Executive Summary / Key Takeaways

• Strategic Pivot and Focused Pipeline: Amylyx Pharmaceuticals has undergone a significant transformation, moving past the discontinuation of RELYVRIO/ALBRIOZA for ALS to focus on a revitalized pipeline led by avexitide for post-bariatric hypoglycemia (PBH) and other promising neurodegenerative programs.
• Avexitide as the Lead Catalyst: Avexitide, a first-in-class GLP-1 receptor antagonist with FDA Breakthrough Therapy designation, is advancing in a pivotal Phase 3 LUCIDITY trial for PBH, targeting a substantial unmet medical need with no approved therapies. Topline data is anticipated in the first half of 2026, with a potential commercial launch in 2027.
• Deepening Neurodegenerative Portfolio: Beyond avexitide, the company is progressing AMX0035 in Wolfram syndrome (positive long-term Phase 2 data) and Progressive Supranuclear Palsy (PSP), with Phase 2b interim data for PSP expected in Q3 2025. AMX0114 for ALS is also in Phase 1, with early cohort data expected in 2025.
• Disciplined Financial Management: Following a significant restructuring, Amylyx has streamlined operations, extending its cash runway through the end of 2026, providing critical funding for upcoming clinical milestones and early commercial preparations for avexitide.
• Significant Market Opportunity in PBH: The estimated 160,000 U.S. patients with PBH represent a growing, underserved market, with analysts projecting the global GLP-1 antagonist market for PBH could exceed $2 billion by 2035, positioning Amylyx for a first-to-market advantage.

A Strategic Rebirth: From ALS Setback to New Horizons

Amylyx Pharmaceuticals, founded in 2013, has embarked on a profound strategic transformation, refocusing its efforts after a pivotal setback. The company initially gained prominence with AMX0035 (RELYVRIO/ALBRIOZA) for ALS, which achieved regulatory approval in the U.S. and Canada, generating substantial revenue, including $380.80 million in 2023. However, the voluntary discontinuation of this product in April 2024, following negative Phase 3 PHOENIX trial results, necessitated a decisive pivot. This period of challenge has reshaped Amylyx into a leaner, more focused clinical-stage entity, now strategically positioned to address high unmet medical needs in both endocrine and neurodegenerative conditions.

The company's current strategy emphasizes a pipeline built on well-defined mechanistic rationales, clear clinical outcomes, and rigorous preclinical data. This approach is critical in the highly competitive biopharmaceutical landscape, where larger, more diversified players like Biogen (NASDAQ:BIIB) and Ionis Pharmaceuticals (NASDAQ:IONS) command significant resources and market presence. Amylyx aims to carve out a niche by pursuing first-in-class or first-to-market opportunities in orphan diseases, leveraging its innovative technologies to differentiate its offerings.

Technological Edge: Unlocking Potential in Underserved Conditions

Amylyx's investment thesis is deeply rooted in its differentiated technological platforms, which underpin its lead assets. The company's approach is to match investigational therapies with diseases where they can make the greatest impact, agnostic of modality.

Avexitide: Pioneering GLP-1 Receptor Antagonism in PBH

At the forefront of Amylyx's pipeline is avexitide, an investigational, first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist. This technology is designed to address conditions characterized by hyperinsulinemic hypoglycemia, notably post-bariatric hypoglycemia (PBH). The core mechanism involves avexitide binding to the GLP-1 receptor on pancreatic islet beta cells, inhibiting the effects of excessive GLP-1. This action mitigates hypoglycemia by decreasing insulin secretion and stabilizing blood glucose levels, effectively restoring glycemic homeostasis.

