Will Meador (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for physicians.

Will Meador (Host): I'm Dr. Will Meador, Associate Professor of Neurology at the University of Alabama at Birmingham. Today, we're diving into a major development in Huntington's disease, a gene therapy that has successfully slowed progression for the first time. Joining me today is Dr. Danny Bega, Associate Professor of Movement Disorders at Northwestern Medicine.

Dr. Bega directs the Parkinson's Disease and Movement Disorder Center, as well as the Huntington's and Wilson's Disease Clinics. He's a nationally recognized leader in the care of patients with complex neurogenetic conditions and a driving force behind Northwestern's innovation and movement disorders. Thank you for joining us, Dr. Bega.

Danny Bega, MD: It's a pleasure. Thank you for having me.

Host: Dr. Bega, can you provide some background on Huntington's disease and what causes it?

Danny Bega, MD: Sure. I'd love to. Huntington's disease is a neurodegenerative disease that causes a combination of neuropsychiatric symptoms, dementia and movement disorder symptoms, typically hyperkinetic movements such as chorea. And it's a progressive disease that as of today doesn't have a cure. We think of it as a prime of life disease in that, unfortunately, it has an average onset in around age 40 or so. And it's a familial disease, so it's inherited in an autosomal dominant fashion. So if someone has Huntington's disease, they have a 50% risk of passing it on. We know the mutation that causes it. We can easily identify the mutation that causes it. And we, as of today, treat it primarily symptomatically.

Host: Yeah. And can you review some of those symptomatic therapies that might address Huntington's symptoms and kind of the prognosis for patients who are diagnosed with it?

Danny Bega, MD: Yeah. Today, what we do day to day is supportive and symptomatic management. So, it actually starts with providing education to patients and families about the disease, because it's a family disease ultimately that affects a lot of people. And social work support, mental health support, genetic counseling support is all part of the management.

And then, from a neurology standpoint, it's managing abnormal movements. We have FDA approved medications to treat chorea. And we use ancillary services like physical medicine, rehabilitation, speech, PT/OT to help with some of the mobility issues and movement issues. And we have effective psychiatric medications for a lot of the psychiatric symptoms. And a lot of it is also supportive care in managing cognitive and functional limitations that occur over time and helping to adapt to those changes.

Host: Gotcha. And obviously, there's been a lot of talk around a recent trial using AMT-130 gene therapy, which showed significant slowing of disease progression. There's a lot of excitement for good reason. Can you tell us about this recent trial and how the therapy was administered?

Danny Bega, MD: Yes. So, one of the things we know about Huntington's disease is that the abnormal genetic mutation leads to an abnormal mutant Huntington protein that's formed. And we believe that that protein, as it builds up in neurons, is damaging to neurons in the brain. And one of the targets of a lot of pharmaceutical company trials is to try to lower the mutant Huntington protein levels in order to slow down disease progression. And this has been attempted in different ways at the DNA level, at the RNA level, at the protein level by different companies. So, what we're seeing with AMT-130, the company uniQure has been developing this drug. What they're doing is they're delivering using a viral vector directly into the brain, a drug that can bind to the mRNA and prevent translation of the mutant Huntington protein. When it binds to the mRNA, the mRNA degrades, and then it can't translate into the mutant protein.

And so, what is exciting about their trial? Previous trials have shown mutant Huntington protein reduction. But what they've not shown is a correlation with clinical outcomes that have been effective. And this is the first time that we're seeing both the mutant Huntington protein reduction, but also more importantly, the clinical outcomes outcomes that we use in the clinic every day and that the FDA looks at that are favorable compared to natural history comparators.

And so, pretty much all of their endpoints, including their primary endpoint, showed a slowing of decline compared to what we would consider a natural history cohort. That includes the primary endpoint was their composite UHDRS, which is sort of a combination of motor functional impairment and cognitive impairment, so this composite score. And they showed that people who received AMT-130 had a slower decline in that score compared to what's normally expected.

