Rare Disease Sales To Soar to $400B+ By 2032 as Small Molecules Resurgent: Evaluate

 

Small-molecule drugs account for nearly half of the most valuable investigational therapies for orphan diseases, according to analytics firm Evaluate.

Despite recent regulatory headwinds, the rare disease space is set to see explosive growth in the coming years, with orphan drug sales projected to exceed $400 billion by 2032, up from $213 billion last year. And small-molecule drugs will account for a hefty slice of that, a new report finds.

Indeed, 45% of the 20 “most valuable” orphan pipeline products are small molecules, according to a report from commercial intelligence firm Evaluate published on Wednesday. Evaluate identified these 20 assets according to their net present value, a financial tool that helps estimate how profitable a product will be.

Far behind small molecules are monoclonal antibodies, which comprise 20% of the top 20 most valuable orphan pipeline assets. Other newer modalities, such as DNA and RNA therapies and cell and gene therapies, account for even smaller fractions of today’s top investigational therapies 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 drugs are Vertex Pharmaceuticals’ cystic fibrosis medicines Alfytrek and Trikafta and BeOne’s blood cancer therapy Brukinsa, according to the firm.

Among the top orphan drug candidates identified in the report 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 projected top orphan pipeline could be part of what Evaluate called a “broader comeback” for small-molecule drugs, powered by a “deeper understanding of disease mechanisms, more advanced chemistry- and data-based tools (including AI), plus small molecules’ inherent advantages,” including convenience and cost.

Still, the Inflation Reduction Act’s pill penalty remains. Under this penalty, small-molecule drugs are only shielded from price renegotiations, while biologics get a 13-year reprieve. This, in turn, could be a disincentive for companies to develop small-molecule therapies.

Evaluate’s report comes at a challenging time for the rare disease space. Drugmakers have had to contend not just with a slew of rejections and safety problems but also with an increasingly inconsistent FDA. Late last year, for instance, the regulator seemingly reversed its previous guidance on uniQure’s investigational gene therapy for Huntington’s disease. Despite having agreed to the biotech’s clinical plan for AMT-130, the agency told uniQure in November 2025 that it “no longer agrees” that an externally controlled study would be sufficient to support an application.

Several other rare disease biotechs, including Capricor Therapeutics and Biohaven, have been thwarted by FDA inconsistency, forced to rejig their development timelines or outright restructure their operations.

Evaluate in its report conceded that this “temperamental FDA” is a major stumbling block for the rare disease space, which also has to “battle for attention with blockbusters in obesity and other common diseases.” Still, the firm projects orphan drug sales to climb “steadily” in the coming years. At the estimated $400 billion revenue by 2032, orphan drugs will account for more than a fifth of all pharma sales that year, Evaluate added.

Besides, the firm continued, there have been some notable policy wins for the rare disease space, in particular the reinstatement of the rare pediatric disease priority review voucher program. The scheme will now run through September 2029.

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