Benzgalantamine (ZUNVEYL): Another Bad Choice for Alzheimer’s Disease

In July 2024 the Food and Drug Administration (FDA) approved benzgalantamine (ZUNVEYL), an oral drug for the treatment of mild or moderate dementia in adults with Alzheimer’s disease.[1],[2] In June 2025, nearly a year later (and three months after benzgalantamine was launched)[3], the FDA released the data supporting the approval.[4]

Benzgalantamine is a prodrug of galantamine (generic only), another drug for Alzheimer’s disease that the FDA approved in 2001.[5] Because it is a prodrug, benzgalantamine is a pharmacologically inactive compound that is converted into galantamine when it is metabolized in the body.[6]

Galantamine is an acetylcholinesterase inhibitor that prevents the breakdown of a neurotransmitter called acetylcholine, which is believed to play a role in Alzheimer’s disease.[7] Public Citizen’s Health Research Group has previously designated galantamine, as well as other acetylcholinesterase inhibitors such as donepezil (ADLARITY, ARICEPT and generic) and rivastigmine (EXELON and generic) as Do Not Use drugs.

Acetylcholinesterase inhibitors have only minimal and transient benefits that do not outweigh the safety concerns associated with drugs in this class, such as gastrointestinal, cardiovascular and neuropsychiatric adverse events.[8] Moreover, the prescribing information for these drugs clearly states that there is no evidence that these drugs alter “the course of the underlying dementing process.”[9]

Because benzgalantamine is a prodrug of galantamine, the FDA, as described in more detail below, only required evidence that the two drugs are similar and did not require additional clinical trials demonstrating its safety and efficacy.[10] Instead, the approval of benzgalantamine relied on the efficacy and safety data for galantamine.

Because the prodrug has not been demonstrated to be more effective or safer than galantamine, Public Citizen’s Health Research Group also designates benzgalantamine as a Do Not Use drug.

Importantly, even though there is no data demonstrating benzglantamine’s superiority over galantamine, a month’s supply of benzgalantamine is more than ten times as expensive ($749) than generic galantamine ($70).

The approval pathway for benzgalantamine

Benzgalantamine was approved under a shortened approval pathway under Section 505(b)(2) of the federal Food, Drug, and Cosmetic Act.[11] This pathway allows manufacturers to use safety or efficacy data of an already approved drug as long as the manufacturer can demonstrate that the new drug shares certain characteristics with the earlier drug.[12]

For benzgalantamine, the manufacturer investigated whether the bioavailability of benzgalantamine was the same as for galantamine.[13] For an oral drug, bioavailability refers to the proportion of a drug that enters the circulation after it is ingested and can have an active effect.

The approval of benzgalantamine was supported by four phase 1 trials.[14] One trial investigated the different doses of the prodrug, and three trials investigated the bioavailability of benzgalantamine compared with galantamine in fed and fasting conditions as well as benzgalantamine’s safety and tolerability. Importantly, all these trials were short, had few participants, and only included healthy, young adults. None of the participants were people with Alzheimer’s disease.

The three bioavailability trials were designed as open-label studies in which trial participants were randomly assigned to either receive benzgalantamine twice daily or galantamine once daily for one week.[15],[16] After a treatment break of one week (called a washout period), the drugs were switched for a second week of treatment, in which study participants received the drug they had not taken in the first week. Between 34 and 41 participants completed each trial. All of the participants were Asian, most were between the ages of 18 and 40 years, and the volunteers were both men and women. The FDA’s drug approval package does not explain why all the healthy volunteers were Asian.

The three trials excluded several categories of potential participants, for example those with gastrointestinal bleeding or a history of obstructive pulmonary disease or severe asthma.[17] During the trials, participants were not allowed to use most other prescription or over-the-counter drugs or supplements.

Based on the design of these trials, it is not clear whether the data collected from such a small number of young, healthy adults are meaningful for people with Alzheimer’s disease — the patient group for which benzgalantamine is intended. This may be of particular concern because the prescribing information states that galantamine concentrations can be 30-40% higher in older adults with Alzheimer’s disease than in young, healthy adults.[18] Comparable information for benzgalantamine concentrations is not yet available.

Moreover, the bioavailability results were not conclusive across all trials. For example, bioequivalence was only demonstrated in participants who were eating and not in those tested while fasting.[19] However, the FDA concluded that the available data were sufficient for approval.

The safety and efficacy of benzgalantamine

The approval of benzgalantamine relied on prior clinical data regarding the safety and efficacy of galantamine.[20] However, in a press release announcing the drug’s approval, the manufacturer said that the prodrug not only has the same therapeutic benefits as galantamine, but that benzgalantamine was designed to be easier for patients to tolerate. As a prodrug, benzgalantamine is “potentially addressing certain tolerability issues,” since it is only metabolized into galantamine after it passes through the intestinal tract.[21] Many Alzheimer’s disease patients discontinue galantamine and other treatments due to gastrointestinal adverse events.

Nonetheless, the prescribing information for benzgalantamine lists the same warnings, precautions and adverse reactions as galantamine, and with language that is nearly the same. As of July 2025 there are no studies directly comparing the tolerability of galantamine and benzgalantamine.

The most common adverse events associated with these drugs are nausea, diarrhea, vomiting, headache, dizziness and decreased appetite.[22] Other severe adverse events include increased risks of gastrointestinal bleeding, especially in patients who are at an increased risk of developing ulcers, and bladder outflow obstruction. Benzgalantamine also is associated with rare but serious and life-threatening skin conditions, including Stevens-Johnson syndrome.[23]

Moreover, since galantamine and benzgalantamine can affect the heart’s conduction system, these drugs can increase the risk of bradycardia and atrioventricular block. Post-marketing studies of galantamine identified additional adverse events, including hallucinations, seizures, hypertension and tinnitus.

