Amylyx’s Dedication to Neurodegenerative Disease Research: Insights Gained and Future Directions

Founded with the mission to discover new treatments for neurodegenerative diseases, Amylyx Pharmaceuticals has provided support and hope for patients with amyotrophic lateral sclerosis (ALS) and other debilitating conditions.

Earlier this year, Amylyx announced their decision to remove Relyvrio/Albrioza from the market based on topline results from the Phase III PHOENIX trial of AMX0035 in ALS. This significant pivot underscores the company’s commitment to scientific integrity.

The decision to withdraw Relyvrio/Albrioza followed a rigorous evaluation process involving the US Food and Drug Administration (FDA), Health Canada and the ALS community. The drug had initially been approved based on earlier promising results from the CENTAUR trial, a multicenter Phase II clinical trial with 137 ALS participants. The CENTAUR trial included a 6-month randomized, placebo-controlled phase and an open-label long-term follow-up phase. It successfully met its primary efficacy endpoint by reducing functional decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and results were published in the New England Journal of Medicine.

However, the Phase III PHOENIX trial results necessitated a reevaluation of the drug’s benefit-risk profile. The trial did not achieve its primary endpoint of statistical significance (p=0.667) in the change from baseline in the ALSFRS-R total score at Week 48, nor did it reach statistical significance in the secondary endpoints.

Despite this setback, Amylyx remains dedicated to its core mission of combating neurodegenerative and other serious diseases and is channeling its resources towards its current pipeline programs.

neurodegenerative disease research — **Amylyx Co-CEOs, Josh Cohen (left) and Justin Klee (right).**

In an interview with Xtalks, Amylyx Co-CEOs Justin Klee and Josh Cohen shared their insights on the scientific findings, regulatory strategies and future directions of Amylyx’s pipeline.

They discussed the implications of the PHOENIX trial results and how these insights are shaping the ongoing development of AMX0035 for other conditions such as Wolfram syndrome and progressive supranuclear palsy (PSP). They also highlighted the potential of AMX0114, an antisense oligonucleotide targeting calpain-2, in treating ALS.

XTALKS CLINICAL EDGE: Issue 3 — Interview with Amylyx Co-CEOs

Xtalks Clinical Edge is a magazine for clinical research professionals and all who want to be informed about the latest trends and happenings in clinical trials. This magazine immerses you in a world where industry leaders, patient advocates and top researchers converge to provide the most insightful perspectives on clinical trials.

Scientific Insights and Next Steps

Discussing the PHOENIX trial, Klee emphasized its significance: “First and most important was testing. In a larger study, we confirmed the safety of Relyvrio, which I think is so important, particularly in diseases where people are already facing some different complications.”

Despite the challenges posed by conflicting results between the CENTAUR and PHOENIX trials, Klee highlighted the importance of continued learning. “We remain very excited about the mechanism of AMX0035 targeting [endoplasmic reticulum] ER stress and mitochondrial dysfunction and believe that those are very important drivers of neurodegenerative diseases,” he said. The company is actively advancing AMX0035 in Wolfram syndrome and PSP.

The PHOENIX trial results underscore the inherent complexity of neurodegenerative diseases, characterized by their heterogeneous nature and variable progression rates among patients. The necessity to delve deeper into the underlying mechanisms of these diseases is clear, and Amylyx is committed to using the data from both the PHOENIX and CENTAUR trials to refine their understanding and approach. This continuous learning process is crucial for developing more effective treatments in the future.

Moreover, the favorable safety profile of AMX0035 bolsters the company’s confidence in its potential for treating other neurodegenerative conditions. The ongoing research in Wolfram syndrome and PSP is particularly promising. Wolfram syndrome, a rare, monogenic disease, provides a unique opportunity to study the effects of AMX0035 in a more controlled genetic context, potentially offering insights that could be applied to broader neurodegenerative conditions.

The company is also preparing to initiate a clinical trial for AMX0114, an antisense oligonucleotide targeting calpain-2 in ALS. This next-generation therapeutic strategy reflects Amylyx’s innovative approach, leveraging advanced genetic technologies to tackle the fundamental biological processes driving neurodegeneration. By inhibiting calpain-2, AMX0114 aims to prevent axonal degeneration, a critical factor in the progression of ALS and potentially other neurodegenerative diseases.

Global Regulatory Strategies

Reflecting on the regulatory outcomes, Cohen stated, “Our regulatory strategy and honestly everything we do flows from our mission, which is to try to help people living with rare and really challenging diseases.” He emphasized their commitment to quickly presenting beneficial data to regulators worldwide, aiming to serve as many patients as possible.

Amylyx employs a proactive and comprehensive regulatory strategy to navigate the complex landscape of neurodegenerative disease treatments. By engaging with multiple regulatory authorities early and consistently, they ensure swift communication of clinical data indicating potential benefits. This approach has taught them valuable lessons, particularly from the differing responses to Relyvrio by the FDA and EMA, highlighting the need for tailored strategies that meet varied regulatory standards.

The company’s commitment to global access involves simultaneous regulatory submissions across different regions, ensuring that new treatments can reach a broad patient population without unnecessary delays. This global perspective is integral to their mission of improving the lives of those living with rare and debilitating diseases.

