Drugs to Watch: Innovation in Alzheimer’s disease research – transcript

Ideas to Innovation

Announcer: The Ideas to Innovation podcast from Clarivate.

Joan Walker: Hello, I’m Joan Walker, and welcome to the Ideas to Innovation podcast. In this brand new series, we’ll be talking to the people who live and breathe the process of turning ideas into innovation. The technologies that we depend on, the medicines that we rely on, the electricity that powers our day-to-day life, they were all once ideas before becoming inventions, inventions that have changed our lives for the better.

Join the conversation with experts and industry leaders to discuss innovation at its core. On June the 7th, the US Food and Drug Administration approved aducanumab, the first new Alzheimer’s treatment since 2003. Aducanumab is a monoclonal antibody that has been shown to reduce the build-up of a protein known as beta-amyloid, that some think might be one of the possible causes of Alzheimer’s disease. While the approval has been applauded by some, it is not without controversy.

Today, we have guests from three biotech companies who are developing potential treatments of Alzheimer’s disease and will reflect on how that FDA announcement might impact their and other’s efforts in finding new ways to combat the disease. We’ll also talk with Jerre Stead, Executive Chairman and CEO at Clarivate about what impact the aducanumab approval might have on people with the disease and those who care about them.

Joining us today are Mei Mei Hu, Chief Executive Officer at Vaxxinity, Hans J. Moebius, Chief Medical Officer at Athira Pharma, Raymond J. Tesi, Chief Executive Officer and Chief Medical Officer at INmune Bio, as well as Jerre Stead, Executive Chairman and Chief Executive Officer of Clarivate PLC, and Jonathan Searles, Senior Director on the CNS and Ophthalmology therapy team at Clarivate. Welcome all, and to get the conversation going, I would love to hear each one of you. Tell us a little bit more about yourself, and more specifically, what sparked your interest in Alzheimer’s disease in the first place? Mei Mei, tell us how you started out in this industry.

Mei Mei Hu: I actually took quite a circular route. I grew up in biotech. I heard biotech discussed at the dinner table, but I walked a completely different direction and was actually trained as an economist and a lawyer, then went into management consulting. About 12 years ago, actually came back through a series of unrelated events, back into the industry. I came back mostly because this seemed to be the area where you can have the most impact on human health. Alzheimer’s is one of the largest areas of unmet need. It presents this privileged position to be working on something that can impact so many.

Joan: Thank you, Mei Mei. R. J., over to you.

Raymond J. Tesi: What got me interested in Alzheimer’s was the frustrations with drug development with anti-amyloid therapies. I asked the question, “There’s great technology, there’s a lot of science behind it, why are they failing?” As I made the deep dive into the role of amyloid in Alzheimer’s disease, it became clear to me that one of the pieces that people weren’t thinking about is that neuroinflammation actually causes amyloid to form and then amyloid causes neuroinflammation. You get this pathologic cycle of neuroinflammation causing plaque formation causing worse neuroinflammation. It is actually the neuroinflammation that causes nerve cell death and synaptic function. My opinion, instead of targeting amyloid which is a strategy, why not target neuroinflammation, not only preventing plaques but also preventing the results of plaque? We went to look for a drug, found XPro1595, and here we are about to start a phase 2 trial targeting neuroinflammation as a cause of cognitive decline. Thank you.

Joan: Thanks, R. J. Now, Hans, how did your interest in Alzheimer’s begin?

Hans J. Moebius: I would kind of mirror that by saying I actually was initially trained as a neuropathologist. I really learned about the underlying structural changes in Alzheimer’s and other dementia’s. Later on, when I did my residencies in neurology and psychiatry, I was actually shocked about how limited our possibilities or therapy were and on the other hand, also how slow academic clinical research is, which then brought me into the industry in the ’90s Big Pharma in Switzerland. From there on, it’s always been my preferred soapbox, if I may say so.

Joan: Jon, tell us a little bit about the one you do at Clarivate related to Alzheimer’s research.

Jonathan Searles: Sure, happy to. I work in the healthcare and data solutions unit at Clarivate, which is part of our broader science group. More specifically, I’m a part of a team of about 15 or so people that conducts various types of market research studies on some of the most prevalent CNS and ophthalmology diseases. In our research, we use a range of methodologies to assess unmet need and opportunity and disease areas to analyze current treatment paradigms in different geographies, examine the impact of reimbursement policy on prescribing, and also create forecasts for current and emerging drugs. Within the CNS team, I lead a small group of analysts who focus specifically on neurological diseases that includes multiple sclerosis, epilepsy, migraine, Parkinson’s, and of course, Alzheimer’s disease.

