a violation.

the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters.

• the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit

program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters.

Like the AKS, the Patient Protection and Affordable Care Act, or the ACA, amended the intent standard for certain healthcare fraud statutes under HIPAA such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses as well as their respective business associates that perform services for them that involve the creation, use, receipt, maintenance or disclosure of individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorneys’

fees and costs associated with pursuing federal civil actions;

the federal Physician Payments Sunshine Act, created under the ACA, and its implementing regulations, which require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program to report annually to the Centers for Medicare and Medicaid Services, or CMS, under the Open Payments Program, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), to certain non-physician providers such as physician assistants and nurse practitioners, and to teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

• the federal Physician Payments Sunshine Act, created under the ACA, and its implementing regulations, which require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program to report annually to the Centers for Medicare and Medicaid Services, or CMS, under the Open Payments Program, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), to certain non-physician providers such as physician assistants and nurse practitioners, and to teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

• federal price reporting laws, which require manufacturers to calculate and report complex pricing metrics to government programs, where such reported prices may be used in the calculation of reimbursement and/or discounts on approved products;

• federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;

• analogous state and foreign laws and regulations, such as state and foreign anti-kickback, false claims, consumer protection and unfair competition laws which may apply to pharmaceutical business practices, including but not limited to, research, distribution, sales and marketing arrangements as well as submitting claims involving healthcare items or services reimbursed by any third-party payor, including commercial insurers;

state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government that otherwise restricts payments that may be made to healthcare providers and other potential referral sources;

state laws that require drug manufacturers to file reports with states regarding pricing and marketing information, such as the tracking and reporting of gifts, compensations and other remuneration and items of value provided to healthcare professionals and entities;

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and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available, it is possible that some of a pharmaceutical manufacturer’s business activities could be subject to challenge under one or more of such laws.

Efforts to ensure that business arrangements comply with applicable healthcare laws involve substantial costs.

It is possible that governmental and enforcement authorities will conclude that a pharmaceutical manufacturer’s business practices do not comply with current or future statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and regulations.

other federal healthcare programs, reporting obligations and oversight if we become subject to integrity and oversight agreements to resolve allegations of non-compliance, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of operations, any of which could adversely affect a pharmaceutical manufacturer’s ability to operate its business and the results of operations.

If any such actions are instituted against a pharmaceutical manufacturer, and it is not successful in defending itself or asserting its rights, those actions could have a significant impact on its business, including the imposition of significant civil, criminal and administrative penalties, damages, disgorgement, imprisonment, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, reporting obligations and oversight if we become subject to integrity and oversight agreements to resolve allegations of non-compliance, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of operations, any of which could adversely affect a pharmaceutical manufacturer’s ability to operate its business and the results of operations.

In addition, commercialization of any drug product outside the U.S.

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In particular, in 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, was enacted, which, among other things, subjected biologic products to potential competition by lower-cost biosimilars;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

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subjected manufacturers to new annual fees and taxes for certain branded prescription drugs;

created the Medicare Part D coverage gap discount program, in which manufacturers must agree to 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;

and provided incentives to programs that increase the federal government’s comparative effectiveness research.

Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA.

On June 17, 2021, the Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court’s decision, President Biden issued an Executive Order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The Executive Order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

In addition, in February 2023, HHS issued a proposal in response to an October 2022 executive order from President Biden that includes a proposed prescription drug pricing model that will test whether targeted Medicare payment adjustments will sufficiently incentivize manufacturers to complete confirmatory trials for drugs approved through FDA’s

accelerated approval pathway.

It is unclear how these or other healthcare reform measures of the executive branch or other efforts, if any, will impact our business.

For example, President Biden has issued multiple executive orders that have sought to reduce prescription drug costs.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

In addition, other legislative changes have been proposed and adopted in the U.S.

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The American Taxpayer Relief Act of 2012 further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

The American Rescue Plan Act of 2021 eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

In addition, other legislative changes have been proposed and adopted in the U.S.

since the ACA was enacted.

