Medivation: Commentary

(from NI February 2008)

Medivation announced that they will initiate a 2 dose-level, 525pt Phase III trial for Dimebon in Alzheimer's in 2Q, and that the FDA has OK'd the use of the oft-cited 183pt Russian Phase II trial as the other pivotal trial. They tellingly emphasized that "We are now a Phase 3 company." Being a Phase III company may impress the Street, but the goal is to get an approved drug, isn't it? Here is our view of their current clinical trial plan for Alzheimer's. And calling a Phase II drug 'Phase III' doesn't make it so. There seems to be little middle ground on Medivation, observers either love their prospects, or hate them.

1) Being told by the FDA that they are OK with the use of the Russian PhII trial as one of the two pivotal trials does not mean that it will pass muster under the far harsher scrutiny of NDA review. Companies have not infrequently had the goalposts moved as they completed their NDA process, one of the reasons that the SPA system, wherein the FDA in theory agrees to be bound by its word (why should that require a special protocol?), was devised. Medivation states that they don't need a SPA because there is a well-defined path to approval for Alzheimer's drugs. That is true, but while they use the same endpoints as their predecessors, they are trying to do so with a comparatively minuscule patient sample: 92 (presuming half of the 183 patient total) Phase II patients from 11 sites in Russia. Plus 175 (one-third of the 525 pt total) coming from some undefined mixture of US, European, and South American sites. Which yields a grand total of 267 patients receiving the 20mg TID dose for which approval is being sought. That, in our view, is a critical departure from the well-trodden path.
2) Even if--and we consider this unlikely--this Phase III trial shows efficacy at the same extraordinary level as the Phase II, relying upon 267 patients has a fatal flaw: It does not adequately sample potential problems. The FDA has been under intense attack for permitting drugs to be sold which turn out to have a risk of low-incidence but serious side effects. 267 patients will not be enough to assuage any doubts about a medication which in theory could be taken by millions. Nor will the 1500 patient safety database that Medivation plans to cobble together from a smorgasbord of past, present, and future trials. Nor will any substandard safety data from its previous use as an antihistamine. Compared to the several thousand pivotal patient samples usually submitted for a drug tapping this size CNS market, 267 seems woefully inadequate.n re 3) There are some criticisms of the trial program that we think are specious. One analyst who is very bearish on Medivation cites the necessity of patients being off of other AD drugs as hamstringing the Dimebon patients with a high number of treatment failures. Medivation is correct is noting that patients stopping other drugs frequently do so because of side effects, often GI in nature, which would not make them treatment 'failures' in the usual sense. Furthermore, so long as they are still in the mild-moderate range when they enroll, having previously been on Aricept or Namenda should not be a significant problem for this trial. eve 4) Medivation hopes to complete this trial in 2010 and file later that year. They may be trying to streamline the pivotal trial process in order to save money, placate investors, and/or sidestep the black hole in AD trial enrollment that is the Elan/Wyeth 18 month duration Phase III for bapineuzemab, which is enrolling 4000 patients (albeit to show disease modification, which is a higher hurdle to surpass). wit 5) Our prediction: If the trial produces statistically significant results, the FDA will decide that a total of 267 patients receiving the target dose does not constitute an adequate trial for a drug that might be used by millions, and will issue an 'approvable' letter, requesting that another trial be done.indi 6) With all due respect to the Huntington's and prostate cancer programs, Medivation's $480 million market cap rests completely upon Dimebon in AD. If Medivation were serious about something other than boosting nearterm valuation, they would be designing a two trial Phase III program to be conducted in parallel. It would slow them down, but not by the several years they cite, and would take the Russian trial wild card out of the equation. Instead, they seem to be trying to figure out the bare minimum requirements, in order to not do anything more than that. We believe this is a serious strategic error.nssen (Wilkinson & Truyon) meta-analysis of trials of three ChEi's reported that Janssen's galantamine (surprise!) kept ADAS-cog levels at baseline after 12 months, with modest declines for drugs from Novartis and Pfizer. This is stabilization on the FDA's favorite endpoint over twelve months.

2) Medivation reported that 69% of patients in their trial were the same or improved over baseline global measures after 12 months. In Borkowska's 2005 report of a study of patients on Aricept or Reminyl, she reported that 83% had stable or improved ADAS-cog scores after 12 months. While this is a more narrow endpoint, it does indicate a marked degree of stabilization. Rachelle Doody, who has been out front with Medivation's results, had herself reported a few years ago that Aricept maintained ADAS-cog over baseline for at least one year.

3) The five positive endpoints, covering several types of cognitive and behavioral function, have also been highlighted. However, broad-brush improvements have been reported before. In 1998, the CoEnzyme Q analog idebenone was reported (in a 450pt trial) to have produced statistically significant improvement on the ADAS-cog and four other measures. While not identical to Medivation's menu, they did attempt to cover a similar range of behaviors and cognition.