Will Eli Lilly's 11th-hour regulatory gambit salvage or sink its Alzheimer's drug?

Eli Lilly ($LLY) didn't just surprise investors with its sudden about-face last week on its long-running Phase III program for the Alzheimer's drug solanezumab. Some investigators with years of experience in the field have been puzzling out the move to downgrade function from a co-primary to a secondary endpoint, even though daily function and improved cognition remain a required combined feature for any pivotal trial design approved by regulators on both sides of the Atlantic.

The bottom line is that Lilly clearly thinks its drug--which failed two earlier late-stage studies only to see Lilly double down, convinced that a second look at the data pointed to a clear clinical pathway that would lead it to one of the Holy Grails of drug research--is going to fail at significantly improving function. Facing the prospect of a repeat, high-wire flop for another one of its pricey home run swings, executives decided to retreat to cognition, hoping that the data would be good enough to argue the issue with regulators, who will be feeling the heat from patients and advocates with no truly effective therapies to turn to.

"None of us have liked the co-primaries," says Dale Schenk, the CEO of Prothena and former CSO of Elan, which handed bapineuzumab over to J&J and Pfizer. (It failed in another big Phase III.) In Lilly's case, adds Schenk, who's not directly involved in Alzheimer's research currently, there is supportive data to suggest their drug is having a clinical effect. Timing may be a factor as well.

But it's not even close to a sure thing. Many of the clinicians in the field would far prefer to see an improvement in function, Schenk adds, with practical evidence that patients are better able to care for themselves day to day, than in cognition, where there's likely to be less agreement on the significance of an observed improvement as "different parts of the brain do different things."

The FDA has modified its position, signaling to developers a couple of years ago that regulators would be more flexible in their consideration of new drugs. But this move still marks a definite stretch.

"I, like my colleagues, who have worked in the AD space, especially around development of disease modifying therapies, are very surprised by the announcement in the change in primary endpoint for Expedition3," notes Enchi Liu, who worked on the bapineuzumab Phase III during a stint at Janssen, in a message to me. "We all know the requirement for a co-primary of cognitive and function to gain approval, and in addition if a disease modification claim is sought that additional supportive data will be required to show that the underlying disease processes has been directly impacted (eg effect on a biomarker). 

"The only guess I have about their move is that there has not been a successful AD program since the last approval for memantine and they are betting on negotiating an approval based on a single primary cognitive endpoint since they will be the first to file after the negative readout of bapineuzumab in 2012. Perhaps they will also use the fact that solanezumab has an effect on cerebrospinal fluid Abeta. So I'm not sure if this will hurt them; they are certainly making a bold move."

If Lilly is successful in getting the FDA to significantly lower the bar on efficacy for Alzheimer's, that kind of move could have a major impact on a variety of programs, including drugs like gantenerumab, which failed for Roche, or crenezumab and possibly even Biogen's closely watched program for aducanumab.

"It will be very interesting for us and the industry globally, to see how the regulators in the different countries will respond to Eli Lilly's amendment submission to demote the functional endpoint ADCS-iADL to a secondary endpoint in their EXPEDITION 3 study," says Andrea Pfeifer, the CEO of AC Immune, partnered with Genentech on crenezumab, now in Phase III.

"As you state in your email, current regulations (eg the recent EMA draft guidance issued for public consultation only last month) for studies in patients with Alzheimer's disease which has progressed to the point where there is an established dementia (as in Lilly's Expedition 3 study)  DO require BOTH cognitive and functional outcome measure to be declared as primary endpoints in pivotal studies and to be positive for drug approval."

"The topic of which endpoints to best use at the different disease stages (prodromal, mild and moderate dementia etc) is a widely discussed one in the industry and with regulators."

That buzz just got louder. And little of it sounds cheering for the Alzheimer's team at Lilly. -- John Carroll (email | Twitter)