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BOSTON -- An investigational drug targeting a key enzyme involved in beta-amyloid protein release dramatically reduced production of the protein in a small, early-stage trial, a researcher reported here.

In a 7-day trial involving 30 patients with mild to moderate Alzheimer's disease, daily doses of 12 to 60 mg/day of a BACE1 inhibitor called MK-8931 led to reductions in cerebrospinal fluid (CSF) levels of both major types of beta-amyloid protein of up to 84%, whereas those given placebo showed slight increases, said Mark Forman, MD, PhD, of Merck Research Laboratories in Whitehouse Station, N.J.

Adverse effects were mostly limited to those associated with the CSF sampling, Forman said at a press briefing held prior to his formal presentation at the Alzheimer's Association International Conference.

No "clinically significant" abnormalities were seen in liver function tests, vital signs, or cardiac markers, Forman said. Last month, signs of liver toxicity had forced Eli Lilly & Co. to stop a trial of a competing BACE inhibitor.

BACE -- an acronym for beta-amyloid converting enzyme, which also is called beta-secretase -- is part of the enzyme system responsible for clearing beta-amyloid from a larger precursor protein. Along with gamma-secretase, BACE has been a long-standing target for drug development in Alzheimer's disease.

Although all previous such drugs have proven ineffective in delaying Alzheimer's disease progression in patients with established dementia, many in industry and academic labs believe that beta-amyloid is still a viable treatment target.

In the current phase Ib study, three groups of eight patients each were assigned to receive MK-8931 at oral doses of 12, 40, and 60 mg/day for a week, with an additional six patients given placebo.

Patients were 50- to 85-years-old, met published diagnostic criteria for Alzheimer's disease, and had Mini-Mental State Examination scores of 15 to 26.

CSF samples were taken repeatedly via a lumbar catheter for 36 hours after the final dose, for measurement of three downstream products of BACE1 activity: the 40- and 42-amino acid versions of beta-amyloid protein (AB40 and AB42, respectively) and soluble amyloid precursor protein-beta (sAPP-beta).

At the end of the study period, patients in the high-dose group showed the following reductions from baseline in CSF levels of the amyloid proteins:

• AB40: 84% (95% CI 78%-90%)
• AB42: 81% (95% CI 74%-89%)
• sAPP-beta: 88% (95% CI 83%-93%)

Responses were dose-dependent, Forman indicated, with patients taking lower doses showing correspondingly smaller, but still significant, reductions in the three proteins relative to baseline. In the 12-mg group, for example, the reductions were in the range of 37% to 47%.

Mean levels of the amyloid proteins increased from baseline in the placebo group, by about 50% for AB40 and 15% for AB42. Forman said this effect had been seen in previous placebo-controlled studies involving other agents. No definitive explanation has been found, but it appears to be an "artifact" of lumbar puncture, he said.

Forman said there were no serious adverse events in the trial. Adverse events were mainly headache, back pain, and other complaints commonly heard from patients with lumbar catheters.

Asked if such dramatic reductions in beta-amyloid protein production, sustained for months or years, could ultimately lead to adverse effects, Forman acknowledged that some risk is possible.

But animal studies have indicated that beta-amyloid can be suppressed for long periods without causing apparent illness, he added.

He said a 3-month, phase II/III study called EPOCH is now underway in some 200 patients, and the investigators are alert for toxicities that may result from prolonged BACE1 inhibition.

"We're going to have to monitor safety very carefully for the duration of the study," Forman said.

Press briefing moderator Mary Sano, PhD, of Mount Sinai School of Medicine in New York City, commented that safety of new drugs may be overemphasized when it comes to Alzheimer's disease.

"We are timid, sometimes, in considering agents that might have some toxicity associated with them -- perhaps more timid than we are in cancer," she said.

"I think it's important to realize that [Alzheimer's] is the second most dreaded disease in the world," she said, citing studies that asked people which illnesses they fear the most. "Balancing risk and benefit is something that we're going to have to be doing with all of our patients."

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