New Hope for Alzheimer's Disease

by Gail Dutton for Genetic Engineering & Biotechnology News:

Optimism Fostered by More Than 150 Firms Working in Space and Countless Approaches.

The global market value of Alzheimer's disease (AD) therapeutics could soar to the $8 billion range once therapeutics are approved that actually change the course of the disease. The current therapeutic market is valued at $3 to $4 billion, shared among drugs that temporarily delay disease progression or address the symptoms but do not alter the underlying disease, according to Ian Sanderson, senior analyst, Cowen & Company.Progress to a cure for AD has been hampered by the lack of information about the biology of the disease, he points out. “Only recently have scientists confirmed that amyloid plaques are associated with the disease, and they still debate whether they are causative or symptomatic.”More than 150 companies are working in the Alzheimer's space, including approximately 15 multinationals and 30 generics companies. Of those, “More than 100 companies have drugs in the pipeline,” according to Aiswariya Chidambaram, senior research analyst for life sciences, healthcare—Europe, at Frost & Sullivan.“More than 50 percent of the drug candidates are in the preclinical phase of development, with just two promising candidates in Phase III trials,” Chidambaram says. There are at least a dozen different approaches, but “drug developers are focusing upon beta-amyloid plaque inhibitors and amyloid synthesis inhibitors.”In Sanderson’s view, “Right now, the most highly anticipated program is at Janssen (which acquired Elan’s AD program in 2009) and Pfizer.” The joint Janssen/Pfizer project fast-tracks bapineuzumab, a monoclonal antibody (mAb) to target and clear ß-amyloid. This vaccine is the first new drug aimed at slowing or even halting AD progression. Fourteen trials are under way, involving 10,000 patients. The first of those trials is expected to report data in August.After Janssen paid Elan $1.5 billion for co-marketing rights in 2010, “Phase II results were mixed, but showed clear evidence of biological activity. Researchers hope a larger study may achieve statistically significant results,” Sanderson says. Compared to placebo, bapineuzumab slowed cognitive decline over 18 months and “could be the first disease-modifying agent to show success.”He predicts the drug will be most effective on the earliest-stage AD patients. In addition to its work with Janssen, Pfizer also has three other therapies in Phase I, one in Phase II, and one in Phase III trials.Last March, the USPTO granted a patent for Antisenilin, developed by Intellect Neurosciences. This therapy is similar to bapineuzumab, but targets either end of ß-amyloid. It is in Phase III trials.Baxter has a Phase III program under way for Gammagard, a naturally occurring plasma-derived immunoglobulin for moderate-stage AD patients. The trial runs until February 2013. Phase II results suggest Gammagard may positively affect brain atrophy and cognition. The compound already is approved for immunodeficiency diseases.AstraZeneca has a nicogenic receptor agonist that upregulates the neurotransmitter acetylcholine to help the remaining neurons function more effectively. The company is also working on another approach with Astex Pharmaceuticals.Roche has three AD compounds in Phase II studies, including the fully human mAb gantenerumab to neutralize ß-amyloid; a humanized mAb that binds to ß-amyloid; and the small molecule inhibitor of monoamine oxidase-B (MAO-B) to halt neuronal damage. Still in Phase I studies, Roche also has a small molecule inhibitor of beta-secretase (BACE), a key enzyme in the production of amyloid-beta peptides.Others developing AD treatments include TransTech Pharma, Memory Pharmaceuticals, and Sanofi-Aventis. Most of the therapeutics in development bind to soluble ß-amyloid in the periphery blood rather than attempting to cross the blood brain barrier, Sanderson points out.

Standard TherapyPfizer’s Aricept, an acetylcholinesterase inhibitor, is the gold standard and is the only drug approved for mild, moderate, and severe AD. The only other FDA-approved drug class to treat AD is NMDA receptor antagonists, Chidambaram says. “These two approaches are only capable of alleviating the memory and cognitive symptoms in patients by either enhancing acetylcholine levels for neuron communication, or maintaining neuronal health. Neither of the drugs restores lost cognitive functions nor provides long-term benefits besides reducing adverse effects of AD,” she elaborates.“The new class of disease-modifying drugs under investigation must be able to modify the disease and slow or prevent its long-term progression. They also must offer better therapeutic efficacy and safety profile,” Chidambaram adds.

Diagnostics

“Diagnostics are becoming more important than therapeutics,” Sanderson points out. Early diagnosis is the key to effectively treating Alzheimer's disease patients. A five-year delay in disease onset could reduce the disease prevalence by 50% during the next few decades and, according to the Alzheimer’s Association, reduce annual healthcare expenditures by more than $50 billion.The challenge is that, as yet, there is no single definitive test for Alzheimer's disease, which is often confused with the symptoms of normal age-related memory loss. “However, there has been significant progress lately in developing novel Alzheimer's disease diagnostic techniques to enable earlier and more accurate diagnoses,” Chidambaram says.Most of the diagnostics work is in the area of brain imaging. “The leader, Eli Lilly, received approval of its Alzheimer's diagnostic April 10. It’s basically an imaging agent to be used for PET scans,” Sanderson says. Called Amyvid, it uses Florbetapir F 18 to bind to brain β-amyloid and estimate that protein’s neuritic plaque density in patients with cognitive impairment.“Results are considered definitive,” Sanderson says. Until this agent became available, a brain biopsy was the only way to determine plaque density. GE Healthcare Life Sciences is investigating a similar radiopharmaceutical for PET imaging called [¹⁸F] Flutemetamol. Results presented at the Society for Nuclear Medicine Annual Meeting in June showed a correlation between imaging and biopsy results.Still in the laboratory, Chidambaram says researchers are also working to advance cerebrospinal fluid (CSF) analysis of phosphorylated tau protein and Ab24, and to further develop functional neuroimaging techniques such as SPECT imaging, fluorodeoxyglucose (FDG), and amyloid PET scanning.“The surrogate biomarkers for Alzheimer's disease play a crucial role in diagnosis of the disease at the early stages and monitoring the disease progress,” Chidambaram says. “The beta-amyloid plaques formed on the surface of the brain cells and the neurofibriliary tangles (tau protein) formed inside the cells are the two most important, hallmark features of Alzheimer's disease. All the 12 different mechanisms of action or hypotheses being tested ultimately target these two key biomarkers of the disease.”Although tau protein and ß-amyloid plaque can be measured in the brain, Sanderson says there is some debate whether the FDA will allow reductions in their levels to be used as endpoints.“Researchers still need data indicating that a change in the levels of either biomarker actually correlates to a change in cognitive function.”

Elderly Rat ModelCharles River Labs is expanding the research options with its elderly Fischer rat model, which is believed to provide a more comprehensive picture of aging than models in which AD is induced in young rats. This enables researchers to gain a more wholistic view of AD, beyond the accumulation of plaque. Consequently, because these rats are allowed to age and develop natural cognitive impairments, results are considered more representative than other models of human aging. In contrast, Sanderson says, “Standard animal models haven’t worked well. It’s possible they had a different genetic predisposition.”Source: https://www.genengnews.com/magazine/186/new-hope-for-alzheimers-disease/Picture: There are at least a dozen different approaches to new Alzheimer's disease treatments, but beta-amyloid plaque inhibitors and amyloid synthesis inhibitors currently top the list. [GordonGrand/Fotolia]