But then, when they looked at their secondary endpoints, they also saw other measures similarly like their functional capacity score also decline slower in the treatment group. So, there's still decline. It's not a cure for the disease, but there is slowing of the decline in those groups. And we hope that's a real effect that we're seeing.

 One of the things that I'm most excited about is this marker in the spinal fluid called neurofilament light. A lot of neurodegenerative diseases are looking at NFL or neurofilament light as a marker of neuronal damage, axonal damage. NFL spills into the CSF when there's neuron loss or degeneration or inflammation in neurons. And in prior studies, some unsuccessful studies have shown ongoing elevations in neurofilament light. And what we expect actually in Huntington's disease natural history is a 10% increase in NFL levels every year on average. And in this study, they actually showed an 8% lowering of NFL levels in the high dose treatment group. And so, that sort of going along with the clinical measures was really exciting and hopeful.

Host: Wow, those are really compelling outcomes, especially looking at the clinical impact of that, which is very exciting to see in this disease. Dr. Bega, what do you think about the methodology, particularly the intraparenchymal delivery of this vector when you think about its implications for safety and maybe scalability?

Danny Bega, MD: Yeah. So, I think there are certainly limitations. The delivery method is it's brain surgery. It's about, in at least the way they did it in the trial, it's a 12-hour long procedure where they inject the drug into the putamen and caudate on each side of the brain. So, it's actually three injections on each side, six injections total, it takes about 12 hours. And so, the question is: is that realistic? Is that feasible if they were to do it that same way outside of a trial?

I think in terms of whether patients with Huntington's disease would do this, I can tell you from my experience with the HD community is that I don't think that that's a barrier to people wanting access to a treatment like that if it does end up being effective. It's a devastating disease. And as I mentioned, it affects people at a time where they really want to need to be active and taking care of their family members and other things. And so, they're willing to go through a brain surgery if it means that this actually will end up slowing down disease progression.

Certainly, in the pipeline of other drugs, there are other enticing, exciting drugs, some of which are oral medications that we hope will also end up showing successful results. And those are actively in human trials today. So, I don't see that as a limitation. But certainly, if we can develop oral drugs, that would be great.

I think one thing we need to think about in scalability, one is, is it safe? That was the other thing that they showed was some people did have swelling in their brain initially in the high dose group when this was done, but they didn't show any problems with anybody recovering. In the few patients who did have brain swelling, either with steroids or symptomatic management, they got better. And any of the side effects that they really saw were around the time of the procedure. But they followed these people for three years now and they didn't see any new side effects over time. We'll have to wait and see if lowering the mutant Huntington protein nonselectively ends up with any long-term problems. Again, they're looking at three years of this small group. It looks good long-term for that period of time, but they are lowering the wild-type Huntington protein too. And so, there are questions about if there are going to be any long-term implications of doing that in terms of potential side effects. And then, remember again, what was reported was only 29 people of which only a subset was the group that showed this benefit, which was the high dose group. And so, we'll have to see if that is a limitation, if that's enough for kind of moving forward in terms of what the FDA thinks and in terms of whether that's enough to take it to the clinic.

So similarly, another limitation is that there is no placebo group conventionally done in this study. So, this wasn't a sham-controlled procedure. It was a surgery. But their comparator group was natural history cohort that wasn't part of the study. And so, whether these results will end up being sufficient for FDA to kind of move it forward to the clinic also. For that reason, we'll have to see, we'll have to wait and see. So while we have a lot of hope, we just have to also accept that these are some points at which it's not clear at this time if the FDA's going to move it forward, if they're going to say we need more data. Or if they're going to say, you know, this is a population that is really in need of a treatment now to slow down their disease. And the signals here look really positive. So maybe, this is something that we can move into the clinic and continue to gather data.

And then, our problem will be a good problem of having to figure out how do we do it in the clinic? How do we get all these people in to have this done? How do we get it paid for? And that's a whole separate set of issues that we're going to have to address.