The Budget Control Act of 2011 and subsequence legislation, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of 2% per fiscal year, which remain in effect through 2031.

The Inflation Reduction Act of 2022, or IRA, includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2025, thereby effectively eliminating the coverage gap;

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and delay until January 1, 2032 the implementation of the HHS rebate rule that would have limited the fees that pharmacy benefit managers can charge.

Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one rare disease designation and for which the only approved indication is for that disease or condition.

If a product receives multiple rare disease designations or has multiple approved indications, it may not qualify for the orphan drug exemption.

Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.

If a product receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption.

The implementation of the IRA is currently subject to ongoing litigation that challenges the constitutionality of the IRA’s Medicare drug price negotiation program.

The effects of the IRA on our business and the healthcare industry in general is not yet known.

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The processes for obtaining regulatory approvals in Canada, along with subsequent compliance with applicable statutes and regulations, require the expenditure of substantial time and financial resources.

For further information, see “Risk Factors.”

The principal steps required for drug approval in Canada are as follows:

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The protocol and the informed consent forms that are signed by subjects, are reviewed and approved by the REB affiliated with the site where the trial will be conducted.

Human clinical trials for new drugs are typically conducted in three sequential phases, Phase 1, Phase 2 and Phase 3, as discussed above in the context of government regulation in the U.S.

Similar to the FDA, Health Canada also accepts foreign clinical

trial data in support of marketing applications.

clinical trials for new drugs are typically conducted in three sequential phases, Phase 1, Phase 2 and Phase 3, as discussed above in the context of government regulation in the U.S.

Similar to the FDA, Health Canada also accepts foreign clinical trial data in support of marketing applications.

Additionally, the manufacture of investigational drugs for the conduct of human clinical trials is subject to cGMP requirements.

New Drug Submission

In Canada, upon successful completion of Phase 3 clinical trials or earlier stage trials if agreeable to Health Canada, the company sponsoring a new drug then assembles all the nonclinical and clinical data and other testing relating to the product’s pharmacology, chemistry, manufacture, and controls, and submits it to Health Canada as part of an NDS The NDS is then reviewed by Health Canada.

Health Canada will not approve the new drug unless compliance with cGMP—a quality system regulating manufacturing—is satisfactory, and the NDS contains data that provide substantial evidence that the drug is safe and effective in the indication and at the dosage studied.

If Health Canada is satisfied that the NDS contains sufficient information, then marketing authorization for the new drug may be granted.

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When a NOC/c is granted, the company to which the NOC/c is issued must make certain commitments to Health Canada, which typically include a requirement to provide confirmatory data to Health Canada to support the safe use and efficacy of the new drug.

Even if Health Canada approves a product candidate, it may limit the approved indications for use of the product candidate, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms.

Health Canada may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.

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It entails satisfactory completion of preclinical studies and adequate and well-controlled clinical trials to establish the safety and efficacy of the product for each proposed indication.

It also requires the submission to the relevant competent authorities of an MAA and granting of a marketing authorization by these authorities before the product can be marketed and sold in the EU Following the UK’s departure from the EU, a separate marketing authorization is required in order to place medicinal

products on the market in Great Britain (under the Northern Ireland Protocol, the EU regulatory framework continues to apply in Northern Ireland and centralized EU authorizations continue to be recognized).

It also requires the submission to the relevant competent authorities of an MAA and granting of a marketing authorization by these authorities before the product can be marketed and sold in the

EU Following the UK’s departure from the EU, a separate marketing authorization is required in order to place medicinal products on the market in Great Britain (under the Northern Ireland Protocol, the EU regulatory framework continues to apply in Northern Ireland and centralized EU authorizations continue to be recognized).

In January 2024, developers of new medicinal products can now submit applications under the Medicines and Healthcare products Regulatory Agency's, or MHRA, International Recognition Procedure, or IRP.

