Disappointments In Alzheimer's Therapeutic Development — A Conversation With John LaMattina
By Rob Wright, Chief Editor, Life Science Leader
Follow Me On Twitter @RfwrightLSL
In January 2020, a reader submitted the following question to Life Science Leader’s editorial advisory board (EAB) for our popular Ask The Board monthly column.
“With the growing number of clinical disappointments in Alzheimer’s Disease, and the related number of big pharma companies pulling away from neurology, how will we meet the mounting cognitive and neurodegenerative needs of an aging world population?”
The question was sent to EAB member John LaMattina, Ph.D., senior partner at PureTech Health and former president of R&D at Pfizer. In his email reply, LaMattina wrote, “I think this topic merits more of a response,” meaning, the space normally allocated for these answers was inadequate for what needed to be said. He suggested we conduct a Q&A over the phone as it might, “prove interesting to your readers.” What follows is an edited transcript of that conversation from early February. Thanks to all our highly engaged EAB members who are willing to share their expertise, and to those readers who continue to pose thought-provoking questions!
What’s the neuroscience pipeline look like in Big Pharma?
I haven’t done in-depth research on every company, but I did do a cursory look, because everybody publishes their pipelines nowadays. At some of the Big Pharma companies’ (e.g., Pfizer, Merck, GSK, AstraZeneca) websites you can see what they have in their pipelines from Phase 1 to Phase 3, and for many of them, there are no neuroscience entries. Merck has only one schizophrenia compound, and it’s still in Phase 1. Of course, Merck is overwhelmed with a 1,000 Keytruda studies, and I don’t think that’s an exaggeration. Amgen has one compound for migraines, which they consider a neuroscience asset. There are exceptions, though. For example, Lilly has a lot of entries in neurosciences (e.g., Alzheimer’s disease), and so does Biogen. Novartis has a neuroscience grouping in their pipeline, but it’s really more MS, spinal muscular atrophy (SMA), Rett syndrome, a drug for addiction, and one for stroke — so not real in-depth. When I was at Pfizer, neuroscience was one of the company’s three key pillars. This is no longer the case. So, while the retreat from neuroscience doesn’t include every company, there has been a large withdrawal, as well as in some other therapeutic areas.
Why the retreat from neuroscience?
The major driver in neuroscience these days is Alzheimer’s. That’s a tough area to work on, as evidenced by the issues that occurred in the various beta amyloid clinical studies that are ongoing, all of which were uniformly negative. We can debate what Biogen might have found, but for the most part, multiple studies were all pretty negative. This poses two problems in the immediate Alzheimer’s area. The first involves largely using biomarkers to get proof of concept (POC) studies in Phase 2 (e.g., beta amyloid levels), and then you launch a Phase 3 study with a lot of patients to see if you can get an effect on cognition. Theoretically, if you’re stopping or reversing Alzheimer’s disease, then you should see an impact. Those studies aren’t incredibly difficult to do, but you still need to figure out when to dose patients. A lot of the early studies took the sickest patients so that any effects would been seen quickly. But when nothing happens, you think, “Maybe we’re not dosing long enough.” So, then you run longer studies, but that didn’t work out. So, you go back to moderate patients, thinking that maybe if an Alzheimer’s patient has gotten too far down the line it’s not going to work. Those didn’t work either. So, then you think, “Let’s go early-stage.” But the problem is, once you go very early on, now you’re dosing people for five or six years to see an effect. This mean having to run clinical trials on at least 1,000 patients, maybe more, for a very long time to see something, and really, you don’t even know how to dose. I suppose there are ways to figure that out (e.g., imaging studies), but it gets complicated. Further, the main theory around Alzheimer’s disease seems to be flawed, despite animal and biomarker studies providing data that looked good. It seems like we keep going back to square one, and there isn’t a plethora of established Alzheimer’s disease mechanisms. And for any new mechanism, you’re looking at a long period of time to prove.
