Two Cleveland Clinic anesthesiologists put their research up for auction in April, hoping for support to develop the Alzheimer’s drug, MDA7. When the bidding ended, Mohamed Naguib, MD, and Joseph Foss, MD, received over a half-million dollars from the Alzheimer’s Drug Discovery Foundation’s “Fund a Scientist” charitable auction.
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With the ADDF award, they can move forward on key milestones in the development program. First, they are expanding the production of MDA7 from small batches made in the research lab. They have hired outside contractors and facilities to produce larger batches and to demonstrate the commercial feasibility of manufacturing the drug. Second, they now can develop, test, and begin projection of an oral version of the drug to be dosed in animals and ultimately in humans.
Soon they will be able to conduct animal studies of how the drug is absorbed and eliminated, followed by the animal safety studies the Food and Drug Administration requires for an Investigational New Drug (IND) application. “Our goal is to meet with the FDA this year, submit the IND and begin the Phase 1 human safety study in 2016, and begin Phase 2 human efficacy studies in 2017,” says Dr. Foss, Director of Clinical Research for General Anesthesiology at Cleveland Clinic.
Launching a new drug: Basic science to translational research
Dr. Naguib led the research team that synthesized MDA7, a cannabinoid type 2 (CB2) receptor-selective agonist, while seeking a treatment for neuropathic pain associated with chemotherapy. As ConsultQD has reported, his work for the past decade has shown that modulating the CB2 receptor can suppress neuropathic pain and inhibit microglial-mediated neuroinflammatory changes linked to amyloid-associated memory loss. Reducing the neuroinflammation associated with increased amyloid deposition represents a step back in the pathway that leads to memory loss in Alzheimer’s disease, he notes.
“We all deposit amyloid in our brains, and under normal conditions microglia play a very important role in removing amyloid and maintaining homeostasis in the CNS. Once the microglia get inflamed and start secreting neuroinflammatory mediators such as cytokines and chemokines, they produce a vicious cycle of neuroinflammation and tissue damage,” explains Dr. Naguib. He began his research at the University of Texas MD Anderson Cancer Center and was appointed in 2010 to the Department of General Anesthesia of Cleveland Clinic’s Anesthesiology Institute.
Dr. Foss brought his expertise in clinical pharmacology to the MDA7 development team in 2013. His role is to guide the translational research required to bring the drug from basic research to clinical practice. Before his Cleveland Clinic appointment in 2005, he led teams at the University of Chicago and at a pharmaceutical company that brought two opioid antagonists through early human phase trials to FDA approval.
Seeking funds to keep research alive in the ‘valley of death’
“Translational research, which has been called the valley of death for drug development, is characterized by a tremendous amount of work and risk,” Dr. Foss says. For example, a 2014 study led by Jeffrey Cummings, MD, Director of Cleveland Clinic’s Lou Ruvo Center for Brain Health, found an extremely high failure rate (99.6 percent) in terms of AD drugs advancing from Phase 1 trials to regulatory review.
Much more money is needed, beyond their generous award from the ADDF auction. Because the Cleveland Clinic researchers have only about half of the funds to take MDA7 to human trials, they recently formed a company called NeuroTherapia. Cleveland Clinic Innovations, the health system’s commercialization arm, provided financial support to launch this spin-off. “Having a company in place allows us to seek grants and meet with potential investors,” Dr. Foss says.
Safety testing of MDA7 for pain and Alzheimer’s indications
The CB2 receptor is not commonly expressed in the CNS in animals or humans who lack an inflammatory condition, and Dr. Naguib’s research has shown MDA7 is very specific for that receptor. “We have not observed any significant toxicities in the animal studies to date, but we’ve been working at therapeutic doses. We’ll be watching very closely to see what sort of side effects we observe at super-therapeutic doses,” Dr. Foss says.
This year’s research is targeted to support the two intended indications for MDA7, Alzheimer’s disease and neuropathic pain. The safety studies in animal models will be common to both indications. For the human safety studies, targeted to begin next year, the trials for Alzheimer’s disease may be somewhat longer than those for neuropathic pain. As no effective therapies exist for these serious indications, the investigators expect an expedited FDA review.
Bringing a new drug from basic science to clinical practice usually takes years. Hope for success and risk of failure are extremely high, especially for a drug that might alter the course of Alzheimer’s disease. After 10 years of research, however, Dr. Naguib remains optimistic. “We’ve traveled a long way already, and we have the patience to do it,” he says.