In an interview with NeurologyLive, Andrew S. Feigin, MD, details ongoing trials that aim to treat Huntington disease, including the notable SIGNAL trial.
Andrew S. Feigin, MD
As the chair of the Huntington Study Group, Andrew S. Feigin, MD, is at the center of some of the most groundbreaking research being conducted in Huntington disease (HD). The disease currently has no FDA-approved disease-modifying therapies, but it is experiencing a heightened degree of attention thanks to several novel therapies that have shown encouraging results.
Feigin, also a professor of neurology and the executive director of The Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone Health
in New York, has long balanced his work in the clinic with his role as a clinical trial investigator. He sees it as an opportunity to provide his patients with not only a potential treatment, but the chance to help foster hope and medical advancements. He sat down with NeurologyLiveTM
to provide updates on some of the most promising therapies currently under investigation and to discuss barriers in HD that can pose unusual challenges for drug development.
Q: As the principal investigator for the ongoing SIGNAL trial, what are some of the distinctive characteristics of the trial and where are you now in the process?
The focus of the SIGNAL trial is a study drug, VX15/2503. It’s a monoclonal antibody to SEMA4D, which is a signaling protein in the body and in the brain that’s involved in, [first], the process by which immune cells—such as microglia in the brain—become activated, and [second], the process by which astrocytes and oligodendrocytes extend and contract their processes in response to injury or inflammation. Even though there’s a normal physiological role for SEMA4D, it can actually have a destructive role in certain situations. Evidence from preclinical transgenic animal models shows that blocking it can ameliorate some of the effects of the huntingtin gene.
The SIGNAL trial is interesting in that it started about 3 or 4 years ago and was designed from the start to have an adaptive design; it wasn’t known how big an effect the drug would have, if any. The study was designed to start with cohort A, which included 36 patients: Roughly half were early symptomatic and diagnosed with Huntington disease, and roughly half [had] prodromal [or premanifest] HD, meaning they have subtle signs but have not reached the level of being diagnosed with HD. That trial was double-blind, randomized, and placebo-controlled. It ran for 6 months, then the people who were on placebo were switched over to the study drug and everybody was followed to the end of the year. We used a series of clinical and biomarker outcome measures to look at those data to get a sense of whether there’s any suggestion that the drug is doing anything, then we used that information to create a sample size power calculation for cohort B. In the end, cohort B [was supposed to have] 240 patients, but we ended up overshooting, so by the end of the recruiting period in 2018, 265 patients had actually [been enrolled] into cohort B. Notably, in light of the interim analysis, we ended up enrolling more patients who were early symptomatic than premanifest. [This occurred] partly because it’s easier to detect clinical changes in people who have symptoms, as you might imagine, and [detection of such changes] is required for approval of the drug, at least as things stand now. People who are prodromal may have subtle signs and symptoms, but it is much harder to detect the effect of a drug on them.
The interim analysis didn’t really prove anything; we weren’t certain whether the drug was working or not. But some encouraging indications [allowed] us to say, “Let’s continue doing this, let’s expand cohort B.” Because of the nature of the way people came into the trial, the majority of people will be in the trial for 18 months. So participants will be randomized, they will get monthly infusions of this monoclonal antibody for 17 months, and then follow up at 18 months. Actually, more than 40 patients who came into the trial very early have agreed to continue out to 36 months in the double-blind portion. Vaccinex is hoping that with a good result, they’ll be able to use this as a pivotal trial.
Q: The study outcomes for SIGNAL mainly focus on imaging. Why are imaging biomarkers so important in Huntington disease, especially in terms of clinical trial design and measuring efficacy?
A couple of very large observational studies have used imaging and other kinds of biomarkers, as well as clinical outcome measures, in people who are symptomatic and in people who are prodromal to get a sense for which of these measures are sensitive to change over time. And the results showed that MRI [magnetic resonance imaging] volume metrics, for example, can measure the loss of volume in a wide range of brain structures involved in HD. Originally, we thought of HD as a disease that causes atrophy in the striatum, mainly the caudate and also the putamen, but we’ve recognized over the last 20 years or so that volume loss is really widespread and seems to have a lot of clinical significance and can measure disease progression. So if you see increasing volume loss, that [often] goes along with clinical decline. Certainly for a premanifest or prodromal population in whom it’s really difficult to measure changes in clinical measures, measuring loss of brain volume and regional brain volume can be very valuable and give you a clue as to whether a therapy is having an effect or not.
