Building a Bold New Path for Ultra-Rare Diseases: A Q&A with Sunitha Malepati
Ultra-rare diseases affect small numbers of patients individually, but collectively represent a vast and largely untapped frontier in medicine. Although many have well-understood genetic causes and viable therapeutic approaches, most lack active development programs because no scalable system exists to carry promising science into the clinic.
The Buffalo Initiative, a program of Renaissance Philanthropy, was created to address this structural failure. By bringing together patient groups, specialized expertise and flexible capital, Buffalo Initiative is building a new model for ultra-rare therapeutic development, one that moves beyond traditional investment constraints. Our goal is to accelerate the translation of patient-driven science into real treatments and demonstrate that ultra-rare drug development can be investable and transformative at scale.
In this conversation, Kumar Garg sits down with Sunitha Malepati, Fellow at Renaissance Philanthropy for the Buffalo Initiative, to discuss a groundbreaking approach to developing medicines for ultra-rare diseases.
Kumar Garg: Sunitha, let’s start with the basics. When we talk about rare diseases, how big is this problem really?
Sunitha Malepati: It’s enormous, Kumar. There are 10,000+ rare diseases affecting 1 in 10 Americans and 400 million worldwide. Roughly 70% of these manifest in childhood. And here's the stunning part: 95% have no FDA-approved treatment. We're talking about a massive unmet medical need, yet it receives a fraction of the attention and investment.
KG: That's staggering. But we have CRISPR, gene sequencing, incredible advances in molecular biology. Why aren’t we delivering treatments?
SM: That’s exactly the paradox. For the first time in human history, we can identify the precise genetic cause of thousands of childhood diseases—80% of rare diseases have an identified genetic cause—and we increasingly have the tools to treat them. Yet the most transformative medicines remain trapped. The problem isn’t the science. It's the system. Traditional drug development simply wasn't designed for ultra-rare conditions.
KG: What do you mean by "ultra-rare"?
SM: Ultra-rare is a distinct subset within the broader rare disease category. While there is no single agreed-upon definition, we are focusing on conditions affecting fewer than 3,000 people in the United States. This population size typically falls outside the scope of early-stage venture investment, which is often the first step toward translating academic discoveries into therapies. The vast majority of ultra-rare disease programs that start in academia never move into clinical trials, even when the biology is clear.
Ultra-rare conditions present unique challenges in research funding, clinical trial design, and treatment development due to extremely small, geographically dispersed patient populations. They make up the majority of all rare diseases, yet they receive less than 1% of orphan drug designations, which represents drug development for rare diseases. Compare that to the largest 5% of rare diseases, which account for 50% of all orphan drug designations. Commercial investment follows market size, not patient need or scientific opportunity.
KG: So there's a massive opportunity being ignored. What changed to make now the right moment to work on this?
SM: What’s changed is that the constraints are no longer scientific. Therapeutic technology platforms are validated, and many rare disease-gene relationships are understood. Just among neurodevelopmental disorders alone, there are over 100 well-characterized genetic diseases with clear therapeutic pathways and zero treatments.
At the same time, regulators are evolving. The FDA is increasingly open to fit-for-purpose trial designs, novel endpoints, and smaller datasets when the disease is well understood, and the patient voice is strong. Regulatory flexibility fundamentally changes the risk calculus in ultra-rare. Even before this evolution, rare medicines have had a 4.5X higher probability of approval versus treatments for common diseases.
The other shift is happening on the ground. For too long, the systems that decide whether new science ever reaches patients were built without the affected families at the table. That is changing. Families are no longer waiting for industry to act. They are stepping in as extraordinary entrepreneurs. Across the U.S., more than 3,000 patient organizations now exist, with over 1,000 formed in the past decade alone. Many are led by parents and caregivers who are trained professionals in other fields, bringing the pedigree and discipline required to succeed. With limited resources, they are building patient registries, funding research, and advancing real therapeutic assets. And unlike traditional actors, these founders don’t walk away when things get hard; their “business” is personal. They are working to cure the diseases affecting their children and loved ones, with urgency, resilience, and long-term commitment that is unmatched.