What You Can Do

Acetylcholinesterase inhibitors, such as benzgalantamine and galantamine, do not alter the course of Alzheimer’s disease. Both drugs have the same minimal benefits and safety concerns. Moreover, without additional data it is impossible to know if the much more expensive benzgalantamine is more effective or safer than generic galantamine. Public Citizen’s Health Research Group recommends against the use of either benzgalantamine or galantamine.

Healthy lifestyle behaviors, including physical and social activity, a healthy diet, maintaining a healthy weight, avoiding excessive alcohol consumption, and stopping smoking, are important for all people at risk of Alzheimer’s disease.[24],[25] Conditions such as high blood pressure, diabetes, high cholesterol, and substantial hearing or vision loss should be adequately treated.
 

References

[1] Alpha Cognition. Label: ZUNVEYL (benzgalantamine). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218549s000lbl.pdf. Accessed July 9, 2025.

[2] Alpha Cognition’s oral therapy ZUNVEYL® receives FDA approval to treat Alzheimer's disease. July 29, 2024. https://www.alphacognition.com/investors/news/alpha-cognitions-oral-therapy-zunveyl-receives-fda-approval-to-treat-alzheimers-disease-. Accessed July 8, 2025.

[3] Alpha Cognition announces the commercial launch of ZUNVEYL (benzgalantamine) for the treatment of mild to moderate Alzheimer’s disease. March 18, 2025. https://www.businesswire.com/news/home/20250319665873/en/Alpha-Cognition-Announces-the-Commercial-Launch-of-ZUNVEYL-Benzgalantamine-for-the-Treatment-of-Mild-to-Moderate-Alzheimers-Disease. Accessed July 8, 2025.

[4] Food and Drug Administration. Drug approval package: ZUNVEYL. June 6, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/218549Orig1s000TOC.cfm. Accessed July 8, 2025.

[5] Alpha Cognition. Label: ZUNVEYL (benzgalantamine). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218549s000lbl.pdf. Accessed July 1, 2025.

[6] Mallhi TH, Butt MH, Ahmad A, et al. Drug-metabolizing enzymes and fate of prodrugs: From function to regulation. In Biochemistry of Drug Metabolizing Enzymes 2022 Jan 1 (pp. 125-139). Academic Press.

[7] A review of long-term treatment with the Alzheimer's disease drug donepezil (ARICEPT) ineffective. Worst Pills, Best Pills News. September 2004. https://www.worstpills.org/newsletters/view/300. Accessed July 8, 2025.

[8] Galantamine: serious skin reactions Prescrire Int. June 2015; 24 (162): 185.

[9] Alpha Cognition. Label: ZUNVEYL (benzgalantamine). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218549s000lbl.pdf. Accessed July 9, 2025.

[10] Benzgalantamine (Zunveyl) for Alzheimer's disease. Med Lett Drugs Ther. 2025 Apr 14;67(1726):59-60.

[11] Food and Drug Administration. Center for Drug Evaluation and Research. 218549Orig1s000. Summary review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/218549Orig1s000SumR.pdf. Accessed July 8, 2025.

[12] Food and Drug Administration. Guidance document. Determining whether to submit an ANDA or a 505(b)(2) application. May 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/determining-whether-submit-anda-or-505b2-application. Accessed July 8, 2025.

[13] Food and Drug Administration. Center for Drug Evaluation and Research. 218549Orig1s000. Clinical review(s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/218549Orig1s000MedR.pdf. Accessed July 8, 2025.

[14] Ibid.

[15] Ibid.

[16] Alpha Cognition announces positive topline results from bioequivalence study with ALPHA-1062 in development for Alzheimer’s disease. August 22, 2022. https://www.alphacognition.com/investors/news/alpha-cognition-announces-positive-topline-results-from-bioequivalence-study-with-alpha-1062-in-development-for-alzheimers-disease. Accessed July 8, 2025.

[17] Ibid.

[18] Alpha Cognition. Label: ZUNVEYL (benzgalantamine). July 2024.https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218549s000lbl.pdf. Accessed July 9, 2025.

[19] Food and Drug Administration. Center for Drug Evaluation and Research. 218549Orig1s000. Clinical review(s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/218549Orig1s000MedR.pdf. Accessed July 8, 2025.

[20] Food and Drug Administration. Center for Drug Evaluation and Research. 218549Orig1s000. Summary review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/218549Orig1s000SumR.pdf. Accessed July 8, 2025.

[21] Alpha Cognition’s oral therapy ZUNVEYL® receives FDA approval to treat Alzheimer's disease. July 29, 2024. https://www.alphacognition.com/investors/news/alpha-cognitions-oral-therapy-zunveyl-receives-fda-approval-to-treat-alzheimers-disease-. Accessed July 8, 2025.

[22] Alpha Cognition. Label: ZUNVEYL (benzgalantamine). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218549s000lbl.pdf. July 9, 2025.

[23] Canada issues warnings on Alzheimer’s disease drugs. Worst Pills, Best Pills News. June 2015. https://www.worstpills.org/newsletters/view/970. Accessed July 8, 2025.

[24] Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404(10452):572-628.

[25] Lancet Commission: Nearly half of dementia cases are preventable. Worst Pills, Best Pills News. January 2025. https://www.worstpills.org/newsletters/view/1637. Accessed July 8, 2025.