Joan: Thank you, Jon. Last but surely not least, Jerre, tell us about your interest in Alzheimer’s disease.

Jerre Stead: Thank you. Thank you all for participating today. My mother ended up having Alzheimer’s. Actually, wasn’t diagnosed for many years. It was some sort of dementia. I always tried to figure out how that makes a difference. I joined the Alzheimer’s Association national board and was very pleased with the progress, but wanted to see things happen quicker. 16 years ago, actually next week, we started the Alzheimer’s Research Institute that Mary Joy, my wife, and I founded, which later became the Banner Alzheimer’s Institute. We’ve been very, very active for years and are very excited about the progress today.

Joan: Absolutely. Thanks, Jerre, and thank you all.

Announcer: The Ideas to Innovation podcast from Clarivate.

Joan: With those introductions and preliminary thoughts shared, let’s get to the heart of today’s discussion. Today, we’re talking about aducanumab and Alzheimer’s disease, an irreversible, progressive brain disorder that slowly destroys memory and cognitive function, and, eventually, impacts the ability to carry out even the simplest of tasks. The most common cause of dementia among older adults, Alzheimer’s disease is currently ranked as the sixth leading cause of death in the United States and affects more than 50 million people worldwide.

Yet, unfortunately, we still do not fully understand what causes the condition in most people. Until recently, the only medications, approved to help Alzheimer’s patients, treat symptoms but do not affect the underlying disease. Let’s look at what else is in the pipeline that might one day help patients and their carers. Jon, coming to you first. I read that aducanumab was one of the molecules that the Clarivate team selected as one of the Drugs to Watch this year. Could you explain why it was selected as a Drug to Watch, and what it means to be a Drug to Watch?

Jonathan: Sure. The Clarivate Drugs to Watch series identifies new therapies that have potential to reach blockbuster sales within five years, and aducanumab easily fits this definition. In the US, our epidemiologists estimate that, today, there are several million prevalent cases of early-stage AD, which would be the target group for most disease modifiers. The large and rapidly growing population, plus the drug’s price, plus high unmet need as we were mentioning earlier, and market demand will drive billions in revenue for aducanumab and really transform today’s generic AD market into a high-cost specialty market.

The drug will also certainly be disruptive, spurring a dramatic shift potentially in the management of AD. It could increase patient presentation. It’s likely to drive more cognitive screening and primary care. It will increase referrals to specialists who will be the primary prescriber base for therapy like aducanumab and who will probably face a big adjustment to accommodate the surge in demand. It will also shift the diagnostic process from one that is mostly clinical today to one that more routinely incorporates the use of biomarkers to confirm diagnosis and select candidates for treatment.

It also introduces a monthly infused biologic with potential safety risks into a treatment landscape that to date has comprised a handful of, as you mentioned, modestly effective symptomatic therapies but also highly safe small molecules, most of them orally administered by patients and caregivers at home. Then, finally, I guess I would say the introduction of the first potentially disease modifying therapy for AD simply marks a huge clinical and commercial and regulatory milestone.

It has the potential, at least, to improve outcomes for some patients. You take that, plus the controversial nature of the product, the financial impact it will have on the healthcare system, especially Medicare, and the effect it could have on drug development which we’ll talk about, all of these factors together make aducanumab a “Drug to Watch.”

Joan: Thanks for that, Jon. Mei Mei, aducanumab, as we’ve already heard, targets beta-amyloid which is also what you’re focusing on. Can you say why you think beta-amyloid is a good target and how your approach at Vaxxinity differs from that of Biogen?

Mei Mei: Sure. There are many ways to evaluate a target for disease, and I’d say, one of the strongest is by looking at genetics. In this vein, the evidence is unbelievably supportive of the role of beta-amyloid in Alzheimer’s disease. For the general population, a genetic marker for the overproduction of amyloid is associated with an increased risk of getting Alzheimer’s, and there are also subsets of familial amyloids where there’s genetic populations who have almost 100% chance of getting a form of Alzheimer’s that’s directly associated with the overproduction of amyloid.

