Two new drugs improve cognition in people with mild cognitive impairment and early signs of Alzheimer's disease
Two new drugs for Alzheimer's disease have shown promise in early testing and will likely progress to the next round of clinical trials according to researchers at the 2013 Alzheimer's Association International Conference.
One drug, called a BACE inhibitor, has been in development for more than 10 years. In very early tests, it dramatically reduced levels of beta amyloid that forms plaques in the brains of Alzheimer's patients.
The second drug is thought to reduce damaging inflammation. Patients with mild mental impairment who took the drug for over a year saw significant improvements in some measures of memory and thinking.
Inflammation in the brain has been implicated in the process and progression of Alzheimer's disease. Microglia are cells that act as the first and main form of active immune defense in the brain and spinal cord where they must react quickly to decrease inflammation and protect sensitive tissues. It has been recently suggested that amyloid plaques in the brains of people with Alzheimer's can stimulate microglia to produce compounds that cause brain cell damage. Thus, microglia have become a novel target for Alzheimer's disease therapies.
CHF5074 (Chiesi Pharmaceuticals Inc., Parma, Italy) is a microglial modulator that, in preliminary studies, has been shown to prevent brain plaque deposition and reduce deficits in transgenic mouse models of Alzheimer's disease.
At AAIC 2013, Joel Ross, M.D., FACP, AGSF, CMD, CPI, of the Memory Enhancement Center of America, and colleagues at Chiesi Pharmaceuticals reported the results of a 90-week (14-weeks double-blind, placebo-controlled study followed by a 76-week open label extension study) trial of CHF5074 at three different doses (200, 400 and 600 mg/day) in people with mild cognitive impairment (MCI). Participants received the same dose of the drug throughout the trial and were monitored for vital signs, cardiac activity, neuropsychological performance and safety.
Seventy-four (74) patients entered the open label part of the study: 26, 21 and 27 in the 200, 400 and 600 mg/day cohorts, respectively. At Study Week 40, 14 patients dropped out: four, two and eight in the 200, 400 and 600 mg/day cohorts, respectively. Three of dropouts were for adverse events: two in the 600 mg/day group (serum creatinine elevation and worsening of cognitive function) and one in the 400 mg/day group (pneumonia). The most frequent treatment-emergent adverse events were gastrointestinal disorders, with diarrhea being reported by 1.4 percent of patients on 200 mg/day, 6.3 percent of patients on 400 mg/day and 16.0 percent of patients on 600 mg/day.
An interim analysis of cognitive tests of 27 patients reaching Study Week 88 showed statistically significant, dose-dependent improvements in participants' cognitive abilities. Study participants who carried one or two copies of the ApoE4 gene, which increases the risk of Alzheimer's, performed significantly better than ApoE4 non-carriers on two of the cognitive tests.
"This is one of the first studies indicating that this neuroinflammatory inhibitor may be able to improve cognition in people with MCI who carry the ApoE4 gene," said Ross. "CHF5074 was well tolerated by people with MCI at doses up to and including 400 mg/day."
Another trial, looked at a drug thought to inhibit production of beta-amyloid. The presence of beta-amyloid plaques in the brain is a well-known manifestation of Alzheimer's disease. One hypothesis holds that the toxins produced by beta-amyloid initiate a cascade of events in the brain that cause Alzheimer's, but it is still unclear to many whether the plaques are a cause or a result of the disease.
Academic and industry researchers have investigated a variety of approaches to slow or stop the production of beta-amyloid and/or clear it from the brain. Yet, to date, some combination of safety concerns and lack of efficacy in slowing or stopping cognitive decline in people with Alzheimer's has plagued all of these attempts. While this has led to further questions about the validity of the amyloid cascade hypothesis, or the possibility of therapeutic intervention through this route, new approaches continue to be tested.
Mark S. Forman, M.D., Ph.D., and colleagues at Merck Research Laboratories conducted a randomized, double-blind, placebo-controlled, multiple-dose study of an experimental medication called MK-8931 in people with mild-to-moderate Alzheimer's. The drug acts by inhibition of beta-secretase (BACE1), one of two enzymes that produce beta-amyloid by breaking down its parent molecule, known as amyloid precursor protein (APP). Participants received 12, 40 or 60 mg of MK-8931 or placebo (n=8 per dose; n=6 for placebo) daily for seven days. Beta-amyloid levels were measured in cerebrospinal fluid (CSF) obtained by lumbar puncture over 36 hours following the final dose.
The researchers found that the drug significantly lowered CSF beta amyloid in people with mild to moderate Alzheimer's in a dose-dependent fashion; at the highest dose, the average reduction from baseline was more than 80 percent. According to the researchers, MK-8931 was generally well-tolerated.
"This is the first demonstration of the lowering of beta-amyloid levels by a BACE1 inhibitor in people with Alzheimer's disease," Forman said. "We believe this candidate presents a unique opportunity to test the amyloid hypothesis." |