A New Era for FOXG1: The Race to First‑in‑Human Trials

Mary 

Welcome to Sounds of Science. I'm your host, Mary Parker. Today's guest joined us on the podcast back in 2024 to share her family's journey with Fox G1 syndrome and the early work of the Fox G1 Research Foundation. Since then, extraordinary progress has been made from regulatory milestones to the FDA granting fast track designation and clearing the IND for FRF001, paving the way for the first in human phase one, two clinical trial. I am pleased to welcome back Nasha Fitter, co-founder and CEO of Fox G1 Research Foundation, who returns to discuss how far the foundation has come and what these breakthroughs mean for families, science, and the future of rare disease gene therapy. 

Nasha  

Thank you so much. Great to be back here. 

Mary 

So Nasha, let's begin with your daughter, Amara. How's she doing today and how has she inspired you through this most recent chapter of progress? 

Nasha  

Yeah, she has her ups and downs, honestly, like so many of our kids. So she still has seizures almost every single day. She has a slew of GI problems. She's got behavioral issues because she's so frustrated with all her medical issues and she still has a lack of speech. So overall, it is a day-to-day hand-to-hand combat, but we are so excited about the progress that we're making and hopeful for the future. 

Mary  

For anyone who hasn't heard your story before, can you briefly share your family's FOX G1 story and how you decided to found the FOX G1 Research Foundation? 

Nasha  

So Amara was diagnosed after she started having seizures at seven months. We got the diagnosis very quickly. Luckily, we did not have a long diagnostic odyssey. And with that diagnosis, unfortunately, as most rare disease families learn, there's just not a lot of options. There's not a lot of information out there and there are no treatments. So I met a handful of other Fox G1 families. We got together. We started a foundation, notably with my co-founder, Nicole Johnson, who also has a daughter with the same condition. And we just decided let's get going. We started building mouse models and cell lines to understand the biology of the disease. We gathered our patients together. We started to classify symptoms with the goal from day one that we want to see a genetic therapy. And here we are, 10 years later. 

Mary 

Well, speaking of which, since you created the foundation, how has the mission evolved since the science has accelerated? 

Nasha  

It has been an evolution. In the beginning, we felt, okay, we're just going to de- risk our disease. That was the hot word that biopharma kept telling us. De-risk it, de- risk it, get your patients together, build a registry, get a natural history study, get mouse models that we can test on. Do this, do that. Just de- risk it enough so we can invest in it. And what we realized is that there was no pharma savior that was running to take our condition to the next stage. And even if there was, what we see during biotech slowdowns is that a lot of the ultra-rare disease programs get shelved. So we made a decision along this journey that we were going to be the sponsor. We were going to do our toxicology, we were going to manufacture drug, and we were going to sponsor our own gene therapy, multi-site clinical trial with the goal of a BLA of an approved drug.And that was an evolution that we never would have dreamed of in the beginning. 

Mary  

So can you explain how your drug FRF001 actually works? 

Nasha  

Yeah, it's very exciting. I still remember the day we got the positive news from our lab that this drug was working because we trialed a slew of different gene therapies as well as antisense oligonucleotides. And this drug is, it's very elegant. We're using AV9, so we know it can penetrate the blood-brain barrier. We know it's safe. And what we will be doing is delivering the drug via ICV. So that is brain surgery where we drill a hole in a patient's brain and deliver the gene therapy, the extra copy of the FOX G1 gene directly into the patient's brain. So it seems very frightening, but actually neurosurgery happens every single day. It's a very common procedure. And that was one of the rationales for doing it this way. And also we're trying to get as much of the drug to the cells, neurons that need it, which are located directly in the brain. Why this is such an elegant therapy is that it works for all FOX G1 mutations because whether you have a gain of function or a loss of function or whatever it may be, you have a missense or a nonsense, all of our children have a lack of FOX G1 protein. And so an extra healthy copy of the FOX G1 gene is going to benefit everyone. And that's one of the fundamental reasons we decided to take this path versus an ASO or going down the CRISPR route. 

