S5, E06: Cure Rare Disease: Continuing a Legacy

Rich Horgan (00:03):
Terry's legacy is an opportunity to have developed a pathway, a way to help develop treatments for other patients who fall into that same bucket as Terry other Terry's, if you will, who have a diagnosis of an ultra rare disease and are left with basically nothing to do if there's any clinical trials out there. And that's a big 'if' given the nature of rare disease and especially ultra rare disease. Many patients are precluded from those trials based on age or ambulation status or any of the number of other factors that go into the clinical trial design, potential therapeutic. And I think the way that he should be remembered, as is reasonably so, is somebody who didn't do this for themselves. He did this for the other patients who we were working and continue to work on therapeutics for patients who are impacted by similarly ultra rare versions of this disease. I don't know. I think that's a pretty selfless thing to do, and it takes a pretty courageous person to put themselves in harm's way so that somebody else who has a similar version or similar rarity of the disease can benefit. It takes a lot of bravery to do that.

Todd Poley (01:44):
Rich Horgan founded Cure Rare Disease in hopes of developing a treatment for Duchenne muscular dystrophy, a rare disease plaguing his younger brother, Terry. This four year journey marked by triumphs and challenges united global scientists and supporters offering hope for Terry and DMD patients worldwide. The organization has since expanded its mission to 15 drug development programs and recruited collaborators across continents begging the question: how many lives might Terry's legacy yet save? I'm Todd Poley, and in this episode of Vital Science, we sit down with Rich Horgan, founder, president and CEO of Cure Rare Disease. We talk through the company's drug development journey with DMD, its collaborative approach to research and where rare disease therapies are headed in the years to come.

Gina Mullane (02:38):
Welcome to Vital Science Rich, we're honored to have you back for another episode. Could you tell us about yourself and your role at Cure Rare Disease?

Rich Horgan (02:47):
It's great to be back, Gina. I'm the founder and CEO of Cure Rare Disease. As you may remember, we're a nonprofit biotech now based out of Connecticut in Woodbridge, focused on the development of advanced modalities for rare and ultra rare neuromuscular and neurodegenerative diseases, and I'm happy to be back.

Gina Mullane (03:10):
Great. So tell us the story of how Cure Rare Disease was born. I'm sure it's a interesting story because it was born from passion and love and all of those nice things.

Rich Horgan (03:24):
Yeah, that's right. I started Cure Rare disease about, geez, six years ago now in an effort to help my younger brother Terry. So Terry's story goes back to the mid-nineties when he was born and diagnosed a few years later with a disease called Duchenne Muscular Dystrophy, DMD as it's abbreviated, is a rare muscle wasting condition for which there's still really no cure, and it's a progressive disease that impacts almost virtually boys, exclusively in young men, and it's caused by a mutation in the dystrophin gene. And the dystrophin gene is responsible for stabilizing the muscle membrane. And so you can think of it as shocks on a car. Without dystrophin, the muscle is fragile and turns over at a much greater rate than you or i's muscle would. That's really where the story started. Years went by and Terry was four years younger than I was, and we grew up together and I watched as the disease started to creep into center stage, and some number of years later, I found myself finishing up business school in Boston and I had an opportunity to try to do something very tangible to change that outcome.

And so I pulled together a group of researchers and clinicians from around the United States and many, many others who helped to support the early mission at the time. And we developed a genome editing technology using CRISPR that we found corrected the mutation in vitro upregulated, the missing protein in vivo. And that story took about three years to unfold until we got FDA approval to dose Terry. Unfortunately, at the time, as I mentioned, DMD is a progressive disease. And so Terry at the time was 27, and 27 unfortunately for somebody with DMD is considered old. And so by that point, Terry had significantly atrophied muscle, including his heart. And so as time went on, unfortunately we were a little too late to save Terry and he passed away in October, and that was a big hit.

