Merck pushes Alzheimer's drug into PhIII trials after clearing a safety hurdle

Merck is stepping up its late-stage program for its controversial BACE inhibitor for Alzheimer's disease. Following a buzz of speculation on Twitter triggered by changes to the clinical trial registry last month, the pharma giant ($MRK) put out the official word today that the data monitoring committee had waved the green flag to move ahead with late-stage work on the beta-secretase drug after wrapping the interim safety analysis on the experience of 200 patients over at least three months on therapy. Now the pharma giant is recruiting new patients while expanding the program with a new Phase III study for early-stage patients--without changing the dosing regimen.

Darryle Schoepp, senior VP and neuroscience franchise head at Merck

Merck updated its public clinical trial registries two weeks ago to note that it was moving ahead with its Phase II/III program for MK-8931. A spokesperson for the company never did respond to a query from FierceBiotech on that, but earlier this year Darryle Schoepp, the VP in charge of neuroscience early development and discovery sciences at Merck, told us that the II/III study involving mild to moderate patients would be quickly followed with a trial for patients demonstrating symptoms of the disease--the early "prodromal" stage that has attracted increased focus from investigators in the field after some high-profile Phase III flops involving more advanced stages of the disease.

There have also been some big question marks specifically for BACE inhibitors, which raised the significance of the preliminary safety review for MK-8931. Back in the summer Eli Lilly ($LLY) was forced to scrap its BACE inhibitor, LY2886721, after collecting abnormal liver tests from patients in a study. That left Merck as the leader in a field that also includes AstraZeneca ($AZN), which is further behind.

The race to develop new Alzheimer's drugs of any kind, though, has been marked by one disaster after the next. Those high-profile failures include Lilly's semagacestat, a gamma-secretase inhibitor that actually wound up harming patients.

Merck and others in the field believe that by inhibiting beta-secretase, a drug can interrupt a cascade of changes in a precursor protein--preventing the production of amyloid beta, which is one of the prime suspects investigators believe has a high probability of causing Alzheimer's. And investigators say that they nailed significant evidence of its impact on amyloid beta in a Phase Ib study of 8931, noting its effect on amyloid beta.

But BACE inhibitors also could threaten patients. Much like gamma-secretase inhibitors, beta secretase is also responsible for multiple physiological functions, raising the prospect of unintended consequences. In particular, it's linked to myelination.

Whether or not Merck can conclude with any certainty that the drug is safe, analysts were happy to score it as a win for Merck, which has been reorganizing its R&D division after a painful 6-year drought in the clinic.

"It is still possible, of course, that safety issues could derail the MRK compound in Phase III, but the fact that it appears to have at least passed a Phase II safety inspection likely means the safety profile is at least somewhat better than prior molecules," writes ISI's Mark Schoenebaum this morning. "Significant EFFICACY risk still exists for this drug - we know from prior data that MRK's BACE inhibitor profoundly lowers A-beta levels, but the expert community is split on whether or not that will matter for patients (and, if it does matter, for which group of patients--MCI, prodromal, mild, or moderate, etc)."

Any signs of progress in this field are followed closely by Wall Street. After all the trial disasters, few analysts like to project peak potential sales anymore. But any drug that makes it past Phase III and gets an approval from regulators will be rewarded by a likely megablockbuster revenue stream from millions of desperate patients. That makes Alzheimer's R&D the biggest lottery in the industry, with a winning ticket worth an overnight fortune.

"We are pleased to receive the DMC's recommendation and look forward to continuing the clinical development program for MK-8931," said Dr. David Michelson, vice president of neuroscience at Merck Research Laboratories, in a statement. "Studies to evaluate potential new treatment options are critical as the global health and financial burden of Alzheimer's disease grows."

- here's the press release

Special Reports: The Alzheimer's pipeline: What's next? | The Top Phase III Disasters of 2012

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