Mary  

So the FDA has now cleared the IND for FRF001, which allows first-in-human clinical trials to start. Yes. Can you walk us through what this milestone means scientifically and for your family and the patient community? 

Nasha  

So scientifically, it's incredible. What we have been able to show the FDA is that our drug meets toxicology and safety rigor, and that's a huge step for any drug, and our efficacy is strong. So we've cleared the first hurdle. So scientifically, this is a really good stage. Operationally, it's also very interesting that now we're moving into, okay, we're going to be dosing patients, which is very different to dosing animals. So it has really opened up us working with a clinical team. We've built a clinical team. We have a chief medical officer that we brought in. We have our clinic sites that are getting up and running. So operationally, it's really moving us from bench science and working with animals into working in the clinic and with doctors and with actual real patients. So that has been a really exciting shift. And then emotionally as a community, our community has been on this journey with us from day one.Our community has fundraised when we were developing our first mouse model and have had faith in us throughout these years. So to be at this point, it's hard to actually put into words what it emotionally means for us when that IND was cleared, what it felt as a community that we have come this way on our own. It was really just an extraordinary feeling. 

Mary  

Well, you've also been granted fast-track designation, which is awesome. Yes. How does this designation change the pace and the structure of your interaction with the FDA reviewers? 

Nasha  

The FDA has a new designation called RDEP. We have that designation as well and the orphan designation. So we've accumulated all the designations and it's absolutely helped. So for example, we just had a type D meeting with the FDA where we laid out a clinical plan of how our hope is that this will be a registrational trial, which means we will not need a phase three trial and how we plan to do that, how we plan to measure progress in the trial. So these interactions, they're made more possible. We have just more oversight with the FDA. And to be honest, from day one, the FDA in our program has been an excellent collaborator and has really helped us. 

Mary  

I also understand this is one of the first parent-led international gene therapy clinical trials ever conducted. So what unique opportunities and challenges come with the foundation serving as the trial sponsor? 

Nasha  

Yeah. I mean, we are making history in that the name of the drug is FRF001. It's not the name of a company, it's the name of a foundation. And our goal is drug approval. It's extraordinarily exciting because we are in control and we can put patients as the sole ... That is our sole investor. We don't have any other investors that we have to make happy. We just focus on patients and we can always do the right thing for patients. That is really exciting. The upside of that is that if you look at the way clinical trials are enrolled, most companies have a lot of trouble getting enrollment into their clinical trials, especially for a one-time gene replacement therapy. For us, in the first 48 hours that this trial went up on clinicaltrials.gov and families could start registering their children, we had over 250 families register of interest to be in this trial in 48 hours. 

Those numbers are kind of unheard of. And so I think that is the upside of a foundation leading this. Our families trust us. We've taken them through this journey with us. We provide good news, bad news, everything. We're very transparent. So we have a team within our foundation that is completely guarded from folks like myself, for example, and the other families that are running the foundation.  I have not looked at what was exactly submitted in the IND to the FDA. So there's things that we've had to create those processes and be very regimented in how we operate within our teams. So those are the challenges. 

Mary  

Well, you've brought together scientists, biotech, regulators, and obviously this very engaged parent community. So what have been some of the most essential collaborations in reaching this point besides helping you segregate the parents from the science? 

Nasha  

Yeah. We couldn't have done this on our own. We've had a slew of collaborators and advisors. The two collaborators who without, we just would not be here are one Citizen Health. So we've actually done our natural history study in a completely unique way where we have only used patient medical records. We have not set up an in- person clinic natural history study where patients have to go in for visits over a number of years. Because of that, we were able to submit to the FDA thousands of years of data collected on families, on patients, and we were also able to really understand what the appropriate primary endpoint would be. So without that study, we would've picked seizures as a primary endpoint. But after looking at these medical records through decades, honestly, that we were able to collect, we saw that the frequency of seizures really varied. 

