Charging into the Storm

Sunitha Malepati entered the world of patient advocacy after her child was diagnosed with a rare, neurodevelopmental disorder. More recently she founded the Buffalo Initiative to change drug discovery and development by creating a fund to invest in scientific enterprises driven by patient organizations and their collaborative networks. We spoke to Malepati about how she grew frustrated with the drug development landscape, how the Buffalo Initiative plans to fund patient advocacy organizations drug development efforts, and what the initiative is doing to reduce the time and cost of developing a therapy.

Daniel Levine: Thanks for joining us.

Sunitha Malepati: Thanks, Danny. I really appreciate you having me on today.

Daniel Levine: We’re going to talk about drug development, rare diseases, and your efforts to create a philanthropic fund to finance rare disease organizations seeking to advance the development of therapies for rare neurological disorders. Perhaps we can begin with your own story and how you got here. You’re an attorney by training, you taught at Georgetown Law, and in your private practice you counseled investment funds. Your daughter though, in 2020 was diagnosed with a rare neurological condition. How did she come to be diagnosed?

Sunitha Malepati: Yeah, I appreciate the opportunity to talk about this story and it all start with my daughter. So, I had no intentions or, quite frankly, interest in being in this space until I realized I had to fight for my daughter. So she was born in 2017 and pretty much within the very first weeks of her birth, we started to notice these abnormal eye movements and we weren’t sure if they were just a function of her being a newborn or if there was something else going on, but it was certainly concerning to us. It wasn’t something we saw in our older son. And when we brought this up with physicians, we were kind of dismissed and told, wait, “she’ll grow out of it.” And then these eye movements sort of evolved into other symptoms we were seeing in her missed milestones, delayed speech hypotonia, these sort of vague conditions that are associated with a lot of neurodevelopmental disorders. And so we went from doctor to doctor and finally got in front of a geneticist who saw the constellation of symptoms we were seeing and agreed to order a whole exome sequencing on her. And that took about almost two and a half years to get to that point.

Daniel Levine: She was ultimately diagnosed with CACNA1A-related disorder. How does it manifest itself and progress?

Sunitha Malepati: Yeah, so CACNA1A is a calcium ion channel gene that plays a central role in how neurons communicate with one another in the brain. So, when there’s a variant on this gene, it results in a wide variety of neurological symptoms ranging from balance and coordination difficulties to epilepsies to these eye movement abnormalities. Kids are developmentally delayed, there’s some cognitive impairment issues. So it is quite a wide spectrum of neurological symptoms that our kids have.

Daniel Levine: What were you told about the condition and what was your daughter’s prognosis?

Sunitha Malepati: Honestly, we weren’t told very much. So we were two months into the world being shut down by the COVID-19 pandemic, and we were logged on to a telehealth zoom appointment with the geneticist who was giving us the diagnosis that day. And she basically said, there’s not a lot that’s known about this disease. We don’t really have much to tell you. There’s not a lot of research going on. Pretty much good luck. She was going to, in her words, regress or degenerate over time, lose her milestones, and there was really nothing out there to be done, just continue to love her, take her to therapy appointments. And so we didn’t find much helpful or actionable information when we were given the diagnosis.

Daniel Levine: Did any treatment options exist or were there treatments for symptoms of the condition?

Sunitha Malepati: Yeah, so right now there are no specific treatment options for CACNA1A and nothing that was specifically designed to treat the underlying cause of these symptoms. But clinicians are prescribing a variety of medications that try to get at certain symptoms that our children are experiencing. So there are anti-seizure medications out there with that range in effectiveness. There’s a drug called acetazolamide that clinicians are prescribing in our community to help with ataxia, and then these stroke-like episodes that happen called hemiplegic migraines, but they really range in effectiveness. Nothing is totally working for everybody and not completely healing the symptoms, but people are on a variety of medications and obviously experience a variety of side effects as a result, but we need more effective therapies for this condition. My daughter currently is not on any medications because none of them that we’ve tried have worked.

Daniel Levine: Is that unusual for someone with a condition?

Sunitha Malepati: No, I would say it’s pretty common. It really was the reason why we’ve come together as a community to try to develop or try to find better treatment options because there’s a huge unmet need in the community. Our kids are often in and out of the hospital with medical emergencies. There are completely debilitating aspects of this condition that prevent our kids from having a great quality of life that they deserve.

