The phase II failure of sembragiline sidelines an unusual pharmacology mechanism from the list of Alzheimer’s disease hopefuls, as well as becoming Roche’s second flop in this intractable indication. For Evotec, Roche’s partner, it represents another setback after last year’s scrapping of a diabetes project by Hyperion Therapeutics.
That said, Roche and Evotec management might not lose too much sleep over it, though the Swiss group will apparently investigate secondary endpoints before pulling the plug. Both companies have bigger fish to fry – in Alzheimer’s and elsewhere.
Indeed, if anything sembragiline’s failure could refocus attention on the rollercoaster fortunes of the amyloid-beta hypothesis, currently undergoing a resurgence of sorts (Vantage point – Alzheimer’s researchers urge patience and earlier-stage patients, July 1, 2015).
Sembragiline (RG1577) had been seen as risky by the sellside. As well as targeting the failure-prone indication of Alzheimer’s it had already crashed out in smoking cessation, and its mechanism, monoamine oxidase B inhibition, is more closely associated with marketed Parkinson’s disease drugs like selegiline and rasagiline.
The design of its phase II study, Mayflower Road, also boded ill, recruiting 544 patients with moderately severe Alzheimer’s. If there is any hope in treating Alzheimer’s it is in testing patients at the earliest stages of the disease; Roche’s crenezumab failed a year ago in two studies in mild to moderate patients.
Any hope for sembragiline now rests in Roche pulling something out of secondary analyses of Mayflower Road in measures including the ADCS-ADL, ADCS-CGIC and behavioural pathology scales. The project missed its primary endpoint of beating placebo on the cognitive behaviour subscale of the Adas-Cog test over 12 months, Evotec said.
Roche having suffered the failures of crenezumab and now sembragiline means investor focus will intensify on another amyloid-beta MAb, gantenerumab, licensed from MorphoSys, and its chances of snatching victory from the jaws of defeat.
Gantenerumab is in a phase III study in mild Alzheimer’s patients, but a pivotal trial in prodromal disease, a form of mild cognitive impairment, was discontinued after failing an interim futility analysis. Roche has reportedly refused to give up on the project.
For Evotec, meanwhile, the sembragiline news comes after another setback, when its partner Hyperion halted development of DiaPep277. Apparently “serious misconduct” involving trial data had been uncovered among employees of Andromeda Biotech, an Israeli company Hyperion had acquired to bring in DiaPep277.
Hyperion has reached a legal settlement with Andromeda’s former owner, Clal Biotechnology. Evotec sued Andromeda in September.
The German company’s broad pipeline reveals several other Alzheimer’s disease projects, the most advanced of which is PQ912, a glutamimyl cyclase inhibitor partnered with Probiodrug, in a European phase II study called Saphir.
Evotec says Alzheimer’s remains a priority area, so attention will switch to the readout of Saphir in a year’s time.