Targeting the Leading Cause of Death in Friedreich’s Ataxia with a Gene Therapy

Friedreich’s ataxia is a rare, genetic, degenerative disorder that affects multiple systems in the body. As the disease progresses, patients typically experience various heart conditions. Hypertrophic cardiomyopathy, fibrosis, heart failure, and arrhythmias are the cause of death in approximately two-thirds of Friedreich’s ataxia patients. Lexeo Therapeutics is developing a gene therapy to treat FA cardiomyopathy. We spoke to R. Nolan Townsend, CEO of Lexeo Therapeutics, about Friedreich’s ataxia, the company’s gene therapy in development, and its pursuit of gene therapies for both rare and common diseases.

Daniel Levine: Nolan, thanks for joining us.

R Nolan Townsend: It’s great to be here. Thank you for having me.

Daniel Levine: Well, we’re going to talk about Friedreich’s ataxia cardiomyopathy, Lexeo, and its efforts to develop gene therapies for both rare and common diseases. Let’s start with Friedreich’s ataxia. For listeners not familiar with the condition, what is it?

R Nolan Townsend: Friedreich’s ataxia is a rare disease that first develops in childhood, and the first symptoms of this disease are, in a lot of cases, gait abnormality and other neurologic symptoms. This typically develops [when] children are in the five to eight years old timeframe, and it typically progresses through childhood into adolescence and into adulthood. The central nervous system component of the disease does progress until the point where a cardiomyopathy or cardiac phenotype associated with the disease emerges in adulthood. It’s actually this cardiac component of the disease that’s a cause of death for 70 percent of Friedreich’s ataxia patients. This is very much a life-threatening disease. It has one recently approved therapy, but what’s unique about it, I think relative to some other rare diseases out there, is it has both a neurologic component of the disease that develops in childhood and this cardiac disease that develops in adulthood, and this develops within the same patient. And so that’s one of the challenges with thinking about therapeutic options for this patient population is that really you have two components of this disease to treat. I would say I’ve met a lot of Friedreich’s ataxia patients. It’s a very challenging disease to live with, but unlike some other neurologic rare diseases, these patients remain totally cognitively intact. They have jobs, they go to school, they have children, they have very fulfilling lives, and I think the efforts to find a treatment for this disease are really focused on ensuring they can live a great quality of life, but also just live longer lives as well.

Daniel Levine: How does the disease typically manifest itself and progress?

R Nolan Townsend: Well, it starts typically with gait abnormalities. So, parents will start to see signs of their children not progressing as well and walking and running, and there’s other components of the disease related to impairment and speech and also the ability to use their hands and legs and so on, and other activities. And so, you see a very clear neurologic phenotype early on, and I think this continues throughout the patient’s lives. But I think in adulthood for a lot of patients, I would say the neurologic disease progresses, but it stabilizes to some extent relative to what you see in the pediatric component, and it’s this cardiac disease that becomes a very serious component of Friedreich’s ataxia in adulthood for patients.

Daniel Levine: You mentioned there was an approved drug for the condition. What’s the prognosis for someone with this condition today?

R Nolan Townsend: So, on the neurologic side, this recently approved therapy from Reata, and now Reata was acquired by Biogen. The therapy is called Skyclarys. This is a therapy that reduces, at least has been demonstrated to reduce, the rate of decline of the neurologic disease, which I think is a great step forward for patients in this disease area. They’ve had no real therapy FDA-approved treatment option for them. So I think that it’s a major step. The FDA demonstrated very substantial regulatory flexibility when it approved this treatment. So I do think now there are patients that have a therapy, and I know a lot of patients are interested in it, and we’re seeing this treatment effect in some patients that are being treated with this therapy. However, there remains a lack of therapeutic options for the cardiovascular component of the disease. And from a prognosis standpoint, in terms of mortality, I don’t think the existing therapy will have a material impact on mortality because that is mediated by the cardiac component of the disease. So, the neurologic component can be, let’s say, addressed to some extent with the existing therapeutic option, but the cardiac component remains, I think a lot of unmet need in that side of things.

Daniel Levine: In terms of Friedreich’s ataxia cardiomyopathy, what actually happens to the heart over time?