IRP will be open to products that already received an approval from one of MHRA’s specified Reference Regulators which includes the United States and Canada.

Clinical Trial Approval

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and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation).

Part I is assessed by a coordinated review by the competent authorities of all Member States of the European Union, or EU Member States, in which an application for authorization of a clinical trial has been submitted (Concerned Member States) of a draft report prepared by a Reference Member State.

Part I is assessed by a coordinated review by the competent authorities of all Member States of the EU, or EU Member States, in which an application for authorization of a clinical trial has been submitted (Concerned Member States) of a draft report prepared by a Reference Member State.

Part II is assessed separately by each Concerned Member State.

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Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated MAA assessment once a dossier has been submitted.

Importantly, a dedicated contact and rapporteur from the EMA’s CHMP, or Committee for Advanced Therapies, are appointed early in PRIME scheme facilitating increased understanding of the product at EMA’s Committee level.

A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

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As with the FDA, the EMA has also issued guidelines to address review and approval of fixed-dose combination products.

This EMA’s Guideline on clinical development of fixed combination medicinal products came into force on October 1, 2017.

The basic scientific requirements for any fixed combination medicinal product are justification of the pharmacological and medical rationale for the combination, and establishment of the evidence base for the relevant contribution of all active substances to the desired therapeutic effect (efficacy and/or safety) and a positive benefit-risk for the combination in the targeted indication.

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Marketing Authorization

To obtain a marketing authorization for a product European Economic Area (i.e., the EU as well as Iceland, Liechtenstein and Norway), or EEA, an applicant must submit an MAA either under a centralized procedure administered by the EMA, or one of the procedures administered by competent authorities in the EU Member States (decentralized procedure,

national procedure or mutual recognition procedure).

To obtain a marketing authorization for a product in the European Economic Area (i.e., the EU as well as Iceland, Liechtenstein and Norway), or EEA, an applicant must submit an MAA either under a centralized procedure administered by the EMA, or one of the procedures administered by competent authorities in the EU Member States (decentralized procedure, national procedure or mutual recognition procedure).

A marketing authorization may be granted only to an applicant established in the EEA.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the EU, applicants have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted (1) a product-specific waiver, (2) a class waiver or (3) a deferral for one or more of the measures included in the PIP (for example, when this data is not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients).

supplementary protection certificate, or SPC, extension (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to 2 years before the SPC expires).

Products that are granted a marketing authorization with the results of the pediatric clinical trials conducted in accordance with the PIP (even where such results are negative) are eligible for six months’ supplementary protection certificate, or SPC, extension (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to 2 years before the SPC expires).

The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid across the EEA.

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At the end of this period, the CHMP provides a scientific opinion on whether or not a marketing authorization should be granted in relation to a medicinal product.

Where the CHMP gives a positive opinion, the EMA provides the opinion together with supporting documentation to the European Commission, who makes the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.

The European Commission may grant a so-called “marketing authorization under exceptional circumstances”.

Such authorization is intended for products for which the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because either (i) the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence;

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Continuation of the authorization is linked to the annual reassessment and a negative assessment could potentially result in the marketing authorization being suspended or revoked.

The renewal of a marketing authorization of a medicinal product under exceptional circumstances, however, follows the same rules as a

“normal”

marketing authorization.

The renewal of a marketing authorization of a medicinal product under exceptional circumstances, however, follows the same rules as a “normal” marketing authorization.

Thus, a marketing authorization under exceptional circumstances is granted for an initial five years, after which the authorization will become valid indefinitely, unless the EMA decides that safety grounds merit one additional five-year renewal.

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Conditional Marketing Authorization

The European Commission may also grant a so-called “conditional marketing authorization”

prior to obtaining the comprehensive clinical data required for an application for a full marketing authorization.

The European Commission may also grant a so-called “conditional marketing authorization” prior to obtaining the comprehensive clinical data required for an application for a full marketing authorization.

