Peer Insight: Funding and Treating Alzheimer Disease With Howard Fillit, MD

Funding Clinical Trials

Howard Fillit, MD, the founding executive director and chief scientific officer of the Alzheimer’s Drug Discovery Foundation (ADDF), sat with MD Magazine to discuss the state of therapies for Alzheimer disease (AD), including funding-related struggles and the burden faced by physicians who treat patients with AD.Despite the potentially huge clinical implications, producing AD therapies is often risky and expensive, so AADF plays a role in helping these ventures get off the ground, Fillit said. “The pharmaceutical companies have big dollars. They can come in phase 3—a phase 3 trial in Alzheimer’s costs $300 to $400 million, and you are going to need 2 or 3 of them, maybe 4, to get FDA approval,” Fillit told MD Magazine. “That is a big risk. You cannot take many of those bets without going out of business, and a lot of Big Pharma companies have left not just Alzheimer [disease] but [also] the whole central nervous system space because it is so risky. You cannot run a company with such large risks, financial and scientific.”

There have even been struggles related to clinical trial funding by venture capitalists, he said: They often operate with decade-long funds, Fillit said, but developing a drug usually takes between 12 and 15 years—a small difference in the long run but enough to keep funders away.

“They are tending to step in late,” Fillit said. “They want to see, generally speaking, phase 2 data. There are some funds that will step in earlier into the preclinical space, but most of them won’t—again, for the same reason. They have obligations to their investors to make money, and that is a good thing, because if a drug is brought to market, everybody wins. But where they can put their money is in a different place than the pipeline.”

Despite those struggles, more than 250 clinical trials are underway for AD therapies, with 126 drugs in the pipeline, according to Fillit. “It is amazing, because when I started in the field in 1980, there were no drugs in clinical trials,” he said.

Repurposing Therapies

The ADDF has supported about 25% of the therapies being developed. Fillit expressed his excitement about the ADDF’s ability to help, as well as the availability of so many targets that biologic part of the condition—and the ability to repurpose them.Of the 126 therapies in clinical development, 17 are repurposed drugs that are on the market for other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson disease. A number of trials are expected to report out in the next year or so, and Fillit stressed the pressing need for these drugs, which could be used sooner rather than later to help patients with AD. Despite multiple advances and some promising therapies, Fillit acknowledged, none offer a cure for the neurodegenerative condition, making those that slow the progression of cognitive impairment more and more important.

“What we need—like in cancer, like in diabetes, like in hypertension, like in HIV/AIDS—[is] combination therapy, because the way this disease evolves is multifactorial,” Fillit said. “You have inflammation, epigenetic changes, neuronal energy failure, mitochondrial dysfunction, hypoxia and ischemia from microvascular disease, protein chaperone misfolding and failure, so we are going to need a combination of drugs to attack this disease.”

Repurposing therapies gives physicians that treat AD a huge advantage: If trial results are positive, Fillit said, then he can start prescribing a drug off-label the next day. “I do not have to wait for FDA clearance. The big opportunity when you discover a repurposing drug that works is that then we can go back and do new chemistry, create new chemical entities, get new indications for unique drugs, and build the space, because we have a proof of concept,” he said.

Physician Burden

For example, riluzole, the only drug that has shown an ability to slow the course of ALS, is being repurposed for patients with AD. Fillit expects the trial to wrap up in about 2 years, which is “pretty quick,” he noted. “We are going to have an answer [soon], unlike when new chemical entities have to go through a regulatory environment that takes 12 to 15 years,” Fillit said. “Once these trials come out, it opens up a new area, but the drugs can be used off-label immediately.”Treating patients with AD is difficult not just because of the lack of options, Fillit said, but also because it places a burden on physicians who provide the hours of care, education, and testing required by patients and their caregivers. That takes a toll on physicians both in their ability to give so much care in a limited amount of time and, due to complications with the health care system, in their reimbursement.

Fillit, who has been working with patients with AD for almost 40 years, understands this all too well. “When you’re treating a person with Alzheimer’s, you’re also treating their caregiver,” he said. “There is always a dyad of the caregiver—the spouse, the daughter, the son, a home aide—there is almost always a caregiver, [because] it is very hard for a person with Alzheimer’s to live alone and not have any services.”

There is no magic bullet for AD, he said—no biomarker like cholesterol or hemoglobin A1C that physicians can use to measure progression. “We are measuring cognition as the primary outcome and function, and it is hard—there is no number,” he said. “It takes an interview or a mini-mental exam or some kind of gestalt about how a patient is doing.”

In addition, patients require education and counseling, which takes a long time. “There are reimbursement problems for payment for a physician to spend an hour with a patient and, after taxes and overhead and rent, to literally come home with $30 to $40 because all these people have Medicare,” Fillit said.

The result: disincentives for doctors to spend time on education, counseling, and arranging the services and long-term care that patients need. “I really think that the problem is sort of structural. I hope that, with the way that medicine is changing, maybe the financial incentives can change so that doctors can take better care of Alzheimer patients,” Fillit said. “But right now, I get patients referred to me who are seeing neurologists and primary care doctors at some of the major academic medical centers—they are just not getting care.”

Fillit likes to quote Hippocrates, who said that the role of the physician is sometimes to treat and often to relieve pain, but always to comfort. Those words apply perfectly to physicians who treat patients with AD: “These patients are suffering. Most of them are not having a good time. It is a long day. Caregivers need, really, a lot of education and counseling on how to deal with the thing…These are people [who] are often 75, 80 years old taking care of someone who is totally dependent or keeps asking them 5 times every minute, ‘Where are we going later?’ And that drives you crazy.

“The challenges [with AD] are enormous,” Fillit said. For physicians, AD is a very difficult illness to treat, and “the right paradigm for care has not been figured out,” he said.

The Clinical Focus condition center at NeurologyLive, MD Magazine's new sister site, provides even more extensive coverage from the Alzheimer’s disease space, as well as updates pertaining to dementia and the latest from the field’s most prominent conferences.