Meryl Comer (00:00):

This is BrainStorm, and I'm Meryl Comer. For too long, Alzheimer's has been framed as a disease where we can address it only once memory loss becomes visible. Now, we're entering an era where a person may be told they have Alzheimer's related biomarkers up to two decades before they have symptoms. That knowledge can be empowering. It can also carry fear, concerns, and uncertainty. Our guest today, Dr. Frank Longo, professor at the Department of Neurology and Neurological Science at Stanford University, and founder and chairman of the board of PharmatrophiX. Dr. Longo, thank you for joining us. What prompted you to focus your Alzheimer's research on synaptic resilience in which the brain's communication network is progressively dismantled when historically the majority of the field focused on amyloid and tau proteins as targets?

Dr. Frank Longo (01:03):

To be sure, the amyloid and, and tau are, are very important, and we, we also work with those, um, uh, factors as well. But the, the bottom line in Alzheimer's disease that unfortunately we lose the synaptic connections, uh, between the neurons over time. And, and it's those synaptic connections that are just critical for cognitive function, our, our memory and other functions. And so we wanted to create a therapy that would protect, uh, those synapses, make them resilient. Our goal was to create a therapy so that everybody could have resilient, uh, connections. And finally, uh, the, the number of synapses that, that are surviving are the best, uh, correlator or relationship to cognitive function. Uh, they, they correlate with cognitive function even better than, than amyloid or tau levels.

Meryl Comer (01:53):

So is this an argument against amyloid directed therapies or an argument that Alzheimer is in fact is too biologically complex for any single target solution?

Dr. Frank Longo (02:06):

I think it's the, the second one. I think our view is that we have multiple forces causing those synaptic connections to degenerate. And so the fact that we have multiple processes promoting the synaptic degeneration is a challenge. Then it becomes a, a game of whack-a-mole. We, maybe we treat the amyloid part successfully, but we've got the other forces continuing, unfortunately. So our goal was to create a therapy that transcends these difficult decisions. And what we found with our approach is that we're handling all three of those. And then finally, more recently, we're very excited about this and we'll be presenting more details at the, uh, ADPD meeting, uh, next year, is that we're blocking important immune processes, including those that occur, uh, in the brain, uh, with our approach. So we, we're addressing all three of these, uh, insults to the synapse.

Meryl Comer (02:59):

So the most important shift moving is moving from asking how do we remove what's been accumulated to asking how do we keep the brain resilient enough to withstand injury in the first place,

Dr. Frank Longo (03:13):

Right? E- exactly. I, I think nature is showing us that resilience is possible, and our job is to understand the mechanisms underlying that resilience, and then harness those in a very powerful way, uh, to make therapies that could prevent the onset of cognitive symptoms or, or at least slow them down or, or, or stop them. So at the same time, I think removing amyloid is a wonderful option to have, and maybe we need to do both. Maybe remove the amyloid with one therapy and then have a therapy like ours that, that confers resilience. Uh, so we're, you know, that's the combination therapy approach.

Meryl Comer (03:52):

What is the P75 neurotropin receptor, and what are you trying to change when you modulate it?

Dr. Frank Longo (04:00):

Great question. The p75 neurotrophin receptor is a, uh, what we call a receptor on the surface of neurons and also immune cells. And what receptors do when they're on the surface of cells, they dictate to that cell what to do, uh, in terms of basic functions. Uh, and so generally there's something outside the cell that binds to that receptor and tells the cell to do something. These are fundamental, powerful biologic decisions that that receptor is, uh, mediating. In the case of the p75 neurotrophin receptor, that's telling the neuron and its synaptic connection whether to live or die. It, it's a fundamental biological fork in the road. And then what our, our re - laboratory team and others around the world started recognizing about 20 years ago is that the degenerative signaling that the p75 receptor promotes has an uncanny resemblance to the degenerative signaling that's occurring in Alzheimer's disease.

Dr. Frank Longo (04:59):

So in, in hu - in people with Alzheimer's, if we look in their brains, they have this degenerative signaling, uh, network or pattern inside their neurons and their synaptic connections and, and it's eliminating their synapses. So we though if we could create a drug or a therapy that controls what that p75 receptor is doing and tell it to turn down the degeneration process and turn up your, your survival promoting process, because this p75 receptor is like a toggle switch. It can go either way, pruning and, and, and death or survival, right? So we ended up creating a drug, uh, that, that, that turns down the degeneration and turns up the survival by targeting that receptor.

Meryl Comer (05:44):

So is this true regardless of whether the initiating injury is amyloid, tau, inflammation, vascular, metabolic dysfunction, or something else?

Dr. Frank Longo (05:56):

Great question, Meryl. This, um, mechanism I'm talking about is so fundamental that it is spilling over into other areas. Uh, it's not limited to just Alzheimer's because this is about as fundamental as it gets when it comes to synaptic connection. This is live or die for synaptic connections.

Meryl Comer (06:13):

Dr. Longo, does this strategy also validate what we're now learning about the mixed dementias that we're now discovering through brain donation autopsies?

