The 2012 discovery by the Cotsarelis group at the University of Pennsylvania that prostaglandin D2 (PGD2) levels are elevated in bald scalp tissue compared to haired scalp opened a new therapeutic angle for androgenetic alopecia. PGD2 directly inhibits hair growth through the GPR44 (DP2/CRTH2) receptor on hair follicle cells. Blocking this receptor should, in theory, remove a brake on follicle regeneration. Setipiprant, a PGD2 receptor antagonist originally developed by Actelion for asthma, became the most prominent compound tested for this indication.

Allergan acquired the development rights and ran a Phase 2 trial in androgenetic alopecia, completed in 2019. The detailed results have not been published in a peer-reviewed journal, but Allergan's announcement indicated the trial did not meet its primary endpoint of hair count improvement versus placebo. Development for hair loss was discontinued. The mechanistic rationale remains plausible, but the translation from preclinical biology to clinical effect failed at this iteration.

Several explanations have been proposed for setipiprant's clinical failure. The drug's potency at the GPR44 receptor may have been insufficient at safe systemic doses. Topical formulation might have been more effective than oral, but wasn't tested in the registration trial. PGD2 blockade alone might be insufficient without simultaneous Wnt activation or other growth pathway stimulation. Newer PGD2 pathway compounds are being developed by other companies, and the basic mechanism remains a credible target, just one that hasn't yet produced a clinical winner.