Put together, this creates an opportunity to build a new, scalable system for patient-led ultra-rare drug development that simply couldn’t exist before.
KG: Patient-led drug development—that's not typical. Why is that approach needed?
SM: When therapeutic programs fail, we usually blame the science. But in ultra-rare diseases, the breakdown often happens much earlier because the development process was never built around families’ real lives. These are most often conditions where parents are the primary decision-makers and caregivers, yet trials and therapies are still designed as if families are an abstraction rather than the end users.
Biopharma has made progress in consulting patients and families on clinical trial design, but that doesn’t solve the deeper gap: most ultra-rare diseases never enter development at all. What’s different here is that parents and families are not just providing input, they are leading. Savvy parent entrepreneurs are navigating established drug discovery and regulatory pathways with the urgency and patient-first focus that a parent who is trying to save their child uniquely has. They’re not lowering scientific standards; they’re integrating lived experience to de-risk strategy early, shaping trial design, endpoints, and feasibility before time and capital are wasted. That combination of patient-first focus, rigor and urgency is what makes patient-led drug development uniquely powerful, especially for diseases the traditional system will never prioritize.
To make this visible at scale, we have built a Patient-Powered Pipeline Tracker, aggregating programs across rare diseases to show this is not anecdotal but a growing, investable pipeline. We also now have a growing body of case studies where patient-led development outperforms traditional models on cost, speed, and feasibility, creating a compelling opportunity for philanthropists and impact investors to back a system that delivers both outsized social return and durable value.
KG: So how does Buffalo turn this into a scalable, investable system?
SM: We're building four pillars. First, a continuous pipeline by maintaining relationships with rare disease networks to identify patient-led programs with validated biology. Second, an accelerator—think Y Combinator for rare disease—providing these extraordinary entrepreneurs with strategic support from toxicology studies to FDA strategy to manufacturing partnerships. Third, open-source knowledge sharing so every program makes the next one faster. And fourth, a blended capital fund with timelines aligned to drug development, not venture exit pressures. We're launching a $50 million fund with a 10-year horizon. The capital structure is a mix of philanthropic early-risk capital and mission-aligned investors with structured returns through equity stakes, royalty streams, milestone payouts, and reinvestment into new programs.
The bigger vision is pioneering scalable infrastructure that inspires copycat efforts and establishes a new ultra-rare investment category. We’re aiming to deliver financial returns, human impact, and systemic change.
KG: Why did you join Renaissance Philanthropy to design this work?
SM: I joined Renaissance Philanthropy because Buffalo requires a platform that can operate where traditional systems break down – across philanthropy, science and capital. Renaissance provides the flexibility, credibility, and interdisciplinary talent to design new structures rather than force ultra-rare diseases into models that were never built for them. In addition, philanthropy plays a catalytic role in this space. It can move first, absorb early risk, and align incentives around patient impact rather than short-term returns. In doing so, we will be able to unlock additional capital, such as program-related investments (PRIs), impact equity, and strategic partnerships, that would not engage otherwise.
KG: Why did you name this the “Buffalo Initiative”?
SM: When a storm approaches, most animals retreat. Buffalo do the opposite. They turn and charge straight into the storm, together as one herd, and in doing so, spend less time in it. That’s the spirit behind the Buffalo Initiative. Ultra-rare diseases are among the hardest problems in medicine, and the Buffalo Initiative exists to face them head-on, collectively.
KG: For philanthropists and impact investors reading this, what’s your call to action?
SM: Help us build what the market hasn’t—yet. Your capital, philanthropic or mission-aligned, can stand up a scalable system for ultra-rare drug development that pairs strong science with entrepreneurs and their communities from day one. The biology is ready, families are organized, and early proof points show this works. What’s missing is flexible capital willing to move first and a reliable system that can enable this work at unprecedented scale. This is an opportunity to unlock an entirely new class of investable assets that will deliver meaningful returns while improving lives for thousands of families who currently have no path forward.
To learn more about the Buffalo Initiative at Renaissance Philanthropy or explore partnership opportunities, get in touch at info@renphil.org.