Given the fact that today’s top treatments for Alzheimer’s disease focus on symptomatic care and are generally seen as having little efficacy in slowing the devastating progression of this disease, investors, scientists and the general population welcome even the smallest indications that a new drug in development could be more efficacious. Better yet, a new drug that would actually address the underlying cause of this debilitating disease that is growing in prominence. The aging of so-called baby boomers is exacerbating the urgency and great area of unmet medical need, while creating attention for companies like Adamas Pharmaceuticals (NASDAQ: ADMS), Biogen Idec (NASDAQ: BIIB) and their much smaller peer Neurotrope, Inc. (OTCQB: NTRP) for their efforts to develop drugs to treat the devastating form of dementia that takes a huge toll on patients and family members.
According to Alzheimer’s Association, Alzheimer’s disease is the sixth leading cause of death in the US and there were 5.2 million Americans living with the disease in 2014, with a new diagnosis happening every 67 seconds. At the current pace, the number of people living with Alzheimer’s in the U.S. age 65 years or older is expected to rise up to 16 million by 2050. By some analyst estimates, a drug that can treat the disease itself can command sales of $20 billion or more, making the financial stakes and potential monetary rewards very high for big pharma as well as emerging biotech companies working on more effective treatments for Alzheimer’s.
Currently, approved therapeutics options are limited mostly to acetylcholinesterase inhibitors, including today’s standard of care, Eisai and Pfizer’s (NYSE: PFE) Aricept (donepezil), and memantine, a NMDA (N-methyl-D-aspartate) receptor antagonist originally synthesized by Eli Lilly in the late 1960’s and now sold under several brand names, including Namenda by Forest Laboratories, a company acquired by Actavis plc (NYSE:ACT) last year for $25 billion.
In December, shares of Adamas jumped more than 10 percent on the FDA approving Namzaric, a fixed-dose combination of memantine hydrochloride extended-release and donepezil to treat moderate to severe Alzheimer’s disease developed by Adamas in partnership with Actavis (through the Forest Labs buyout). The two drugs act upon separate mechanisms, meaning that they are often prescribed in tandem for Alzheimer’s patients. Cumulatively, both drugs focus on increasing or regulating certain neurotransmitter functions to compensate for the effects of an accumulation of beta-amyloid plaques outside of neurons and an abnormal form of the protein tau in the brain are hallmarks of Alzheimer’s disease. Namzaric is expected to be launched in the U.S. in the second quarter of 2015.
In the development pipeline, Biogen Idec (NASDAQ: BIIB) has been greeted with fanfare for its 194-patient Phase 1 trial of BIIB-037 that showed improvement in cognition in Alzheimer’s patients after 54 weeks of treatment. Early data was promising enough to advance the drug candidate straight into a Phase 3 trial. Notably, BIIB-037 seems to be working by reducing beta amyloid plaque, a toxic form of a normally benign protein that is known to buildup in the brain of Alzheimer’s patients. While Biogen has created a buzz with the early-stage trial, optimism has been somewhat tempered by the fact that bapineuzumab, a highly-touted drug co-developed by Johnson&Johnson (NYSE: JNJ) and Pfizer that also showed a reduction in the plaque, failed to outperform placebo in Phase 3 trials in patients with mild to moderate Alzheimer’s, leading to the big pharmas abandoning the development program.
Neurotrope, Inc., a New Jersey based biotechnology company working in collaboration with the Blanchette Rockefeller Neuroscience Institute (BRNI), has taken a novel approach to the treatment of Alzheimer’s, addressing the disease not at the level of the plague but further upstream by activating a cascade of events that has the potential improve function of existing neurons and increase synapse formation.
Neurotrope’s lead compound bryostatin, which is derived from the marine invertebrate Bugula neritina, is an activator of protein kinase C epsilon (PKCe, or PKCe). PKCe is an enzyme instrumental in the complex pathway of biochemical events in a neuron that is expressed at reduced levels in Alzheimer’s patients. Neurotrope licenses bryostatin from BRNI to advance the drug candidate for neurologic indications in a horizontal expansion of two decades and approximately $200 million in extensive research conducted by BRNI and the National Cancer Institute on bryostatin as an oncology therapy. The clinical exposure of bryostatin to more than 1,000 patients in that research established a well defined safety profile, enabling Neurotrope to forego large portions of early-stage research and move directly into mid-stage clinical studies of bryostatin.
Prior research in mouse models of Alzheimer’s disease have shown that activation of PKCe by bryostatin results in the formation of important proteins such as Brain Derived Neurotropic Factor and other downstream proteins resulting in improved memory and learning as well as increased synapse formation. In addition activation of PKCe results in the increased activity of enzymes can degrade amyloid and that can reduce formation of toxic amyloid and tau proteins. Thus as an upstream effector bryostatin is a unique treatment for Alzheimer’s disease and not dependent on the reduction of amyloid or tau.
On February 24, 2015 Neurotrope announced positive top line results from a double blind, placebo controlled Phase 2a safety study for bryostatin-1 in the treatment of Alzheimer’s disease. Bryostatin met its primary endpoint demonstrating preliminary safety and tolerability. The company is currently evaluating secondary endpoints including the efficacy of a single dose of bryostatin in the treatment of patients with the disease, its pharmacokinetics and pharmacodynamics and to correlate the changes in PKCe with plasma levels of bryostatin and with improvement in cognitive function. This data should set the stage for a Phase 2b trial (proof-of-concept, double blind versus placebo study) of bryostatin in patients with moderately severe to severe Alzheimer’s.
Additionally, the potential pipeline for bryostatin beyond Alzheimer’s disease is quite intriguing. Neurotrope is completing lab research to move forward with bryostatin for Fragile X and Niemann-Pick Type C, two devastating diseases with no effective treatments that qualify for Orphan Drug designations and other FDA pathways to expedite development.
As the pharmaceutical and biotechnology industries focus on new treatments, our understanding of Alzheimer’s disease and how to combat it will continue to evolve. Today, the common denominator for treatments in pharmaceutical market is that they are comprised exclusively of symptomatic therapies that ultimately deliver little therapeutic benefit to Alzheimer’s patients to arrest progression. Additionally, generic alternatives coming to market are expected to sap sales from current leaders like Aricept, Namenda and Novartis’ (NYSE: NVS) Exelon. One thing is for certain when it comes to a disease of this magnitude, any treatment that can deliver actual therapeutic benefit to Alzheimer’s patients has the potential to become “The Next Blockbuster” in the pharmaceutical industry and the company responsible for that treatment will reap the financial rewards of that success for years to come.
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