Heptares is gearing up to advance a candidate from its muscarinic M1 receptor agonist program into Phase II in patients with Alzheimer's disease, schizophrenia or Lewy body dementia. While specifics of which drug to aim at which indication are still being decided, Heptares has seen enough in its first clinical data to continue pursuing a target that has shown more promise than most in Alzheimer's.
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| Heptares CEO Malcolm Weir |
Eli Lilly ($LLY) and others went after M1 hard in the 1990s, culminating in a 393-person Phase III trial that linked an agonist of the receptor to improved cognition in patients with mild to moderate forms of Alzheimer's. However, while efficacy data from clinical trials of that drug, Lilly's xanomeline, were encouraging, the side effect profile proved intolerable. In the high-dose arm, more than half of the participants dropped out because of side effects. With attempts to improve the side effect profile by increasing the selectivity of the drugs falling short, interest in M1 and the related M4 target waned.
Armed with a structure-based drug discovery technology that has attracted deals with AstraZeneca ($AZN), Pfizer ($PFE) and other notable drugmakers--plus a $400 million takeover by Sosei--Heptares has spent years working to realize the potential of M1 agonists. The initiative has centered on the identification of the structure of the receptors, a process that has shown there are no differences in the amino acid side chains that line the site that normally binds acetylcholine. "You can see why people struggled to get selectivity," Heptares CEO Malcolm Weir told FierceBiotech.
Heptares thinks its technology has enabled it to achieve such selectivity, resulting in molecules that are expected to hit M1 while avoiding the adverse event-triggering M2 and M3. Clinical data to back up this claim arrived this week. Heptares gave a M1 agonist, HTL9936, to 28 healthy elderly subjects. "At levels we would expect to be therapeutically beneficial, we don't see any of the side effects that were seen with previous drugs, which is very encouraging," Weir said. Heptares also saw signs of engagement of the target in the brain, giving it reason to believe the drug can improve cognition.
A fuller test of the efficacy of the drug is scheduled to start later this year, by when Heptares expects to have data from a Phase I trial of its other M1 agonist, HTL18318. "We have two molecules in the clinic, with different [pharmacokinetic] properties but very similar pharmacology," Weir said. "We haven't completely worked out our plans yet for which one would go to which indication." Weir and his colleagues are weighing up the merits of each drug in three indications--Alzheimer's, Lewy body dementia and schizophrenia--each of which could be the focus of a Phase II trial.
Heptares is planning to start one or more Phase II trials around the turn of the year. In parallel, the team is advancing M4 agonists toward the clinic. The M4 target is involved with psychosis, giving Heptares reason to believe that pairing a drug from the preclinical program with a M1 agonist could lead to a combination that tackles two facets of Alzheimer's disease and schizophrenia. Alzheimer's, a disease commonly associated with cognitive decline, can also cause hallucinations and delusions, while people with schizophrenia suffer from problems with cognition as well as psychosis.
A dual M1/M4 agonist could address both sides of the diseases. Heptares will move a M4 agonist into Phase I early next year to start gathering data to back up this hypothesis, a process it knows will be long and littered with potential pitfalls. "There's still a long way to go in this game," Weir said.
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