But what came from that was, and Terry's legacy is an opportunity to have developed a pathway, a way to help develop treatments for other patients who fall into that same bucket as Terry other Terry's, if you will, who have a diagnosis of an ultra rare disease and are left with basically nothing to do if there's any clinical trials out there. And that's a big 'if' given the nature of rare disease and especially ultra rare disease. Many patients are precluded from those trials based on age or ambulation status or any of the number of other factors that go into the clinical trial design, potential therapeutic. And so that's really where we find ourselves today.

Gina Mullane (07:05):
Well, at Charles River, we were all really devastated to hear about Terry, and I'm thankful to have you back today to tell us more about that journey and where you're headed now. I think you already said it really great, but I was wondering as you look back as to what it took to get to today, what are you most proud of?

Rich Horgan (07:33):
Yeah, I mean, it's not so much of what I'm proud of. I think as you asked the question, I'm more proud of the people who joined forces to try to change this outcome. I'm proud of the people who came from totally unrelated backgrounds who had never met each other before, all broadly united in the effort that they worked in science, somehow, whether in academia, whether in a CRO, whether in a manufacturing company, a hospital, a consultant, so on and so forth. I'm proud of the ability to have mustered a group, raised a lot of money over a very short period of time to affect what we thought would be a very positive change. Your comment about the people at Charles River is a true one. I mean, so many people at Charles River contributed to this cause to help Terry's drug get advanced into the clinic.

Folks like Lauren Black and Keith Sutton and Marge Ferguson, the names go on and on and on. And there's so many people at Charles River that I never had the chance to really meet who contributed in some way, shape, or form to this mission. And it's sort of that thing where the good memories still are kind of sharp, if you will. They're sort of, bitter is not the right word, but they don't evoke happiness yet – they sort of evoke a feeling that, geez, we are so close. But I think thinking about all the people who worked the late nights and pushed through despite what seemed like an impossible task at the time, it makes me feel good about what we did. We were really doing this for the right reasons. There was no money involved in terms of making money off of this drug. There was no other reason to do this than an altruistic reason of trying to help someone. And I think that it kind of restores your faith in humanity. Although of course the outcome was not what any of us had hoped or thought would happen. The idea that a group of people could come together make sacrifices in terms of their time, in terms of their bandwidth to see this through is inspirational.

Todd Poley (10:10):
Duchenne muscular dystrophy, or DMD, affects approximately one in 5,000 to 7,500 males globally. It begins with muscle weakness in the legs and progressively impacts the lungs and heart. Typically leading affected individuals to require a wheelchair by around age 10. Despite limited effective treatments, corticosteroids often provide relief and the FDA approved mone and alternative corticosteroid in November, micro dystrophin developments are showing some promises. Well, researchers are trying to work around the gene's large size and related delivery difficulties with micro or mini versions of the gene. Overall, DMD remains a formidable and often fatal disease with family serving as 24/7 caregivers and most patients succumbing to the disease in their early twenties. But ongoing research, including potential drug approvals, offer some hope for future relief. Let's hear more from Rich on Terry's experience with DMD.

Gina Mullane (11:17):
Now, I know Terry had a rare form of DMD. Can you tell us more about his particular mutation?

Rich Horgan (11:25):
Yeah, so it's a good question because it raises one of the challenges in treating the disease because the gene is so big. Mutations occur along the gene, which has 79 exons. And so with mutations being very heterogeneous across the gene, it makes it harder to treat. So there are some hotspots of where mutations occur in the 45 to 55 range of the gene, but Terry's mutation fell very much so outside of the hotspot. Terry's mutation is one of the rarest out there which made developing a treatment commercially almost impossible. And so that's why we took the route of developing something more mutation specific for him, because that, at least in my eyes, was really one of the only ways to approach it.

Gina Mullane (12:19):
Last year, Terry was treated with a special gene therapy designed just for him using CRISPR activation technology. Can you tell us more about how that works?

