Setipiprant (INN; developmental code names ACT-129968, KYTH-105) is an investigational drug developed for the treatment of asthma and scalp hair loss. It was originally developed by Actelion and acts as a selective, orally available antagonist of the prostaglandin D<sub>2</sub> receptor 2 (DP<sub>2</sub>). The drug is being developed as a novel treatment for male pattern baldness by Allergan.
Acting through DP<sub>2</sub>, PGD<sub>2</sub> can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment. A phase 2A study to evaluate the safety, tolerability, and efficacy of oral setipiprant relative to a placebo in 18- to 49-year-old males with androgenetic alopecia was completed in May 2018 and did not find statistically significant improvement.
Setipiprant proved to be well tolerated and reasonably effective in reducing allergen-induced airway responses in asthmatic patient clinical trials. However, the drug, while supporting the concept that DP2 contributes to asthmatic disease, did not show sufficient advantage over existing drugs and was discontinued from further development for this application.
Data from phase II and III clinical trials did not detect any severe adverse effects to setipiprant. The authors were unable to identify any pattern of adverse effects that differ from placebo, including subjective reporting of symptoms and objective laboratory monitoring.
While setipiprant mildly induces the drug metabolizing enzyme CYP3A4 in vitro, the interaction appears to not be clinically relevant.
Setipiprant binds to the DP<sub>2</sub> receptor with a dissociation constant of 6 nM, representing potent antagonism of the receptor. The DP<sub>2</sub> receptor, also called the CRTh2 receptor, is a G-protein-coupled receptor (GPCR) that is expressed on certain inflammatory cells, such as eosinophils, basophils, and certain lymphocytes. For its mechanism of action in the treatment of allergic conditions, setipiprant's DP<sub>2</sub> antagonism prevents the action of prostaglandin D<sub>2</sub> (PGD<sub>2</sub>) on these receptors. The DP<sub>2</sub> receptor mediates the activation of type 2 helper T (Th2) cells, eosinophils, and basophils in the lungs, which are white blood cells implicated in producing the inflammatory response the characterizes allergic conditions. Activation of DP<sub>2</sub> on Th2 cells by PGD<sub>2</sub> induces the secretion of inflammatory cytokines (interleukin (IL) 4, IL-5, and IL-13), which cause an increase of eosinophils in the blood, remodeling of lung tissue, and hypersensitivity of lung tissue to allergens.
Setipiprant does not antagonize the thromboxane receptor (TP). The bronchoconstricting properties of PGD<sub>2</sub> are not inhibited by setipiprant, since these are mediated by the TP receptor. As a point of contrast, ramatroban is a selective TP antagonist and DP<sub>2</sub> receptor antagonist.
Setipiprant does not appreciably inhibit the activity of the enzyme cyclooxygenase 1 (COX-1), which is responsible for the synthesis of prostaglandins (including PGD<sub>2</sub>).
Prostaglandin D2 synthase (PTGDS) is an enzyme that produces PGD<sub>2</sub>. In men with androgenic alopecia, the enzyme PTGDS is elevated in the bald scalp tissue, as well as its product PGD<sub>2</sub>. PGD<sub>2</sub> inhibits the growth of hair follicles through its activity on the DP<sub>2</sub> receptor, but not the DP<sub>1</sub> receptor. Theoretically, setipiprant's DP<sub>2</sub> receptor antagonism may counteract the activity of PGD<sub>2</sub> in hair follicles, thereby stimulating hair growth.
The oral bioavailability of setipiprant is 44% in rats and 55% in dogs, which suggests that it should be orally bioavailable in humans. The half-life of setipiprant in humans is about 11 hours. The maximum concentration in plasma (C<sub>max</sub>) is 6.04 and 6.44 mcg/mL for setipiprant tablets and capsules respectively, with an area under the curve of 31.88 and 31.50 mcgÃÂhours/mL for setipiprant tablets and capsules respectively. C<sub>max</sub> was reached between 1.8âÂÂ4 hours after oral administration. The tablet and capsule formulations are bioequivalent.
Setipiprant appears as a light yellow to yellow colored solid. Based on general guidelines, the powder form is considered stable for 2 years at 4 degrees C, and for 3 years as -20 degrees C. When dissolved in a solvent, setipiprant is stable for 1 month at -20 degrees C, and 6 months at -80 degrees C. It is considered soluble in DMSO at concentrations âÂÂ¥ 36 mg/mL.
Setipiprant was initially researched by Actelion as a treatment for allergies and inflammatory disorders, particularly asthma, but despite being well tolerated in clinical trials and showing reasonable efficacy against allergen-induced airway responses in asthmatic patients, it failed to show sufficient advantages over existing drugs and was discontinued from further development in this application.
However, following the discovery in 2012 that the prostaglandin D<sub>2</sub> receptor (DP/PGD<sub>2</sub>) is expressed at high levels in the scalp of men affected by male pattern baldness, the rights to setipiprant were acquired by Kythera to develop the drug as a novel treatment for baldness. The favorable pharmacokinetics and relative lack of side effects seen in earlier clinical trials mean that fresh clinical trials for this new application can be conducted fairly quickly. , setipiprant is currently under development by Allergan for the prevention of androgenic alopecia after their successful acquisition of Kythera.