Daniel Levine: You are vice president of the CACNA1A Foundation, which has been one of the Chan Zuckerberg Rare as One initiative grantees. How has the CACNA1A Foundation thought about the pursuit of therapies for people with CACNA1A-related disorders?

Sunitha Malepati: Yeah, so the CACNA1A Foundation was founded in 2020, the same year my daughter was diagnosed with this condition. And it’s really the first and only global patient-centric organization focused on finding effective treatment options and ultimately a cure for CACNA1A related disorders, the way we’ve thought about it at the CACNA1A Foundation is that there are a variety of stakeholders that need to be brought together to really think about how we go about pursuing treatment options for this community. And so we are laser-focused on ensuring that not only clinicians and researchers and drug developers are working on this condition, but working in concert with the patient community. And we have built this collaborative research network to do just that. So, we are getting all of the involved stakeholders together to really think about the research that needs to be done to work together and collaborate towards a single mission, which is a cure for CACNA1A-related disorders.

Daniel Levine: The rare disease space is being transformed by patient advocates who are engaging directly in drug development efforts, whether it’s funding research and ensuring there are things like natural history studies, animal models and biomarkers to enable drug development, and establishing companies to carry promising therapeutic candidates into the clinic. What’s driving this approach?

Sunitha Malepati: I think quite frankly, the system is failing the vast majority of rare diseases. I mean, I think we know the statistics, right? Ninety-five percent of rare diseases don’t have a single FDA approved therapy, and a lot of these diseases don’t have a viable business model, necessarily, for industry to really take a look and invest dollars into developing a therapy. So patient advocates, with the advent of tools that are easily accessible, are taking this upon themselves because they can’t wait for someone to come along and sort of save their kid. And we are left with no choice but to develop these natural history studies, animal models, and invest in biomarker research, just as the CACNA1A Foundation has done for this community because no one else was doing it. And we really are this next generation of patient advocate that Global Genes likes to call us, but we’re not just going to sit by and wait for someone to come—where we have to do it ourselves.

Daniel Levine: What’s the case for patient advocates taking the lead in drug development?

Sunitha Malepati: I think for the first time in our collective history, we are at this really unique moment in time where the science has never been this promising for genetic conditions like CACNA1A and other neurodevelopmental disorders, paired with the sophistication of the parents who are coming into this problem. And really it’s a combination of their savvy in other industries and then their child gets this diagnosis and they come and they bring their skillsets to this problem. And we are at a time where we can start to develop research relationships directly between researchers and clinicians who are seeing our families, as well as funders who want to support this work. So, we’re really uniquely positioned, given our sort of skin in the game, to get to a viable treatment options, but also because we have access to these tools and can deploy them to work on these diseases.

Daniel Levine: As you think about the challenges of developing therapies for rare diseases, are there things that an approach driven by rare disease patient organizations might be well suited to address?

Sunitha Malepati: Absolutely. I think right now, patient communities, we don’t have time to wait and we’re ideally positioned to accelerate these breakthroughs for our communities because the return on our investment is our kids. They’re our children’s lives. And so what we’re doing right now is breaking down research silos. We’re uniting our communities with researchers and clinicians to accelerate scientific progress more quickly and efficiently. And patient organizations are leading the process in a number of different ways: the science, we’re identifying patients, organizing research networks, developing tools and data resources. I mean all of the things necessary to solve a particular scientific problem. And there’s no other actor in the system that’s doing that. I mean, there are a lot of big science funders that are looking at umbrella approaches. There are research dollars going to answering basic scientific questions, but the people that are answering the questions that are most meaningful to patients are the patient communities themselves.

Daniel Levine: You’re a founder of the Buffalo Initiative. What is the Buffalo Initiative and what problem is it trying to address?

Sunitha Malepati: Yeah, so the Buffalo Initiative really is an intentional ten-year effort to rewrite the way therapeutic discovery happens, particularly for childhood brain diseases. And our goal is singular in mind. We really want more treatments for kids, and we’re challenging the way this traditional scientific expert-driven research model happens. And we’re going to be investing in a scientific enterprise that’s driven by patient organizations and their collaborative networks. So, community-led research efforts is really the focus of the Buffalo Initiative, and what we’re going to do is expand participation, leadership, and thought partnership of community-led research efforts so that we can see that the therapies that are being developed for rare diseases are actually driven by the expertise and experiences of those who are directly impacted.