In terms of disease modification, we also use an outcome measure in SIGNAL which looks at brain metabolism with 18
F-FDG PET [18
F-fludeoxyglucose positron emission tomography]. A lot of evidence in the literature suggests that regional brain metabolism can be quite sensitive to disease progression over time, and it gives you slightly different information from brain volume because FDG brain metabolism can be acutely changed, at least theoretically,
by therapy. So we are using both of those outcome measures in the SIGNAL trial in both cohorts, and in cohort A, results from both the MRI volumetric scan and the FDG PET signaled that the drug might have a positive effect. While the results didn’t conclusively prove anything, it looked like things were moving in the direction favorable to the study drug, for sure.
Q: What are your thoughts on some of the other therapeutic agents in development for HD?
Roche, Ionis, and Genentech are working together on an antisense oligonucleotide, HTTRX
[now known as RG6042], which basically decreases the translation of the huntingtin protein from the RNA and diminishes its production. That is a non–allele-specific approach; they’re just knocking down the production of normal huntingtin protein and the mutant huntingtin protein. [The agent is] delivered intrathecally; originally, they thought they would have to administer it once per month, but the trial is going to actually involve doing it every 2 months and every 4 months to see if there’s any difference in efficacy. It’s going to involve 660 patients over 2 years, and everybody’s very excited about it. There are still a lot of unknowns and a lot of uncertainty about whether it’s going to work, but that’s why we do these trials.
There are questions: “Does it matter that it’s not allele-specific? And could there be problems related to knocking down normal huntingtin?” But if you talk to people who know about this field, I think most would say we just don’t know, or, actually, it’s one of the things we’re going to find out from this trial.
On the other hand, you have Wave Life Sciences, which has a couple of SNPs [single nucleotide polymorphisms] that are associated with the abnormal gene mutation that is involved in their therapy, so they’re only knocking down the abnormal mutant huntingtin and leaving the normal huntingtin alone. Whether that’s important or not, we don’t really know, but it is a different approach. And then other types of therapies, which I think are more traditional gene therapies, are being developed by Uniqure and Voyager Therapeutics. These are delivered via adeno-associated viral vector through a surgical procedure into regions of the brain that they’re interested in. This kind of RNA interference approach has the advantage of being a 1-time procedure: People come in, they get the thing infused surgically, and then they’re done. There’s no coming back every 2 months for a lumbar puncture, and so again, it’s a very rational approach that makes a lot of sense. Just like with the ASOs [antisense oligonucleotides], a lot of questions arise in terms of what brain regions need to be targeted. If you target the striatum, which is essentially what Uniqure is doing, will that really translate into a brain-wide effect? Some data suggest it might, but we don’t have a clear answer yet.
Q: Do you feel that we’re disproportionately focusing on symptomatic patients versus those who are at risk but haven’t begun to show symptoms?
About 90% of people who are at risk for HD don’t get genetically tested. I think that’ll change a lot if a therapy [is developed]. The current trials mainly focus on symptomatic and early symptomatic subjects, but if the results look promising, I think there will be no shortage of people to do a trial in premanifest or prodromal HD. The issue is whether it will be necessary, or will the FDA say, “Well, you have approval, and it probably will work in prodromal”? I’ve heard a lot of discussions at meetings about this, and I think that if Roche is successful in their trial, the FDA may require them to do a trial in premanifest, and I think they would gladly take on that trial. It will be doable at that point because people will see that something out there will actually be helpful to them.
As of right now, it can be a challenge to do a trial in premanifest subjects because not too many of them know their genetic status, and you don’t want to link participation in a trial with getting genetic testing, as that would be considered unethical. But as soon as a therapy that looks promising emerges, I think a lot more people will start to get tested for sure.
Q: As a clinician and a researcher, are you hopeful for the future?
I think we have the most promising therapies in development ever. [The field has] really come a long way. Whether the therapies work is far from proven, and we have to be cautious and do these trials in a careful way, but I think that it’s really a promising time. Other types of small molecules may be effective for reducing mutant huntingtin, and a lot of other symptomatic therapies exist for various aspects of the disease as well. It just seems to be a time when HD has a lot of interest, so we just have to make sure that we have the capacity to do all the trials that people want to do and hopefully, quickly get answers.
That is where the Huntington Study Group can be really instrumental: We are more of a professional, caregiver-facing organization and we’re very involved with patients. Many pharmaceutical companies could benefit from working with the Study Group to do multicenter clinical trials, because we have very good, close relationships with our centers—about 120 HD clinical research sites—and with the investigators and coordinators at those sites. So I think we bring a lot to the table to potential sponsors who want to do clinical trials in HD.