Such conditional marketing authorizations may be granted for product candidates intended for treating, preventing or diagnosing seriously debilitating or life-threatening diseases (including medicines designated as orphan medicinal products) or in a public health emergency, if (i) the risk-benefit balance of the product candidate is positive, (ii) it is likely that the applicant will be in a position to provide the required comprehensive clinical trial data post-authorization, (iii) the product fulfills an unmet medical need and (iv) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

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The timelines for the centralized procedure described above also apply with respect to the review by the CHMP of applications for a conditional marketing authorization.

A conditional marketing authorization can be converted into a standard centralized marketing authorization (no longer subject to specific obligations) once the marketing authorization holder fulfils the obligations imposed and the complete data confirm that the medicine’s benefits continue to outweigh its risks.

Regulatory Data Protection in the EU

In the EU, innovative medicinal products approved on the basis of a complete and independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

Data exclusivity, if granted, prevents applicants for authorization of generics or biosimilars of these innovative products from referencing the innovator’s preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization, for a period of eight years from the date on which the reference product was first authorized in the EU.

During an additional two-year period of market exclusivity, a generic or biosimilar MAA can be submitted and authorized, and the innovator’s data may be referenced, but no generic or biosimilar medicinal product can be placed on the EU market until the expiration of the market exclusivity.

The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Even if a compound is considered to be an innovative medical product so that the innovator gains the prescribed period of data exclusivity, another company nevertheless could also market another version of the product if such company obtained marketing authorization based on an MAA with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Even if a compound is considered to be an innovative medical product so that the innovator gains the prescribed period of data exclusivity, another company

nevertheless could also market another version of the product if such company obtained marketing authorization based on an MAA with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Periods of Authorization and Renewals

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Once authorized, orphan medicinal products are entitled to ten years of market exclusivity in all EU Member States and a range of other benefits during the development and regulatory review process including scientific assistance for study protocols, authorization through the centralized marketing authorization procedure and a reduction or elimination of registration and marketing authorization fees.

During the period of market exclusivity, a marketing authorization may only be granted for a “similar medicinal product”

with the same orphan indication if:

During the period of market exclusivity, a marketing authorization may only be granted for a “similar medicinal product” with the same orphan indication if:

(i) the marketing authorization holder for the original orphan medicinal product consents to the authorization of the second orphan medicinal product;

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or (iii) it is established that the second product is safer, more effective or otherwise clinically superior to the original orphan medicinal product.

A “similar medicinal product”

is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

The period of market exclusivity may, in addition, be reduced to six years if at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation because, for example, the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity.

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These include:

Compliance with the EU’s stringent pharmacovigilance or safety reporting rules must be ensured.

• Compliance with the EU’s stringent pharmacovigilance or safety reporting rules must be ensured.

These rules can impose post-authorization studies and additional monitoring obligations.

The manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice.

• The manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2017/1572, Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice.

These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of

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The aforementioned EU rules are generally applicable in the EEA.

Reform of the Regulatory Framework in the European Union

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval.

In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.

Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.

Data Protection Regulation in the European Economic Area and United Kingdom

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The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the EEA/UK, including the U.S., and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million (£17.5 million) or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

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Brexit and the Regulatory Framework in the United Kingdom

The UK formally left the EU (commonly referred to as “Brexit”) on January 31, 2020, and the EU and the UK have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide for wholesale mutual recognition of UK and EU pharmaceutical regulations.

At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework continues to apply in Northern Ireland).

Except in respect of the new EU Clinical Trials Regulation, the regulatory regime in Great Britain therefore largely aligns with EU regulations, however it is possible that these regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.

However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new framework mentioned below which will be put in place by the MHRA, the UK’s medicines regulator, from January 1, 2024, the MHRA has stated that it will take into account decisions on the approval of marketing authorization from the EMA (and certain other regulators) when considering an application for a Great Britain marketing authorization.

On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA will be responsible for approving all medicinal products

destined for the UK market (i.e., Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, so the UK government and the EU will enact legislative measures to bring it into law.