Daniel Levine: You attended an event where Michael Hund of the EB Research partnership spoke. This was the inspiration for the name Buffalo Initiative. Can you explain?

Sunitha Malepati: Yeah. So, Michael Hund is this incredible visionary leader of the EB Research Partnership, and he gave a keynote address at the Chan Zuckerberg Initiative’s Science and Society meeting. And in that opening of the keynote, he talks about how buffalo act very differently in a rainstorm. So, for those of you who don’t know, most animals retreat in a storm, and as he tells it, buffalo behave very differently. When a storm approaches buffalo turn and charge directly into the storm and by facing the storm head on, they actually minimize the time spent in the storm. And this behavior, I think really resonates with us as rare disease parents whose children were diagnosed with these devastating brain diseases. And we didn’t retreat. We actually kind of formed these herds and we ran head first in the storm to try to solve these diseases for our kids. And so, we’re professionals turned leaders of patient organizations and we’re focused on finding treatments just like buffalo were focused on getting through the storm when they were faced with one.

Daniel Levine: I know the model for the initiative is evolving, but how does it work? What would constitute an investment that the initiative would make and is it focused on translational research or would you expect to fund clinical development as well?

Sunitha Malepati: Yeah, so the Buffalo Initiative is really going to marry the promising state of the scientific field that I talked about with the growing sophistication of these patient organizations. And to do that, we’re really going to take on three main programs. One is a fund, and the fund itself will be a grant making program that will enable patient organizations to align researchers and industries towards the priorities that are important to them. And we’re really going to start this with a pilot initiative of five different organizations that are at the stage between preclinical [and] proof of concept research and try to get them to their first-in-human clinical trial. And so, we’re planning to invest between $2 and $8 million per organization for those pre-specified studies needed to get them to human clinical trials. And the second piece of the initiative is really around building this shared infrastructure so that we can reduce inefficiencies and enable the development of therapies in a shorter amount of time and hopefully more cost effectively. So, what we’re hoping to do in that sort of bucket of work builds a pipeline of biotech partners who are experienced in drug development and are committed to co-investing with patient organizations to take their translational proof of concepts to commercialization. We’re planning to build a team of technical consultants who are able to help with questions and problem solving around therapeutic development, manufacturing, and regulatory requirements. And then finally, we are going to develop sort of this open science infrastructure that systematically measures, evaluates, and harvests the collective learnings of these patient organizations we’re investing in. The final piece of really what the Buffalo Initiative is aiming to do is to be a thought leader in this space to drive how we think about therapeutic development in terms of patient-centricity, how we shape the discourse around that, and the practice of community-led therapeutic development. I think right now, unfortunately, we’re seeing that patient-centric drug development is often extractive and tokenistic, and we really don’t have patient engagement efforts that are being institutionally funded, whether it be through large philanthropies or even the government. And we’re kind of left out of those traditional scientific efforts. And so, what the Buffalo Initiative is trying to do is also change how people view how the drug development process views patient advocacy organizations and our work in really furthering research, like real scientific research, and how we could partner better together.

Daniel Levine: To that end, I know you, you’re putting a data sharing requirement on projects you fund. Why are you doing that and can you explain how that works?

Sunitha Malepati: Yeah, this comes directly from what we’re seeing in the field. So a lot of research to date is done in silos because there’s no actual requirement that science be openly shared. And in the rare disease field in particular where there’s a shortage of data that’s available and we’re really trying to maximize the usefulness and effectiveness of the data that exists, we really have to adopt these open science transparency principles and we don’t have time to wait for all of these studies to get published. So any investment that the Buffalo Initiative makes as part of giving those dollars to the organization will be a requirement that the results of the studies are actually shared back to the Buffalo Initiative and with the network that we’re creating with these other organizations, because we know that learnings that are made across other disease areas will impact related diseases. And so we don’t want this information to be siloed and prevented this actionable information. We want it to be out there and used so that we can make progress more quickly and not be duplicative.

Daniel Levine: Sunitha Malepati, founder and vice president of the CACNA1A Foundation and founder of the Buffalo Initiative. Sunitha, thanks so much for your time today.

Sunitha Malepati: Thank you, Danny. Appreciate it.

This transcript has been edited for clarity and readability.

The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.