This isn’t new. Many of the diseases that we treat today, that are associated with biomarkers, have been discovered via genetic links. One of the most common examples is cholesterol. It took over 50 years though to find out how to develop a drug to prove that the link between cholesterol and heart disease, but it’s a very strong and linear way of connecting. In that sense, amyloid, we believe, is definitely implicated in Alzheimer’s. It doesn’t mean that it’s easy to treat and figure out how the mechanism works, but Biogen’s aducanumab or aducanumab has really paved the way for further exploration.

In terms of how our Vaxxinity differs, we’re in active approach, which means that what we do is we teach the body to develop antibodies to neutralize this toxic oligomeric beta-amyloid. The alternative aducanumab is where you actually produce these antibodies outside the system [unintelligible 00:12:39] that and have to passively inject on a monthly basis. One of the advantages is, one, we’re more convenient. We turn your body into a drug factory. As a result, you don’t have to get treated as often. We can get quarterly or bi-annual treatments, and it’s simply a cost and sustainability of treatment as well. Rather than costing quite a lot, ours is much more affordable and ultimately accessible to the large population around the world. Those are the main differences and what I consider and why I consider beta-amyloid to be a very good target still.

Joan: Thanks for that, Mei Mei. Now, Hans, in your career, you have been involved in extensive R&D projects focusing on Alzheimer’s disease. What was it about the Athira approach that convinced you to join as CMO two years ago?

Hans: My answer is I was impressed by the sound basic science that Athira has produced in almost a decade before hitting the clinic with ATH-1017, our lead compound. I have been very critical in the past of projects that are jumping all too quickly into this stage. I think that I would like to refer to Mei Mei, it’s all in the genetics. The Allen Institute for Brain Science has shown that the MET receptor is the predominant key element for brain homeostasis and neurotrophic action.

Athira has chosen a path for small molecule, not a vaccine or an antibody, that is crossing the blood-brain barrier, and with very high specificity, activating the HGF/MET system and that has a pluripotent downstream effect via secondary messengers intra-neuronally that are on the neurotransmission level, and I’m referring, I think to R. J. before, but one of them is also inflammation. On the basis of broad preclinical experimentation and safety, Athira made the step into the clinic. That is a convincing approach, also using translational biomarkers or measures that are a departure from proteins that are still being used as predictors for provocative effects, actually the basis for aducanumab approval, not clinical efficacy.

Joan: Great. Thank you. Now, R. J., we’ve already heard about two approaches, beta-amyloid and improving neuronal health by promoting natural repair systems. Can you tell us about the approach you’re taking at INmune Bio?

Raymond: Yes, thank you. First, I’d like to make two quick comments on earlier statements that were made. One, in the lead-in, the comment was made that cognitive decline in early Alzheimer’s disease is irreversible. I think that’s too low of a bar for us to set. In other words, our view is that the two things that cause cognitive decline are synaptic dysfunction and neuronal cell death. Early cognitive or early AD has defined as MCI and maybe early mild AD is probably, at least in our opinion, a synaptic dysfunction disease. That means the nerve cells are, in fact, intact, but you’re just unable to tap the information that’s in those cells.

If you repair synaptic function, re-establish those synapses, you should actually get the patient back towards normal. We think that, this decreasing the rate of decline of cognition, is a bit of a low bar. We think that we can do better. We meaning the biopharma field, and certainly, we at INmune Bio. The second thing in the Drug to Watch comment, one thing I think was not mentioned was that when aducanumab was approved, we walked from the darkness to the light. What do I mean by that? In the drug development field, and I think the other two people can agree with this, there was considerable, shall we say, doubt among investors that a drug was ever going to be approved and getting investment could be challenging.

As soon as that approval occurred, suddenly, the conversation of how to fund drug development in Alzheimer’s disease became one you could have in polite company became vibrant, and most importantly, became productive. As you know, since financing or funding is the lifeblood of our industry, having funds come to small companies like ours to allow innovation is what’s really going to change the field. Aducanumab really was the key that opened a very important door. Finally, what are we doing? Well, I mentioned in my introduction, we’re all about neuroinflammation. We target soluble TNF, which is a very important cytokine in the chronic inflammatory cascade which drives glial activation in the brain.