Rich Horgan (12:30):
Yeah, so it's true. The therapeutic we developed was and is a CRISPR transcriptional activator. The technology used a deactivated Cas9 to introduce a set of VP16s with the hope that it would upregulate the cortical isoform of the gene. When we took a muscle biopsy from Terry very, very early on in the project back in 2018, we found that there was elements of dystrophin present, which was curious because the mutation he had was an inactivating mutation. And so what we hypothesized is that Terry's body was trying to naturally upregulate dystrophin using that alternative iso form, the cortical isoform, which is found typically not in skeletal muscle, but rather in the brain. And so our therapeutic strategy was to use that deactivated Cas9 and the VP64s to upregulate that cortical isoform of the gene in hopes that it would provide functional improvement. Forter, especially in his heart, which we all know is of course critical to life.

Gina Mullane (13:36):
So can you walk us through the days leading up to dosage of the therapy, some of the risks you were aware of and what was involved in that treatment?

Rich Horgan (13:48):
Yeah, there was a lot of excitement in the days leading up to there was excitement, but there was also sort of very, very realistic caution around the challenge of delivering AAV to an older patient. A year prior, we'd seen the patient in the Pfizer clinical trial pass away an older patient, I believe the patient was 16 at the time. And so we went in with eyes wide open. For the most part, I would say the team was comprised of, I would say, relative leaders in the field. And so we were cautiously optimistic that this could affect some sort of positive change.

Gina Mullane (14:31):
So Rich – Terry was a brave warrior, an advocate who was really determined to fight this disease. And sometimes things don't go the way we planned or hoped. Can you take some time and share a story about Terry that might surprise us and tell us how you hope that Terry will be remembered?

Rich Horgan (14:52):
Yeah, I completely agree. He was very brave. Terry was one of the smartest people I knew. He graduated from Cornell and worked there full time afterward. And Terry went into this with a very much so eyes wide open. I would say he really knew more than we as family did in some ways about his own body and where he was in terms of the disease. And so with that being said, I think it underscores the bravery with which he moved into this clinical trial knowing that a patient who was older passed away a year ago, although a different drug, still an AAV, knowing that he was losing function, certainly had already lost function of his legs, but was now losing function of even his hands. And so if I put myself in his shoes, I think like wow, knowing all that, it again underscores the bravery with which he went into this trial.

I think the way that he should be remembered as is reasonably so is somebody who didn't do this for themselves in reading some of Terry's messages, it very much so illustrated somebody who was doing this not because they thought they were going to get up and walk again, not somebody who thought that they were going to be cured of a disease that had progressed so far and so long. He did this for the other patients who we were working and continue to work on therapeutics for patients who are impacted by similarly ultra rare versions of this disease, but are much younger and who have a good chance, a possible chance at seeing a really meaningful outcome from a potential therapeutic down the road. And so, I dunno, I think that's a pretty selfless thing to do, and it takes a pretty courageous person to put themselves in harm's way so that somebody else who has a similar version or similar rarity of the disease can benefit. It takes a lot of bravery to do that.

Gina Mullane (17:17):
When Cure Rare Disease was founded, it was focusing on Terry's specific DMD mutation. But are there other diseases you're investigating and other modalities and platforms at this point?

Rich Horgan (17:31):
You're right that when we started, we were almost solely focused on developing Terry's therapeutic as progress was made. And as time went on, other families and researchers reached out to us with a similar challenge that they were impacted by an ultra rare disease. And so since then we've started developing and are well into developing almost to the point of IND submission therapeutics for other diseases targeting different neuromuscular genes such as several LimbGirdle subtypes, ADSSL1, as well as neurodegenerative diseases like SCA3 beyond genome editing, which we generally employ for the DMD ultra rare mutations we've started. And most of these diseases that are well into development and almost at the point of IND submission are leveraging gene replacement and antisense oligo technologies. And so the way we really look at it is when faced with a disease, what tool in the proverbial toolbox gene replacement, gene editing, antisense oligos is best poised to treat that disease. And so where we stand now, we've got four or five programs late in preclinical development, beginning large scale manufacturing, and then a number of other programs that are in that either early discovery or pharmacology stage around the point of pre IND submission. So it's an exciting time to see the evolution of CRD despite the tragic outcome at what it's capable of doing as a collaborative effort.

Gina Mullane (19:06):
And can you explain to us how important patient voice is in the drug development process, not only in design, but also in the clinical trials?

