Latest / BioSpace / Fragile X at a turning point: Breaking through the clinical bottleneck
Transcript
- speaker-0: My name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denatured. In this episode, you'll hear from Hilary Rossolo, Executive Director at the National Fragile X Foundation, and Jordi Babrega, co-founder and CEO at Connected Therapeutics. We'll discuss the future of Fragile X research and why the field has struggled to translate scientific promise into clinical progress and what it will take to finally break through. Hilary and Jordi, thank you so much for joining me on this podcast. Very curious to hear what you both have to say about Fragile X. So if you can introduce yourselves, that would be great. Hilary, why don't we start with you? speaker-1: Sure. Thanks so much, Jennifer, for having us both on your podcast. Like you said, my name is Hilary Russello and I'm the executive director of the National Fragile X Foundation, which is the oldest and longest running international, national nonprofit focused on Fragile X. speaker-2: Jordi? Yeah, thank you for having me, Jennifer. It's a pleasure to be here. My name is Jordi Fabrega. I'm co-founder and CEO of Connecta Therapeutics. Connecta Therapeutics is a biotech company based in Barcelona, and we are developing new treatments for unmet medical needs in the CNS. And our leading program is a first in class molecule, CTH120, currently in phase two clinical trials in fragile legs. speaker-0: Let's start defining Fragile X for our audience. Let's what is the disease about? What are some of its symptoms? Anything along that line to kind of set the scene. speaker-1: Jordi, you should fill in from a scientific perspective. So I should probably tell everybody I am not a researcher or a clinician, just a passionate patient advocate. So let's see, fragile X is a genetic and hereditary condition. Usually when you hear Fragilex, we're talking about fragile X syndrome, which is a rare disease component of the condition. It's the most common ⁓ single gene link to autism and the most common hereditary genetic form of intellectual and developmental disability. So people with Fragile X may have learning differences, behavioral challenges, but they're also loads of fun, have incredible visual memory skills, great senses of humor. ⁓ and what's interesting about FragileX is there are associated conditions that are attached to the premutation or is a carrier condition of Fragile X, which is becoming, I think, perhaps a little bit more widely known in other genetic conditions. But when I entered the space, this was novel in Fragilex. And so you see things like tremorataxia condition associated with the premutation as well as a primary ovarian insufficiency. It's an X-linked condition, so it's on the X chromosome. And so you'll see differences in the presentation between males and females because this FMR1 gene helps create this protein that's integral in many of the functions of daily life. And so whether you're making no protein trace or maybe a bit because your other X has sort of this functional FMR1 gene, that impacts the presentation. of Fragile X syndrome. So speaker-0: Let's talk about ⁓ a bit more serious now after that great initial ⁓ the setting the scene for fragile X. It's seen a number of failed trials over the years. So from both the patient and the company side, what do you think has been the main reason progress has been so difficult? speaker-2: Okay, so Fragile X biology is complex as with many neurodevelopment conditions. it's not easy to tackle. From our understanding, from our point of view, the main reason is that the previous development programs focus on a single molecular targets. But we understand that restoring brain function may require broader and more pleiotropic approaches. This is what our case with CT-AID, which acts as neuroplasticity modulation properties of the brain. ⁓ but that is affecting the vast majority of neurodementive disorders. So this is one reason. The other reason may be that many trials relief heavily on caregiver reporting outcomes, ⁓ which are valuable but can lead to placebo effects. And it's what causes some clinical trials to fail. In any case, rather than failures, what we see is previous studies should be viewed as important learning experience and... These lessons are shaping better design clinical trials today. speaker-1: So well said. I mean, I just want to reiterate every point you just made, Jordi. Both of us just left ⁓ the National Fragile X Foundation's 20th International Fragile X conference, and this conversation just came up. ⁓ and what we landed on is that while there have been these negative trials or these failures, we're always learning and it sets us up so well for how to change and adapt for the next trial. But I think in terms of there's there's potential placebo effect, which is not uncommon, especially in rare diseases. And we certainly see that in Fragile X. And we have some work to do on nailing down endpoints and think considering what might work in terms of performance based outcome measures or biomarkers or things that complement or better support in addition to those caregiver reported ⁓ outcome measures. So there's a lot of interest and work being done, but we've certainly ⁓ had a lot of heartache. Yeah, along the way. And I think that's fair to say too. speaker-0: And I think you make ⁓ the last two points actually are very nice segue into the next questions, Hillary, in that one of the recurring challenges, as you mentioned, seems to be endpoint selectional placebo effects. So what kind of outcome measures do you think are most credible for fraudule acts going forward? speaker-1: Yeah, what a good question. I mean, I think it's a combination of many things and there's probably not one perfect outcome measure, just like there's not one gonna probably be one perfect treatment ⁓ for fragile X syndrome given the heterogeneity of the condition. But I think performance based or direct assessment outcome measures are great because they they take out some of the subjectivity that we all have, whether we're a clinician, reporter or a parent reporter. ⁓ things like EEGs, right? ⁓ or if we can establish firmer biomarkers in Fragilex