LONDON – Another Alzheimer's disease program has run into problems, with Sosei Group Corp. and partner Allergan plc halting development of HTL-0018318 after cynomolgus monkeys in a toxicology study developed neoplastic tumors.

The tumors occurred at doses and durations exceeding those used in the approximately 310 healthy volunteers and patients with mild to moderate Alzheimer's who have received the orally administered muscarinic M1 receptor agonist to date.

Peter Bains, CEO of Sosei, said the voluntary pause is a precautionary measure. The animal toxicology findings have been reported to the FDA and the Japanese PMDA. Sosei will now undertake a thorough scientific investigation drawing on data from previous preclinical and clinical studies, to try and establish the cause. The aim is "to assess whether human clinical development of HTL-0018318 can resume in the future," said Bains.

While not all of the human data are available as yet, to date the compound has been well-tolerated with no serious adverse events.

HTL-0018318 came into Sosei's portfolio via its $400 million acquisition of G protein-coupled receptor (GPCR) specialist Heptares Therapeutics Ltd., of Cambridge, U.K. (See BioWorld Today, Feb.24, 2015.)

The product has completed a phase Ib European trial in mild to moderate Alzheimer's disease, in which patients were dosed for 28 days. Sosei is awaiting the results of the study. In Japan, enrollment had started in a 172-patient phase II trial in Lewy body dementia, but no patients have been dosed.

Meanwhile, the cynomolgus monkey toxicology study was part of Allergan's preparations for a U.S. phase I study.

Malcolm Weir, founder and CEO of Heptares and chief R&D officer at Sosei, said extensive animal tests of HTL-0018318 had involved dosing rats for three months and nonhuman primates for six months, with no ill effects. "We have done a lot of different toxicology testing and not seen any problems of this nature. That's why it's a surprise," he told BioWorld.

Allergan and Sosei will cooperate to investigate why the tumors occurred and then see if the mechanism is intact in humans. "If we understand the reasons for the toxicity well enough and clearly enough, we could have grounds for going back into humans," said Weir.

There are examples of adverse animal toxicology causing clinical studies to be suspended but subsequently restart once the cause was uncovered, Weir noted.

At least six months

The toxicity signal seen in HTL-0018318 is not in any way related to Heptares' technology, in which each compound is individually designed around GPCR structures elucidated by the platform.

Nor does Weir believe the problem is linked to HTL-0018318's mechanism of action as a M1 agonist, noting Aricept (donepezil), the only approved therapy for Alzheimer's disease, works – at least in part – through M1. "[Aricept] has been given hugely, to loads of people and there have been no tumors," Weir said. "If the problem was mechanism-related you would expect to see [the same toxicity] after 20 years of use."

Tokyo-based Sosei estimates the hold on HTL-0018318 will last at least six months. In the event that clinical development cannot restart, the company has other M1 agonists it could move forward.

Bains said the cost of trying to identify the cause of the toxicity will be covered under the agreement with Allergan. While Sosei's external R&D expenditure will decline, there will be an impact on revenues, with a major milestone payment that was due from Allergan in 2019 no longer expected to be paid.

Sosei has nine other partnered GPCR programs, several of which involve multiple targets. It also has five wholly owned in-house GPCR products. "Sosei is not a one-product company," said Bains. The cash position is strong, with $200 million on hand. That is sufficient to fund programs until well into 2020, he said.

Under the terms of the agreement with Allergan signed in April 2016, Sosei received an up-front payment of $125 million and is eligible to receive milestone payments of up to approximately $665 million on successful phase I, II and III development and launch of the first three licensed compounds in multiple indications. That is to be followed by approximately $2.5 billion in royalties on sales.

Allergan also committed up to $50 million for a joint research and development program to advance candidates through phase II studies. The agreement covers first-in-class selective small-molecule agonists of M1, M4 and dual M1/M4 agonists.

Sosei subsequently amended the terms of the agreement to get full ownership of HTL-0018318 in the treatment of Lewy body dementia. In November 2017, the company raised $200 million from international investors to fund phase II development and to advance the five other in-house programs into the clinic. (See BioWorld Today, Jan. 9, 2017.)

Shares in Sosei (TYO:4565) ended at JPY1,824 (US$16.24) at the close of trading on Tuesday, a rise of 1.22 percent. Over the past year, the stock has fallen by 17.56 percent.

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