Host: Yeah. And I think that's exciting news. It really makes us think about how we're going to apply this in the future. What do you think the future of HD care looks like in a specialized clinic like yours if such a therapy becomes available, and specifically thinking about the touchy subject of prodromal HD patients?

Danny Bega, MD: Yeah, great question. I think we're already seeing more people coming to be tested presymptomatically because they're hearing about potential clinical trials that they might want to have available to them. It used to be that most people would come when they were thinking about family planning, which of course still is one of the main reasons that people come. But now, we're seeing more and more, they're hearing about studies and they're wanting an opportunity to potentially participate. And that's a reason that more and more people are coming to be tested.

So, we're already seeing that shift. And I'm sure that if a drug was available that was able to slow down progression, we'd see a tremendous increase in people getting tested. And then, the patients who are prodromal, early symptomatic, you know, those are going to be the ones that are more typical of those who are included in the trials. And so, that is a group that we see as the target for most of these trials today. But I think we all want to move these trials to the earliest possible stages to delay onset and to slow down progression at its earliest possible point.

But all of this doesn't change the fact that we still need the things that I mentioned at the beginning: the symptomatic management, the supportive care that we provide in the clinics; that's still going to be needed and potentially, actually now over a longer period of time. Because if we take a disease that is right now about a 15-year long course, and we successfully slow it down, now we're treating people for 20 years or 25 years, which would be great.

But it doesn't mean that there's a longer period of time now to manage symptoms to help people to control different issues. So, we're still going to need all the symptomatic treatments and the multidisciplinary care that we provide potentially for a greater group of people. We still need to take care of the people today with symptoms too, who may not be eligible for the trials. And so, we don't want to forget about that. Like, the day-to-day care still needs to be optimized.

Host: Right. And that would be a great problem to have, right? If the prevalence is increasing because patients are able to live longer with this advanced therapy. And kind of zooming out on that topic, thinking about other monogenic or neurodegenerative diseases, do you think such a therapy might be applicable in other situations?

Danny Bega, MD: I do. I think that these types of therapies are being looked at particularly for trinucleotide repeat disorders because they have similar mechanisms and targets. And so, there are, I don't know, a hundred or so other trinucleotide repeat disorders, a lot of them are in neurology, that many of these companies are exploring well. So, I do think there's other applications that we're going to see.

Host: Yeah, that's exciting. And so, for neurologists listening or other providers, as these therapies move forward through studies, what should we be looking out for and how should we plan to integrate these findings into our practice?

Danny Bega, MD: Yeah. I think one thing is balancing the messaging. We want to provide hope, and I hope that patients and providers listening who are dealing with Huntington's disease, I hope that they take from this the message of there is hope, and there's so much going on in the field and we're advancing, we're making progress. At the same time, I don't want people to mistake a headline of a success for the sense that there's a cure today. There's a lot of education that has to happen around what does this actually mean, which is why I'm glad we're doing this, because we don't yet know for sure. But we have something in our hands that is going to slow down the disease. But we're really hopeful based on this data, and this is the best data we've seen so far. But we need to balance that. I think that's important.

I think remembering that we still need to take care again of people today about their mental health, about their physical health, about their current symptoms still need to be controlled and managed. And so, I think it's important not to put all of our focus on just one headline. And we need to keep getting people to participate in research because we're not done. The work is really exciting and only beginning, because there are all these other companies developing drugs that we need people to participate in. And I think we're going to keep improving on this. And I'm sure this is the first of many positive headlines that we're going to see over the coming years from many different companies. So, I'm excited about that.

Host: Yeah, it's definitely exciting and a pivotal moment, it seems like, in Huntington's research. Well, Dr. Bega, thank you for sharing your insights and helping us understand the broader impact of this exciting development. For our listeners, you can learn more about Northwestern Medicines Movement Disorder Center and their work on Huntington's disease at Breakthroughs for Physicians, which can be found at nm.org/neuro. And that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. Thank you for tuning in.