syndrome, I think that would be fabulous. But I do believe there's always gonna be a place for these caregiver or self reported measures. Sure. Because ultimately you're the one experiencing ⁓ the change. So speaker-2: I completely agree with Hillary. Difficult question to answer because the endpoint selections also depends on the mechanism of action of the drug. this is something to take into consideration. But in other cases, as Hillary said, when defining the clinical endpoints, you need to have a multi-dimensional approach. So having caregivers and patient report outcomes are very important. because there you capture the meaningful changes in daily living and real world functioning. But also you need independent clinical perspective. So you need clinical rate outcomes in this sense. And especially important right now is the objective functional assessments like EEG or eye tracking, actigraphy. There is some of them already that have been using different clinical trials that are less vulnerable to placebo effects. So this is important. And of course, at this moment, we don't have a clear biomarker in blood and plasma that will be perfect, but it's something that I think in the next years we will find some more. speaker-0: Yeah, I think it's perfect what you're saying upon building the past knowledge. I mean, even though past trials have not been successful, you have learned so much and especially how to address this condition as as you mentioned both of you, the variability behind that. So let me ask you on that point. So when you think about the core symptoms of fragile X and the huge variability, what about designing trials for adults versus children? speaker-2: I can start with that. ⁓ yes, although all patients share the same genetic mutation, the clinical presentations are different. So, stratification is a key element to consider during the clinical trials design. Although current stratification often includes gender and age, that is important because ⁓ maybe the goals and differs across the lifespan. But additional factors should be also considered, like cognitive ability, behavioral profile. symptom severity and also coexisting conditions. So all these stratification has to be considered well-defined in clinical trials because it's really important. speaker-1: So well said. I mean, inherent to Fragile X is the variability. And I think the best designs, right, in account for that. And yes, variability is in human nature, right? We're all unique, but the trends in Fragilex are why we can even have trials. And I think that's an important message for both families and researchers, right? We want to pull out those trends or those symptom profiles and get the best ⁓ shot on goal. I know I hear that phrase a lot. And and maybe You don't fit into that inclusion criteria in this trial right now, but the it is so well intentioned in that the design is trying to find the most homogenous group to track that change ⁓ and then broaden the indication as we move forward. So and then Jordy pointed this out beautifully that there's so much differentiation in terms of age and what the focus or unmet need is. And so I think just designing the program in a way that pulls that information along with the complement of what you're trying to achieve movement on i is really the key. speaker-0: Yeah, that that does make sense. Now you've t both talked about the patient aspect and obviously with a patient advocacy group, Hillary, y'all are very much of very deep insights into this. So we know that patient support clearly matters beyond the trial itself. So what are the biggest unmet needs families raise most often, especially as patients age into adulthood? speaker-1: Yeah. This is like the question I think that we get asked the most often from our perspective. So I mean, if you zoom out, patient advocacy organizations are critical to any community, right? Because they're the place where you land. They give you good unbiased information. They provide you with community. They're there to celebrate the wins, but also just be hear you, right? When you need to talk about the hard stuff too. And I think that's the beauty of communities like ours. ⁓ But yeah, I mean, i if you're talking about the biggest unmet needs across the lifespan, especially as we age into adulthood, you sort of zoom out from fragile X specific ⁓ challenges, right? Things that maybe you're approaching at school age or in IEP meetings, et cetera. And you're looking at what lots of broader IDD communities are looking at, which is what does employment look like? What does independence look like? And certainly this big big question of what happens when the parent or caregiver is gone. And so if we can find treatments right that address these lifelong trajectory questions and provide support, I think that's really what people are looking for ultimately. So obviously gains in in in any and all aspects are fabulous. But if we can solve that burning question that keeps people up at night, what happens when I'm gone, I think that would be a huge win. speaker-0: So you're positioning Jordi as C T H one twenty as a neuroplasticity modulator with potential disease modifying effects. Why is that mechanism attractive in Fragilex and what evidence gives you confidence? speaker-2: So CTH120 targets a new kind of infection. In fact, it targets the TRKB, that's tropomyosin receptor kinase B, Pathway. So it's a new mechanism that has been never tested in fragile leg syndrome. So in this sense, it's something that can add to the neurodevelopment community. Pathway is a key regulator of synaptic function, neural connectivity, and neuroplasticity. Neuroplasticity is a property of the brain that is affecting much a lot of neurodermal conditions. And by recovering neuroplasticity, you recover also a lot of the clinical manifestations in fragile legs. And we are quite confident in this sense because we have a strong preclinical evidence in animal models acting both in cognition and behavioral fragile legs manifestation that is really good. And also we have ⁓ encouraging early human safety data. with a very safe profile and some insights of CNS activity in healthy volunteers during phase 1. I know phase 2 results will provide the