Hit-and-miss PhIIIs leave Lundbeck and Otsuka’s latest Alzheimer’s program in a precarious position

Seven months after Lundbeck and Otsuka reported a Phase III flop for their Alzheimer’s drug idalopirdine, the partners are back with a hit-and-miss score on easing Alzheimer’s agitation for their blockbuster therapy Rexulti (brexpiprazole).

Already approved for schizophrenia and major depression, the collaborators were looking for the first approval of an antipsychotic specifically for agitation triggered by Alzheimer’s dementia, a condition that afflicts millions of people in the US and millions more worldwide. Agitation can be expressed in many ways, running from wandering to aggressive behavior.

But in trying to gain positive data regulators want to see from two big late-stage studies, researchers scored a hit on the primary — change from baseline in the Cohen-Mansfield Agitation Inventory total score — in one study but missed in the second, though the drug did achieve the key secondary endpoint assessing the severity of agitation.

Is it enough for an approval?

Lundbeck didn’t spell out the data, which makes this too tough to call. Regulators have been signaling their flexibility when it comes to Alzheimer’s, a field which has seen nothing but failure for disease modifying and symptomatic drugs over the last 15 years. So it’s a possibility. With Rexulti on the market already, and likely in use for dementia-related agitation, analysts were expecting a clear win. But it may just come down to the safety profile.

“Importantly, in the two Rexulti studies overall mortality was low (0.86%) with no deaths considered to be treatment related,” noted Jefferies’ Peter Welford. He added:

Lundbeck and partner Otsuka plan to meet with the FDA to discuss these Rexulti data. Typically we believe regulatory authorities require two positive studies to support approval but we note equivocal study outcomes are common in CNS indications. Furthermore, no drugs are US approved specifically to treat agitation associated with dementia, despite the widespread use of antipsychotics. Rexulti’s comparatively clean safety profile could potentially allay class-wide concerns and numerous initiatives are ongoing to decrease the off-label use of antipsychotics in nursing homes.

One likely line that the companies will take focuses on their takeaway that the data varied by country. The data separation between placebo and drug was particularly poor in Russia, they said, which could be due to standard of care rather than the quality of the medicine. Russia and Eastern Europe have been regularly held out as problematic locations for drug trials, which makes you wonder why Lundbeck and Otsuka’s team decided to include the country in a worldwide trial in the first place.

It will be up to the FDA now to signal which way this application could go.

The two partners have been vexed by Alzheimer’s, like most other companies in this field. They recently wrote off their 5HT6 symptomatic drug after it flopped in studies. Antipsychotics, though, are not your run-of-the-mill kind of Alzheimer’s drug, opening up some new opportunities to follow.

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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