You have to get rid of soluble TNF without affecting transmembrane TNF because transmembrane TNF is actually important for neuronal and oligodendrocyte function. Why am I mentioning oligodendrocyte? Isn’t Alzheimer’s disease a gray matter disease? No, absolutely not. The first manifestations of the disease are in the white matter. Demyelination is an important part of this disease. When you’re targeting therapeutics for Alzheimer’s disease, there are targets in the white matter, there are targets in the gray matter. There are abundant targets. In the end, innovation will win. We believe that neuroinflammation is a key pathology, and that’s what we target.

Joan: Thank you. Jerre, in your introduction, you told us about your involvement with the Banner Alzheimer’s Institute. Could you explain in more detail how it seeks to help people affected by Alzheimer’s disease?

Jerre: Yes. We set it up 15 years ago with three goals. One was to become the center in the country and the world of helping patients and families. One of the things we learned when my mom was finally diagnosed as there was a very little education about how to prepare. Today, we’ve accomplished that for actually thousands of patients all over the country and the world now. We, actually, certify centers around the world and being able to provide the education that so badly needed for the patients and for the families.

Two, we said, we were going to try to do our best to provide a leadership role in finding drugs that would provide prevention. We focused on prevention. Many of you probably know, but we’ve run five large studies for pharmaceutical companies. What  R. J. just said, I’m so excited about it because the breakthrough of that approval, even though it’s an important one from the science standpoint, it’s a much more important one from a financing standpoint for research because our hearts were broken over the years with many of the major pharmaceutical companies in the world stopping because of not feeling they were going to get the funding to accomplish that. That’s a huge breakthrough.

The third thing we’ve done, and coincidently later today, I am hosting Dr. Eric Reiman who leads the Banner Alzheimer’s Institute, and Dr. Aaron Cohen who is one of the top three or four brain surgeons in the world, to continue the subject which is how do we try our very best to bring consensus together on the best protocols because one of the things that I saw and still do is that because of the complexity of the disease, there is an enormous amount of money spent around the world without focus of trying to balance that money into three or four major efforts.

By the way, the ones you are hearing today from our panel which I’m very thankful for, are all very exciting ones. This is a wonderful thing to be able to talk about. I have a great goal. Our goal now today with Banner Alzheimer’s and the Alzheimer’s Association is that before the end of this decade, the decade we are now in, we’ll find a prevention that will give us the chance to take this disease off the leading killer issue we all live within the world today. So, it’s very exciting.

Joan: Thank you, Jerre. Now, Jon, we’ve been introduced to some alternative approaches in the development of treatments for Alzheimer’s disease. When you look at the R&D landscape for AD treatments, which are the most popular targets and what additional interesting approaches are you seeing?

Jonathan: Sure. In preparation for this, I took a look at Clarivate Cortellis Life Sciences platform. It shows more than 700 drugs actively in development for AD, globally. The bulk of them are in discovery and pre-clinical phases, but there are about 200 or so in clinical development. The pipeline is very large. Beta-amyloid, to me, thus appear to be one of the most common targets to various mechanisms, but there really is a diverse mix of novel mechanisms of action, like, the interesting strategies that Mei Mei and Hans and R. J. just discussed, and a range of others.

One thing I might call attention to is the increase number of anti-tau approaches that are in development now, tau tangles, like, amyloid plaques or pathological hallmark of AD, but one that historically has lagged behind amyloid as a target for drug development, but in recent years, we’ve seen a surge in development here. They are about 2000 or so compounds in phase 1 and phase 2 trials which encourages the experts that we talked to in the field, but clinical success still here is far from certain. In fact, we’ve already seen the failure of two anti-tau monoclonal antibodies in early AD, one from Roche late last year, and in fact, another just reported yesterday by Biogen that has now been discontinued.

We await more results, and in fact, we might get some read out soon from trials that might complete this year from companies like Genentech and AbbVie and others. The last thing I might just recently mentioned is the past few years is also seen increased development focus on the neuropsychiatric symptoms of dementia including agitation and psychosis. These are very disruptive and distressing symptoms and they frequently lead to patients being placed in nursing homes. There are no therapies that are currently approved for these symptoms.

I think there’s some important development ongoing in the symptomatic space as well, led by companies like Lundbeck and Otsuka and Acadia, and smaller companies, like Axsome and BioXcel. These have potential maybe for some approvals in the next years if efficacy is demonstrated. There’s a lot of exciting things ongoing.