The tangible benefits of avexitide have been demonstrated across five prior clinical trials in PBH. In a Phase 2b trial, the 90 mg once-daily dose, now being evaluated in the pivotal Phase 3 LUCIDITY trial, achieved a statistically significant 53% reduction in Level 2 hypoglycemic events (p=0.004) and a 66% reduction in Level 3 hypoglycemic events (p=0.0003). New exploratory analyses presented at ENDO 2025 further highlighted a 64% least-squares mean reduction (p=0.0031 vs. baseline) in the composite rate of Level 2 and Level 3 hypoglycemic events, with over half of participants experiencing no such events during treatment. The pharmacokinetic profile supports once-daily dosing, maintaining therapeutic exposure for a full 24 hours, ensuring continuous protection against unpredictable hypoglycemic episodes. This robust efficacy and a generally well-tolerated safety profile, replicated across trials, provide a strong foundation for its potential commercialization.

For investors, avexitide's first-in-class status and Breakthrough Therapy designation signal a significant competitive moat. There are currently no FDA-approved therapies for PBH, and existing off-label treatments offer minimal patient satisfaction and lack robust clinical evidence. While a competitor, MBX Biosciences, is developing a once-weekly GLP-1 antagonist, Amylyx's lead in Phase 3 development positions it for a potential first-to-market advantage, which is crucial for capturing market share and establishing pricing power in this underserved orphan indication.

AMX0035: Targeting Neurodegeneration's Core Pathways

Amylyx continues to advance AMX0035, an oral, fixed-dose combination therapy, in neurodegenerative diseases where ER stress and mitochondrial dysfunction are implicated. This technology aims to slow or mitigate neurodegeneration by addressing these two interconnected central pathways that lead to cell death.

In Wolfram syndrome, a rare, monogenic, progressive neurodegenerative disorder affecting approximately 3,000 people in the U.S., AMX0035 has shown promising results. Positive long-term Week 48 data from the Phase 2 HELIOS trial demonstrated sustained stabilization or improvement in pancreatic beta cell function, glycemic control, and visual acuity, contrasting with the expected disease progression. This suggests AMX0035 could offer a meaningful impact in a disease with no approved treatments.

For Progressive Supranuclear Palsy (PSP), a fatal tauopathy affecting an estimated 23,000 U.S. patients, AMX0035 is believed to be the first brain- and cell-penetrant agent to demonstrate significant tau reduction in cerebrospinal fluid (CSF) in a prior Alzheimer's trial. This technological differentiator positions AMX0035 as a potentially disease-modifying approach in PSP, contrasting with other investigational agents that primarily target extracellular tau or downstream effects.

AMX0114: A Novel Approach to ALS

AMX0114, an investigational antisense oligonucleotide, represents Amylyx's continued commitment to ALS, albeit with a new technological approach. It is designed to target calpain-2 (CAPN2), a calcium-activated protease implicated in axonal degeneration. Preclinical studies showed potent, dose-dependent, and durable reduction in CAPN2 mRNA and protein levels, leading to improved neuronal survival and reduced neurofilament light chain (NfL) levels—a key biomarker for axonal degeneration. This targeted inhibition aims to prevent a destructive driver of ALS progression. While the FDA has placed a clinical hold on AMX0114 in the U.S. due to dosing restrictions, Health Canada has cleared the Phase 1 LUMINA trial, which dosed its first participant in April 2025. The company remains confident in its ability to address FDA's concerns and ultimately pursue U.S. development.

Future Innovation: Long-Acting GLP-1 Antagonist

Further underscoring its conviction in the GLP-1 pathway, Amylyx has partnered with Gubra AS to develop a novel long-acting GLP-1 receptor antagonist. Initial efforts have already shown promising potency values in vitro and in vivo, along with extended in vivo half-lives. This strategic initiative aims to expand the company's reach into other rare diseases where GLP-1 receptor antagonism could be beneficial, potentially creating a next-generation asset to complement avexitide.

Financial Resilience and Focused Investment

Amylyx's financial performance in the first half of 2025 reflects its strategic pivot and disciplined cost management. Following the discontinuation of RELYVRIO/ALBRIOZA, the company reported no product revenue for the three and six months ended June 30, 2025, a stark contrast to $1.0 million in Q2 2024 and $87.6 million in Q1 2024 from prior sales. This revenue shift underscores the company's transition to a pure clinical-stage model.

