Allergan and Sosei Halt Alzheimer’s Trial Over Safety Concerns
By Mark Terry
HTL0018318 is a selective small molecule muscarinic M1 receptor agonist. It is being developed for cognitive issues in patients with Alzheimer’s disease and other dementias, including dementia with Lewy bodies.
The drug was in Phase I clinical trials in the United States, sponsored by Allergan, and in a Phase II clinical trials in Japan sponsored by Sosei. The trial in Japan was for patients with Lewy body dementia. An additional Phase Ib clinical trial in Alzheimer’s disease has finished in Europe and is currently being analyzed. That trial is sponsored by Sosei’s subsidiary Heptares Therapeutics.
The safety concerns arose in a single animal toxicology study in non-human primates. That study was evaluating different dosing levels of the drug over a nine-month period. A rare tumor was observed at doses and durations higher than those used clinically in humans to date. So far, the drug has been investigated in 310 humans in the U.S. and Europe, including health patients and patients with mild to moderate Alzheimer’s disease. In humans, the drug has been well-tolerated with no serious side effects at the tested doses for up to 28 days.
The companies have reported the safety issues to the U.S. Food and Drug Administration (FDA) and the Japan Pharmaceutical & Medical Devices Agency (PMDA). At this point, the companies’ scientists are reviewing all data accumulated so far.
As a result of these findings and the suspension of the trials, the start of a planned Phase II trial in Alzheimer’s and Lewy body dementia will be delayed by at least six months. Sosei notes that because of the delay, its revenue will be impacted next year because it doesn’t believe it will receive a major milestone payment from Allergan in 2019 related to the progress of the program.
The two companies entered the global research-and-development and commercialization partnership in April 2016 under a deal where Allergan licensed exclusive global rights to a portfolio of novel subtype-selective muscarinic receptor agonists. The deal was potentially worth $3.35 billion. Allergan paid $125 million up front and Heptares was eligible for milestone payments of up to $665 million linked to successful Phase I, II and III clinical development, as well as launch of the first three licensing compounds for multiple indications. There was an additional $2.5 billion tied to certain annual sales milestones for several years after launch. Heptares is also eligible for up to double-digit tiered royalties on net sales. Allergan also committed up to $50 million to R&D.
“We were very surprised to see these results given the safety profile HTL0018318 has exhibited across all previous animal and clinical studies,” said Tim Tasker, Sosei’s chief medical officer, in a statement. “We have taken these steps in the best interests of patient safety which is our number one priority. We are committed to working with clinical investigators, R&D teams and our regulatory authorities to understand better the reason for the findings from this animal toxicology study and so enable the human clinical development program with HTL0018318 to continue as soon as possible. We remain confident that this compound has the potential to deliver important benefits to patients with AD and DLB.”