A conversation with Eric Siemers, MD, CMO, Acumen Pharmaceuticals
A longstanding approach to diagnosing and developing drugs for Alzheimer’s disease has been to target amyloid plaques in the brain. Later, researchers began looking into tau tangles and the role they play in the disease. The amyloid-beta (Ab) peptide and the tau protein occur naturally in all brains, but the formation of amyloid plaques and hyperphosphorylated tau is what is believed to cause the clinical symptoms of Alzheimer’s to begin and progress.
Acumen Pharmaceuticals, for its part, is tackling the disease from the amyloid angle, specifically targeting toxic soluble Ab oligomers. Their latest study is evaluating sabirnetug (ACU193), a monoclonal antibody, for its efficacy in slowing cognitive and functional decline as compared to placebo in participants with early Alzheimer’s.
Critical to this trial is its novel way of screening patients. Medical testing can be frequent, long, uncomfortable, and even downright painful for patients. Take PET scans, which are required for confirmation of an Alzheimer’s diagnosis. They require an IV injection and subject patients to up to an hour in a confined space. Having one typically also requires a patient to travel outside their doctor’s office. On the provider side of things, they require scheduling, equipment, and expertise — which also means they’re costly.
In this Q&A, the company’s chief medical officer, Eric Siemers, MD, discusses sabirnetug’s mechanism of action, as well as its novel screening method and trial design that keeps both the clinical site and patient experience in mind.
What’s the current approach in Alzheimer’s research, and how is sabirnetug’s mechanism of action different than what we see in the landscape currently?
Eric Siemers, MD: The monoclonal antibody that we’re studying is called sabirnetug, and we’ve completed a Phase 1 trial in patients rather than volunteers, as is typically done. We really had a lot of interesting biomarker data generated from patients, which we wouldn’t have been able to do if we had gone with volunteers. The study ongoing right now is a Phase 2 study with three arms— two active arms and a placebo. We were able to enroll the 542 people in just over 10 months, which is pretty remarkable. And I think it tells you something about the enthusiasm that our clinical sites had for this antibody and its mechanism.
The mechanism is a bit unique, in a very good way. The field has been relatively focused, and I would argue maybe to a fault, on amyloid plaque reduction in the brain. People with Alzheimer’s disease have these plaques in the brain that you can see with a PET scan, and if you have a drug that is intended to reduce the plaques, it makes your PET scan look better. The question is: Does it do anything for people clinically?
It seems to, although the effect is relatively modest. But we target amyloid-beta oligomers (AβOs). Our antibody binds to these oligomers. These oligomers bind to neurons to induce downstream pathology, such as tau hyperphosphorylation, which is the other hallmark of Alzheimer’s disease. With Alzheimer’s, you have amyloid plaques, and then you also have tangles made up of hyperphosphorylated tau. AβOs induce tau hyperphosphorylation, disrupt long-term potentiation, and induce large calcium influxes into cells, which is always a bad thing to happen. If you want to target plaque, which acts as a reservoir for AβOs, you have to get rid of it. There’s a lot of clinical data now to show you can’t just lower plaque a little bit and see effects on symptom progression. So, we are just going directly at the toxic oligomers.
Our trial was a fairly typical Phase 1 in terms of single ascending dose and multiple ascending dose cohorts. In the multiple ascending dose, the patients only had three administrations of the drug. Even with just three administrations, we started to see changes in phosphorylated tau and an inflammatory biomarker called glial fibrillary acidic protein. I didn’t really expect to see it. I just wanted some experience with the assays, but we actually saw a drug effect with just three administrations of sabirnetug. So, that gave us a lot of enthusiasm to go forward with Phase 2.
Phase 2 was designed as a registration quality study. We used the Phase 1 data, including the biomarker effects, but also something that we call target engagement, which is a measure of how much oligomer is bound to sabirnetug. We picked two doses, 50 milligrams per kilogram and 35 milligrams per kilogram, based on the target engagement and some other things that we looked at in the Phase 1 trial.
For our Phase 2 trial, ALTITUDE-AD, at the end of the 18-month placebo-controlled period, there is an open-label extension during which everyone will receive the antibody. The placebo-controlled portion of ALTITUDE-AD will end at the end of 2026, and that’s when we’ll have top-line results.
You said that you were able to go straight into patients as opposed to healthy volunteers. What enabled that decision?
It’s more difficult to do a Phase 1 first-in-human study in patients rather than volunteers. There’s no question about that, but we also wanted to measure some biomarker changes and some potential safety issues, which could only be done with patients.
Because we couldn’t get the data we needed from a Phase 1 with healthy volunteers, we made the decision that even though it was harder to do a Phase 1 study in patients, it would be worthwhile. And we did generate convincing biomarker data.
The patient populations for Phases 1 and 2 were essentially the same, but we used a biomarker to screen patients for our Phase 2 study. It’s called pTau217. That wasn’t available at the time of the Phase 1 study. At that time, if you looked at people with a clinical diagnosis of mild cognitive impairment or mild dementia, as it turned out in our Phase 1, over 60% of people had negative PET scans for amyloid. In other words, they did not have Alzheimer’s disease. So, in the bad old days before we had PET scans, those people would just go into your trial because you didn’t know any better.