Operating expenses have been significantly impacted by the restructuring plan initiated in April 2024, which included a 70% workforce reduction. Selling, general, and administrative (SG&A) expenses decreased by 28% to $15.6 million in Q2 2025 from $21.6 million in Q2 2024, and by 61% to $31.3 million in H1 2025 from $79.4 million in H1 2024. This reduction in SG&A is a direct result of reduced payroll, personnel costs, and consulting services, demonstrating effective cost control.

Research and development (R&D) expenses, however, show a strategic reallocation of resources. R&D increased by 17% to $27.2 million in Q2 2025 from $23.3 million in Q2 2024, driven primarily by a $7.1 million increase in spending on the pivotal Phase 3 LUCIDITY trial for avexitide and a $3.6 million increase for AMX0035 in PSP. This was partially offset by a substantial 92% decrease in spending on AMX0035 for ALS, from $9.4 million in Q2 2024 to $0.8 million in Q2 2025, reflecting the shift away from the discontinued ALS program. For the six months ended June 30, 2025, R&D expenses were $49.3 million, down 18% from $60.0 million in H1 2024, primarily due to the significant reduction in ALS spending, which masked the increased investment in avexitide and PSP.

The company's liquidity position is a critical component of its investment thesis. As of June 30, 2025, Amylyx held $180.8 million in cash, cash equivalents, and marketable securities, with an accumulated deficit of $684.0 million. A public offering in January 2025 raised approximately $65.5 million in net proceeds, bolstering its financial runway. Management projects this capital will be sufficient to fund operations and capital expenditures through the end of 2026. This runway is crucial for reaching key clinical milestones and initiating commercial preparations for avexitide. The company expects total combined R&D and SG&A expenses (excluding stock-based compensation) to be in the range of $30 million to $40 million per quarter for 2025, indicating a sustained but controlled investment in its pipeline.

Market Opportunity and Competitive Landscape

Amylyx's strategic focus on orphan conditions with high unmet needs positions it in markets with less direct competition compared to broader therapeutic areas.

The market for Post-Bariatric Hypoglycemia (PBH) represents a significant opportunity. An estimated 160,000 people in the U.S. suffer from PBH, a chronic and debilitating condition that typically manifests 1 to 3 years post-surgery. Recent prevalence models suggest approximately 167,000 individuals experience medically important PBH, with 119,000 from Roux-en-Y gastric bypass and 48,000 from sleeve gastrectomy. The absence of FDA-approved treatments means patients currently rely on dietary modifications and off-label drugs with limited efficacy and satisfaction. This creates a clear path for avexitide to be a first-to-market therapy. While bariatric surgery trends show a slight uptick in Roux-en-Y procedures, the overall patient pool for PBH is expected to grow, reinforcing the long-term market potential. Analysts project the global market for GLP-1 antagonists in PBH could exceed $2 billion by 2035, with a significant portion in the U.S., assuming a strong market share for Amylyx.

In the neurodegenerative space, Amylyx faces a different competitive dynamic. For ALS, the company's previous commercial product, AMX0035, failed in Phase 3, highlighting the inherent challenges in this field. Now, with AMX0114, Amylyx is pursuing a novel antisense oligonucleotide approach, differentiating itself from prior efforts. In PSP, AMX0035's ability to reduce tau in CSF, as observed in a prior Alzheimer's trial, offers a unique mechanistic angle compared to other investigational agents. The PSP market, affecting an estimated 23,000 U.S. patients, currently has no approved therapies, providing another first-in-class opportunity.

Compared to larger biopharmaceutical companies like Biogen, Amylyx operates with a more concentrated pipeline and fewer resources. Biogen, with its established portfolio in neurological disorders and treatments like Tofersen for SOD1-ALS, benefits from greater scale, global reach, and diversified revenue streams. Amylyx's strength lies in its targeted innovation and agility in niche orphan markets. Similarly, Ionis Pharmaceuticals, a leader in antisense technology, has a sophisticated platform for genetic medicines. While Ionis's technological depth is significant, Amylyx's AMX0035 offers a multifaceted neuroprotective approach. Cytokinetics (CYTK), focused on muscle biology, presents a more specialized competitive angle. Amylyx's competitive strategy is to leverage its focused R&D and potentially cost-effective combination therapies to gain market share where larger players may not have a direct, first-in-class solution. The lack of approved therapies in its target indications also means Amylyx does not anticipate step therapy restrictions from payers, which could facilitate market access if its candidates are approved.

