Small Molecules Resurgent in Orphan Pipeline
Orphan drugs are often newer modalities, like cell and gene therapies, multi-specific antibodies or oligonucleotide-based therapies. Rare, genetically-defined conditions provide important testing grounds for mechanisms that subsequently find their way into broader use – as is happening now with CAR-T cell therapies and T-cell engaging bispecific antibodies as they spread outside hematology into autoimmune diseases.
The most valuable orphan pipeline candidates showcase a broad range of mechanisms – from multi-specific antibodies, fusion proteins and oligonucleotide-based conjugates to cell and gene therapies. But small molecules make up almost half of the top ten most valuable orphan pipeline candidates, despite accounting for just three of today’s top-selling marketed orphan drugs (Alyftrek, Brukinsa and Trikafta)
Figure 7: Top 20 orphan R&D modalities
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.