Joan: Thank you, Jon. Now, turning back to our biotech guests, Mei Mei, Hans, and R. J. Could you each tell us what proof of concept or principle for your approach you’ve already seen and describe where each of your programs is in the clinical development timeline, and when you anticipate hitting your next milestone? Mei Mei.

Mei Mei: We are very excited because we are using a new technology for chronic diseases in terms of an active vaccination approach. The first proof of concept we’ve hit is to be able to show that we can consistently and safely break immune tolerance in virtually 100% of elderly patients. That basically means that we’re able to turn the body into a real drug factory safely, yet 100% of folks to develop this anti-bodies and at therapeutically meaningful levels. I think it’s one of the first times that any technology has shown these. Moreover, in our amyloid vaccine program, we’ve ran two clinical trials thus far.

They have shown– we’ve tested a number of cognitive and biomarker endpoints and, let’s say, we have a proof of principle that shows trends in all of her secondary endpoints. We see some dose-dependent response where we see slowing up disease progression as measured by this cognitive measures as well as by biomarkers that measure amyloid in the brain. We’re currently preparing for a large scale trial for prevention abroad and a treatments in the US and other countries. We hope to start that in the next 12 months, potentially even accelerated given last week’s aducanumab approval.

I think as the others speakers have mentioned, one of the benefits of the FDA decision is kind of a renewed interest both from investor, scientific sentiments in this phase. It really will allow for more research to occur at a more rapid pace. As you know, Alzheimer’s trials do take quite some time. We are looking at– our next milestone will be the start of the trial within the next 6 to 12 months.

Joan: Thank you, Mei Mei. Hans.

Hans: Sure. I can only agree what was said before, namely, we must not forget that there is more than cognition to Alzheimer’s disease, and in particular, pharmacoeconomics also very much driven by BPSD, behavioral and psychiatric signs of dementia. They deserve more attention. There is more attention now. There are several companies following that. At Athira, we have been using quantitative EEG as a non-invasive fully translatable instrument to predict cognitive decline. In humans, we have been using event-related potential, P300, which is well established in the literature to go hand in hand with cognitive improvement with currently marketed drugs.

We were able to show that ATH-1017 has three to four times the efficacy in terms of improving in P300 latency, which is nothing but a reflection of synaptic health if you will because it’s a summary potential in measuring processing speed in large neuronal networks. We have leverage that to consistently show pharmacodynamic effects, but also to show that with gamma power and quantitative EEG, ATH-1017, those dependently influencing brain activity, and thus, we were able to move on quickly and we have currently a phase 2 and a phase 3 trial running.

Joan: Thanks, Hans. R. J.

Raymond: Thank you. First of all, I want to just comment on the earlier speaker talking about the importance of education and to families in this disease. One of the things that made me chuckle with the whole run up to the aducanumab approval was people were so focused on the patient. There’s no question, the patient is important, but when you’re developing a drug for Alzheimer’s, you’re really developing a drug for the caregiver and the family, as much as you’re developing a drug for the patient, that the impact of dementia on the primary caregiver and the nuclear family is undeniable. It is life-changing and it is very rarely understood by many, not only in the field and outside the field that haven’t experienced it.

The whole role for education is key, and people need to realize that we are actually treating a much– We’re not treating one, we’re treating a bunch of people with a single drug. If you can affect the patient with dementia, you change the lives of many. Now, onto us, we focused on neuroinflammation. We approached our clinical development as a two-step process. The first trial was to prove that our drug decreased neuroinflammation in patients with Alzheimer’s disease. We did this in a short clinical trial with our primary biomarkers being neuroimaging. We look at white matter free water, which is a validated biomarker of neuroinflammation in these patients.

XPro1595, which is pegipanermin, which is the USP name, is actually decrease neuroinflammation in all these patients, which is great. That was we met our goals, but people said, “Okay, you decrease neuroinflammation, so what?” The, so what is, what are the downstream effects of decreasing neuroinflammation? Once again, we turn to our imaging techniques. In the white matter, we look at apparent fiber density, which is a measure of the health and quality of the axons in the white matter tracks on the brain. We show that over a nine-month period, we actually dramatically increase the number and quality of the white matter or the axons in those white matter tracks.

