New Alzheimer's Therapy Targets And Approaches Reported At Alzheimer's Association International Conference 2013

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Jul 14, 2013, 08:30 ET

BOSTON, July 14, 2013 /PRNewswire-USNewswire/ -- Results of four research trials investigating new targets for therapies in Alzheimer's disease, and incorporating novel approaches to participant identification and selection, were reported today at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston.

The trials involve four compounds that target physical changes in the brain associated with the development and progression of Alzheimer's disease. Two drugs are intended to reduce brain inflammation, one is thought to inhibit the production of an abnormal protein in the brain known as beta-amyloid, and the fourth promotes brain cell regeneration.

"The Alzheimer's disease epidemic is here. It is vital that we accelerate the pursuit of novel ideas and strategies to treat and prevent Alzheimer's disease," said Maria Carrillo. Ph.D. Alzheimer's Association vice president of medical and scientific relations. "While many of the trials reported at AAIC 2013 are still in early stages, they represent a promising diversification of the Alzheimer's treatment pipeline and translate to new hope for a world without Alzheimer's disease in the future."

Microglial Modulator Reduces Inflammation and Improves Cognition in People with MCI

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."

MK-8931 (BACE1 Inhibitor) Lowers Beta Amyloid in People with Mild to Moderate Alzheimer's

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, the fluid that surrounds the brain and spinal cord) 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."

Allopregnanolone Regenerative Therapy to Begin Phase 1 Trials

According to Roberta Brinton, Ph.D., of the University of Southern California, both aging and Alzheimer's disease are characterized by a decline in the ability of the body (including the brain) to self-renew and repair, but the capacity for regeneration is retained, albeit at a decreased level.

Allopregnanolone (also known as Allo) is a neurosteroid found in the brain and bloodstream. In previous studies, it has shown promise as a potential regenerative therapy to promote brain cell creation and improve cognitive function in older animals and animal models of Alzheimer's disease.

At AAIC 2013, Brinton reported the design of a Phase 1, multiple ascending dose, clinical trial of Allo in participants diagnosed with MCI due to Alzheimer's and mild Alzheimer's, with doses administered once-per-week for 12 weeks to establish a safe and tolerated dose. Because Allo is naturally expressed in the brain and reaches relatively high levels during the third trimester of pregnancy, the scientists were able to advance beyond the time limits of a typical first stage of safety testing.

Secondary goals of the trial include assessing potential short-term effects of Allo dosing on cognition and MRI indicators of AD and informing a subsequent Phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy.

"Allopregnanolone is a well-characterized agent with a very promising track record of promoting neural stem cell generation and restoring cognitive function in animal models of Alzheimer's," said Brinton. "We consider Allopregnanolone a first in class regenerative therapeutic for MCI and Alzheimer's. Our hope is that, through further research, we will add Allo to the roster of Alzheimer's treatments.

"A critical issue to consider for potential regenerative therapies for Alzheimer's is the ongoing and progressive burden of brain cell death caused by the disease. It is not sufficient solely to generate new neurons and to promote their survival; it is necessary to reduce the ongoing burden of pathology for there to be long-term benefits for cognition and function," Brinton added. "We were very encouraged to discover that Allo reduced the burden of Alzheimer's pathology. Our latest findings are very exciting as they show that Allo increases the energy capacity of the brain. This is important because the generation of new neurons, new synaptic circuits and synaptic transmission all require substantial energy."

Phase 3 Trial of Pioglitazone to Delay Onset of MCI in Cognitively Normal Elderly (1) Uses Genetics to Enrich the Study Population and (2) Is Designed to Verify New Diagnostic Criteria

International trials to delay onset of MCI due to Alzheimer's disease are complex in design, requiring careful consideration of case definition, site characteristics, selection of primary outcome metrics and methods to ensure appropriate cultural and psychometric validation. They require innovations in approach to recruit the most appropriate study population, provide consistent MCI diagnoses across countries and to ensure the credibility of their results.

Kathleen A. Welsh-Bohmer, Ph.D., of the Joseph and Kathleen Bryan Alzheimer's Disease Research Center at Duke University Medical Center, and her colleagues at Zinfandel and Takeda Pharmaceuticals International, Inc., are currently initiating an international Phase 3 trial of low dose pioglitazone, a medication which at higher doses is approved for treatment of type 2 diabetes, as a therapy to delay onset of MCI due to Alzheimer's. The trial will begin enrollment in 2013. In earlier human studies, treatment with pioglitazone was associated with decreased markers of brain inflammation.

Study participants will be cognitively normal individuals who carry genetic risk variations in the APOE and TOMM40 genes that are associated with an increased risk of earlier onset of symptoms of Alzheimer's. By recruiting people with this genetic combination, the researchers believe they will enrich the study population so more participants will get MCI and/or Alzheimer's during the course of the trial.

In addition, the study includes applying and validating the new NIA/Alzheimer's Association diagnostic criteria for MCI due to Alzheimer's (Albert, et al., 2011; Alzheimer's & Dementia: The Journal of the Alzheimer's Association) and determining an appropriate set of cognitive tests that would work effectively in all study sites around the globe by taking into account, for example, language and cultural differences.

"Since this is an international trial, with sites in the U.S., Europe, Australia and Russia, it is vitally important that we apply standards that can be used and validated seamlessly around the world," said Welsh-Bohmer. "This study is meant to operationalize the NIA/Alzheimer's Association diagnostic criteria, which represent new standards."

"The new procedures under development for this trial may serve as useful tools for application in other global trials to prevent the onset of symptomatic Alzheimer's," she added.

About AAIC
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.

SOURCE Alzheimer's Association