The evolution of non-oncology rare approvals in the U.S.

The Orphan Drug Act of 1983 (ODA) was a pivotal moment in rare disease drug development, providing financial incentives such as tax credits, fee waivers along with regulatory incentives such as market exclusivity and faster approval timelines. Prior to the ODA, developing drugs for rare diseases was commercially risky, with only about two drugs per year being approved for rare disease. The period between the 1990s and the 2010s saw the number of orphan drug designations more than quadruple, especially among neurology and endocrinology diseases.

As we can see in the figure below, that trend has continued to move upward this decade, with last year seeing 21 non-oncology rare disease drug approvals. 

So what factors in the market are driving the trend today? We found five that we believe are contributing to the increase.

1. There’s more regulatory support to get treatments to rare disease patients faster
   
   Governmental regulatory support has been a major factor in the increase in orphan drug approvals. In 2017, the FDA implemented the Orphan Drug Modernization Plan—aimed at reducing the backlog of approvals without compromising on process. More recently, in 2023, the FDA’s Center for Drug Evaluation and Research (CDER) initiated the Accelerating Rare disease Cures Program. Its mission is to drive scientific and regulatory innovation and engagement to accelerate the availability of treatments.
   
   Added to this, the Center for Biologics Evaluation (CBER) set up its own Rare Disease Program dedicated to advancing the development and timely approval of safe and effective biologics to improve the lives of children and adults living with rare diseases.
   
   And in 2024, the FDA launched the Rare Disease Innovation Hub to serve as a point of collaboration and connectivity between CBER and CDER with the goal of ultimately improving outcomes for patients.
2. Companies have leveraged real-world evidence to supplement trials and demonstrate effectiveness
   
   In rare diseases, the limited number of patients can make it difficult to conduct large-scale, randomized controlled trials. The rise in real-world evidence (RWE) usage has allowed companies to supplement these trials by providing additional context and data. Natural history studies, for example, track the progression of a disease over time in a patient population. This data can then be used to compare against patients receiving a new treatment, helping to demonstrate the treatment’s effectiveness.
3. The ‘pipeline in a pill’ approach is gaining traction for pharma
   
   Increasingly orphan products are being approved for multiple indications. As a result, many pharmaceutical companies have taken a “pipeline in a pill” approach. What that means is companies identify molecules that can target a wide array of pathways and have potential across different indications.
   
   Products such as Alexion’s Soliris and Ultomiris, Argenx’s Vyvgart, Agio’s Pyrukynd and Johnson & Johnson’s Nipocalimab have all been approved or are in pipeline (with expected approvals in the near future) for more than four indications. 
4. Pharma is collaborating with partners to drive drug development
   
   There’s a growing trend toward collaboration among pharmaceutical companies, academic institutions and patient advocacy groups to drive orphan drug development. Partnerships such as Pfizer’s tie up with Boston Children’s Hospital to develop gene therapy for Duchenne muscular dystrophy can enhance research capabilities and provide a platform for resource sharing.
   
   The National Organization for Rare Disorders (NORD) and its Rare Disease Research Grant Program exemplify how pooling resources can accelerate research. NORD collaborates with pharmaceutical companies, academic institutions and patient organizations to fund and support research into rare diseases. 
   
5. Curative gene therapies are on the rise
   
   By addressing the root genetic causes rather than just managing symptoms, curative gene therapies are transforming the treatment of rare diseases. These therapies work by introducing functional copies of mutated genes or directly modifying faulty DNA sequences. Over the last five years, more than 15 such therapies have been approved in the U.S. across different rare diseases. Vertex’s Casgevy and BlueBird Bio’s Lyfgenia, for example, were approved for the same indication of sickle cell disease.

In the first quarter of 2025, the FDA approved seven novel drugs, of which two were for non-oncological rare diseases. It’s on track to approve ~30 novel drugs this year (according to the FDA’s PDUFA calendar at the time of this writing). Of these, ~50% (~14) are non-oncological rare disease approvals, and a number of those first-to-market products are for ultra rare diseases. These include Ultragenyx’s UX111 for Sanfillipo syndrome and Sentynl/Cyprium Therapeutics’s CUTX-101 for Menke’s disease.

The future of orphan drug approvals appears promising, characterized by increased designations and approvals, a focus on underserved populations, advancements in biologics and gene therapies and a highly supportive regulatory framework. As these trends continue to evolve, they hold the potential to significantly enhance treatment options for individuals affected by rare diseases while fostering innovation within the pharmaceutical industry. 

The growing interest from big pharma companies only reinforces the optimistic industry outlook. Sanofi, AstraZeneca and Biogen have all been focusing and prioritizing rare diseases drug development (both organically and inorganically). It’s a decisive industry shift from the commercially risky days pre-1983.