Whereas movement was pretty stable. And that's something that if we had a small group of parents, sorry, patients going from clinic site to clinic site, we wouldn't have picked up on because it's a very heterogeneous. Most rare diseases are very heterogeneous. You actually need to look at a large sample size. So that allowed us to put this study together and submit it to the agency. And because of that, we have alignment from the FDA that we can use these medical records, data from these medical records as a control for patients. So we are not going to have to have a placebo control trial. That's a game-changer for us. And also, we want to use this study as a registrational, as I mentioned, as a registrational trial. So without Citizen, we just wouldn't have been able to do it and we would've had to spend millions of dollars on an in- person natural history study that frankly wouldn't have been as good. 

The second collaborator has been Charles River. Charles River has dived deep. We have worked with them for toxicology, but also for manufacturing. And we aren't manufacturing a pill. This is a biologic. It is complicated. There are so many variables. And Charles River has really worked with us to ensure the highest quality product in a budget that we can afford in a timeline. And they've had the same sense of urgency as we have. And so that collaboration has allowed us to act like a biotech company, honestly. So that, I would say on the biological scientific side, we've had Charles River and on the clinical side, we've had Citizen, and that's allowed us to accelerate and do what we've been able to do. Honestly, we'll be developing a gene replacement therapy in under $25 million in a very short amount of time. 

Mary  

Well, any drug that is described as complicated also I assume is very expensive. So what role does fundraising play within the Fox G1 Research Foundation and where does the money go? 

Nasha  

You can't do anything without money. You can have all the hopes and strategies and ideas, and without money, it falls short. And that is the reality of rare diseases, and that's why we have what's known as the value of death for rare diseases. For us, we have been lucky. I am so lucky. My co-founder, Nicole Johnson, really spearheads fundraising. We have a really great philanthropy board chaired by Tom Horton, a grandfather of one of our patients, one of our families, and they have really brought together and created energy around what we're doing. And what's helped us is to say, look, we're doing this for Fox G1, but we're working on a blueprint, truly a unique blueprint that any other rare disease group can take forward. And that has created a lot of excitement for others to get involved in our cause. And what we've seen over the years is people will donate a little to begin with, but we deliver. 

We deliver, we communicate, and they see that, "Hey, I'm going to get an ROI on my philanthropic dollars." And so we've been able to go back and get the same donors to give more and more over the years. But fundraising is hard, it's exhausting, it's painful. Fundraising for a disease that no one's heard of is incredibly challenging, but that has been the key. Without the funds, we wouldn't have been able to get to where we are. 

Mary  

No, it makes perfect sense. So as IFRF001 moves into first in human dosing, what does early success look like in phase one, two, not just for safety, but for the patients? 

Nasha  

Look, I mean, all the work we have done, if the drug doesn't work, none of it matters. And so we're praying and we're hoping that science is on our side. We are hopeful to see no pun intended movement in our movement scale. We are really hoping to see something that is very binary. A child that wasn't able to roll is now able to roll. A child that couldn't sit up is able to sit up. We are looking for that type of measurement because this is a gene therapy. It comes with side effects. It is expensive. So we want to see dramatic change. That's what our hope is. And that's what we're banking on and really praying for. 

Mary  

Well, besides the more expensive gene replacement therapy, what other therapeutic approaches or platforms are you exploring for FOX G1? 

Nasha  

So we have a pipeline. We have more advanced gene therapies that we're also working on. This is just our first drug. This is FRF001. We'll have 002 soon and 003. So we do have a line of other opportunities. We are looking at ASOs. We are also looking at CRISPR approaches. We really do love gene therapy though, because again, you can have one drug for the entire population, whereas with both ASOs and CRISPR, it would be much more personalized. And right now, the way that these drugs are delivered and the costs don't justify that with the size that we have, which is about 2,000 patients around the world. We're looking at all different modalities. We're hopeful for better capsids to come out in the future, and we will continue investing and understanding the biology better and better over the years. 