Dr. Frank Longo (06:23):

Yeah. So the, the approach of addressing what, what I call a fundamental deep biology is very relevant, uh, to the question you're mentioning. What the field is really learning more and more is that there's very little pure Alzheimer's. And I saw a recent estimate that maybe only 5% of Alzheimer's patients is really just what we call pure Alzheimer's with amyloid and tau only, that in fact, for most people, there are other factors going on. Uh, some of the, uh, vascular degenerative processes that come from vascular disease are common. Uh, uh, another common additional, uh, factor is, are some of the Parkinson's related factors. So our therapy might be a perfect match for this more recent view that Alzheimer's i- is in fact a, a, a mixed, uh, dementia.

Meryl Comer (07:11):

At what stage would you ideally test a neuroprotective treatment? You know, is it subjective cognitive concerns? We're all concerned. Mild cognitive impairment, biomarker positive, but asymptomatic, or even genetically high risk adults before measurable pathology?

Dr. Frank Longo (07:32):

Yeah, that's such an important, uh, question. Can this, this drug be beneficial in Alzheimer's? It looks like it can from our test so far. But this mechanism of action of conferring synaptic resilience, I think would be perfect for a preventative, uh, for people to take this drug even before symptoms start. And people that have, you know, blood tests or brain scans, you know, we call those biomarkers that indicate they're particularly high risk, uh, their cognition is still normal, that might be a perfect time to start this drug, uh, to make their synapses more resilient, um, to prevent their accumulation of abnormal tau. You know, that's what we think this drug could do. And potentially thereby to delay onset, you know, considerably. Our drug can be taken orally. There are no IVs or injections, uh, necessary. And of course, we need a drug to be relatively safe for that.

Dr. Frank Longo (08:25):

And, and so far, I th - we think our safety profile would fit with being a preventative drug.

Meryl Comer (08:31):

So in a disease that may ultimately require long-term treatment, potentially before symptoms, how important is ease of use, uh, to whether prevention is scalable and equitable?

Dr. Frank Longo (08:45):

Using a drug for prevention, of course, it involves many, many years, right? So we have practical challenges with that. Uh, there has to be an ease of use, you know, that, that's what we're developing, an oral pill. That's number one. Number two, the, the monitoring. You know, with the current, uh, FDA approved Alzheimer therapies, you know, we have to have our patients take on the, uh, roughly six MRI scans, so over the or, or initial six months or so, and then perhaps repeat them at some frequency after that. Uh, you know, uh, that's not scalable. You know, the goal would be to meet all those requirements, easy to take, uh, not too expensive, uh, relatively safe. I mean, every drug has some kind of side effects, but something manageable and, and not, not too, uh, dangerous, not too much monitoring, expensive monitoring required. And ultimately, our goal would be a drug that's accessible to everybody, uh, not only throughout the United States, but everybody in the world.

Meryl Comer (09:45):

Women have historically been underrepresented or insufficiently analyzed in medical research because tau is showing itself to be much more prevalent in women as a factor. Have your studies looked at sex and gender?

Dr. Frank Longo (10:02):

Uh, yes. So we have been looking at potential sex and gender effects, both at the mouse level and in our human trials so far. Uh, in our human trials so far, we're not detecting, you know, big differences be- between men and women, you know, but we're, we're monitoring that. Uh, interestingly, uh, one of the recent analyses that we did at collaborating with, uh, Dr. Paul Toredow in Indi- Indiana University, he and his team have developed an advanced way of looking at brain networks, um, and, uh, in living people. And there, they see, uh, male versus female differences in the brain networks and, and how they're affected in Alzheimer's disease. This was exci - uh, presented last July at AAIC in London. We were so excited. They found a statistically significant, uh, effects on slowing down the loss of these brain networks. And he saw the male versus female difference in our trial, and he saw effects in both men and women.

Dr. Frank Longo (10:59):

Now, the effects were somewhat different, as he might have predicted from his earlier work. So we're continuing to carefully monitor, uh, men versus, uh, women. And, you know, so far, fortunately, it looks like the drug could be effective for, for both. Uh, you mentioned tau, particularly affecting women, and, um, uh, in our human trials so far, uh, we're seeing important effects on tau related, uh, mechanisms in the people. In our phase 2A trial, uh, we had a significant lowering of, of the tau, uh, biomarker, Tau-217. We are currently in, uh, analyzing another tau, uh, blood test that has come out recently. It can be tested in blood or spinal fluid called Tau 243. And we'll be, we're very, um, looking forward to presenting those findings at the CTAB, uh, meeting coming up in Boston. You

Meryl Comer (11:49):

Know, there's such excitement around, uh, the phase 2A trials. What does, uh, phase three look like? Uh, how is it evolving? Uh, where is your adequate funding for this? Uh -

Dr. Frank Longo (12:04):

We're designing what we call a phase 2B/three, where initially we'll call it a 2B, where we'll be focusing on, on biomarker work, and then the same patients in the 2B then will merge into an ongoing, the phase three trial. So the phase 2B will become a, a phase three. Uh, the way we've designed it so far, we've been fortunate to have some of the leaders in the field help us with, with the design. Uh, Dr. Jeff Cummings, Dr. Lon Snyder, we, we've had really some remarkable colleagues weigh in on many iterations of this trial design because we really wanna get, get it right. The cost of trials really goes up steeply when you transition from phase two to phase three. So, you know, we successfully completed a phase 2A trial, uh, but to do a, a phase three is hundreds of millions of dollars. And that's where the, the current valley of death in the, in the field re- really is.