Faced with the types of challenges Alzheimer’s disease drug development presents, biopharmas are asking, “Do we want to invest some billions of dollars in this over the next five to 10 years, or, do we want to go after something where there’s a major medical need? Something where we can run clinical studies in Phase 2 and 3 of maybe only 1,000 to 3,000 patients? Something where there’s favorable pricing or strong patient advocacy?” You’ve seen a retreat from areas that require long-term studies and a lot of funds to get to the goal line (i.e., Alzheimer’s disease) to others where there’s still a high unmet-medical need, but without the same level of investment. As for the retreat from other neuroscience diseases (e.g., depression, anxiety, and schizophrenia), there are already drugs in the market to treat those diseases. And while these therapeutics aren’t perfect, they’re all generics, which means they’re cheap. So, if you’re working in an area that’s well served (i.e., depression) with drugs either soon becoming or already generic, then whatever you’re coming up with must be really good and superior to existing drugs. And, even if in comparative studies you’re able to show that your drug is superior to what’s already out there, payers, when they get a newly diagnosed patient, are going to have them go through drug A, B, C, and D (all generics). Only if the patient fails on those will they then have the chance to be put on the new medication. While a drug developer may be able to charge a premium price for its new treatment, the reality is that the market size has been greatly reduced right out of the gate. Furthermore, in an area like depression you have a white-coat effect (i.e., high response to placebo), meaning, the patient might not necessarily be better on drug A, B, or C, but they think they are, so they never get to yours. As such, companies are weighing the benefit of trying to develop a new treatment for something like depression versus working in areas where there is less competition (e.g., oncology and rare diseases).
Given the high rate of failure in Alzheimer’s drug development, should we be looking at creating some type of international drug development consortium focused on the disease?
Getting people to work together, especially early, is certainly important. But perhaps we need to consider diverting a lot more of the NIH-funded research away from oncology (at the moment), as we seem to have plenty of promising pipeline activity going on there. Before long I anticipate cancer being similar to AIDS from the standpoint of becoming (for the most part) a treatable disease controlled using cocktails of drugs, whereas in Alzheimer’s, there’s almost nothing. And, as fewer people die from traditional things (cardiovascular disease) and live longer, we must remember — Alzheimer’s is a disease of the ageing, so we can expect to see more of it. Further, there could be those who live for 10 to 12 years with the disease. But, if these patients can’t live independently, Alzheimer’s could prove to be a tremendous drain on the economy. From my perspective, Alzheimer’s disease is a field ripe for small biotech startups interested in exploring different things. And if these startups can get something to proof of concept, then it could be taken on by a bigger company with the funds to take it the rest of the way.
Might Alzheimer’s be an area for digital therapeutic companies?
Akili Interactive is using technology that came out of UCSF (University Of California San Francisco) to use video games to help patients with cognitive disorders. In fact, Akili is in front of the FDA trying to get approval for this technology for ADHD. But the company is also looking at enhancing cognition in patients with cognition difficulties in major depressive disorders and schizophrenia. Although I don’t know if Akili is doing anything in Alzheimer’s, it seems exploring different approaches to treatment is warranted.
What about the work in depression being done by Sage Therapeutics?
Sage Therapeutics has been through some interesting times. They have a drug that’s given in the hospital intravenously to treat postpartum depression (PPD). As it was proven to work, they got an FDA approval. But then the company took an oral analog of that and ran a depression trial, which didn’t work. This is one of the major challenges in CNS drug development (i.e., things with tremendous potential that don’t work, you don’t necessarily know why, other than the possibility that maybe the placebo responded well, which happens a lot in depression trials). Now you’re faced with having to run another study or two with no guarantees you’ll be successful.
Anything you’d like to add?
There are many who believe we are in the dawn of a new neuroscience era. However, I would add that the big difference from a decade ago is the impact payers are having on medicines. Just because the FDA approves the drug, doesn’t mean it’s going to be on an insurance company’s formulary. In fact, insurance companies have been very hard on reimbursing or putting on formulary a variety of FDA-approved drugs. From Sarepta Therapeutics’ Duchenne muscular dystrophy (MD) drug all the way through the PCSK9 inhibitors, insurance companies are making biopharmas justify that their patient is the exact same as those in the Phase 3 trial used by the FDA to approve the drug. How insurance companies are impacting how health is managed in the U.S. is a whole other area worthy of exploration in this country.