In Search Of Rare Disease Treatments, Nonprofits Can Lead the Charge

The biopharma sector has transformed countless lives with innovative therapies, yet an estimated 85-90% of rare diseases lack any approved treatment. The economics of developing new medicines for some of these patient populations often just do not add up.

In recent years, nonprofit and philanthropic organizations have been trying to solve this market failure, combining and scaling up models from across the biomedical research ecosystem. By de-risking early-stage research, catalyzing investment and accelerating the path to approval and access, these groups are working to change the rare disease research and development calculus and boost the impact for patients.

Toronto-based Conscience is among the mission-driven organizations deploying innovative strategies — from venture philanthropy and open science to AI-enabled drug discovery — to bring potentially life-changing treatments to the clinic faster and more efficiently.

Ryan Merkley, Conscience’s CEO until early 2025, told In Vivo before his departure:

“In a perfect market, there would be an available drug at a reasonable price accessible to every person in every jurisdiction. As we know, that’s just not the case.”

In a perfect market, there would be an available drug at a reasonable price accessible to every person in every jurisdiction. As we know, that’s just not the case.

Ryan Merkley, Conscience

Merkley added: “Even in a successful market, the market can fail at the edges, which means people get left behind.”

Bridging The Valley Of Death

One major bottleneck in rare disease drug development is the so-called “valley of death”—the preclinical phase where promising academic research often stalls due to lack of funding and expertise to advance towards human trials. The Oxford-Harrington Rare Disease Centre, a transatlantic partnership between the University of Oxford and the Harrington Discovery Institute in Cleveland, aims to bridge this gap by nurturing high-potential projects with financial, scientific and managerial support.

“The financial model underlying what we do is absolutely essential,” Matthew Wood, director and chief scientific officer of the Centre and professor of neuroscience at the University of Oxford, told In Vivo. “We do the early-stage drug development and de-risk the programs with philanthropy.”

The Center can commit close to $500,000 of philanthropic funds to support each project initially, only then bringing in investment funds to support further development.

Launched in 2019, the Centre leverages Oxford’s deep bench in rare disease research—nearly 400 scientists spread across departments of medicine, genomics, data science and more—as well as Harrington’s cadre of industry-trained drug development experts. The goal: to launch at least 40 new rare disease drugs towards the clinic within a decade.

While venture philanthropy and public-private partnerships have been used for years to advance research on diseases of low commercial priority, the Oxford-Harrington Centre’s model of embedding a “biotech-like” drug development organization within an academic institution is distinctive in aiming higher.

By providing mentorship, funding and project management support to promising academic projects, the Centre aims to help close the translational gap between discovery research and commercial development in a more integrated and efficient way.

“The idea is to get to the drugs,” Wood emphasized. “Our only metric of success is the number of new rare disease drugs we can develop.”

Leveraging AI For Open Drug Discovery

While Oxford-Harrington focuses on advancing preclinical assets, other nonprofits are working to make the drug discovery process itself more efficient and collaborative through open science and AI. Launched in 2023, Conscience, a self-described nonprofit biotech, focuses on conditions like rare diseases, pandemic preparedness and antimicrobial resistance –areas where the business case often does not justify investment despite clear medical need.

Conscience’s strategy addresses this market failure through two key mechanisms. First, it aims to lower the financial barriers to drug discovery by leveraging computational models and AI.

As Merkley noted, “if we can get better starting points faster, especially in these conditions where the cost of finding the starting points can be really high, maybe we can change the way in which the balance sheet works for those opportunities.”

To that end, the nonprofit runs the Critical Assessment of Computational Hit-finding Experiments (CACHE) competition. CACHE invites companies and researchers worldwide to put their AI algorithms and predictive models to the test by proposing solutions to specific drug discovery challenges.

In its inaugural round, focused on discovering novel inhibitors of the LRRK2 protein implicated in Parkinson’s disease, 23 teams from industry and academia submitted over 2,500 virtual compound predictions. Conscience then partnered with the University of Oxford to experimentally test and validate each submission in the lab.

The result was a trove of openly available data on the performance of different computational methods—an invaluable resource for advancing the field of AI-powered drug discovery.

Results from the third challenge were announced in late 2024, with 23 computational teams ultimately yielding four truly novel molecules with binding affinity to a site on coronaviruses that helps the virus evade the human immune system.

Conscience also promotes open science collaboration to reduce redundant research efforts. Doing so is key, Merkley pointed out, saying that a critical inefficiency in the current system is that “you can have multiple companies working on the same failed target... and they don’t know for years and years and never tell each other that they’ve abandoned that target.”

