Allergan and Sosei have voluntarily paused development of HTL0018318 after tests in nonhuman primates uncovered unexpected toxicology findings. Phase 1 and 2 clinical trials of the muscarinic M1 receptor agonist are on hold while the partners investigate the toxicology results.
The worrying results are from a single study in nonhuman primates that was investigating different dosing levels over a nine-month period. After administering HTL0018318 at doses and for durations exceeding those tested in humans to date, Allergan and Sosei saw a toxicological finding they described as “neoplastic, rare tumor.” Allergan and Sosei had previously administered the drug to animals for up to six months without causing any serious adverse events.
In response to the surprise finding, Allergan and Sosei have pumped the brakes on their clinical trials. HTL0018318 is currently in an Allergan-sponsored phase 1 in the U.S. and a phase 2 trial in patients with dementia with Lewy bodies (DLB) in Japan. The drug was set to advance into another phase 2 in Alzheimer’s and DLB, but that plan is on hold. Sosei thinks the start of the trial will be delayed by at least six months.
The delay is a blow to an R&D effort designed to yield drugs free of the side effects that scuttled previous M1 receptor agonists. Having seen Eli Lilly’s xanomeline fail on safety grounds, Heptares set out to design a more selective M1 receptor agonist. That led it to a $400 million takeover by Sosei and a licensing deal with Allergan worth $125 million upfront and many times that in milestones.
Following the deals, Allergan and Sosei continued to smoothly advance HTL0018318 through the clinic, generating data in 310 healthy volunteers and patients with mild-to-moderate Alzheimer’s disease. The current clinical data suggest HTL0018318 has a clean safety profile, but the trials have only tested the drug for 28 days.
As it stands, the pause on clinical development only affects HTL0018318. Allergan and Sosei are working on other muscarinic receptor drugs, including a phase 1 M4 agonist and a preclinical asset that targets M1 and M4.
The activity puts the partners at the forefront of an uptick of interest in the targets. Elsewhere, PureTech’s Karuna has raised $42 million to rehabilitate Lilly’s xanomeline by mitigating its negative effects on peripheral nerves.