By prioritizing transparent communication and collaboration with regulators, Amylyx is better positioned to address concerns promptly and build trust with healthcare professionals and patients.

Supporting Patients Amidst Market Withdrawal

Amylyx’s decision to transition current Relyvrio patients to a free drug program demonstrates their unwavering commitment to patient care. “We long felt like it was critical to have a very significant free drug program. ALS is a relentlessly progressive and universally fatal disease, and we think that anyone who has ALS and who was on Relyvrio as of April 4 should be able to continue accessing it if they and their physician wish,” Klee explained.

This program is designed to ensure that patients currently benefiting from Relyvrio can continue their treatment at this time without interruption.

Maintaining Company Culture Amid Workforce Reductions

Amylyx has prioritized a strong, mission-driven culture. Co-CEOs Klee and Cohen personally participate in final-round interviews for every hire, underscoring their commitment to this mission.

The recent workforce reduction was a strategic decision to focus resources on critical clinical milestones. Cohen explained, “The company culture is something we’ve always cared tremendously about and prioritized quite a lot. Ultimately, we’re doing the workforce reduction to give ourselves the resources to keep advancing for patients in need.” This decision was made with transparency and support to mitigate its impact on affected employees while ensuring the company’s long-term viability.

To support remaining employees, Amylyx has implemented measures to maintain morale and foster resilience. By keeping patient care at the core of its operations, Amylyx aims to inspire and retain a dedicated workforce.

Amylyx also focuses on attracting new talent aligned with their values and mission. They believe their patient-centered mission will continue to draw individuals passionate about advancing new therapies for communities with significant unmet needs, and little to no effective treatment options. Emphasizing their commitment to patient outcomes and innovative research, Amylyx aims to build a highly-skilled, motivated team.

Public Perception and Reputation Management

Despite the market withdrawal, Amylyx remains focused on its core mission. “We have always said, and we always will, that we make all of our decisions based on what’s best for the patients that we’re trying to serve, their families and the medical community who are supporting them,” Klee asserted. This patient-centric approach underscores their commitment to making a positive impact.

Innovative Approaches in Neurodegenerative Disease Research

Amylyx is exploring several innovative technologies to address neurodegenerative diseases more effectively. One of their promising approaches involves antisense oligonucleotides (ASOs) for ALS. Cohen explained, “We’re developing an antisense oligonucleotide that we hope to bring to clinic later this year for ALS. ASOs offer a targeted approach that can stop cells from producing specific proteins involved in neurodegeneration.” This precision allows for targeted intervention at the genetic level, potentially slowing or halting the progression of diseases like ALS.

In addition to ASOs, Amylyx is heavily invested in the use of biomarkers. Biomarkers provide measurable indicators of biological processes, allowing researchers to monitor disease progression and treatment efficacy with greater accuracy. This integration into clinical trials enables more robust and objective assessments of therapeutic impact, enhancing overall reliability.

Amylyx’s approach also includes collaborations with leading academic institutions and leveraging cutting-edge technologies. By partnering with experts and utilizing the latest advancements in biomedical research, Amylyx is positioned to accelerate the development of new therapies. These collaborations enhance their research capabilities and foster a multidisciplinary approach to tackling complex neurodegenerative diseases.

Addressing Challenges in Neurodegenerative Disease Development

Addressing the challenges in neurodegenerative disease research, Klee remarked, “We can’t biopsy the brain… it’s a lot harder to measure.” This difficulty in directly studying brain tissue complicates the understanding and treatment of these conditions. The lack of straightforward diagnostic tools and the complexity of disease mechanisms make it imperative to develop innovative research methods and treatment approaches.

One major challenge is the heterogeneity of neurodegenerative diseases. Patients with the same diagnosis can exhibit vastly different symptoms and disease progression rates, complicating the development of universal treatments.

Furthermore, the progressive nature of many neurodegenerative diseases poses a challenge for clinical trials. Long trial durations are often required to observe significant changes in disease progression, which can delay the availability of new treatments. To address this, Amylyx is incorporating biomarkers and other surrogate endpoints in their trials to provide early indicators of treatment efficacy. This strategy can help expedite the drug development process, bringing new therapies to patients more quickly.

In addition to clinical and biological challenges, there are significant regulatory hurdles. Neurodegenerative diseases often require innovative regulatory strategies to demonstrate efficacy and safety effectively. Amylyx’s proactive engagement with regulatory authorities worldwide aims to streamline this process, ensuring that promising therapies can reach patients without unnecessary delays.

Long-Term Vision for Amylyx

Looking ahead, Cohen outlined Amylyx’s long-term goals: “We measure our success by the impact we have on patients’ lives. Over the next five to ten years, we aim to help many patients achieve better outcomes and build a team that shares our mission.” Amylyx’s commitment to leveraging new technologies and remaining persistent in their pursuits will guide their evolution and efforts to make a significant difference in the world of neurodegenerative diseases.

Cohen highlighted their focus on building a collaborative and innovative work environment. “We believe that a strong, value-driven culture is essential for achieving our long-term goals,” he said. “By fostering a sense of purpose and passion among our team members, we can continue to push the boundaries of what’s possible in neurodegenerative disease research and treatment.”