R Nolan Townsend: So classically in Friedreich’s ataxia, and frankly this is the case in many other genetic cardiomyopathies, you see a hypertrophy associated with the disease. So a thickening of the heart walls, and this is what mediates, let’s say, the symptoms of heart failure that you would typically see with Friedreich’s ataxia. A lot of experts will call it a hypertrophic cardiomyopathy, so it looks like hypertrophic cardiomyopathy, which is a classic cardiovascular disease and can progress towards heart failure. You also see other symptoms, arrhythmias. We see other symptoms related to just shortness of breath and dyspnea, so there’s a number of symptoms related to it, but I say the primary one that’s most evident is this hypertrophy of the heart. So, a thickening of the heart walls.

Daniel Levine: Lexeo is developing LX2006, a gene therapy to treat the condition. What is it and how does it work?

R Nolan Townsend: So, Friedreich’s ataxia is a disease, what you would think of as a loss of function disease, meaning the frataxin protein is insufficiently expressed in the heart and the brain. This insufficient amount of protein leads to mitochondrial dysfunction. This mitochondrial dysfunction ultimately is the cause of the disease to hypertrophy and leads to the symptoms of cardiomyopathy that we see as a component of it. And what we’re doing is using a cardiac-trophic or a highly cardiac vector that has high cardiac affinity to deliver the frataxin gene to the heart. This gene expresses the functional protein, it restores frataxin in the heart and therefore in the mitochondria. That restoration of frataxin results in normalizing of mitochondrial energetics and normalizing of cardiac function in several different murine models or mice studies in which we evaluated this. We’ve also moved this program into clinical studies. We have some preliminary data from our lowest dose cohort that looks promising, and we’re moving the program through its higher doses and hopefully towards later stage studies next year.

Daniel Levine: Is the expectation that this is a gene therapy that would be given to any person with Friedreich’s ataxia, or would there be a need for there to be a certain level of disease progression evidenced in the heart?

R Nolan Townsend: In our current clinical trial, the inclusion criteria is for patients that have some symptoms of the cardiovascular disease, and they could even be the early or mild symptoms. Our current clinical trial has excluded the most advanced patients that may exhibit symptoms of cardiomyopathy. So, we’re really in this kind of middle swathe of patients—mild to moderate—that represent the majority of the patients with the cardiovascular component of Friedreich’s ataxia. That’s our current clinical trial design. I think it’s too early to comment on what a multiple label for therapy would be, but I would envision that at least we would be studying a similar population in future studies, and hopefully we can find a way that this therapy will be an option for patients in the most advanced stages of the disease as well. I would say the patients that have no symptoms of the disease, let’s say they have the neurologic phenotype, they do not have any cardiac symptoms yet. I’d say we still need some time to understand what type of therapy we can deliver for those types of patients. And so that’s typically the pediatric population. And here we’re focused on adults.

Daniel Levine: I imagine that’s from a clinical point of view, a bit of a challenge in that someone has to be progressed enough to show improvement but not too far gone that you can’t show signs of reversing the disease or at least halting it. What are you using as an endpoint?

R Nolan Townsend: Yeah, the challenge you highlighted is one that is, I would say, a commonplace certainly in cardiovascular gene therapy, but frankly we see it in other disease areas as well, that you want patients that have a disease progressed enough where you can show a treatment effect or an improvement in either biomarkers or symptoms. But if a disease is too far progressed, you have the risk that you will not be able to rescue the phenotype or you will not be able to, let’s say, reverse the disease pathology. So you have to find this kind of Goldilocks place where the disease has progressed enough where you could show a benefit, but it’s not too far progressed where you can’t rescue the phenotype. Now, for us with endpoints for this particular study, we’re looking at left ventricular mass index, which is effectively evaluating hypertrophy. What we would hope to see is improvement in hypertrophy across the patients that we’re treating. We’re also looking at troponin, which is a biomarker that evaluates cardiomyocyte cell death. So, it’s another vantage point in which to look at benefit in which these patients typically have the elevated troponin versus for example, normal individuals. And the third biomarker we’re looking at is cardiopulmonary exercise testing peak VO2, which is a measure of exercise tolerance. So, it’s looking at effectively cardiac output, and it’s a proxy for that. So these are the three key early signs of efficacy that we are looking to evaluate. I think they all look at three different things, but we’re really, this will give us the earliest signals of whether the therapy’s having the effect that we’re seeking.

