Alzheimer’s is the major focus of the just-released September issue of NeuroPerspective, and we have already received a number of comments and questions. One of the big questions is –what will come next for solanezumab? This presumes that the release of further data in October provides the basis for a ‘next.’ One of our comments that has elicited the most questions was this: “Those analysts who believe that Lilly could file a NDA on these results alone, having failed on all primary endpoints, need to reduce their intake of hallucinogens, and Lilly should not continue to be coy on this point, it undermines their credibility.”
For the sake of efficiency, we will respond to these questions here:
Question #1) Given the almost completely unmet need of Alzheimer’s, would this not be the FDA’s best opportunity to break precedent and drastically accelerate approval?
NP: The FDA has indicated some willingness to compromise, but approving a drug for a huge market like Alzheimer’s on the basis of two Phase III trials where the primary endpoints were missed, hence constituting failure in the usual framework, is a bridge too far. Had they hit the primary on just one, and had a consistent pattern of trends in the other trial and on secondary endpoints, that might have been an opportunity, but this is not it.
Question #2: Why the caution? The safety profile seems generally acceptable.
NP: The first drug made available as a possible disease-modifier will be sought after by the families of millions of patients. Some of them will be too far advanced to benefit, but there will also be millions of individuals who perceive their Age Associated Cognitive Decline as the harbinger of dementia, and will want treatment now, even if their prodromal status is unclear. The lack of dramatic safety signals in the 2-3000 individuals who have received solanezumab will not be sufficiently reassuring to the FDA when contemplating a demand that could involve a universe of five to ten million people in the US alone. Not if they are not really sure that it works. And approving solanezumab as a drug of undefined merit will demolish the clinical trial prospects for other programs which might eventually have been proven to be more effective.
Question #3: Why is Lilly’s credibility at stake here?
NP: I am already assuming that there is some signal that Lilly is reasonable in thinking that it warrants holding the presentation at a suitably high-profile venue, AAN. But NP has yet to hear from anyone not working on Wall Street who thinks filing is a potential option. Lilly should not hold out false hopes, they should know better.
Question #4: But what if it is a very strong signal in the pooled data for improved cognition?
NP: There is a mismatch between the success in the pooled data (and how much success, with what p-value, we do not know) and the failure on the prospectively defined mild AD cognition endpoint in the second trial (again, how badly failed, at what p-value, we also do not know). If the results are in the same ‘direction’, but one set fell just short of p=.05, that could mean a modest treatment effect, of unknown clinical import. If the data in the two trials is not consistent, that boosts the likelihood of a fluke that pulled the pooled data results just into statistical significance.
Question #5: What is the best that can be hoped for from the FDA?
NP: Proactive assistance in designing a single Phase III trial, emphasizing the mildest population that can be reliably defined, that might show a treatment effect on the primary cognition endpoint–with reassurance that this, along with the existing data, might suffice for filing.
Question #6: I am in business school, but do not yet qualify for employment as an analyst on Wall Street. Which means that it is difficult for me to obtain hallucinogens. What can I do?
NP: That is covered in the curriculum of any accredited MBA program. Check the syllabus.