On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply from January 1, 2025.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, an accelerated assessment procedure and new routes of evaluation for novel products and biotechnological products.

All existing EU marketing authorizations for centrally authorized products were automatically converted (grandfathered) into Great Britain marketing authorization’s free of charge on January 1, 2021.

Since January 1, 2024, a new framework for the approval of marketing authorizations has been put in place, whereby the MHRA may have regard to decisions on the approval of marketing authorizations made by the EMA and certain other regulators when determining an application for a new Great Britain marketing authorization.

There is now no pre-marketing authorization orphan designation in Great Britain.

Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MAA.

The criteria are essentially the same, but have been tailored for the Great Britain market, i.e., the prevalence of the condition in Great Britain (rather than the EU) must not be more than five in 10,000.

Should an orphan designation be granted, the period of market exclusivity will be set from the date of first approval of the product in Great Britain.

Pricing Decisions for Approved Products

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Some countries provide that products may be marketed only after a reimbursement price has been agreed.

Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

Some countries may require the completion of additional cost effectiveness assessments that compare the cost-effectiveness of a particular product candidate to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

For example, EU Member States have the option to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

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There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.

Japanese Approval Process

Japan Government Regulation of Drug Products

Regulatory framework of pharmaceutical products in Japan is based on various laws and regulations, consisting mainly of Pharmaceutical and Medical Device Act ("PMD Act").

The Ministry of Health, Labour and Welfare ("MHLW") is the principal regulatory authority overseeing development, manufacture and commercialization of drugs and medical devices and to instruct as well as supervise drug and medical device companies to secure product quality and safety.

The Pharmaceuticals and Medical Devices Agency ("PMDA") is the regulatory agency working together with the MHLW to assure safety, efficacy and quality of products.

PMDA is authorized to conduct scientific reviews of clinical trial and marketing authorization applications for drug and medical devices;

and monitors their post-marketing safety.

The PMDA is also responsible for providing compensation for patients suffering from adverse drug reactions caused by drugs and medical devices.

Overall, being a member of the International Conference on Harmonization (“ICH”), Japan has pharmaceutical regulations fundamentally similar to those of the United States and the EU.

Non-clinical studies are performed to demonstrate the health safety of new chemical or biological substances.

Non-clinical studies must be conducted in compliance with the principles of Japanese good laboratory practice, or GLP, which reflect the Organization for Economic Co-operation and Development requirements.

Currently, Japan and EU have a mutual recognition agreement for GLP, and data generated compliant with EU requirements will be accepted by the Japanese authorities.

There is no similar agreement with the United States.

Clinical trials in Japan must be conducted in accordance with Japanese regulations based on ICH guidelines governing good clinical practices, or GCP.

If the sponsor of the clinical trial is not established within Japan, it must appoint an entity within the country to act as its caretaker who should be authorized to act on the sponsor’s behalf.

The sponsor must take out a clinical trial insurance policy, and, according to the industry agreement, should put in place a common compensation policy for the injuries from the trial.

Prior to the commencement of human clinical studies, the sponsor must complete an evaluation of the safety of the investigative product and submit a clinical trial notification and clinical trial protocol to the authorities in advance, upon agreement of the IRB of the participating institutions.

When the authorities do not comment on the notification, the sponsor may proceed with the clinical trial.

Any substantial changes to the trial protocol or other information submitted must be cleared by the IRB and notified to the authorities.

Medicines used in clinical trials must be manufactured in accordance with GMP.

To market a drug in Japan, we must obtain regulatory approval.

To obtain regulatory approval of an investigational drug, we must submit a new drug application.

The evaluation of new drug applications is based on an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety, and efficacy.

The volume and quality of the clinical data are key determinants of the approval decision.

Clinical trial data generated overseas is accepted as part of the data package consistent with the ICH recommendation.

Typically, a clinical trial in Japanese participants is required to ensure that data are extrapolatable for the Japanese population.