Daniel Levine: This is a condition that not only affects the brain and the heart, but can affect organs throughout the body, and speech and hearing and the nervous system. Is there reason to believe that the therapy could benefit other symptoms associated with the condition, or do you expect it just to benefit the heart?

R Nolan Townsend: It’s possible that there is a benefit to other organs. So we’re using what’s called a ubiquitous promoter in our gene therapy construct, which means we should see expression of the frataxin protein in all organs, the liver, the skeletal muscle, and so on. So it may be that there is an ancillary benefit for these other organs that are not the target or focus of the therapy, but it may be that we do see some other benefit in other organs as well.

Daniel Levine: What’s the development path forward?

R Nolan Townsend: So, we are currently in a phase 1/2 study. I think with positive results here, we will be seeking alignment with the FDA to move to a phase 2 or phase 2/3 study. That phase 2/3 study, we would hope to be registrational and we would be looking at a BLA following the completion of that later stage study. In classically rare diseases like this with high unmet need, the FDA is typically willing to work with companies to move very quickly through the different stages of development to get a therapy to patients as quickly as possible. So we’re really focused on that. We know that this is a life-threatening disease, and this is a therapeutic option that can truly impact mortality associated with this disease.

Daniel Levine: The company is not only developing gene therapies for rare diseases, but also more common ones. It’s developing several candidates for Alzheimer’s disease. How does pursuing an indication like Alzheimer’s for a gene therapy differ from pursuing a gene therapy for a monogenic disease?

R Nolan Townsend: Yeah, so this is a very interesting question you asked, and I think a lot of this is tied to where do we see the gene therapy field heading beyond this current focus in monogenic rare diseases? And maybe to explain this, I can just take a step back and explain the genetics that sit behind Alzheimer’s disease because I think it’s important to the question that you asked. And so what we now understand about Alzheimer’s disease is that the genetics play a major role in determining the likelihood of developing the disease or frankly protection against developing the disease. And the a APOE gene is the key to that determination. APOE3, which is one genotype that is 80 percent of the population. This confers normal risk of developing Alzheimer’s disease. However, if you an APOE4, especially in APOE4 homozygote, this confers a substantially higher risk of developing Alzheimer’s disease. And this is to the order of magnitude of 15 to 20 times higher likelihood than an APOE3 or higher than normal. Interestingly, if you’re an APOE2, which is about 8 percent of the population, you have a lower risk than normal of developing the disease. And typically, APOE2s, a lot of them may not develop Alzheimer’s disease within their lifetime. But the most interesting part, at least to us, is that if you’re an APOE2 for heterozygote, so one allele of APOE2, one allele of APOE4, the existence of these two alleles moves someone back to normal, wo back to the APOE3 level likelihood of developing the disease. So, this is the thinking behind our program where we’re using APOE2 as a therapeutic, which we believe can stop or slow many of the pathogenic processes that are believed to be associated with Alzheimer’s disease. What I’m describing is us focused on correcting the genetics of the disease rather than a downstream pathogenic mechanism of the disease. And this is a unique approach, I think, for a disease of the profile of Alzheimer’s, that we’re not focused on a single pathogenic mechanism, that we’re actually looking to treat the totality of a very complex disease using gene therapy. And I’d say this is not unlike other approaches for other diseases. Probably the one unique element of this is just how many patients there are that are APOE4 homozygotes that we’re looking to treat. So, there are more than 900,000 APOE4 homozygotes in the U.S. making this one of the largest populations that any gene therapy is looking to address. So, I’d say that’s one of the major differences is that if you’re working on a rare disease like Friedreich’s ataxia, there are probably 5,000 to 6,000 patients in the U.S. and we’re working on a disease in Alzheimer’s where there could be 900,000 patients. And that has its own unique challenges from scaling and manufacturing. But I think we’re up to that challenge. We know that the unmet need for APOE4 is very high.

Daniel Levine: Where in the course of the disease would you hope to treat people?

R Nolan Townsend: So, our phase 1/2 study is treating patients who are anywhere from mild cognitive impairments (MCI) through to moderate dementia. It’s a pretty broad swathe of patients. I think we will need to review the data from our phase 1/2 study to determine what’s the ideal population we’d be considering in the upcoming studies. So I think our data readout will guide us towards that and more to come as we get the data from the study.