answer, but we are quite confident that it will work. speaker-0: Great. And then Jordi, where where are you at in development at this point? What's the next stage? speaker-2: Yeah, we have a phase two ⁓ clinical trial ongoing in Spain. Okay, we have involved two hospitals, two the major hospitals here. They have a lot of experience in fragile X community. One of them has the biggest unit in fragile X patients. So at this moment we are recruiting. We have already some participants recruited. So, and we expect to have top-line results next year. very exciting moments. Okay. speaker-0: Fantastic. Okay. Hillary, I don't know you were gonna say something, you a big smile on your face, so speaker-1: No, I'm just this is music to my ears. I'm just ⁓ quietly giving you the thumbs up over here, yeah. speaker-0: Fantastic, fantastic. So you both mentioned the importance of working across the lifespan ⁓ of fragile eggs. So how do you think about the sequencing of adult and pediatric development? I mean, is there a certain point where it switches of the symptoms or the care, or it tends to be more of a gradual trajectory? speaker-2: I mean, sometimes how do you tackle the different ages? It depends on the regulatory pathway. Because with new molecules as ours, adults are required to be studied first, where you establish all the safety, the dosing, the dose, and you look for early efficacy signals. It's important. And then you move to children. For us, it's been important as early intervention could... produce greater and more durable benefits. So pediatric studies require especially careful safety evaluation. That's why we are going first in adults and then going to the pediatric population. Both programs inform one to other. Adult studies optimize dosing, improve safety, and guide the pediatric development. So in this case, in our case, we have already started the pediatric development plan. We have performed all the toxicology studies. and we are forcing future pediatrics clinical trials. And also we have reproductive toxicology studies in place, also to include females, which shall be in potential in next future. So we are very inclusive in this way. We want to include all the fragile x community. speaker-1: I think from my perspective, they're both great populations to study and many people flex. I think Geordie said the best, right? That many groups start in adults because of the safety data, because you can provide proof of concept. And then I think the other argument is that with children, they potentially have the greatest benefit given just the longer term you have with them. But you need to typically establish pretty good safety profile in order to do that. ⁓ and so some groups make the argument to start. in the pediatric population, but you know essentially ⁓ there's in my from my perspective, there's no wrong place to start and we just appreciate you starting. You know what I mean? Yeah. speaker-0: Right or wrong. ⁓ ⁓ So fair point. So that's looking ahead, what would success look like for the fraudulex field over the next few years? Is it just a first approved therapy full stop? Is it better biomarkers? You mentioned a bit about that, Jordi, more reliable endpoints, or simply a more sustainable trial ecosystems? There's a lot to pack in there. speaker-1: I mean, my answer is yes. I don't know. ⁓ the above. Yes, all of the D, all of the above. Of course, we are families have been waiting for that therapy right to cross the finish line for a long time. ⁓ but as I mentioned before, I don't I don't think any of us are convinced that one therapy, especially one that targets a specific symptom, is going to be the end all be all. And so being able to set up sort of The foundational pieces of research that we need in order to move many treatments forward is key. That's where the biomarkers come in, the more reliable endpoints, the sustainable trial ecosystem. And I think what I'll say selfishly is that we've built really good programs, especially at the National Fragile X Foundation, to support you in doing this work, to leverage the learning we've had from all these trials. And we have a really robust. clinical trials committee that's there to help guide you as you design your program preclinical through execution of your child. And we have a sort of parallel group in our family advisory committee where you can get that lived experience feedback. And so one of my favorite things about this community is that they talk to one another, the professionals and the families. And that's where I ultimately think there's going to be success. So I'm very hopeful. ⁓ and I think Connecta is doing a great job of like embodying all the things that I've just referenced. speaker-2: also very optimistic because I think the environment is there. mean, we have the community that is engaged and supportive in the clinical trials. That is also thanks to the National Fractal Disease Foundation and other associations that really have very good activities and supporting families and also engaging all the stakeholders involved. So I foresee all of them. But if I needed to choose one, well, I see in the next future a first approved therapy that will be a major milestone for everybody. It is not simply to approve a drug, but also to deliver therapies that produce a meaningful improvement in the functioning, independence, learning, communication, quality across the lifespan. Maybe the first drug will be not the drug that will solve all the manifestations, but probably will be a good point. to validate the field, start, the drug will start and others will come over again. We are much better positioned today than it was a decade ago because now we have a deeper understanding of the biology, improved trial methodologies, biomarkers, and a stronger partnership with the Fragile X community. It's very important. speaker-0: Perfect. I I always like ending a podcast in a very optimistic note. So this is perfect. So thank you so much, Jordi. Thank you so much, Hilary, for joining this episode of Denature. It's been fascinating. If you'd like to listen to more episodes, please turn to biospace.com or shoot me an email to send me a pitch at jennifer.smith hyphenparker at biospace.com. Thank you very much.