Then, when we went to our Phase 2 trial, there was this new blood biomarker pTau217 that we used as a screener. At the first screening visit, patients would have some general medical questions and then get blood drawn for pTau217. If you were above a certain cutoff, you had a PET scan or spinal fluid to make sure you had Alzheimer’s disease. What we found with the Phase 2 blood screening test, is that 17% of screened patients were amyloid negative.
So, we went from over 60% negative to 17%, which is exactly what we wanted. We didn’t want it to be zero, because that meant we were too conservative in our cutoff, but it lowered the frequency of those negative scans by a lot, which is beneficial in a lot of ways.
Tell me more about the plasma screening protocol, pTau217. Did it save money, save time, or improve patient identification?
It was all three of those things. And when we designed the Phase 2 study, that test was relatively new, so we spent a lot of time looking at data to see exactly what the cutoff should be. I think it’s really good for patients because if you’re going to screen fail, it’s a lot better to do it with the blood test than with the PET scan.
Additionally, the cost of the screening process was 40% lower when we used the blood test than when we did PET scans. It’s a cost savings, and it reduces the burden on the site because these trials are complicated. They have to schedule a PET scan, and it’s a little bit complicated to get the PET ligand to the site. A blood test is a lot easier for the sites. That’s one of the reasons why we’ve recruited so rapidly, because the sites like the protocol.
So far, have you had feedback from the sites or the patients about this trial design?
We don’t receive direct feedback from the patients. But we do talk to the sites and the investigators. It was probably a combination of things, but the sites and the investigators really seemed to like the protocol. Part of it was the screening. But there were other things that we built into the design.
We have an open-label extension, but prior to that, there are two active arms and one placebo arm. You go into the study and for the first 18 months, your chances are two out of three that you’re on the investigational drug. But then, at the end of the 18 months, the original placebo group goes on to active treatment. So now everybody’s on active treatment. And then for the open-label extension, it’s a 100% chance that you’re on active treatment.
One of the things I try to do in designing trials is to incorporate things you can do in clinical practice. Now, that’s not always possible, but screening with pTau217 is something that could be used. We’re starting to hear this anecdotally from people in practice. For instance, somebody comes in to see their primary care doctor and says they’re having some memory problems and their mother had Alzheimer’s disease. Now, the primary care doctor doesn’t have to send them to a neurologist, which takes forever to get in, or send them to get a PET scan or spinal fluid. Now, the primary care doctor can just send a tube of blood and get the pTau217. If that’s abnormal, then you take the next step of referring the person to the specialist. And I think that’s one of the things that made our trial attractive. The principal investigators at the sites are thinking this is something they can apply to their clinic patients.
What is your advice for trialists who want to think outside the traditional way of doing things, whether that’s introducing a new screening process or a new biomarker?
Early in my career, I was a site principal investigator and did a lot of clinical trials. So, I know what things make it simpler and what things make it too complicated. I think a lot of people do this; you try to make it user-friendly for the sites. And that involves the physicians there, the principal investigators, but also the study coordinators; they are people you really want to make this user-friendly for, because they do a lot of the work. It’s really useful to think as if you were at a site and say, “I’m thinking about a patient going into this protocol. First of all, is the drug good? And then look at the protocol and say, ‘Is this really doable?’” And that’s the lens you have when you’re finishing off your protocol. You have to make this user-friendly and something that people will want to participate in. And again, having an open-label extension is helpful because people know they’re going to be on a drug.
That probably goes a long way with patients. And it sounds like, too, that you are obtaining the scientific objectives while also keeping the PIs and their staff and the patients in mind for one protocol that’s going to serve everyone’s needs.
That’s exactly it. And sometimes you are surprised. We’re always learning things. In our Phase 1 study, the very first time patients came in, they had to do computerized cognitive testing and do it a couple of times to learn how to do it. That took about an hour. The thing that people liked the least in that study wasn’t the lumbar punctures; it was the cognitive testing. They actually minded the blood tests more than the lumbar punctures, too. And the reason is that in a Phase 1 trial, you take a lot of blood. Fortunately, we did a semi-structured exit interview at the end of Phase 1, and that’s how we collected that data. It’s not intuitive, that’s for sure. But that’s why you do the studies.
About The Expert:
Eric Siemers, MD, has more than 25 years’ experience overseeing clinical trials of neurodegenerative disease and joined Acumen as chief medical officer in 2018. He joined Eli Lilly and Company in 1998 and was responsible for several clinical trials for Alzheimer’s compounds, including five Phase 3 studies as well as Phase 1 and 2 studies. Prior to Lilly, Dr. Siemers founded the Indiana University Movement Disorder Clinic, where his research included Parkinson’s and Huntington’s disease. Dr. Siemers served on the NIA/Alzheimer’s Association working group that proposed new research nomenclature for Alzheimer’s disease utilizing biomarkers and clinical symptoms. He was a founding member of the Alzheimer’s Association Research Roundtable and was on the steering committee for the Alzheimer’s Disease Neuroimaging Initiative. Dr. Siemers earned his MD with Highest Distinction from the Indiana University School of Medicine.
