Lilly’s Failed Solanezumab: Could It Get Another Chance In A ‘Silicon Valley’ FDA?

Alzheimer drug’s development was discontinued after third disappointing Phase III trial, but given the kind of FDA commissioner candidates getting meetings with the President, maybe Lilly should reconsider.

On November 23, 2016, Eli Lilly & Co. broke the disappointing news that its anti-amyloid drug solanezumab failed to meet the primary endpoint of the Phase III EXPEDITION3 trial in patients with mild dementia due to Alzheimer's Disease. (Also see "Lilly’s Thanksgiving Turkey: Lessons From Another Failed Alzheimer’s Program" - Pink Sheet, 30 Nov, 2016.)

“There were no new safety signals identified in the study. Lilly will not pursue regulatory submissions for solanezumab for the treatment of mild dementia due to AD,” Lilly said in a late November statement announcing the EXPEDITION3 trial. Two previous Phase III trials, EXPEDITION and EXPEDITION2, also failed.

Lilly’s decision not to move forward with a submission to FDA for solanezumab is, of course, the default position any drug developer would take given three trials, three strikes.

But the political context in which Lilly made the decision to stop the sola program has shifted dramatically. There might be an opportunity forthcoming for Lilly to reconsider its decision.

At the time the EXPEDITION3 results were announced, Barack Obama was president, Sylvia Burwell was HHS secretary, Robert Califf was FDA commissioner, and John Lechleiter was CEO of the company. Just two months later, all the aforementioned are private citizens or retired (Lechleiter is still chairman of Lilly’s board).

Most significant, there is a new influence coming in from the Western frontier: President Donald Trump met with two potential FDA commissioner nominees on Jan. 12, both of whom have ties to Silicon Valley billionaire investor Peter Thiel.

The only two confirmed meetings with Trump for FDA were with former HHS official James O’Neill, who works with Thiel as an investor and at Silicon Valley think tanks, and Valley entrepreneur Balaji Srinivasan, whose company (21.co) a bitcoin startup counts Thiel among its investors. And both are proponents of an exodus – literally.

The old unwritten rules of the commissioner position were that the nominee had to have an MD and no ties to industry. Only three times in history has that not been the case.

The meetings with O’Neill and Srinivasan suggest Trump appears ready to defer to Thiel’s vision of a Silicon Valley-style disrupter at the agency. Whether either or both take high-level positions at FDA or HHS, there is a different kind of thinking about evidence to support market approval affecting leadership choices. (For more thoughts on the “Silicon Valley FDA,” tune in to our recent podcast.)

‘New Competitor’ To The Paper Belt

Here is a snapshot as to how Srinivasan views the world – or at least how he did not that long ago.

In a 2013 Y Combinator talk titled, "Silicon Valley's Ultimate Exit," Srinivasan described a battle of ideas taking place between Silicon Valley and the “Paper Belt.” For context, the speech was given four years ago and was deliberately focused on big ideas.

However, the talk is instructive as to how the geographic focal point of innovation – Silicon Valley – views the rules and laws that have accumulated over time in the US.

Srinivasan disparagingly refers to an old system that has ruled over the US and run its course: the “Paper Belt,” described in the talk as the four cities that have traditionally run the country: Los Angeles (entertainment), Boston (education), New York (finance and publishing), and Washington, DC (“because of laws and regulations”).

Srinivasan argued that a “new competitor” has emerged to the Paper Belt – Silicon Valley. “We are becoming stronger than all of them combined,” he said, noting that Silicon Valley has Washington, DC in its sights. “It is not exactly clear that the government can ban something it wants to ban anymore.”

The running theme through Srinivasan’s talk was that of reforming systems either through voice – expressing displeasure from within through different platforms – or exit – voluntarily leaving those systems, confining structures, or countries.

“The ultimate counter argument is exit. We want to show what a society run by Silicon Valley would actually look like without actually affecting anyone who still really believes the Paper Belt is actually good,” he said.

His definition of an exit is to build an “opt-in society” outside the US run by technology. “This is where Silicon Valley is going.”

He describes a scenario or principle, where 3D printing will turn regulation into digital rights management (similar to how the music and movie industry dealt with pirating). “It will be impossible to ban physical objects from medical devices to drones to cars. You can 3D print all of these things and there are entire three-letter agencies devoted to banning goods.”