A data compliance review, on-site inspection for good clinical practice, and audit and detailed data review for compliance with current good manufacturing practices are undertaken by the PMDA.

Once the review organization completes its review, the matter is considered by the advisory committee of experts, and the government grants approval upon positive recommendation from the committee.

Orphan Drug Designation and Exclusivity

If the product is designed for treating certain “intractable diseases” or those whose patient size is limited to be less than 50,000 patients, we may be able to obtain designation as an orphan drug product if it demonstrates addressing high medical need.

Drugs designated as orphan drugs are entitled to receive financial aid, tax relief on research expenses, reduction of application and consultation fees, PMDA’s guidance and advice, priority review, and extension of the reexamination period up to a maximum of 10 years for drugs.

New drug creation premium will also be applied at the time of calculation of drug price for the product.

Expedited Development and Priority Review Programs

The whole approval process takes 12 months under the standard review regime.

MHLW has introduced several expedited development or review programs for especially important and innovative drugs, at least including:

Special Approval System for products required to prevent the spread of diseases that may seriously affect public health, such as COVID-19.

This is intended to be used in limited circumstances where there are no other available therapy and the product has been approved for use in certain foreign countries.

There are an expedited approval review process, special exceptions made for GMP review, national certification, containers, and packaging and labelling, etc.

License for Pharmaceutical Business

Separate from the approval requirement, it is also mandatory to possess a license of an appropriate class for the manufacturer to commercially distribute the product in Japan.

To receive such license, the manufacturer or seller must, at the very least, employ certain manufacturing, marketing, quality, and safety personnel.

The licensing requirements for drug manufacturing/marketing businesses include the appointment of a general marketing compliance officer of drugs, etc., who is a pharmacist, and compliance with Good Quality Practice (GQP) for quality control and Good Vigilance Practice (GVP) for post-marketing safety surveillance.

Non-Japanese companies who possess only the product approval may designate an appropriate license holder in Japan to commercially distribute the product, rather than distributing it on its own.

The license is valid for five years.

PMD Act requires a license for marketing authorization when importing to Japan and selling pharmaceutical products manufactured in other countries.

It also requires each manufacturing site of a foreign manufacturer to be certified as a manufacturing site of pharmaceutical products to be marketed in Japan.

Regulatory Exclusivity

Marketing authorization holders must perform post-marketing surveys on new drugs so that efficacy and safety can be reconfirmed by reexamination by the MHLW for a specified period after marketing approval, in general, for at least six years.

The concept of the risk management plan has been incorporated in reexamination.

In this aspect, applications for generic drugs cannot be filed until completion of the reexamination.

Branded products are protected from generics during this period.

Regardless of the type of drugs, MHLW may extend the reexamination period to a period not exceeding 10 years, if the minister believes that the extension is particularly necessary.

In general, drugs containing new active ingredients will earn 8 years reexamination period, and drugs with new routes of administration will earn 6 years.

There is no specific period for pediatric drugs in this regard, but the reexamination period may be extended (not exceeding 10 years) as needed to collect clinical data required for the reexamination of dosage or administration for pediatric use.

Intellectual Property Right Protection

The patent term is 20 years from the time of application as a rule.

However, if the patent cannot be implemented because of laws and regulations to ensure safety of drugs and regenerative medicine products, etc.

the patent term can be extended for a maximum of 5 years.

There is also the Orange Book which lists information about drug approval;

however, this is not US-style patent linkage.

The MHLW will not approve generic drugs until the substance patent or the application patent of the original drug expires and production of the active ingredient becomes possible.

Pricing Decision

Pricing approval for the product is required in order to be applied for redemption of health insurance.

Once approved and marketable, drugs are also subject to regular post-marketing vigilance of safety and quality under the standards of Good Manufacturing Practice.

In Japan, the National Health Insurance system maintains a Drug Price List specifying which pharmaceutical products are eligible for reimbursement, and the MHLW sets the prices of the products on this list.

