Background

Benzgalantamine is an inactive prodrug of galantamine. It was approved by the FDA in July 2024 for the treatment of mild to moderate Alzheimer’s dementia. It comes in delayed-release tablets of 5, 10, or 15 mg.

Originally synthesized as GLN-1062/Memogain, this benzoyl ester is more lipophilic than galantamine, in order to facilitate its entry into the brain, where it is enzymatically cleaved to release the active drug. The compound was developed at Galantos Pharma in hopes of increasing the brain bioavailability and reducing peripheral side effects of galantamine. Additional goals were to increase the effective dose in the brain and deliver a therapeutic effect rapidly, without the gradual titration up to effective dose that is commonly necessary with oral acetylcholinesterase inhibitors.

In 2013, GLN-1062 was sold to the Canadian company Neurodyn for clinical development. In March 2020, Neurodyn changed its name to Alpha Cognition, and GLN-1062 became ALPHA-1062.

Preclinically, GLN-1062 was reported to improve cognition more strongly than did comparable doses of galantamine in mice, and to reduce vomiting in ferrets. Another study claimed five times higher potency than galantamine in rescuing scopolamine-induced memory impairment in mice, as well as improved memory performance and reduced plaque load in 5xFAD transgenic mice. Pharmacologically, GLN-1062/Memogain was reported to reach 10 times higher concentration in the brain than blood (see Maelicke et al, 2010; Bhattacharya et al., 2015). 

Findings

In September 2014, Neurodyn issued a press release claiming that an initial trial in healthy young and old volunteers showed positive results. According to the company, the study primarily compared safety, tolerability, and pharmacokinetics of intranasal Memogain to the daily recommended oral dose of galantamine (16 mg) and donepezil (10 mg). All tested doses of Memogain were reportedly safe and well-tolerated; participants reported nausea at 16 mg of galantamine but not until 44 mg of Memogain. The company further claims that Memogain heightened vigilance and short-term memory in both young and old volunteers compared with untreated controls. The study was conducted in The Netherlands, and results were published after peer review (Baakman et al., 2016).

A second Phase 1 tested seven days of 5.5, 11, or 22 mg twice per day, or placebo, in 48 healthy elderly participants, also in The Netherlands (WHO trials registry). According to published results, nasally delivered Memogain was well-tolerated up to highest dose. A direct comparison of 11 mg Memogain to 16 mg oral galantamine documented fewer instances of diarrhea, nausea, or vomiting with Memogain; however, participants had more nasal discomfort and irritation with increasing dose. Treated participants improved in a test of attention, similar to the single-dose results (Bakker et al., 2020).

In September 2021, Alpha Cognition announced the acceptance of a new drug application for ALPHA-1062, a delayed-release, oral tablet form of the prodrug (press release). The company predicted that this prodrug will be absorbed intact into the small intestine, and activated in the liver, reducing GI side effects. The company is seeking marketing approval on the basis of bioequivalence, where the drug need only demonstrate comparable pharmacokinetics to marketed versions of galantamine. In 2022, Alpha Cognition reported positive results from two bioequivalence studies comparing a single dose of 5 mg ALPHA-1062 to 4 mg galantamine hydrobromide (name brand Razadyne) immediate release, or to 8 mg extended release in healthy adults (June press release; Aug press release). In September 2023, the company filed for FDA approval (press release).

On July 29, 2024, the FDA approved benzgalantamine for mild to moderate Alzheimer’s dementia. It will be sold beginning in 2025 under the brand name Zunveyl. According to the company, the rate of gastrointestinal adverse events in the equivalence studies was below 2 percent, and no insomnia was observed.

No trials of benzgalantamine are listed in clinicaltrials.gov.