The organization’s approach is particularly notable in how it handles intellectual property. Rather than pursuing traditional patent protection, Conscience makes its discoveries available under permissive licenses. “We want to give those discoveries the best possible opportunity to get picked up and worked on,” Merkley explained.

This approach allows multiple companies to potentially develop the same foundational research - something Merkley sees as a feature, not a bug: “The best thing that could happen, in our view is that three companies all want to work on a target. That’s certainly not the problem we have right now.”

Conscience has attracted some big pharma partners, including AstraZeneca, Bayer and Boehringer Ingelheim, and secured CAD $49m from the Canadian government, which it leveraged to bring in a total of CDN $105m through partner matching, demonstrating substantial institutional support for this alternative approach to drug development. Roughly one-third of the organization’s funding is allocated to promising results that would not typically receive market funding.

The idea is to carry the ball as far down the field as we can in a way that makes it more likely that that research will get into the clinic and ultimately to the patient

Merkley, Conscience

“The idea is to carry the ball as far down the field as we can in a way that makes it more likely that that research will get into the clinic and ultimately to the patient,” said Merkley.

The Power Of Patient Engagement

One nonprofit that has yielded significant patient benefit is Genethon, founded initially as a research institute in 1990 by the French Muscular Dystrophy Association (AFM), Genethon was formed to decode and map the human genome, track the genes responsible for genetic diseases and use this knowledge to produce innovative therapies. This was at a time when gene therapies were only a dream. In 1992, Genethon indeed produced the first map of the human genome, outpacing US teams and boosting global efforts to decode and ultimately sequence the genome.

Since then, Genethon has grown into an integrated gene therapy organization spanning fundamental research, preclinical and clinical development as well as biomanufacturing. Genethon’s work is sustained by an annual national telethon (inspired by the Jerry Lewis telethon for the American Muscular Dystrophy Association) that has raised over €90m per year since 1987.

This long-term funding from a patient-led organization has allowed Genethon to pursue projects that would be deemed too risky or small-market by traditional industry actors. However, the institute’s research has also led to some commercial successes, including Zolgensma (onasemnogene abeparvovec-xioi), the landmark gene therapy for spinal muscular atrophy developed by Novartis using Genethon’s initial research. The organization currently has 13 experimental therapies in clinical trials for a variety of genetic diseases, ranging from muscular dystrophies to sickle cell disease.

“Our success is very much linked to the fact that we have been backed by a patient association, and we have a not-for-profit model,” Frederic Revah, CEO of Genethon, told In Vivo. “If we had been backed by VCs or a pharma company, we would have been closed down after a couple of years.”

Similarly, the Michael J. Fox Foundation (MJFF), founded in 2000 by the eponymous actor following his Parkinson’s diagnosis, has also achieved impressive impact by leveraging the power of patient engagement. The Foundation has galvanized hundreds of thousands of patients to participate in research as donors, advocates, and clinical trial volunteers.

One standout success is the Parkinson’s Progression Markers Initiative (PPMI), a landmark longitudinal study that has enrolled over 1,500 participants across 50 global sites to identify biomarkers of disease onset and progression. Breakthroughs from PPMI, now in its 15th year, are enabling smarter and faster clinical trials.

Our success is very much linked to the fact that we have been backed by a patient association, and we have a not-for-profit model. If we had been backed by VCs or a pharma company, we would have been closed down after a couple of years.

Frederic Revah, Genethon

One key achievement from the PPMI is the development of the alpha-synuclein seeding assay, a cerebrospinal fluid test that can detect the hallmark pathology of Parkinson’s disease years before the onset of clinical symptoms. This finding opens up new possibilities for earlier diagnosis and intervention. By recruiting at-risk individuals before significant neurodegeneration has occurred, clinical trials may have a better shot at demonstrating the efficacy of neuroprotective therapies.

PPMI has also shed light on the potential of dopamine transporter (DAT) imaging as a tool for tracking disease progression and therapeutic impact. DAT scans, which visualize the density of dopamine-producing neurons in the brain, are now being used to confirm Parkinson’s diagnoses and assess the biological effects of investigational drugs in clinical trials. This imaging biomarker, alongside the alpha-synuclein assay, is helping reduce uncertainty and improve statistical power in trial designs.