Daniel Levine: Given that you’re treating such a potentially large population, how do you expect that to impact pricing of any gene therapy?

R Nolan Townsend: That’s a great question, and I think it’s certainly a complex one, and I’ll take a step back and just provide some thoughts on pricing for therapies like gene therapy and others. So I think my view is that what society has always wanted from the biopharmaceutical industry is cures to diseases, single intervention or single administration, and you never have to think about the disease again. Well, the technology to be able to deliver that in a way is here: it is gene therapy, it’s gene editing, it’s cell therapy to some extent. But what that requires is different approach or different way of thinking about pricing of medicines, that we actually price medicines considering that they are a cure to the disease versus a therapeutic option where it’s a pill every day or it’s an infusion every month or every week, that the industry and payers reorient themselves around potential cures. And then what that means for the company’s revenues and P&Ls and what that means for the budget impact for payers needs to be really carefully considered. So I would say, let’s use Alzheimer’s as an example. There are amyloid antibodies that have been approved and probably more are coming. These amyloid antibodies patients would likely have to continue to be treated for the entirety of their lives from when they’re diagnosed with Alzheimer’s disease. So theoretically, if you could introduce a gene therapy that offsets all or even a portion that cost. And when you think about the cost, it’s not just the direct cost of therapy, it’s all of the ancillary costs of the disease. But let’s say you can have a treatment effect with a single administration gene therapy, and you are either no greater than the aggregate cost of an amyloid antibody. I think society would appreciate the cost benefit of that type of therapeutic option. So I think we won’t know what this particular therapy, what the price will be until we see the effect size. And we know that it’s reaching a product profile that’s compelling. But I do think from a theoretical standpoint, the ability to replace therapies that patients are being treated with every day, every month, every week with a single administration therapy is something that society should support and something that we should find a way with payers to reimburse appropriately.

Daniel Levine: Last year was a difficult one for biotechs looking to raise money, with the exception of an $8 million offering by another company, Lexeo was the only rare disease related company to successfully complete an IPO in 2023. What led to the decision to go public and how did the experience compare with past fundraising efforts in which you’ve been involved?

R Nolan Townsend: It’s a good question, and I didn’t think of it that way, that we were the only rare disease company to go out last year. I think the first thing I’d start with is that an IPO is very simply a financing. So we really looked at the company’s fundamentals, where we were with the progression and de-risking of our pipeline, what were the upcoming clinical data readouts that we had. And I think we believe based on our fundamentals that, this was last year, Q4 was the right time for us to access the public markets, and we certainly found support from investors with respect to that. I think what was exciting for investors was that we had preliminary data from two of our three key programs that was showing some signs of some effect, but we also had upcoming data readouts across several programs that we were working towards. And I think that picture of some de-risking of key programs, but yet more data to come was one that was compelling for them. And I think that’s where we saw the opportunity to access to public markets. I think the fact that we were a rare disease company, I couldn’t comment on why there were others that didn’t go out last year except to say that I think we have a very interesting pipeline here. We’re really working on some diseases and some disease areas that have a substantial amount of potential, not only in the therapies that we’re developing now, but also the read through of a success in these programs to other, let’s say, cardiovascular genetic diseases that we can address with our platform. So, I think we were very excited about what’s coming from Lexeo and where things are headed.

Daniel Levine: And how far will existing cash take you and what’s the plan for raising additional capital.

R Nolan Townsend: Our existing cash brings us to Q4 of 2025, so it’s roughly two years of runway. We have three clinical data readouts in 2024, so our Friedreich’s ataxia program, our desmosomal PKP2 arrhythmogenic cardiomyopathy program, and then the APOE4 Alzheimer’s program that we discussed. So I think on the other side of these readouts certainly should be substantial de-risking we would expect from the programs, and I think there should be a window to raise more capital. But I would note that on the back of these readouts, we still have 12 months of cash. I think it’s more than sufficient runway to progress even beyond the clinical readouts that we have in the plan today.

Daniel Levine: R Nolan Townsend, CEO of Lexeo Therapeutics. Nolan, thanks so much for your time today.

R Nolan Townsend: Absolutely. Thank you for having me.

This transcript has been edited for clarity and readability.