Merck Makes A 'Speculative' Step Into Alzheimer's

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Although several rivals have recently experienced setbacks with Alzheimer’s compounds, Merck hopes to defy the odds with plans to take a pill into a Phase II/III study with patients who suffer from mild-to-moderate stages of the disease. And while one analyst calls the move speculative, the decision underscores an ongoing willingness to place big bets on tackling Alzheimer’s, a market that may offer the pharmaceutical equivalent of a Powerball payoff.

To be specific, Merck (MRK) will test a beta-amyloid precursor protein site-cleaving enzyme, or BACE, inhibitor, which the drugmaker notes is the first drug with this type of mechanism to advance to this stage of clinical research. The Phase II portion of the new trial will enroll 200 patients and be completed by late 2013. The Phase III segment would then begin with 1,700 patients, and there is speculation that  second Phase III trial might also be attempted with only earlier-stage patients.

The decision comes after Bristol-Myers Squibb halted testing of an Alzheimer’s compound, and Pfizer and Johnson & Johnson gave up on their bapineuzumab compound, which failed to meet two Phase III primary endpoints in patients with mild-to-moderate stages of disease (read here). Eli Lilly, however, is proceeding with its solanezumab compound, which slowed cognitive decline in patients with mild disease, but showed no statistically significant reduction in functional decline (see this).

“Merck is committed to advancing the understanding and treatment of Alzheimer’s disease,” says Darryle Schoepp, a senior vp and head of neuroscience and ophthalmology at Merck Research Laboratories, in a statement. The trial, by the way, will study one of three oral doses of the compound, called MK-8931, which will be administered daily versus a placebo.

The effort underscores that a significant level of interest remains, at least among some researchers and executives, to study compounds in later-stage patients, despite the recent setbacks. For its part, Merck notes that its BACE inhibitor recently demonstrated a reduction in cerebral spinal fluid, or CSF, a biomarker, in a Phase I study. By contrast, Roche recently doubled the size of a trial testing a compound in patients with early-stage disease. And so one analyst, while noting that Merck may give Lilly a ‘run for its money,’ expresses caution.

In a research note, ISI Group analyst Mark Schoenebaum writes that Merck could end up on the same timeline to market as Lilly  if the FDA asks Lilly to do another confirmatory Phase III trial of its compound. If not, though, Merck would be about three years behind. He adds that the Merck drug “appears to prevent (almost entirely) the formation of new amyloid beta plaques in the brain.” The Lilly drug, however, leads to removal of existing plaques.

But while he called the 90 percent reduction in CSF “impressive,” Schoenebaum points out that “the meaning of bio-markers is no longer clear.” Why? The Pfizer and J&J compound had good biomarker data, but no clinical impact, while the Lilly data revealed some clinical impact despite very mixed biomarker data. And he continues, “we do not believe that Merck has any clinical efficacy data at this point upon which it is basing its Phase II/III decision. Thus, one must still view the Phase III as highly speculative.”

Indeed, there is increasing belief that, to be truly effective, a drug will have to combat the disease in its earliest stages, before signs of dementia appear. Although the biomarker data is encouraging, as Schoenebaum points out, this is far from a reliable predictor. Merck obviously needs the data to get to Phase III, but a payout is far from clear. The odds, in fact, may yet wind up resembling a ballooning Powerball kitty.