In September 2018, Sosei and its partner, Allergan, voluntarily suspended clinical development of HTL0018318 in light of results from a nine-month study of the muscarinic M1 receptor agonist in nonhuman primates.
At the time, Sosei predicted the need to investigate the toxicology data would delay the start of a Japanese Phase II trial of HTL0018318 in dementia with Lewy bodies (DLB) by at least six months. However, 14 months later, the Phase II DLB trial is yet to get underway.
The ongoing delay has prompted Sosei to withdraw the planned trial, which was gearing up to start when the toxicology data froze activities last year.
In its third quarter results, Sosei said, “Start-up activities for this study were underway when development of HTL0018318 was suspended in September 2018 and have been on hold ever since. The group expects a different clinical trial approach will be required in the future and has taken this decision to minimize unnecessary expenditure on clinical trial activities.”
Elsewhere, Sosei unpacked how the withdrawal will ‘minimize expenditure’, noting that the move will reduce its contract research organisation spending.
Sosei expects to provide an update on its investigation into the toxicology findings by the end of the year. Once in a position to restart clinical development, Sosei plans to file a new notification to run a Phase II DLB trial in Japan.
It is unclear at this stage whether that Phase II trial will test HTL0018318. Sosei said the Phase II filing will cover the study of HTL0018318 or “another novel M1 agonist.”
Sosei and Allergan have continued to work on other M1 agonists while investigating the safety of the lead asset, potentially putting them in a position to switch candidates, if the safety issue proves to be real and limited to HTL0018318. The issue relates to the observation of a “neoplastic, rare tumor” when HTL0018318 was given at doses and durations beyond those administered to humans to date.
The toxicology finding derailed a development program designed to avoid the side-effects that held back earlier M1 receptor agonists. Eli Lilly generated late-phase evidence that its M1 receptor agonist, xanomeline, improves cognition in the 1990s but stopped work in response to intolerable side-effects that led to a high dropout rate.
Karuna Therapeutics is working to rehabilitate xanomeline by combining it with another drug that may improve its tolerability profile. A Phase Ib study of the combination in elderly volunteers is due to start by the end of 2019, furthering Karuna’s efforts to develop it in Alzheimer’s disease psychosis.