Dr. Frank Longo (12:56):

The NIH has funded every stage of our work, uh, even the, the phase 2A trial, but the NIH is really not designed to fully fund a phase three, uh, trial. Uh, they could fund a s - a small part of it, but not the whole trial. So we'll be, uh, working to raise that money privately to augment, uh, NI- NIH funding.

Meryl Comer (13:16):

What would equitable prevention look like in practice for rural communities, communities of color, lower income families, and people whose first encounter with the disease is an exhausted caregiver?

Dr. Frank Longo (13:32):

I think there are at least three elements, uh, uh, to your question a- a- about, you know, equitable availability. Uh, number one, we don't have enough neurologists or geopsychiatrists or geriatricians in, in our country. Uh, we have to make this very doable for our primary care, uh, colleagues, um, uh, so the patients can get to, uh, uh, physicians have more accessibility to physicians who can manage this. Number two, the blood tests are getting more and more accurate at lower and lower costs, fortunately, right? So the third component is now, what can we do about it? And so the third part is, is there a t - uh, a treatment that I can get to, uh, that I can afford, uh, that re - doesn't require too much expensive monitoring, that I don't have to travel or go to a specialized center to get to? And I think a drug like ours, it doesn't have to be ours, but with a profile of ours that's orally, uh, um, you know, administered, is relatively safe, doesn't require a lot of expensive monitoring, that would be the third part.

Dr. Frank Longo (14:36):

We're

Meryl Comer (14:36):

Eager to see what happens. Uh, I think you've made clear that prevention is not reduced to a lifestyle checklist, right? Uh, future relation. <laugh>

Dr. Frank Longo (14:46):

I, I think lifestyle strategies are very important. Mm-hmm. I am so inspired, you know, by, by the, the finger study that was done in Europe more recently, the pointer study in the United States. I'm so inspired by those findings because, uh, with those studies, they're, they're drilling down as to why are those lifestyle changes helpful, and I really think they are helpful. I've always advocated that for my patients. And we're finding that those lifestyle changes do affect the biology that, that my team and others have been studying. And that's why I'm excited about them. They're affecting real biology. I mean, these are real treatments, and I think they will serve a role. I look at them as the platform. I would never say to a patient, "Hey, don't worry, you can take a pill." No, I would say, "Do, have a healthy diet, try to get your exercise, do what the Poynter study's educating us all on, but, you know, that's, will be helpful.

Dr. Frank Longo (15:40):

Unfortunately, it might not be completely enough, right? So then on top of that, let's come along with a powerful biologic therapy, and between the two, let's make sure you never get this disease."

Meryl Comer (15:52):

We'll keep doing all these things that you've just mentioned. We're just waiting for the science to catch up, right? <laugh>

Dr. Frank Longo (16:00):

For sure. I think we have fantastic science in the field right now, and we're getting better or better at harnessing that science. I hope our program is just one example of, of harnessing what I call a very powerful and deep biology. I think that this disease, Alzheimer's, is unfortunately a very powerful disease, unfortunately. It, it, it, this disease addresses fundamental mechanisms of whether a synapse, synaptic connection survives or not. It is a powerful disease. So, uh, my feeling is we need to come at it with a powerful treatments, not just trimming around the edges, uh, but really equally or more powerful treatments. And I, I think that's what we're getting to now.

Meryl Comer (16:43):

What do you see as an opportunity for political leaders, uh, in terms of, uh, pushing to accelerate the development of new therapies?

Dr. Frank Longo (16:52):

I think the opportunities for political leaders is to recognize the time is now. I mean, these numbers are gonna keep exploding of people and families, uh, in, uh, you know, suffering with this, you know, that's the human cost, which of course is the most important, but the cost to our country, you know, the, the time is now. And I think there could be additional government programs, uh, in parallel or, or separate to what our colleagues at NIH could do that could really jumpstart programs like ours and make a phase three possible, perhaps a, a public-private partnership, uh, you know, through like, like ARPA-H is a good example. They could do innovative, potentially large scale programs, uh, to get a technology across the finish line, uh, perhaps, you know, partnering with the private sector. Uh, we would be a great prototype. We're ready to go if that kind of program existed.

Dr. Frank Longo (17:44):

We're close to, uh, the, uh, some, a solution, and now we need to get across the finish line and we're, we're ready to go.

Meryl Comer (17:52):

Our guest today has been Stanford neuroscientist, Dr. Frank Longo, founder and chairman of the board of pharmatrophiX. His research is also a commitment to earlier action, reducing risk across the life course, testing better intervention sooner, and ensuring advances reach every community. That's it for this edition. If this conversation helped you, please share it with someone who may be quietly worried about their own memory or someone they love. I'm Meryl Comer, thank you for brainstorming with us.

Speaker 3 (18:30):

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