BACE Inhibitor Dramatically Reduces Amyloid-Beta

Pauline Anderson

November 12, 2012

There is mounting enthusiasm about a novel agent that appears to profoundly reduce amyloid-β (Aβ) in the brain.

New research found that a single or multiple daily dose of this agent (MK 8931; Merck), which inhibits the enzyme that sets in motion the build-up of Aβ in the brain, resulted in up to a 94% reduction in cerebrospinal fluid (CSF) Aβ after 36 hours.

The agent "can dramatically lower Aβ levels in a way that has never been done before, and at doses that are well tolerated, "said Mark S. Forman, MD, PhD, from Merck Research Laboratories. "It really gives us an opportunity to answer a scientific question that we don't believe has been adequately addressed in the Alzheimer disease field, which is whether dramatically reducing Aβ levels in the brain has an impact on the progression of Alzheimer's Disease (AD) — also known as the amyloid hypothesis."

The results were presented at the Clinical Trials on Alzheimer's Disease (CTAD) 2012 conference in Monaco.

Merck's agent appears to mimic a mutation on the Aβ precursor protein (APP) gene that protects against neurodegenerative disease and age-related cognitive decline.

Amyloid Formation

APP, which is found on the surface of neurons, is cleaved into fragments by the β-secretase enzyme (β-site APP cleaving enzyme or BACE). This process precipitates the formation of Aβ, which is toxic to neurons and is the hallmark of AD.

Dr. Mark S. Forman

A rare mutation in this gene, carried by only about 1% of population, seems to slow the function of the βsecretase enzyme. The protective role of this mutation was discovered by researchers in Iceland and published online in Nature July 11, and reported by Medscape Medical News at that time.

Merck carried out 2 randomized, double-blind, placebo-controlled studies in healthy volunteers aged18 to 45 years. The study at a site in Belgium tested an increasing single dose (20-500 mg).in 40 participants (30 receiving the BACE inhibitor; 10 receiving placebo). Another US study assessed an increasing multiple dose (10-250 mg) in 48 participants (36 receiving active treatment; 12 receiving placebo).

Using samples collected via lumbar catheterization, investigators measured 3 biomarkers — CSF Aβ40, Aβ42, and sAPPβ — 36 hours after dosing.

One of the biomarkers — sAPPβ — is produced when BACE cleaves, explained Dr. Forman. That molecule is further metabolized by γ-secretase (another enzyme linked to the amyloid process) to Aβ species, including Aβ40 and Aβ42.

A BACE inhibitor blocks production of Aβ wherever it's produced, explained Dr. Forman. In previous animal studies, Aβ was measured not just in the plasma and CSF but also in the brain itself. In human studies, CSF is used as a sort of surrogate for the brain.

The studies showed dose-dependent reductions in Aβ. Even with relatively low doses — as low as 40 mg — Aβ levels in the CSF decreased more than 80%. At higher doses, the reduction was as high as 94%, said Dr. Forman.

Unique Mechanism

Similar reductions were seen for all biomarkers. "All 3 of them behaved in parallel; there was very little difference in the level of Aβ reduction, or the time course of the reduction, between the 3 different species that we measured," said Dr. Forman.

Both single and multiple doses of MK-8931 were generally well tolerated, with adverse events, including headache, nasal congestion, dizziness, and back pain, being generally mild to moderate in intensity.

Dr. Forman and his colleagues have completed a small phase 1B study looking at pharmacodynamics in patients with AD who received the BACE inhibitor for 7 days. Those data are being analyzed and will be presented at the Alzheimer's and Parkinson's Diseases Conference (AD/PD) meeting in March 2013.

Further studies are set to begin before the end of this year to test whether long-term administration of the BACE inhibitor affects cognitive function in patients with AD, said Dr. Forman.

Michael Rafii, MD, PhD, director, Memory Disorders Clinic University of California San Diego Perlman Ambulatory Care Center, and assistant professor of neurosciences at UC San Diego, who attended the CTAD meeting, found the research very exciting because it demonstrates the efficacy of a unique mechanism.

"BACE inhibitors are a different class than γsecretase inhibitors and immunotherapy, and target a different enzyme," said Dr. Rafii.

The new results add to the "very nice coherent picture that is emerging" to indicate that the area of APP — the location where the enzyme cleaves to produce Aβ — is the target of interest, said Dr. Rafii.

But he added that although "a single dose that lowers Aβ for some number of hours is great", it's important to remember that in AD, Aβ levels have been elevated in the brain for decades. Reductions probably have to be maintained for a long time — and interventions administered early on — to have any clinical effect, he said.

Dr. Forman is an employee of Merck Research Laboratories.

Clinical Trials on Alzheimer's Disease (CTAD) 2012 conference. Abstract OC4. Presented October 29, 2012.

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