Rich Horgan (19:16):
Yeah, absolutely. I mean, I think the idea of patient voice is critical. It's this idea where you need the patient input. You need to understand what's important to the patient. You need to understand what are we trying to get out of improving function from this patient, and what are we trying to do here? At the end of the day, I think it's easy to get sort of caught up in the ivory tower theory of, okay, all these patients want to run and walk again. And of course, while that's true, there's incremental steps to getting there for DMD for really any other disease that's can be treated by gene therapy. And it takes time, but you need everybody at the table and you need to understand what the patient considers to be a definition of success.

Todd Poley (20:08):
Researchers have gained valuable insights from Terry's case contributing to the safer development of gene therapies and influencing the future of CRISPR based treatments. These findings published in the New England Journal of Medicine indicate that treatment failure didn't stem from CRISPR itself, but was likely an immune reaction to the viral vector used to deliver the therapy. Each data point collected helps paint the picture of how a potential drug or how a class of modality can work. These learnings enable researchers to refine dosing approaches for future patients, particularly older individuals, promoting increased safety in the ongoing development of gene therapies. Let's hear more from rich on how these therapies could impact patients' lives.

Gina Mullane (20:55):
So looking ahead to these emerging therapies that are hitting the market, how can we make sure they're accessible to patients who really need them?

Rich Horgan (21:06):
I'm glad you asked this. Accessibility is one of the biggest issues facing gene therapy today. Accessibility not only of approved therapeutics such as Zolgensma and the potential approval of some upcoming therapeutics which are approved or may shortly be approved, and insurance will probably eventually cover those therapeutics. It's also the issue of what about the ultra rare diseases that are too rare in nature to be able to ever have full FDA approval to unlock the ability for insurance to cover it? And that's one of the things that we're focusing heavily on at Cure Rare Disease over a year ago. I brought on Eric Faulkner previously from Novartis, who's one of the leading thought leaders in reimbursement strategy to design a blueprint of what it could look like to create a financing pathway for non-commercializable ultra rare diseases. This is the long tail of ultra rare disease that people have been hesitant to touch because there is no clear way to get paid for them, more or less.

And so a year later, we've developed a blueprint with the support of the Muscular Dystrophy Association and their funding to conceptualize a practical and tangible way to pay for ultra rare disease therapeutics. And so that blueprint, that white paper has been completed, and we're getting stakeholder feedback now from different groups, payers, regulators, manufacturers, so on and so forth to understand the perspective where the gaps that we have. And we'll be presenting this paper both in publication as well as in presentation in the coming months. And I think this is something that I really encourage folks to reach out about. If there's one big thing I could leave you with from this conversation is the idea and the tangible plan that's been developed and is being iterated upon as we speak is one that could lift all boats in terms of developing therapeutics for patients who have historically been overlooked and neglected. And this is one of the most important things we face as an industry today, is how do we make sure that even the rarest of the rare can benefit from treatment?

Gina Mullane (23:17):
Well, it sounds like there's a lot of work to be done, and you've recruited allies for the cause. In what ways has the rare disease community increased disease awareness and the advances in treatment in recent years?

Rich Horgan (23:31):
I think there's a number of ways that the rare disease community has increased our ability to treat rare diseases and awareness. I think this community is one of the most engaged and passionate communities out there. This community is one that will show up to Capitol Hill to advocate for congressional funding, approvals, you name it. This is a community that will show up and advocate and rally for the cause. And so engagement is one of the biggest things that the patient community can do. Donating samples and adding to biobanks is another. I would say the other thing that this community is good at is fostering collaboration. Rare disease, of course, by nature is very rare. And so it generally almost always takes a collaboration to be able to advance a therapeutic from bench to bedside. And so the rare disease community is great at that. They need to keep doing that. Fighting disease is one of those battles that it's very much so a marathon, and you have to just keep pushing even when you're tired and you just want to sit down and say, well, let me take a breath. You just need to keep pushing and being steadfast about how do we keep going and going and going and going