However, as MJFF deputy CEO Sohini Chowdhury noted, there is still work to be done in refining these tools and developing a more comprehensive suite of biomarkers and outcome measures. Non-motor symptoms like cognitive impairment, which can be highly disabling for patients, remain difficult to assess objectively. There is also a need for more sensitive and specific measures of disease progression that are well-correlated with patient-reported outcomes and quality of life.

For its successes, Chowdhury credits the Foundation’s patient-centric mission and partnership-driven approach with rallying diverse stakeholders behind its ambitious research agenda.

“We’re not here to make money, get publications or win awards,” she told In Vivo. “We’re here to service a community and fulfill our promise of doing everything we can to develop new therapies.”

Working With Pharma And Ensuring Market Access

Both Chowdhury and Genethon’s Revah noted the tension inherent when patient-fueled nonprofits work with pharma – a necessary partner if they wish to translate scientific findings to marketed treatments.

Chowdhury acknowledged that while the MJFF’s primary focus has been on accelerating the development of new treatments for Parkinson’s disease, the ultimate goal is to ensure these therapies are widely available and affordable for patients.

“This is something we’ve looked at closely, trying to understand what we can put in place or how we can move forward to get the greatest access,” Chowdhury said. “It’s something you don’t want to lose sight of, even if the roadway is quite a long one.”

For Chowdhury, ensuring access and affordability is a complex challenge that will require collaboration and compromise among all stakeholders in the biomedical ecosystem. The key is finding ways to work with pharma in a way that aligns with the MJFF’s mission and values, while also recognizing the practical realities of drug development and commercialization.

It really is about understanding how to work with pharma partners without giving up the principles and the values that are core to what we’re doing.

Sohini Chowdhury, Michael J. Fox Foundation

“It really is about understanding how to work with pharma partners without giving up the principles and the values that are core to what we’re doing,” Chowdhury said. “And I think that we’ve been able to successfully do that. In cases where there hasn’t been a meeting of minds, you end up not establishing a partnership and you walk away. But if you can find that like-mindedness, then you really can do great things together.”

Genethon’s Revah noted that the question of how to ensure gene therapies are priced fairly and made widely available to patients remains a difficult point of discussion with industry partners when it comes to licensing.

The organization tries to secure commitments from its pharmaceutical partners that “price should not be an obstacle to access to the drug,” but this can be challenging to codify in licensing agreements.

“We defend the notion of fair and controlled prices, but on the other hand, this is a notion that is, from a contractual perspective, difficult to put in writing,” he said.

The tension between Genethon’s mission to serve patients and the commercial priorities of the industry reflects a broader dilemma in the rare disease space. While non-profit and philanthropic initiatives play a crucial role in de-risking and accelerating the development of potentially transformative therapies, the ultimate impact of these efforts depends on the accessibility and affordability of the resulting products.

Revah suggested that innovative policy solutions, such as reimbursing the cost of experimental therapies during clinical trials for diseases with no established market, could help bridge this gap. However, he emphasized that truly aligning incentives and ensuring equitable access will require a fundamental rethinking of how society values and pays for biomedical innovation.

“If we want to make these drugs available, it is a matter of national solidarity,” he said.

The Road Ahead

For its part, Conscience is exploring new models to sustainably finance high-risk, high-reward research, such as launching the Developing Medicines through Open Science (DMOS) project to support promising early-stage projects that focus on developing drugs for “ignored diseases.” Conscience can provide up to CAD $15m to help small and medium-sized enterprises establish proof of concept for an open science path to drug development and to translate innovations into affordable medicines.

“In spaces where the market is already failing, where we already know that the business models may not justify the kind of investment that other conditions might merit, maybe that’s a good place for companies to work together and explore different ideas,” Merkley said.

Meanwhile, the Oxford-Harrington Centre’s Wood sees opportunities to leverage the UK’s National Health Service and the country’s relatively agile regulatory system to accelerate rare disease therapy development.

“The chief executive of the MHRA (Medicines and Healthcare products Regulatory Agency) believes we can get development of some of these drugs down to under a year if we accelerate the regulatory pathway for rare diseases,” said Wood. “That would principally involve rethinking requirements like animal toxicology for well-established drug platforms and instead doing more safety assessments in patients.”

Despite the promise of such reforms, realizing the full potential of rare disease R&D will require systemic and cultural shifts in how society values and incentivizes innovation for small patient populations.

“One of the solutions is philanthropy de-risking, but that is not sufficient on its own,” Wood said. “There are multiple things that need to change.”

For the estimated 400 million people worldwide living with a rare disease, the outcome of those changes could be life-altering.