Mary  

And looking ahead, what changes do you hope to see in the diagnosis and the care and the therapeutic access for FOX G1 patients? 

Nasha 

I mean, the exciting thing is once you have a therapy, they include your gene in a newborn screening panel. I think that will really open up diagnoses. So very excited about that. And just in general, I think genetic testing becoming more prevalent will be incredible for rare diseases, having more patients to understand the disease and bring these therapies too. But going forward, I do have a lot of hope that drug development is getting more efficient, that we're seeing the scientific progress at a rate that is kind of unbelievable. And my hope is that all of these trickle down into operations. The operations are really what's slowing us down in drug development. It's not so much the science, and I hope we just get better and better. We're already seeing more regulatory flexibility and eagerness to work with rare disease groups and families and companies, and we need everything working in a good circle. 

We just need the operations to work better. 

Mary  

What would you like to say to any parents who might be facing a FOX G1 diagnosis? 

Nasha  

I would say you have a lot of hope. When me and my co-founder and other families who've been at this journey for the last decade, think about what we've done. One of the things that gives us the most happiness is that a new family who gets this diagnosis is never going to have to go through what we have gone through. And they're going to be told, yes, you have this devastating diagnosis, but guess what? There is a therapeutic approach that was developed by a group of other parents. And again, these are hard emotions to put into words, but a new family should be very hopeful for the future of their children. 

Mary  

And finally, what do you want scientists and regulators to know about the urgency behind the FOX G1 movement? 

Nasha  

What we hope to convey is it is possible. It is possible to develop this drug in the timeframe that we have with the amount of money that we have raised. Normally, drug development takes hundreds of millions of dollars to create something like a gene therapy for an ultra-rare disease. We have not cut any corners. In fact, we have brought more rigor, and I think one reason that we have received so much FDA buy-in is because the rigor of the data that we have submitted. What we want to show is that is possible, but it does take a different way of development and just looking at how do you create a drug for a small group of people. You cannot use the same processes as you did when creating a drug for a large amount of people. You have to think differently. You have to have different types of people working on it. 

We really need to think about the amount of time that is wasted in academia, in basic science that doesn't even get translated more often than not. And we have to think about the incentives that academics have that really honestly slow down drug development and the consortiums we have and the amount of, honestly, nonsense that groups get sucked into. Drug development is actually pretty mathematical. There are certain experiments you need to do. There are certain modalities of therapies that we have. And I think we just need to start working as efficient startups and really thinking of ourselves in that way. So that's what I would tell scientists and regulators. I think we're already seeing it. We need more flexibility. You have to look at rare diseases differently. Having a control, a double-blinded placebo, yes, that's a gold standard, but that can't work when you have a disease of a few hundred patients. 

So how do we think about things differently? How do we look at medical records and see what we can decipher from those records and how we can match that data to the scales that we use within a clinical trial? How can we improve care, actually, day-to-day care of patients so we can use that data and collect that data so we could use that in a clinical trial. So there's lots of work that needs to be done, but I think there's a lot of smart people working on these problems now, and I'm hopeful for the future. 

Mary  

Well, it can be hard to be the Trailblazer. You are the one leading the way, but the people who are right behind you and the patients who are going to come right after you, I think will be very grateful. 

Nasha  

Thank you so much for saying that. And honestly, I've learned so much from the foundations that have come before me and the drug developers before me. And I think this is a community that pays it forward. 

Mary  

Absolutely. Well, thank you so much for joining us, Nasha. We really appreciate you taking your time to talk to us about your drug journey and the Fox G1 Research Foundation. 

Nasha  

Thank you, Mary. 
Mary  

Nasha Fitter is co-founder and CEO of Fox G1 Research Foundation. Stay tuned for the next episode of Sounds of Science. Until then, you can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts. Thanks for listening.