FDA approves benzgalantamine for symptomatic relief of mild-to-moderate Alzheimer’s disease with reduced side effects

On 29th July 2024, the U.S. Food and Drug Administration approved benzgalantamine (Zunveyl) for the symptomatic treatment of mild-to-moderate Alzheimer’s disease.¹ Benzgalantamine is considered a new-generation acetylcholinesterase inhibitor, building on existing drug mechanisms to improve the side effect profile.

Alzheimer’s disease (AD) is a common, progressive, neurodegenerative condition; by 2050 the prevalence is estimated to have doubled in Europe and tripled globally.² AD is characterized by the accumulation of amyloid beta plaques in the brain and the spread of tau pathology.

Although there is no cure for AD, there are a range of drugs approved by the FDA for the management of symptoms. In mild-to-moderate cases, therapies aim to maintain independence and dignity for patients. These therapies include the acetylcholinesterase inhibitors (AChEIs): galantamine, rivastigmine, and donepezil.³ AchEIs operate by blocking the breakdown of acetylcholine (ACh) by acetylcholinesterase (AChE). ACh is intrinsically linked to thinking and memory pathways and thus, enhancing ACh transmission helps to mitigate the cognitive symptoms of AD.³ While these agents do not stop the progression of the underlying disease process, they are associated with modest improvements in cognitive function and activities of daily living.

Despite the success of the AChEIs, they are linked to gastrointestinal disturbances including nausea, vomiting, diarrhea, as well as insomnia. These adverse effects have reduced tolerability and patient compliance. It is reported that up to 55% of patients discontinue their treatment after one year due to these adverse events.¹

Benzgalantamine is an oral, prodrug formulation of the FDA-approved AChEI, galantamine.¹ It has been developed by Alpha Cognition and is designed to treat symptoms of AD while minimizing the side effects associated with galantamine. With the addition of benzoyl ester, the binding of galantamine to the enteric nervous system is inhibited, thus preventing the overstimulation of enteric nerves that cause gastrointestinal side effects.⁴ Benzgalantamine is absorbed in the small intestine and metabolized in the liver into the active drug, galantamine. The active drug is carried to the brain via the circulatory system, where it blocks the activity of AChEI. It is also an allosteric potentiator of α7/α4β2 nicotinic receptors in the brain, enhancing the release of ACh from presynaptic neurons.¹

The FDA approval is based on the findings from chemistry, manufacturing, and controls information, as well as data from studies that demonstrated the bioequivalence of benzgalantamine to galantamine immediate release (IR) and extended release (ER) formulations.¹

In Phase I single ascending dose (SAD) and multiple ascending dose (MAD) trials, the safety of the drug was determined. Increasing doses of the benzgalantamine drug were administered to healthy patients. Findings demonstrated a ≥90% reduction in the gastrointestinal side effects typically associated with galantamine.⁴ Its is hoped that the improved safety profile of benzgalantamine may enable more patients to start treatment and stay on therapy longer.

Bioequivalence studies were also conducted, which determined the pharmacokinetic equivalence of benzgalantamine to galantamine ER and IR formulations.^5,6 In a two-treatment, two-period, crossover study, 40 subjects were randomized to 5mg benzgalantamine twice daily or 8mg galantamine ER once daily for 7 days.⁶ Patients subsequently underwent a one-week washout period and crossed over to the other treatment arm. The results of this two-treatment study found that benzgalantamine was bioequivalent to galantamine, achieving an area-under-the-curve of 107% and peak exposure of 127%, relative to galantamine ER. The Cmax was determined to be in between that of galantamine IR and galantamine ER. The data also demonstrated the delayed-release profile of benzgalantamine.⁶

“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, Alpha Cognition.¹

Based on these data, the FDA has granted approval for oral benzgalantamine for the treatment of mild-to-moderate AD. This marks the first AChEI drug that has limited gastrointestinal side effects, a key cause of treatment discontinuation amongst patients with AD.¹

Alpha Cognition plan to ensure broad access to benzgalantamine by working closely with healthcare providers, insurers, and patient advocacy groups to support the distribution of benzgalantamine. It is forecast to be available as a prescription medicine in pharmacies in 2025 Q1.¹ Benzgalantamine is also being developed in combination with memantine for the treatment of moderate-to-severe AD.

Written by Matthew Rimmer

Reviewed by Juliet Lawrence

References

1. Alpha Cognition Inc. Alpha Cognition’s Oral Therapy ZUNVEYL® Receives FDA Approval to Treat Alzheimer’s Disease. [Press Release] 29th Jul 2024. Accessed 29th Jul 2024.
2. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet. Apr 2021;397(10284):1577-1590.
3. Marucci G, Buccioni M, Ben DD, et al. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology. Jun 2021;190:108352.
4. Alpha Cognition Inc. Alzheimer’s: ALPHA-1062. Accessed 29th Jul 2024.
5. Alpha Cognition Inc. Alpha Cognition Announces Positive Results from Pivotal Study with ALPHA-1062 in Development for Alzheimer’s Disease. [Press Release] 22nd Jun 2022. Accessed 29th Jul 2024.
6. Alpha Cognition Inc. Alpha Cognition Announces Positive Topline Results from Bioequivalence Study with ALPHA-1062 in Development for Alzheimer’s Disease. [Press Release] 22nd Aug 2022. Accessed 29th Jul 2024.