Outlook and Key Catalysts

Amylyx's near-term outlook is defined by several critical clinical milestones that will shape its future trajectory. For avexitide in PBH, the pivotal Phase 3 LUCIDITY trial is on track to complete recruitment by the end of 2025, with topline data anticipated in the first half of 2026. Management has expressed confidence in the trial's powering, noting that even a 35% reduction in hypoglycemic events would provide 90% power to detect a difference, while results similar to prior Phase 2b data (53-66% reduction) would yield substantially more than 90% power. If approved, a commercial launch is expected in 2027, with early preparations already underway.

In the neurodegenerative pipeline, the Phase 2b portion of the ORION trial for AMX0035 in PSP, which completed enrollment of 139 participants in January 2025, is expected to deliver efficacy and safety data from an unblinded interim analysis in Q3 2025. This readout will be pivotal for a go/no-go decision on advancing to the Phase 3 portion. For AMX0035 in Wolfram syndrome, the positive long-term Week 48 data from the HELIOS trial, presented in May 2025, will inform the design of a Phase 3 trial, with an update expected in 2025. Lastly, early cohort data from the Phase 1 LUMINA trial of AMX0114 in ALS is expected by the end of 2025. These catalysts represent significant value inflection points for the company.

Risks and Challenges

Despite the promising pipeline, Amylyx faces inherent risks common to clinical-stage biopharmaceutical companies. The success of its investment thesis hinges heavily on the successful development, regulatory approval, and commercialization of avexitide and AMX0035. Clinical trials are expensive, time-consuming, and prone to failure, with unexpected side effects or insufficient efficacy potentially delaying or halting programs. The FDA's clinical hold on AMX0114 in the U.S. highlights regulatory uncertainties, although the company is confident in addressing these concerns.

Market size estimates for rare diseases like PBH, Wolfram syndrome, and PSP, while significant, are subject to imprecision and challenges in patient identification. The competitive landscape, though less crowded in orphan indications, still includes rivals like MBX Biosciences in PBH, and larger players with broader R&D capabilities. Intellectual property protection is crucial, and the patent application process is expensive and uncertain, with risks of challenges or circumvention. Furthermore, ongoing securities class action litigation related to the past commercial performance of RELYVRIO could incur substantial costs and divert management attention. Macroeconomic conditions, including inflation and geopolitical instability, also pose risks to supply chains and financing.

Conclusion

Amylyx Pharmaceuticals stands at a critical juncture, having strategically refocused its efforts following the discontinuation of its prior commercial product. The company's investment thesis is now firmly anchored in the potential of its revitalized pipeline, particularly the first-in-class GLP-1 receptor antagonist, avexitide, for post-bariatric hypoglycemia. With no approved therapies for PBH and a growing patient population, avexitide represents a substantial market opportunity, supported by compelling Phase 2 data and a clear path to a potential 2027 launch.

The disciplined financial management, evidenced by significant cost reductions and a cash runway extending through 2026, provides the necessary foundation to execute on multiple upcoming clinical catalysts. The interim data for AMX0035 in PSP, the Phase 3 design update for Wolfram syndrome, and early data for AMX0114 in ALS will be crucial in validating the broader pipeline's potential. While risks inherent in drug development persist, Amylyx's focused strategy, technological differentiators, and commitment to addressing high unmet medical needs position it as a compelling, albeit speculative, opportunity for discerning investors seeking exposure to innovative therapies in orphan diseases. The coming 12-18 months will be pivotal in determining the long-term value creation potential of this transformed biotechnology company.