Upon marketing approval, the manufacturer or seller begins negotiations regarding the reimbursement price with the MHLW, which is generally determined within 60 to 90 days.

Historically, Japan performs scheduled biannual price adjustments as a cost-reduction method but recently there have been additional adjustments in the years in between.

New products judged innovative or useful, that are indicated for pediatric use, or that target orphan or small population diseases, however, may be eligible for a pricing premium.

The government has also promoted the use of generics, where available.

Rest of the World Regulation

For other countries outside of Canada, the EU and the U.S., such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

For other countries outside of Canada, the EU and the U.S., such as countries in the Middle East, Africa, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

Additionally, the clinical trials must be conducted in accordance with GCP requirements and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

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In the U.S., government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drug products they will pay for and establish reimbursement levels.

The availability and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford a drug product.

The availability and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford a drug

Sales of drug products depend substantially, both domestically and abroad, on the extent to which the costs of drugs products are paid for by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, private health coverage insurers and other third-party payors.

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Obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical and cost-effectiveness data for the use of our product on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained.

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product.

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product.

Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on its investment in product development.

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CMS decides whether and to what extent a new drug product will be covered and reimbursed under Medicare, and private payors tend to follow CMS to a substantial degree.

However, no uniform policy of coverage and reimbursement for drug products exists among third-party payors and coverage and reimbursement levels for drug products

can differ significantly from payor to payor.

Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a drug product is:

However, no uniform policy of coverage and reimbursement for drug products exists among third-party payors and coverage and reimbursement levels for drug products can differ significantly from payor to payor.

Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a drug product is:

• a covered benefit under its health plan;

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Any formulary used by a Part D prescription drug plan must be developed and reviewed by a pharmacy and therapeutic committee.

Government payment for some of the costs of prescription drugs may increase demand for drugs for which we obtain marketing approval.

Government payment for

some of the costs of prescription drugs may increase demand for drugs for which we obtain marketing approval.

Any negotiated prices for any of our products covered by a Part D prescription drug plan will likely be lower than the prices we might otherwise obtain.

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The required 340B discount on a given product is calculated based on the average manufacturer price, or AMP, and Medicaid rebate amounts reported by the manufacturer.

As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although under the current state of the law these newly eligible entities (with the exception of children’s hospitals) will not be eligible to receive discounted 340B pricing on orphan drugs.

As the required 340B discount is determined based on average manufacturer price, or AMP, and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the required 340B discount to increase.

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Although the results of the comparative effectiveness studies are not intended to mandate coverage policies for public or private payors, it is not clear what effect, if any, the research will have on the sales of our product candidates, if any such drug or the condition that they are intended to treat are the subject of a trial.

It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s drug could adversely affect the sales of our product candidate.

If third-party payors do not consider our drugs to be cost-effective compared to other available therapies, they may not cover our drugs after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow us to sell our drugs on a profitable basis.

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For example, in the EU, pricing and reimbursement schemes vary widely from country to country.

Some countries provide that

products may be marketed only after a reimbursement price has been agreed.

Some countries may require the completion of additional studies that compare the cost effectiveness of a particular therapy to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

Some countries provide that products may be marketed only after a reimbursement price has been agreed.

Some countries may require the completion of additional cost effectiveness assessments that compare the cost effectiveness of a particular therapy to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

Other countries may allow companies to fix their own prices for products, but monitor and control product volumes and issue guidance to physicians to limit prescriptions.

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Our human capital is integral to helping us achieve our goal to end the suffering caused by neurodegenerative diseases.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

The objectives for our human capital resources include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards and cash-based performance bonus awards.

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We file Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, proxy statements and other information with the SEC.

Our filings with the SEC are available on the SEC’s website at www.sec.gov.

We also maintain a website at http://www.amylyx.com.

We make available, free of charge, in the Investors section of our website, documents we file with or furnish to the SEC, including our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any exhibits and amendments to those reports.

