Conference Coverage

BACE1 inhibitor markedly decreased CSF amyloid in Alzheimer’s


AT AAIC 2013

BOSTON – A drug that blocks the formation of two brain-toxic amyloid beta peptides cleared most of the protein fragments from cerebrospinal fluid in patients with mild to moderate Alzheimer’s disease who took it in a 7-day phase I study.

The CSF load of amyloid beta 40 (Abeta40) dropped by a mean of 90% and that of Abeta42 by a mean of 86%, compared with a placebo group, Dr. Mark S. Forman reported at the Alzheimer’s Association International Conference 2013.

The drug, called MK-8931, is an inhibitor of the beta-secretase 1 enzyme (BACE1), which is also known as beta-site amyloid precursor protein (APP) cleaving enzyme 1. It changes the point at which the APP splits into the Abeta40 and Abeta42 peptide fragments. Researchers hope this alteration might prevent the proteins from forming, and so prevent the buildup of amyloid brain plaques that is a diagnostic hallmark of Alzheimer’s disease.

Dr. Mark Forman

The placebo-controlled study randomized 30 subjects to three dosage groups (12, 40, and 60 mg) of eight patients each and a placebo group of six patients. The medications were administered once daily for 7 days.

Patients underwent lumbar puncture at baseline to assess CSF levels of Abeta40 and Abeta42. Samples were also drawn hourly for 36 hours after the last dose was administered.

"There was a profound, steady-state reduction in CSF Abeta peptides," Dr. Forman said. The reductions were similar to the results of a prior safety study performed in 40 healthy young adults.

Adverse events reported in two or more subjects in at least one dose group included headache, dizziness, nausea, vomiting, insomnia, and back pain. All adverse events were generally mild to moderate in intensity and transient in duration. No dose-dependent increase in the incidence of adverse events was observed.

The study didn’t examine any cognitive outcomes, Dr. Forman said in an interview. Those will be assessed in the next phase of development of MK-8931 – a phase II/III study called EPOCH, which began recruiting subjects in December 2012. The 78-week trial aims to enroll up to 1,700 patients with mild to moderate Alzheimer’s, randomizing them to the 12-, 40-, and 60-mg doses.

EPOCH’s primary endpoints are changes in the cognitive subscale score of the ADAS-Cog (Alzheimer’s Disease Assessment Scale) and the change from baseline in the score of the ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) scale.

So far, manipulating APP to inhibit toxic amyloid production has been difficult. Earlier this year, Eli Lilly pulled the plug on its investigational BACE1 inhibitor, LY2886721, because of abnormal liver enzymes identified during routine monitoring of subjects taking it.

Safety concerns also caused Lilly to yank semagacestat from development in 2010. Semagacestat was also designed to change the APP cleavage point, but it targeted gamma-secretase instead of beta-secretase. Although the drug decreased CSF levels of Abeta42 by up to 65%, patients who took it actually had a significantly greater decline in cognition and function than did the placebo group. They also had a slight increase in skin cancers.

"One thing we are really concerned about is the long-term data from the semagacestat trial, where people actually got worse instead of better," Dr. Forman said. "We don’t know if that’s a reflection of some off-target activity or reducing amyloid in the brain. What will long-term BACE inhibition do? It’s an unknown. But we think the potential upsides outweigh the risks with this compound."

In an interview, Maria Carillo, Ph.D., agreed. "I’m excited that BACE1 is being pursued as an earlier intervention in the amyloid process. It will help prove that the amyloid hypothesis is worth pursing and give us an additional amyloid strategy."

Because Alzheimer’s seems to deliver a number of pathologic hits, effectively treating it will call for a varied armamentarium, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. "At the end of the day, we have to know how to tackle all of them – tau, amyloids, inflammation, and energy pathways."

Merck funded the study of MK-8931. Dr. Forman is the company’s director of clinical research.

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