A proof-of-concept (POC) study (phase 2 study) of a first-in-class drug, S-5751, was carried out in patients with allergic rhinitis, because PGD2, through DP1, has been reported to be a potent elicitor of nasal congestions in humans, and S-5751, a DP1 antagonist showed excellent efficacy in an allergic rhinitis model. To evaluate the efficacy of this drug for treating allergic rhinitis, a double-blind, placebo-controlled phase 2 study was conducted in more than 600 patients with seasonal allergic rhinitis. However, clear efficacy was not seen in either the total nasal symptom score or other secondary endpoints such as nasal congestion and sneezing. It was considered that one of the reasons why efficacy was not shown may have been because the efficacy was masked by a high placebo effect due to a much lower pollen count in the year of the study than in a typical year. To minimize the placebo effect, we conducted a subanalysis of the clinical study by limiting the study population to those patients with a high score for nasal symptoms at the baseline; this included approximately one-fourth of the total number of patients. As a result, a tendency toward reduction not only in the total nasal symptom score but also in scores for other symptoms such as sneezing, congestion, and rhinorrhea was seen in patients treated with S-5751 at doses of 100 and 400 mg twice daily compared to those treated with placebo.
To confirm whether a sufficient DP1 antagonistic action was produced by S-5751 in humans, a PGD2 provocation study was conducted in healthy volunteers. The dose-response curve for nasal airway resistance induced by increasing doses of PGD2 was partially but significantly shifted to the right by treatment with S-5751 at 400 mg twice daily. However, MK-0524, a DP1 antagonist newly developed by Merck, demonstrated complete suppression of PGD2-induced nasal congestion , indicating that S-5751 was insufficient to produce a maximum pharmacological effect in subjects even at the highest dose. Therefore, further development of S-5751 was stopped and we made the decision to switch to a back-up compound even though no back-up compound had been established yet at that time.
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