Todd Poley (24:46):
To keep this momentum Cure Rare Disease takes a collaborative approach to drug development. When deciding to develop a therapeutic, they first study the existing ecosystem, including academics, clinicians, and research models. They then virtually engage with current experts and identify a leading researcher to develop early therapeutic prototypes. This could be a gene replacement therapy, antisense, oligo nucleotide or genome editor. Once some progress has been made together with the academic institution Cure Rare Disease's translational team including toxicologists, regulatory leads and manufacturing leads gets more involved. They guide the program from early development in academia to late preclinical development, scaling up manufacturing, conducting toxicology studies, and eventually submitting the IND. Clinicians are also involved downstream to ensure a seamless transition to the clinic. Rich and his team put a high value on collaboration, openly sharing findings and developments, which leads to efficiency for not only their own research, but rare disease drug development at large.

Gina Mullane (25:53):
Speaking of collaboration, in 2020, cure rare disease partnered with Charles River scientists to insert CRISPR into the adeno-associated virus or AAV system. Can you tell us how this CRISPR activation works?

Rich Horgan (26:09):
So CRISPR activation works to sort of do exactly as the name implies. It use a deactivated Cas9 to upregulate, along with a set of VP16 transcriptional activators– the targeted mutation. So we targeted it toward a cortical form of dystrophin. You could target it to different targets as well, but that's what we used it for. And we found that it performed well in vitro before packaging it into AAV. And then we found that it worked well in vivo once it was packaged into at the time in AAV nine.

Gina Mullane (26:45):
And what made this partnership sustainable and successful and actually lead to getting the therapy to Terry, the first of its kind in the us?

Rich Horgan (26:55):
Yeah, there's a lot of things that worked well about this. One of the things that worked well was the input from scientific advisory services that we received, the input from folks like Lauren Black, Keith Sutton at the time, David Fischer and others who helped to develop the pharmacology experimental design, the toxicology experimental design, baking into the perspective the FDA's potential needs on this. Now, this was a first inhuman, so what challenges does that raise? The transgene was a first in human. The capsid had been in human before being an AAV9. And so having that breadth and depth of knowledge from the Charles River team allowed us to benefit from the vast number of programs that they'd seen and worked on before. I forget what the stat is. I think it's like 90 plus percent of INDs Charles River's touched, which is, I mean, how can you not take advantage of that experience?

It was also the willingness to work with us as a nonprofit, being a non-commercial entity, there are different needs. And of course, at the time we were building the ship as we were flying it, one of those needs was what can we do in terms of the economics associated with this? And Charles River was really great about that. I would say not only the scientific degree of rigor that one would expect from a leading company, but also the compassion and empathy that is less often found among industry was something that Charles River really had and continues to have. And that's something that goes from the top with the CEO and Jim there to all the way down to the folks that we work with on a day-to-day basis, and everybody in between that we continue to work with. So I really would say of our collaborations, especially in industry, this has been one of the most, if not the most fruitful collaboration and one that's really helped touch a lot of lives. Since then we've engineered a number mutation-specific mice together. We've run additional pharmacology, additional toxicology studies. We've run next generation AAV studies to shift away from AAV9 to more myotrophic capsids. This work is enabled by, in a great part, Charles River and its team.

Gina Mullane (29:11):
We're honored to be part of your journey. So what do you expect to be on the horizon for rare disease research and drug discovery?

Rich Horgan (29:19):
Yeah, so the future for rare disease drug discovery, I would say continues to be a bright one. This past year or two, we've seen the pullback of sponsors working on rare disease therapeutics. That is unfortunate. But what is fortunate, despite the recent challenges, is that the tools and technology for the most part are there to treat these diseases. Are they perfect? No. Can they get better? Yes, absolutely. Will they get better? Without a doubt, the tools and technology are there, and that gives me confidence that this is not a problem that fundamentally disagrees with physics, with biology. This is very much so a humankind problem in the sense that we need to rally resources and willpower to be able to develop the next generation set of rare disease therapeutics. What we also need to develop is the system in which to do this. How do we pay for it is one of the leading questions.