Then using cortical disarray measurements, we measure the cortical stacks, which are in the gray matter, which you can determine the quality of both neuronal survival and synaptic function or synaptic connections in the gray matter and we showed over nine months that you see improvements in the cortical disarray measurements. That is to say in these 70-plus-year-old patients when you get rid of neuroinflammation, you actually see remodeling of the brain in a positive way. I graduated medical school in 1982. I was gobsmacked by these results because I was taught the brain could not change after adolescents.

We see it’s remodeling, but so what? Well, we need to not– We measured neurocognitive impacts on these patients, but we had a broad range of patients with MMSE from 24 all the way to 12 in this trial. It was a mix, but we have a couple of anecdotes. Our favorite anecdote is a patient that showed– Had to retire from his job because of dementia and took the drug for– He was actually been on the drug for a year. At six months, he went back to work. He actually showed improvement, and all his colleagues and his clinicians said that he had no evidence of dementia.

It’s an anecdote, but the fact is, if you get rid of neuroinflammation, you seem to get remodeling of the brain and the important areas associated with cognition, which is the white matter tracks associated with the temporal lobe and the cortical stacks in the gray matter in the temporal lobe. This seems to translate into benefits of cognition. You can imagine we’re quite excited. We’ll be initiating a phase 2 trial in the fourth quarter. It will be a blinded randomized placebo-controlled trial. One of the great advantages of going after neuroinflammation instead of amyloid or tau, the trials are much shorter than the typical amyloid trial, which is 18 months.

Joan: Thanks, R. J. Now, Jerre, hearing what our biotech colleagues have to say, how inspired and optimistic are you about the future for Alzheimer’s patients?

Jerre: I just want to thank Jon and our three guests today because this has just been a very positive, exciting step forward in our pursuit of excellence for around the world to make this disease a history. I’d say two things, five years ago this week, I had the honor of speaking to 5,000 executives and researchers in Toronto, all focused on the disease and what we’re going to do. That gave me great hope, and I asked them to stay focused, stay positive, and be convinced that together we could make this happen. Today, because of listening to this group, I have a better more positive belief than ever before that we will indeed be winners in this race for success and the survival, as both R. J. and I said, for millions, multi-millions of people. It’s very unusual, I go any place today and talk with anybody that has not had a family impact. I’m very optimistic, very hopeful. I’ll continue to raise the funds that we need at Banner Alzheimer’s Institute, and I thank you all very much.

Joan: Lovely. Thank you for that, Jerre. Jon, developing new medicines is a lengthy and difficult exercise and probably no more so when tackling neurodegenerative diseases. We heard that aducanumab is the first new Alzheimer’s treatment to be approved in almost two decades. What has been the delay and what can we learn from the aducanumab experience?

Jonathan: From my vantage, there are a number of challenges that historically have made progress in this area difficult. First and foremost, despite truly incredible progress that is continuously made in our understanding of Alzheimer’s, there are still knowledge gaps that persist regarding our understanding of the underlying causes of the disease and the complex pathophysiology of the disease, which has made pinpointing targets for disease modification difficult in the past.

In terms of clinical development, failed trials of disease modifiers in the past, probably recruited patients too late in the disease process to show benefit, for example, in mild to moderate disease. As a result, most trials now enroll patients with “early AD” which R. J. defined earlier comprises mild cognitive impairment due to AD and early mild AD. Patients are also now screened for evidence of AD pathology prior to enrollment to ensure that patients with non-AD dementia are not recruited, which could have confounded past trials that relied on clinical diagnostic criteria.

In addition, some of the endpoints that historically had been used to measure cognitive outcomes like the ADS cog might not have been sensitive enough to detect subtle changes in cognition early in the disease process, which has led to the use of other primary endpoints in modern trials. I would also say it’s important to remember that each drug is different, not only fundamentally by different mechanisms of action, but even within a mechanism, there are different binding profiles or different specificities for their targets among different drugs. This may have contributed to the failures of prior anti-amyloid approaches, some of which might not have had a very robust effect on amyloid, to begin with.

To the second point of your question about lessons learned from aducanumab, I guess a few things come to mind. In my view, the trials were well-designed. They were sizable. They had an appropriately long timeframe. They enrolled patients early in the disease, which I assume contributed positively to the results. The results of the one positive trial highlight the importance of dosing. Only patients who received the highest dose for longer periods of time showed benefit. We’re seeing the importance of dosing elsewhere. Roche has increased the dose of its anti-amyloid drug gantenerumab, in its latest phase 3 study, and insufficient dosing might’ve contributed to the failure of Eli Lilly’s solanezumab several years ago.

