Sosei and Allergan have been forced to call a halt to testing of a drug for Alzheimer’s disease and other forms of dementia after cancer was seen in non-human primate studies.
The compound – called HTL0018318 – is in a phase 1 trial in the US run by Allergan and a phase 2 trial in Japan run by Sosei, but recruitment will be suspended while the partners investigate the toxicity signal. It has already completed another phase 1 study and – according to the partners – has been well-tolerated with no evidence of cancer in around 310 patients treated to date.
The upshot however is that a broader phase 2 programme for the drug in Alzheimer’s and dementia with Lewy bodies (DLB) will be delayed by up to six months, setting back a development milestone payment from Allergan, says Sosei.
The drug is one of the lead candidate from a $3.35bn licensing deal Allergan agreed with Sosei’s Heptares Pharma subsidiary two years ago, covering global rights to a portfolio of muscarinic agonists for the treatment of major neurological disorders, including Alzheimer’s disease.
HTL0018318 acts as a selective M1 agonist that could provide another way of treating the symptoms of dementia by improving cholinergic neurotransmission, acting via a different mechanism to already-approved anticholinesterase drugs for Alzheimer’s like donepezil.
It’s a mechanism explored some years ago when Eli Lilly was trying to develop an M1 agonist called xanomeline in Alzheimer’s, although that programme that eventually abandoned by the company because of off-target effects that compromised the drug’s tolerability.
Since then xanomeline has been resurrected by start-up Karuna thanks to the addition of an additional compound (trospium chloride) designed to reduce its side effects. Karuna is initially developing it as an antipsychotic but also has plans in Alzheimer’s – and the delay to HTL0018318 could give it a chance to catch up.
The big question for both companies is whether propping up an already-failing cholinergic neurotransmitter system will be able to improve on drugs like donepezil, which have transient benefits at best.
Sosei stressed that the findings had no impact on the development of a selective M4 agonist covered by the Allergan partnership, called HTL0016878, that started clinical testing in as a treatment for neurobehavioural symptoms in Alzheimer’s last year.
“We were very surprised to see these results given the safety profile HTL0018318 has exhibited across all previous animal and clinical studies,” says Tim Tasker, Sosei’s chief medical officer.
“We are committed to working with clinical investigators, R&D teams and 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.”