Orphan drug sales are expected to exceed $400 billion by 2032, up from $213 billion last year, according to a report released by commercial intelligence firm Evaluate on Mar. 13. The report highlights that small-molecule drugs will make up a significant portion of this growth in the rare disease sector.
The findings matter as they point to a shift in the types of therapies leading innovation for rare diseases, with small molecules regaining prominence despite recent regulatory and policy challenges. This trend could influence research priorities and investment decisions across the pharmaceutical industry.
According to Evaluate, 45% of the top 20 most valuable orphan pipeline products are small molecules, determined by their net present value—a measure used to estimate future profitability. Monoclonal antibodies represent only 20% of these assets, while newer modalities like DNA and RNA therapies and cell and gene therapies account for even smaller shares among leading investigational treatments for rare diseases.
"Small molecules make up almost half of the top ten most valuable orphan pipeline candidates," Evaluate wrote, "despite accounting for just three of today’s top-selling marketed orphan drugs." These include Vertex Pharmaceuticals’ cystic fibrosis medicines Alfytrek and Trikafta, as well as BeOne’s blood cancer therapy Brukinsa. Among promising candidates are Revolution Medicine’s pan-RAS inhibitor daraxonrasib for pancreatic tumors, Priovant’s dual TYK2/JAK1 blocker brepocitinib for autoimmune diseases, and Cogent Biosciences’ bezuclastinib for systemic mastocytosis.
The report suggests that advances in understanding disease mechanisms, improved chemistry- and data-based tools such as artificial intelligence, along with inherent advantages like convenience and cost-effectiveness, are driving renewed interest in small-molecule drugs. However, it also notes ongoing challenges such as the Inflation Reduction Act's pill penalty—which provides shorter protection from price renegotiations for small-molecule drugs compared to biologics—and regulatory uncertainty from agencies like the Food and Drug Administration (FDA).
Evaluate acknowledged that inconsistent FDA decisions have created obstacles for companies developing rare disease treatments. The agency has reversed previous guidance on some investigational therapies and forced several biotechs to adjust development timelines or restructure operations. Despite these hurdles, Evaluate projects steady growth in orphan drug sales over the coming years. At an estimated $400 billion in revenue by 2032, orphan drugs would represent more than one-fifth of all pharmaceutical sales that year.
