Small molecules make up almost half of the 20 most valuable orphan drugs in development across biopharma, according to an Evaluate analysis.
A total of 45% of the top 20 orphan drugs in biopharma pipelines are small molecules, overshadowing the next largest modality—monoclonal antibodies—which only accounted for 20%, according to Evaluate’s 2026 Orphan Drugs Report published this morning.
The report’s authors singled out daraxonrasib, a small molecule pan-RAS inhibitor being developed by Revolution Medicines. The projections of $4 billion in sales in 2032 reflect “the considerable unmet need in pancreatic cancer, due in part to the ineffectiveness of immunotherapy in this setting,” they said.
Revolution has harnessed this hype to its advantage, securing a potential funding infusion of up to $2 billion from Royalty Pharma in return for a slice of the profits if daraxonrasib makes it to market.
Evaluate analysts noted that only three of the top-selling orphan drugs on the market—Vertex’s cystic fibrosis therapies Alyftrek and Trikafta, as well as BeOne Medicines’ blood cancer drug Brukinsa—are small molecules, leading the report’s authors to describe this modality as now “resurgent” in orphan R&D.
“This evolution in orphan modalities may reflect a broader comeback for small molecules, driven by deeper understanding of disease mechanisms, more advanced chemistry- and data-based tools (including AI), plus small molecules’ inherent advantages of target accessibility, convenience, manufacturing and cost,” they wrote in the report.
The most valuable orphan drug in development is Corcept Therapeutics’ glucocorticoid receptor antagonist relacorilant, which is only predicted to reach net sales of over $3.5 billion by 2032 but calculated as being worth almost $14 billion in net present value terms. Evaluate analysts listed the FDA’s rejection of an approval application in Cushing syndrome over a need for more evidence as highlighting the “regulatory risks inherent in orphan drug development.”
Still, the report’s authors noted that a recent phase 3 win in ovarian cancer had “continued to prop up overall sales forecasts for the drug.”
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When it comes to drilling down into therapy areas, oncology continues to dominate the orphan drug market—accounting for 38% of sales in 2025. However, Evaluate’s analysts pointed to dealmaking trends that suggest the reign of orphan cancer drugs is “under continued pressure from drugs for autoimmune, cardiovascular, blood and CNS conditions.”
As evidence, they looked at trends in orphan drug dealmaking, highlighting Novartis’ $12 billion purchase of late-stage dystrophy biotech Avidity, as well as Johnson & Johnson’s $14.6 billion deal for CNS-focused Intra-Cellular Therapies.
Overall, the analysts concluded that the “core drivers of orphan drug R&D remain strong,” thanks to incentives like tax credits, fee waivers and terms of market exclusivity.
With “barely” more than 5% of rare diseases currently addressed by an orphan drug, there remains “plenty of growth potential,” the report’s authors added.
By 2032, the analyst predicts that orphan drug sales will account for more than 21% of all prescription pharmaceutical sales, rising from 15% in 2022, and generate an expected $400 billion-plus in global sales.