And as I mentioned a few minutes ago, that's something that we focus on heavily, is the ability to figure out, okay, how can we develop a new financing mechanism, a new reimbursement mechanism so that ultra rare disease patients can be treated? And so with the continued advocacy, with the continued passion of families of researchers, with the continued desire and drive to see a better future, I am very confident that we will see a brighter future for rare disease patients. We ourselves, of course, are one player in this ever-growing ecosystem, but three of our therapeutics are advancing into that late preclinical IND-enabling stage, which is exciting to see what comes over the next year or two, a number of clinical trials sponsored by cure disease to develop therapeutics for patients, again, who have been neglected and forgotten simply because their disease prevalence is too low. And so we continue to look for partnerships. We continue to build collaborations with academia, with industry. We have advanced into looking at how can we provide tools, humanize mouse models, cell lines to help bolster industry's effort to develop therapeutics and treatments. And that's working. We're seeing a strong pull from industry at taking advantage of those tools. And that's great. So in conclusion, I would say that the future is bright and it continues to require that persistent steadfast determination to make the vision of a future free from rare disease, a reality.

Gina Mullane (31:52):
You've certainly shown that you and your team have that determination. How do you hope to help pave the way for future innovation?

Rich Horgan (32:00):
So we're doing our part to pave the way for future innovation in a number of ways. We've got several therapeutic programs that are approaching that IND submission phase over the next year or so. Therapeutics aimed at rare muscle and rare neurodegenerative diseases. And while drug development's a significant part of what we do, the other way in which we're paving the way for rare disease is through the development refinement and eventually launch of what we would propose as a novel strategy to reimburse ultra rare therapeutics that are non-commercial. And so this will take time, but this is one strategy that could certainly be one that raises the tide for all boats in rare disease and may offer a potential solution for these patients who have simply had no way to pay for a therapeutic development effort before and time will tell, but that's in part what we're trying to do to change the outcome for these patients who are impacted by these rare and ultra rare diseases moving forward.

Gina Mullane (33:06):
What do you hope Terry's legacy and that of Cure Rare Disease will be?

Rich Horgan (33:11):
It's a good question. I think my hope for Terry's legacy is that by the time we've moved on, I've moved on whatever you want to say, that we've got a way, a very clear and tangible way for patient families to sponsor and begin drug development programs that meaningfully end in a therapeutic approval. Now, will every drug work? Certainly not. But if there's a way for families, for researchers, for clinicians to develop therapeutics without needing to raise millions, tens, hundreds of millions of dollars from some sort of funding source that requires commercialization, then that would be a very great outcome. I would say developing a new treatment pathway for those who've been forgotten is a real testament and honor to his legacy.

Gina Mullane (34:07):
How can the listeners of Vital Science help get you there?

Rich Horgan (34:12):
I think it comes down to engagement. A certain subset of listeners will really resonate with this, and to those of you, I say reach out and engage, and engagement looks like so many different things. It looks like supporting the science we do, hosting events, volunteering. If you come from a technical background, there's so many ways to engage. It really comes down to the individual and how they are currently in life and where they find themselves. But I think the broadly applicable statement here is reach out and engage. Some of our best people have come from initially emails that said, Hey, I've heard X, Y, Z, and I, I'd love to talk to you.

Gina Mullane (34:52):
Very inspiring and motivating for sure.

Rich Horgan (34:55):
Thank you for having me. I really appreciate it. And if folks want to reach out and learn more, I encourage them to go to cureraredisease.org.

Todd Poley (35:06):
Rich Horgan is the founder, president, and CEO of Cure Rare Disease. Looking ahead to our next episode of Vital Science in March, we'll hear from Sarah Almond of Mission Therapeutics, a global leader in autophagy, a quality control process that could lead to the prevention of Parkinson's disease. Until then, thanks for listening. Did you know that Charles River has a sister podcast, Eureka's Sounds of Science? This monthly podcast shares scientific patient and advocacy perspectives on trending issues in the drug development industry. You can subscribe to Vital Science and Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts.