A report released by the Cleveland Clinic last month shared some disappointing news. Its second assessment of the Alzheimer drug pipeline revealed a slow period in drug development with only eight new agents entering Phase I since 2016.
In order for an agent to be approved by 2025—a goal set in the Obama administration—it must currently be in mid- to late-Phase II to be on track. While there are promising agents in all phases of the pipeline, high drug failure rates, lack of clinical trial participants as well as lack of funding can slow the path to approval.
The report, a comprehensive analysis based on the federal website ClinicalTrials.Gov, also outlined solutions to the roadblocks. Recommendations included ways to speed up clinical trial recruitment, employing repurposed drugs already approved by the FDA, and innovative funding opportunities. Drug Discovery & Development (DDD) spoke with Jeff Cummings, M.D., director, Cleveland Clinic Lou Ruvo Center for Brain Health and lead author of the paper, about how making these changes may still make it possible to reach the 2025 goal.
DDD: The paper stated 54,073 participants are needed to complete an Alzheimer’s trial. How can focusing on biomarkers facilitate the recruitment of qualified participants?
Jeff Cummings, M.D.: Biomarkers are essential to successful recruitment of a population of patients that truly have Alzheimer’s disease. The field is moving toward earlier and earlier treatment of patients, and in some cases we have prevention trials where people have no symptoms. Because of the biomarkers we know that they are at a very high risk of developing Alzheimer’s disease in the next few years. We can do a scan and show that they already have the protein of Alzheimer’s in the brain. As far as we know those people are on their way to developing Alzheimer’s disease but they don’t have a sufficient level of brain injury yet to have symptoms. Of course, that’s where we want to stop it, right when there are no symptoms. In prevention trials we are entirely dependent on biomarkers because that’s the only way we know the individual is a candidate for therapy.
Biomarkers are critical in terms of the early identification of patients who can participate in trials before they either have any symptoms or when they have mild cognitive impairment.
In the case of mild cognitive impairment, about 50 percent of affected individuals have Alzheimer’s and 50 percent don’t. You don’t want to put all of them in a trial with an Alzheimer’s drug. Half of them would get the side effects without the appropriate brain changes to respond to the drug.
DDD: What are there other obstacles in recruiting?
Cummings: There is a huge problem of recruitment for many diseases throughout the nation. The problem goes beyond Alzheimer’s disease; there is a general lack of awareness by the public of either the availability or the importance of clinical trials. The only way to get to new therapies is through clinical trials. There’s essentially no brain disease which is adequately treated right now with the current medications. Within the neurology space, we need many, many more clinical trial volunteers. But with other diseases, such as cancer and cardiovascular diseases, there is often too few people lining up for trials. It takes too long to identify them, recruit them, and educate them, and bring them into trial. We are losing valuable time that could be devoted to testing the drug’s effects.
DDD: Why are people not enrolling in clinical trials?
Cummings: Participating in trials is just not part of our culture. The science has not penetrated into the public consciousness in a way that makes them aware— the public just does not think about this. They are not aware that their condition often allows them to participate in a clinical trial and get great care in the trial setting. They are not aware that we are absolutely rigorous about the standard of care delivered in clinical trials and that they would be contributing to advancing therapies that they may need or their children may need.
In the Alzheimer’s trials, we insist that participants are on the existing standard of care. On top of that, they are randomized to either drug or placebo and there is an opportunity in most clinical trials—not all—to eventually be on active treatment after the blinded period is done.
One of the things that I think has to happen in this country is more public service announcements, a public spokesperson, or celebrities coming forward and saying that they are in a clinical trial to raise the consciousness of the need to participate in trials in order to get to a place where we have better medications for many more diseases.
DDD: Is trial recruitment the biggest bottleneck in the drug pipeline?
Cummings: It’s the biggest reason that Phase III trials, in particular, are slow. It’s also one of the biggest costs of Phase III trials. In many cases now, it takes us longer to recruit patients into a trial than it does to execute the trial itself. Let’s say the study has an 18-month treatment period, it may take us 24 months or more to recruit the patients and take them through the 18 months of therapy. So it’s longer to recruit the patients than it is to treat them in the trial. If we had many more volunteers and the capacity to engage them, we should be able to recruit a trial like that in six months and then the whole trial, including recruitment, would be done in 24 months. That would be a savings of 18 months or more and would get us so much closer to new drugs sooner.
DDD: Does the general public understand how long a trial takes?
Cummings: You wake up and your Google alert says, “Breakthrough in Alzheimer’s!” and that breakthrough is always in a mouse and the implications of that story is that this will soon be in humans. In truth, it takes 13 years on average to get from the mouse experiment to FDA approval. When a breakthrough occurs it’s a decade-and-a-half from what could be a market approval—and the mice have proven to be very poorly predictive of human success so a mouse breakthrough rarely predicts a human breakthrough.
DDD: What other obstacles did the report reveal?
Cummings: The observation in the paper that I think is so important is how few agents are in Phase I, because except for repurposing drugs, all the drugs that wind up in Phase II and Phase III come from Phase I. If we have a very poor entry in Phase I that tells you that you are not going to have the opportunity to develop a whole repertoire of treatment. That’s what we need—we don’t want just one treatment for Alzheimer’s, we want it to be like cancer or cardiovascular disease with precision medicine that allows us to match the patient’s profile against a selection of treatments. We don’t have that. We’re going to have to have several major treatments approved and in order to do that we need to populate Phase I much more robustly. That I think is one of the alarming parts of our study—the under population of Phase I—and what that predicts is the lack of development of a great repertoire of treatments down the pipeline.
DDD: What about repurposed agents?
Cummings: The attraction of repurposed agents is that you can skip Phase I and therefore bring in drugs in Phase II and Phase III. The reason I’ve been de-emphasizing that in our discussion is that usually these agents have very poor patent protection. They’ve already been approved for another condition and have been on the market so therefore pharmaceutical companies—that are in this for the revenue aspects in addition to the disease treatment aspects—are rarely interested in pursuing them. They don’t really represent an important alternative avenue because there is so little interest in them. But, there is a theoretical advantage. In fact, at the Cleveland Clinic we are pushing two drugs ahead that are in this repurposing channel, but we are doing it as academicians and not pharmaceutical companies with all the limitations that go along with that.
DDD: What can you tell us about those two drugs?
Cummings: One was developed for Parkinson’s disease. It was developed as a motor disorder treatment but it showed improvements in memory so we thought it should be tested in Alzheimer’s patients. We’re in clinical trials now. It’s called rasagiline.
There’s also a cancer drug that had a remarkable effect in mice with Alzheimer’s-type changes and we have completed a clinical trial showing that it also reduces the toxic protein in the brain of humans. Now that drug needs to be tested further in additional trials to confirm our current observations and determine if it is a likely treatment for Alzheimer’s. If that drug was a novel agent and we were a pharmaceutical company, we would already have done that. But we’ll have to wait for federal opportunities to advance the agent.
DDD: What about other strategies to support clinical trials?
Cummings: Insurance companies and Medicare are going to be major beneficiaries of any success in the treatment of Alzheimer’s disease. Medicare is paying out billions of dollars’ worth of care to Alzheimer’s patients and so are insurance companies. And yet, they are not required to help finance any of the drug development for the drugs that will benefit them so much financially. I think a great dialogue at the national level would be, can these financial entities that will derive great benefit from successful therapies, participate in supporting drug development? For example, without making a financial contribution, if Medicare said to everybody signing up for the program when they are 65, “Have you considered a clinical trial?” That would be enormously helpful, because as we’ve discussed, people don’t think about clinical trials. If the government said that to them, we’d probably get many more volunteers. They wouldn’t have to invest anything but they could substantially help the enterprise that they are going to benefit from in such a major way.
DDD: Was there anything that surprised you in the report?
Cummings: A very positive observation that we made was that in Phase II, there are many more targets of therapy. If you look at Phase III, most of the treatment is aimed at one single protein, amyloid. We have not been able to move amyloid targets to benefit patients yet. I think it’s very important that we begin to look at other pathways that might have beneficial effects so I was very encouraged to see that in Phase II many pathways are being explored; there’s not so much concentration on just one target. The fact that there are many biologically plausible targets that are being explored in Phase II gives me a little more optimism that were likely to be successful with some of those Phase II agents.