United States: February 29, 2024: The "Rarest Day Of The Year"

Rare Disease Day took place on February 29, 2024. Created in 2008, Rare Disease Day is observed on the "rarest day of the year"—February 29 in leap years (February 28 in non-leap years)—as a way to galvanize the global rare disease community around the goal of achieving "equity in social opportunity, healthcare and access to diagnosis and therapies for people living with a rare disease." To mark Rare Disease Day, Congress, the White House, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) held a series of events highlighting the challenges that the rare disease community faces today. The events brought together patients, patient advocates, pharmaceutical companies, providers, academic medical centers, scientists, and others to share the personal impact of, and current scientific advances in, rare diseases.

As noted by NIH Director Dr. Monica Bertagnolli during the White House Forum on Rare Diseases, "rare diseases are not rare." There are more than 10,000 known rare diseases affecting about 1 in 10 people in the U.S., and more than 90% of these diseases have no FDA-approved treatment for such diseases.

Throughout these events, several important themes emerged:

1. AI Holds Great Promise in Rare Diseases

A frequent topic of conversation at the events was the ways in which innovative uses of artificial intelligence (AI) and machine learning (ML) are being deployed or could be applied in the future to streamline rare disease diagnosis to address the well-known "Diagnostic Odyssey" endured by rare disease patients, and optimize treatment, by identifying new drug targets and reducing overall drug development time.

As evidence of the Biden administration's belief in the potential for AI/ML, during the White House Rare Disease Forum, Renee Wegrzyn, Ph.D., Director of the Advanced Research Projects Agency for Health (ARPA-H), announced a new initiative designed to "accelerate drug discovery and improve patient outcomes by repurposing approved medications to treat rare and currently untreatable diseases," the ML/AI-Aided Therapeutic Repurposing In eXtended uses (MATRIX) project. MATRIX will develop an open-source machine learning platform to identify and validate existing drugs in an effort to validate their use in diseases without current therapies. In furtherance of this project, ARPA-H made a $48M grant to the non-profit organization Every Cure and cited the possibility of further funding opportunities to "validate the most promising drug-disease matches in clinical trials."

Other programs currently underway are already beginning to fulfill this promise. Dr. Ed Neilan, Chief Medical Officer of the National Organization for Rare Disorders (NORD), described his optimism about a project led by Deep Genomics called BigRNA, "the world's first RNA foundation model for RNA therapeutics" which, according to the website, can help to identify drug targets and new biological mechanisms, predict molecule-target interactions and design therapeutic candidates. Dr. Joni Rutter, Director of the NIH National Center for Advancing Translational Science (NCATS), described the work of the Biomedical Data Translator Consortium, which integrates trusted data sources across 150 databases in an effort to draw novel connections from biomedical information, which can help establish relationships between drugs and diseases or genes.

2. Rare Disease Patients Play Key Role Driving Rare Disease Drug Development

In recent years, there has been a widespread and growing recognition of the contributions that people living with rare diseases can play in drug development and review processes. Throughout the events of last week, discussion focused on the progress in this realm to date and what more can be done going forward.

Dr. Janet Woodcock, former leader of the Center for Drug Evaluation and Research (CDER) at the FDA, attended the White House event and was applauded for her role in originating and driving the patient-focused drug development (PFDD) efforts at the FDA. Patients at the events repeatedly recognized the value of participating in the various forums the FDA has established for soliciting patient experiences in an effort to inform the review process (such as FDA-Led PFDD public meetings and FDA Patient Listening Sessions).

During the FDA's Rare Disease Day event, Kevin Bugin, Ph.D., Deputy Director of Operations in CDER's Office of New Drugs, described the numerous additional ways in which patients have increasingly become integral to the entirety of the development process, including helping to define clinical trial design and meaningful endpoints and assisting in trial recruitment. Dr. Bugin also stressed the need to involve patients early in the drug development program to assist in these efforts.

Patient registry data derived from programs, like NORD's IAMRARE® program, has allowed patients to drive their own research, developing and controlling the data derived from such registries. Increasingly, registry data have played a pivotal role in producing therapies for diseases without treatments, such as the first-ever treatment for Friedreich's ataxia (FA), the approval for which was based in part on registry-derived natural history.

3. Incentives to Innovate Must Be Preserved

At each of the Rare Disease Day events, there was widespread recognition of the positive and enduring legacy of the Orphan Drug Act (ODA). Enacted in 1983, the ODA established financial incentives to attract and sustain industry interest in developing treatments for patient populations that had previously been considered too small to be financially viable. Despite the success of the ODA in driving the increased number of orphan drugs on the market today (according to the FDA's database, there are more than 1,200 orphan drug approvals), there was general agreement at the events of last week that, given the well-known and persistent challenges of developing a drug in small populations, the need for unique incentives remains just as strong today. At the Energy & Commerce Committee hearing, praise for the ODA and its many contributions was exhibited on a bipartisan basis. However, when it came to the impact of the Inflation Reduction Act (IRA) on the incentives provided under this landmark law (which exempts from price negotiation drugs with a single orphan drug designation and approval only within such designation), a significant difference of opinion arose. The view of the majority, as reflected in the hearing and in the staff memo, is that the IRA "has disincentivized developing innovative treatments for rare diseases," (the roster of legislation considered at the hearing includes bills that would change the IRA to address such concerns) while several members in the minority defended the IRA and its promise of delivering lower cost drugs to patients.

Beyond the ODA, many speakers at the events cited the importance of other incentives, such as the Rare Disease Pediatric Priority Review Voucher program at the FDA, which will need to be reauthorized in 2024 (members at the hearing discussed a bill to accomplish such reauthorization).

4. Partnership With Federal Agencies Involved in Rare Diseases is Vital

There was robust representation by the federal government at the Rare Disease Day events. Leadership from the highest levels of the FDA and NIH, including FDA Commissioner Robert Califf and NIH Director Monica Bertagnolli, White House officials, and dozens of scientific and career staff made a strong showing in a clear recognition of the critical role of government in making progress toward addressing rare diseases.

Dr. Rutter described NCATS' commitment to continuing to act as the "home for rare diseases at NIH" where she and her team strive not only to discover new treatments, but also to work toward access and availability for all people. She stressed their collective focus on tackling "many rare diseases at a time" and leveraging approaches like platform technologies to achieve that goal. Dr. Rutter also described the work of the NCATS-funded Rare Disease Clinical Research Network, which consists of over 20 research consortia across the country working with 160 patient groups and studying 280 rare diseases. According to Dr. Rutter, RDCRN has contributed to 11 new drug approvals, with more to come.

Julie Tierney, Deputy Center Director in the FDA's Center for Biologics Evaluation & Research (formerly FDA Chief of Staff) stressed that the FDA should not be considered the agency at the end of the drug development process; instead, she noted that the FDA wants to be engaged "in the beginning, early and often." Tierney also described the numerous programs and strategies employed at the FDA to help support rare disease drug development and review, such as the FDA's efforts to clarify expectations around accelerated approval, particularly of molecularly‑targeted therapies. Tierney further described rare disease-focused programs focused on the goal of early engagement with the FDA, like the Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot program (which builds upon the model used in "Operation Warp Speed" to speed delivery of COVID-19 vaccines) and the Rare Disease Endpoint Advancement (RDEA) Pilot Program.

Rare Disease Day 2024 was both a celebration of the many accomplishments of the past and a recognition that there is much more to be done to better address the needs of people living with rare diseases.

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