FDA Approves New-Generation Acetylcholinesterase Inhibitor ALPHA-1062 for Mild-to-Moderate Alzheimer Disease

Elaine Peskind, MD

(Credit: LinkedIn)

According to an announcement, the FDA has approved Alpha Cognition’s ALPHA-1062 (Zunveyl), a prodrug of an approved acetylcholinesterase inhibitor (AChEI), galantamine, as a treatment for patients with mild-to-moderate Alzheimer disease (AD). ALPHA-1062, a delayed-release oral tablet formulation, is considered a new-generation AChEI inhibitor, with expected minimal gastrointestinal adverse events (AEs).¹

“I am very excited about the approval of Zunveyl, which we believe offers better tolerability for patients with AD. We have always believed in the efficacy of galantamine but have been limited in its use because of tolerability issues. To now have an agent with the efficacy of galantamine, but that also offers the hope of better tolerability, will provide physicians a great option to treat patients,” Elaine Peskind, MD, the Friends of Alzheimer’s Research Professor of Psychiatry at the University of Washington School of Medicine, said in a statement.¹ “This advancement marks a meaningful step forward in improving the quality of life for those living with Alzheimer and their families. As a geriatric psychiatrist specializing in AD, I am eager to incorporate this new treatment into our practice and see the positive difference it will make.”

The approval was based on results from 4 studies demonstrating the bioequivalence of ALPHA-1062 to galantamine and galantamine extended-release (ER). Across those studies, only 2% of treated patients had AEs from treatment, with no cases of insomnia observed.²

ALPHA-1062 is absorbed in the small intestine as an insert drug. Binding with AChE in the gastrointestinal nervous system is blocked by the addition of a benzyl ester to galantamine. This reduces overstimulation of local neurons, reduces gastrointestinal AEs, and increases bioavailability. Once absorbed, ALPHA-1062 is metabolized in the liver to the active drug and galantamine is carried to the brain in the circulatory system. The hope is that the improved safety profile of ALPHA-1062 may help to optimize the effectiveness of treatment by enabling patients to start treatment and stay on therapy longer.

“The approval of Zunveyl is a pivotal moment in the fight against Alzheimer's disease as it is only the second oral AD treatment to be approved in more than a decade. Zunveyl was designed to addresses a critical need for a tolerable and effective treatment that can potentially enhance patients' daily lives with improved long-term outcomes,” Michael McFadden, chief executive officer at Alpha Cognition, said in a statement.¹ “We are delighted, as this represents a major breakthrough in Alzheimer treatment, providing hope to millions of patients, families, and caregivers affected by this devastating disease.”

For years, AChE inhibitors were the only specific pharmacologic treatments approved for AD dementia until the recent class of antiamyloids. Although their benefit has shown to be modest, a significant body of evidence supports their effectiveness for improving cognition and their cost-effectiveness. Data from a 2021 published study using over 16,000 patients from the Swedish Dementia Registry showed that ChEI use was associated with higher Mini-Mental State Exam (MMSE) scores at each visit (0.13 MMSE points per year; 95% CI, 0.06-0.20).³

Additional data from the analysis showed that ChEI users had a 27% lower risk of death (OR,0.73; 95% CI, 0.69-0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65–0.76) and lower risk of severe dementia (0.69, 95% CI 0.47–1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07–0.28). Notably, galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia.

"We are excited to launch Zunveyl and bring this much-needed treatment option to patients suffering from AD," Lauren D’Angelo, chief operating officer at Alpha Cognition, said in a statement.¹ "Over the coming months, our team will work diligently to prepare for this launch, ensuring that healthcare providers have the information and patients have the resources and support they need. Zunveyl offers dual-action benefits with the established efficacy of galantamine and no insomnia. It was uniquely designed to bypass the gut with the potential of minimizing GI side effects. We believe that Zunveyl’s unique combination of these attributes will make a meaningful difference in the lives of those affected by this debilitating disease. We look forward to collaborating with our partners to ensure a successful rollout and broad accessibility."

In August 2022, Alpha Cognition announced positive results from one of its bioequivalence studies of ALPHA-1062, comprising 40 adult healthy volunteers. Patients were assigned 1:1 to either ALPHA-1062 5 mg twice daily or galantamine hydrobromide 8 mg ER capsules once daily, for 7 days. After a 1-week washout period, patients were then crossed over to the other treatment arm and dosed for 7 days. In addition to demonstrating bioequivalence, the therapy achieved an area-under-the-curve and peak exposures of approximately 107% and 127%, respectively, compared with those generated by galantamine hydrobromide ER.⁴

All told, C_max results for ALPHA-1062 was bracketed between galantamine hydrobromide IR and ER (lower than IR, higher than ER) providing a robust and enhanced data set for the NDA filing. According to the company at the time of the release, the data further described the delayed release profile of ALPHA-1062 and added to te NDA data set by characterizing the therapeutic and acceptable exposures compared to both the immediate-release and extended-release products.

"We are excited to launch Zunveyl and bring this much-needed treatment option to patients suffering from AD," Lauren D’Angelo, chief operating officer at Alpha Cognition, said in a statement.¹ "Over the coming months, our team will work diligently to prepare for this launch, ensuring that healthcare providers have the information and patients have the resources and support they need. Zunveyl offers dual-action benefits with the established efficacy of galantamine and no insomnia. It was uniquely designed to bypass the gut with the potential of minimizing GI adverse effects. We believe that Zunveyl’s unique combination of these attributes will make a meaningful difference in the lives of those affected by this debilitating disease. We look forward to collaborating with our partners to ensure a successful rollout and broad accessibility."

REFERENCES
1. Alpha Cognition’s Oral Therapy ZUNVEYL® Receives FDA Approval to Treat Alzheimer's Disease. News Release. Alpha Cognition. Published July 29, 2024. Accessed July 29, 2024. https://www.alphacognition.com/investors/news/alpha-cognitions-oral-therapy-zunveyl-receives-fda-approval-to-treat-alzheimers-disease-
2. Alpha Cognition Announces FDA Acceptance of New Drug Application for ALPHA-1062 for Mild-to-Moderate Alzheimer’s Disease. Alpha Cognition. December 7, 2023. Accessed July 27, 2024.
3. Xu H, Garcia-Ptacek S, Jonsson L, et al. Long-term effects of cholinesterase inhibitors on cognitive decline and mortality. Neurology. 2021;96(17):2220-2230. doi.10.1212/WNL 0000000000011832
4. Alpha Cognition Announces Positive Topline Results from Bioequivalence Study with ALPHA-1062 in Development for Alzheimer’s Disease. News release. Alpha Cognition. August 22, 2024. https://www.alphacognition.com/investors/news/alpha-cognition-announces-positive-topline-results-from-bioequivalence-study-with-alpha-1062-in-development-for-alzheimers-disease#xd_co_f=NDEzMjFlNjUtNGYzOS00MDY2LTgxZjQtYmU5YTUxMzQ5ZTMw~