It’s also worth pointing out that some companies developing disease modifiers, including Biogen with aducanumab have bypassed traditional phase 2 studies. The downside here is that this introduces additional risk. When you think about the many late-phase failures that have happened, or even trial design modifications that have been needed, which occurred with aducanumab, this, to me, underscores the importance of robust proof of concept studies. Then finally, I would just say, the observed benefit with aducanumab is limited, and the drug is not risk-free. To me, the signal is the ample opportunity that exists for more targeted therapies or entirely novel approaches that could be safer and potentially more effective.

Joan: Thanks. Now, we highlighted that the aducanumab approval is seen as controversial in some quarters. Why has the approval not being universally welcomed?

Jonathan: There are many reasons for the mixed response with aducanumab. I see them falling into a few main themes. First is the lingering questions about the drug’s effectiveness. The two phase 3 studies for the drug were not completed and the results are divergent and based on post-hoc analysis. The FDA advisory panel that reviewed the product last November felt that those data were insufficient to meet the regulatory threshold for approval. There are others that agree with that assessment and have expressed concern that the decision sets maybe the wrong precedent by potentially lowering the bar for approving efficacy in AD.

In the accelerated approval, the FDA took the position that a reduction in beta-amyloid is reasonably likely to show clinical benefit, and that very way, well be true but the amyloid hypothesis itself is still a topic of intense debate in the field. There’s also been concern raised about the drugs broad labeling for the treatment of Alzheimer’s disease, even though the clinical trials were conducted in early AD. This isn’t the same approach that was taken with the symptomatic therapies we have for AD whose labeled indications match the clinical trial populations, mild to moderate AD or moderate to severe AD. As a result, the decision of eligibility is likely going to be left up the payers.

Right now, all eyes are on CMS to see what coverage restrictions they might impose. That brings me to my next point, which Mei Mei mentioned earlier, is the cost. There’s been a lot of criticism about the cost of aducanumab, which has a list price of $56,000 per year at the maintenance dose. According to a recent analysis conducted by the Institute of Clinical and Economic Review, that price point well exceeds the value of the drug based on their most optimistic interpretation of the data.

In fact, last week, the Alzheimer’s Association which is hailed the drug’s approval, called that price unacceptable and expressed concerns about out of pocket costs for patients and families and inequities and access that no doubt there are more expensive products on the market, including those relevant to this demographic, but the total cost of the drug to Medicare, the administration, the testing, the monitoring, could be staggering. I guess, finally, many have voiced concerns about the impact on drug development. There’s concern that recruiting AD patients into trials will become harder with the drug on the market.

There’s concern that investment, while it will grow, could be channeled disproportionately towards one mechanism at the expense of other innovative approaches that are also sorely needed. As R. J. and Mei Mei and Hans have mentioned, perhaps we’ve moved into an area, from the darkness to the light. As R. J. said, that investment will now sort of meaningfully grow across the board in really important ways. I certainly look forward to hearing any additional thoughts on that.

Joan: Thank you for that, Jon. Now, to wrap up this fascinating conversation, I’d like to end on an upbeat note. I’d like to ask each of you to tell us what you are seeing that should make us all be a bit more optimistic about the future treatment options for Alzheimer’s disease patients. Mei Mei.

Mei Mei: Every decision has pluses and minuses, but a good decision is one that has more pluses. In this case, the aducanumab approval has been so “controversial” because the sponsor’s rollercoaster ride that they took us on, but what it really shows is that the FDA has a willingness to be flexible in this area. That’s incredibly encouraging. They’re trying to operationalize the concept of flexibility, and it takes courage to do that. I applaud the FDA for their decision.

It has massive implications. The first is, of course, it means that there’s another treatment available for Alzheimer’s patients. Like wine, we only find out what we like with options. It’s the same for patients. The more treatments that are available, the better that clinicians can cater to each individual. Beyond that, it opens up the area of research, and it reinvigorates the field in both investment and scientific interest and curiosity. That always bodes well for not only the drug development industry, but ultimately for patients because it gives them more opportunity for breakthroughs in the future. I think it’s a fantastic outcome for the field.

Joan: Thanks for that, Mei Mei. Over to you, Hans.

