GLP-1 RAs and Alzheimer's: Assessing Residual Value After Rybelsus' Setback

The recent failure of Novo Nordisk's Rybelsus (semaglutide) in its Phase III trials for Alzheimer's disease has cast a shadow over the therapeutic potential of GLP-1 receptor agonists (GLP-1 RAs) in this indication. While the drug showed improvements in Alzheimer's-related biomarkers, it failed to significantly slow cognitive decline in early-stage patients, leading to the discontinuation of extension trials and a sharp market reaction. However, the story is not entirely bleak. The residual therapeutic and investment value of GLP-1 RAs in Alzheimer's remains a subject of debate, with experts highlighting potential pathways for future development and alternative developers stepping into the fray.

The Rybelsus Trial and Its Implications

Novo Nordisk's EVOKE and EVOKE+ trials, which evaluated Rybelsus in over 3,800 patients with mild Alzheimer's, concluded without meeting their primary endpoints of slowing disease progression as measured by CDR-SB scores. The company has since terminated the one-year extension of these trials, signaling a reduced commitment to further development for this indication. While the results were disappointing, they were not entirely unexpected. Analysts had long warned that translating epidemiological data-such as the observed 70% reduced dementia risk in GLP-1 RA users-into clinical success in late-stage trials is fraught with challenges.

The failure has raised critical questions about the mechanism of GLP-1 RAs in Alzheimer's. Experts like Howard Fillit of the Alzheimer's Drug Discovery Foundation suggest that Rybelsus' biomarker improvements could still support its use in combination therapies or preventive strategies. Ivan Koychev of Imperial College London adds that the drugs' potential in preclinical stages-before symptoms manifest-remains unproven but warrants further exploration.

Market Reactions and Investor Sentiment

The market's response to the trial failure was swift and severe. Novo Nordisk's stock plummeted 10% following the announcement, marking a four-year low. This decline reflects broader investor concerns about the company's reliance on GLP-1 RAs for new revenue streams, particularly in the competitive diabetes and weight loss markets. Wall Street analysts had previously estimated a low probability of success for the trial, but the magnitude of the stock drop underscores the sector's sensitivity to clinical setbacks.

Despite the immediate fallout, some analysts remain cautiously optimistic. Success in the upcoming topline data presentation at the CTAD conference on December 3, 2025, could still provide clarity on Rybelsus' potential. If the data reveals nuanced benefits-such as subpopulation efficacy or biomarker-driven insights-investors might reassess the drug's value. Conversely, a definitive failure could accelerate a shift toward alternative therapeutic approaches.

Residual Therapeutic Potential

The therapeutic case for GLP-1 RAs in Alzheimer's is far from closed. Retrospective studies, such as the TriNetX cohort analysis, demonstrate a 70% reduced dementia risk among GLP-1 RA users, suggesting robust neuroprotective effects. These effects are hypothesized to stem from mechanisms like reduced neuroinflammation, amyloid burden, and improved cerebral blood flow.

While Rybelsus has faltered, other GLP-1 RAs are under investigation. Liraglutide, Novo Nordisk's older injectable formulation, showed promise in slowing brain volume loss in mild Alzheimer's patients. Tirzepatide, a dual GIP/GLP-1 agonist, is also being explored for its potential to address multiple biological pathways in Alzheimer's (https://www.alz.org/blog/2025/glp-1s-and-alzheimer-s-what-you-need-to-know). Additionally, next-generation GLP-1 drugs are in development, offering hope for improved efficacy and safety profiles.

Experts argue that GLP-1 RAs could still play a role in combination therapies. For instance, pairing these agents with anti-amyloid monoclonals like Lilly's Kisunla or Eisai's Leqembi might yield synergistic effects. The Alzheimer's Association's Maria Carrillo has emphasized the need for further research into such combinations, even as she acknowledges the current limitations.

Investment Opportunities and Risks

The failure of Rybelsus has not extinguished all investment potential in the GLP-1 RA space for Alzheimer's. Alternative developers and therapeutic approaches are gaining traction. For example, Biogen and Ionis Pharmaceuticals' Tau-silencing agent BIIB080 is set to report Phase II results in 2026, offering a competing pathway for disease modification. Similarly, companies exploring Tau-targeting or neuroinflammation-focused therapies could attract capital as the market shifts.

Investors should also consider the broader pipeline. While Novo Nordisk's focus on Alzheimer's may wane, its dominance in diabetes and obesity-two conditions with overlapping pathophysiology-ensures continued demand for GLP-1 RAs. The challenge lies in balancing short-term setbacks with long-term opportunities.

Conclusion

The Rybelsus trial miss is a significant blow, but it does not invalidate the entire GLP-1 RA class for Alzheimer's. The residual therapeutic value lies in biomarker-driven insights, preventive applications, and combination therapies. For investors, the key is to differentiate between a temporary setback and a fundamental shift in the therapeutic landscape. While the immediate future may favor alternative approaches like Tau-silencing agents, the long-term potential of GLP-1 RAs-particularly in earlier intervention or adjunctive roles-remains a compelling, albeit uncertain, proposition.

As the dust settles on this trial, the December 3 data presentation will be critical. Until then, the market will remain in flux, with investors weighing the risks of overcommitting to a single class of drugs against the rewards of pioneering a novel therapeutic frontier.