For biopharma, Srinavasan forecast that society is not far off from individuals being able to 3D print medicines at their discretion and agencies like FDA will not be able to ban or reasonably enforce a ban of that practice.

Would Sola’s Secondary Endpoints Be Enough?

O’Neill’s vision sounds less revolutionary compared to Srinivasan, but it is not that different. His comments are more muted compared to the ones Srinivasan made during that Y Combinator talk.

O’Neill advocates for rolling back the evidentiary standard for premarket approval – with safety as the determining threshold – and for unfettered free commercial speech. (Also see "Trump Meets With Two US FDA Commissioner Candidates; Third Still Lurking" - Pink Sheet, 12 Jan, 2017.)

“We should reform FDA so there is approving drugs after their sponsors have demonstrated safety – and let people start using them, at their own risk, but not much risk of safety,” O’Neill said in a speech at an August 2014 conference called Rejuvenation Biotechnology, according to the Bloomberg story that was first to break news of O’Neill’s consideration for FDA. “Let’s prove efficacy after they’ve been legalized.”

Oh, and O’Neill is a true believer in Seasteading – creating free floating societies or countries at sea.

But that is a digression. In a December 2009 talk at the Seasteading Conference titled “Health Innovation at the Frontier”, O’Neill said the health care industry operates in an “effective cartel system” and as health care is protected from the market forces that drive innovation and service, “people are suffering very significant health consequences that in a free market they would not suffer.”

What does this have to do with solanezumab? The drug might be the perfect test case for a libertarian FDA.

Back to the data. True, solanezumab has failed three times in large trials to evaluate efficacy. In EXPEDITION3, there was no statistically significant slowing in cognitive decline compared to patients treated with placebo; there was an 11% reduction in decline (p=.095), as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale, which assesses a person's cognitive functions, including memory, attention and language abilities, according to Lilly’s statement.

But there were a number of positive secondary clinical endpoints of interest. Lilly acknowledges that because the primary endpoints were not met, the p-values for secondary statistical analyses were not adjusted for multiple comparisons. Here are the results of secondary endpoint measures from Lilly’s detailed release of data from EXPEDITION3:

• Patients treated with solanezumab had a 13% slowing of cognitive decline (p=0.014) compared to patients treated with placebo as measured by the Mini-Mental State Examination (MMSE), a common questionnaire used to test complaints of memory problems.
• The Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale showed a 15% slowing in decline (p=0.004) between patients treated with solanezumab and patients treated with placebo. The CDR-SB scale measures cognitive and functional performance through interviews with patients and family members.
• Patients treated with solanezumab had a slowing of decline in complex activities of daily living (conversation, making a meal, or shopping, for example) compared to patients treated with placebo. This finding represented a 14% slowing of decline (p=.019) as measured by the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL).

One could see Lilly making a very persuasive argument to FDA Commissioner Srinivasan or FDA Commissioner O’Neill that given the debilitating disease, the millions of patients and caregivers affected by Alzheimer’s, and the positive markers in the trial, solanezumab is worth taking a chance on.

Like any prescription drug, there were adverse events observed related to solazenumab, but nothing new in EXPEDITION3, with the most notable being a statistically significant increase in spinal osteoarthritis (1.1% v. 0.4% for placebo). Still, that would seem to meet O’Neill’s threshold.

What about the reviewers? Senior career FDA review managers have for decades served as buffers against political appointees who have sought to drastically shakeup the agency and viewed themselves as protectors of the agency’s evidentiary standards. That would almost certainly be the case whoever is named FDA commissioner.

And if sola were submitted for approval in a Silicon Valley FDA, you can bet there would be open opposition – if not an “exit” of medical reviewers and senior career officials.

But there’s a catch. Not to beat a dead horse, but the procedural steps that played out in the approval of eteplirsen are a recent pointed reminder of the hierarchy in making ultimate approval decisions that are delegated from the HHS secretary down the chain to division directors. Highly respected former review managers readily acknowledge that delegation of authority. (Also see "The Eteplirsen Approval: Former FDA Officials Weigh In On The Science" - Pink Sheet, 29 Sep, 2016.)

Would a Commissioner Srinivasan or Commissioner O’Neill approve solanezumab? Maybe. Maybe not. The point, though, is it may be a point for Lilly to reconsider when just two months ago it seemed unfathomable.

From the editors of the RPM Report