Hans: I’d like to emphasize, in a way of us what was said before, the approval of aducanumab is certainly also a paradigm shift at the FDA, which shows more emphasis on biomarkers. We will see how this is going to play out in the future with other alternative approaches. What’s important, it’s invigorating the field. It is also in keeping with my experience talking to the FDA on our biomarker approach and we will see readout of our first pilot trial towards Easter next year, I think, and of our first potentially pivotal trial with ATH-1017 towards the end of next year. I think that will be an important calendar also because it’s the first highly specific small molecule agonist approach to the most important neurotrophic system in the brain, which is depleted in Alzheimer’s disease.

Joan: Thank you. And R. J.

Raymond: I’m on record of saying that we have entered the golden age of Alzheimer’s disease drug development. It’s for all the reasons that have been said. I like to look at the regulatory changes as the FDA, the CNS division, really taking the perspective that the oncology division has taken. If you look at the way oncology drugs are developed, there were small trials, heavy use on biomarkers, really targeting special patient groups based on selection criteria. That’s where we need to go and are going in CNS. The regulatory change is a critical point.

The second has already been mentioned as the influx of funds. Without financing, you can’t have the innovation. When I look at the cancer field, I think you’re beginning to see people look towards Alzheimer’s as the place they want to be in the next three or four years. If you get all these great minds focused on solving such a difficult disease, progress will be made. Finally, I think that the most important part of aducanumab approval is that you now have the opportunity for combination therapy. Why am I so excited about combination therapy? There is almost no complex disease on the planet Earth that is not treated with combination therapy. Look at cardiovascular disease, look at oncology, the list goes on.

Why have we assumed that Alzheimer’s disease was going to be treated with monotherapy? It is a complex disease. There’s probably multiple disease types under that Alzheimer’s disease umbrella. Combination therapy is where we will end up in a majority of the patients. You need that first drug approved, so you can then start doing combination therapy. That’s the future and we’re excited about it.

Joan: Thank you. And Jonathan, please.

Jonathan: Sure. Thank you. To me, there are many reasons to be optimistic about the future. First, and I think this panel really confirms its view. It’s just really encouraging how large and mechanistically diverse the AD pipeline is, which increases the chances that future disease modifiers will deliver even better outcomes. Yes, there’s monotherapies, but just like R. J. said, potentially, more importantly, in synergistic drug combinations. I would say awareness of the disease is likely at an all-time high, a part of the golden age that R. J. mentions. I think that’s likely to translate directly into the important work in education he alluded to that needs to happen.

Two other points, there’s a lot of exciting research ongoing. Blood-based biomarkers in Alzheimer’s disease, which could improve diagnosis and simplify and expand access to biomarker testing at a much lower cost. Then finally, harkening back to something Jerre mentioned earlier, I’m impressed by the growing number of prevention trials ongoing in AD, which are trying to assess the efficacy in this case of several antibody approaches, in slowing the course of the disease through earliest possible intervention that is in patients who are at risk of developing AD but don’t yet showed symptoms. To me, these trials are going to be an important piece of the puzzle in our ability to maximize clinical outcomes for AD patients over the long-term. It’s really exciting to see this research ongoing. I think there are many reasons to be hopeful.

Joan: Hans, you’d like to add something?

Hans: It was mentioned a moment ago that we will enter into a phase of combination treatments. I would like to remind the audience that Namzaric is a combination of memantine, which I brought to the market, and donepezil. That’s called Namzaric. That has been approved for a long time. The willingness of the FDA to approve combo drugs in AD is certainly a given. Also, the willingness of the market to pick that up is a given. I think, in the future, we will see probably less combinations that are targeting neurotransmission. We will see more combinations that are targeting fundamentally different approaches.

There, I see, certainly, benefits when, for example, combining a neurotrophic drug like [unintelligible 00:50:06] compound with either a commercialized drug or also aducanumab for that matter. There’s no reason not to believe that it should even increase benefit for subjects, but we can do better, and I’m confident we will.

Joan: Thanks for that, Hans. Well, that’s all the time we have for today’s conversation. Thank you, Mei Mei Hu, Hans J. Moebius, R. J. Tesi, Jerre Stead, and Jon Searles. It’s been a fascinating insight on how the life sciences sector is tackling one of the most devastating diseases. The work you’re doing is very important to all those affected by Alzheimer’s disease.

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