We make available, free of charge, in the Investors section of our website, documents we file with or furnish to the SEC, including our Annual Reports on Form 10-K, Quarterly Reports on

Form 10-Q, Current Reports on Form 8-K and any exhibits and amendments to those reports.

We make this information available as soon as reasonably practicable after we electronically file such materials with, or furnish such information to, the SEC.

The other information found on our website is not part of this or any other report we file with, or furnish to, the SEC.

Environmental, Social, and Governance (ESG)

The values that drive our mission to one day end the suffering caused by neurodegenerative diseases are at the heart of how we do business.

Our commitment to audacity, curiosity, engagement, accountability, and authenticity compels us to be responsible members of the global community.

We are committed to better understanding our impact on the world, what we are doing well, and where we can improve.

In 2023, we formed an ESG Committee to lead the effort to help us formalize our environmental, social, and governance journey as we grow.

This Committee reports to the Executive Leadership Team and is comprised of a cross-functional team of employees.

As a virtual company, we recognize the importance of working with vendors and suppliers whose practices demonstrate a commitment to sustainability.

With our recent rapid growth, we have now implemented a procurement function and are introducing a process to evaluate new vendors’ sustainability efforts.

Environmental

As a company, we have grown quickly.

Many of our employees choose to work remotely, but we have implemented features such as recycling programs and automatic lighting at our facilities.

Amylyx expects its contract manufacturing, packaging and supply partners to maintain a similar ESG program, compliant with local laws and regulations, and retains the ability to conduct periodic audits to review these programs.

That said, we acknowledge that there is work to do in this area, and looking at our environmental impact will be part of our future work.

Our commitment to people is stated in our core values and reflected in our actions.

We are dedicated to the discovery and development of potential treatments for people living with neurodegenerative diseases.

People living with the diseases we focus on are our true north, and we continue to work closely with the ALS and other neurodegenerative disease communities.

This includes seeking their input on our clinical trial designs and recruitment materials as well as regularly engaging these individuals and caregivers for their feedback on multiple topics, including barriers to access to multidisciplinary care and to approved treatment.

To ensure we continue to listen to and understand the needs of the neurodegenerative communities, we invite individuals to share their perspectives monthly at our all-company meetings.

We are also proud to feature people living with ALS and their caregivers in our promotional and other external materials.

As we advance novel drug candidates in our pipeline, we are committed to ensuring equal access for all to clinical trials and, in particular, to clinical trials comprised of people with diversity of gender, age, socioeconomic background, color, ethnicity, and more.

In regions where our product is approved and commercially available, we have a dedicated team that can provide a number of services, including education and access support.

For eligible patients, we offer financial support programs to help with affordability.

We believe the best way to get helpful medicines to the most people who are qualified to receive them is to move through regulatory processes, following each country’s rules.

In some cases, however, we may be able to provide an investigational drug for use even if it is not yet approved or is still being studied, providing access to treatment to certain individuals who otherwise would have no access.

As an employer, diversity is also important, including having representation of diverse views and backgrounds at the highest levels of the organization.

Three of our seven senior executives are women.

Our board is committed to increasing diversity as we add additional members over time.

At present, of our six board members, two are women, one who is ethnically diverse.

We have posted a board diversity matrix on our website.

We care about the health and wellbeing of our employees.

• Flexible and remote work arrangements to all employees

• Unlimited time off

• Medical, dental, life, and disability insurance

• 401(k) plan with a company contribution

• Paid parental leave

• An employee assistance program

Our Board of Directors is responsible for overseeing the business and management of the Company.

As part of our governance practices, we are committed to high standards of ethics, which are reflected in our Code of Business Conduct and Ethics, which applies to our directors, officers, employees and designated agents.

This Code is posted on our corporate website.

We have an independent chairman, and four of our six board members are independent.

Our Audit, Nominating and Corporate Governance, and Compensation Committees are comprised solely of independent directors.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business