Toreforant

Data from preclinical and clinical studies support the evaluation of histamine 4 receptor antagonists in the treatment of asthma. Toreforant is a selective histamine 4 receptor antagonist that could be effective in patients with eosinophilic asthma.

To evaluate the efficacy and safety of toreforant in patients with eosinophilic, persistent asthma that was inadequately controlled despite current treatment.

In this phase 2a, multicenter, randomized, double-blinded, parallel-group, placebo-controlled, proof-of-concept study, 162 eligible patients were randomized (1:1) to placebo or 30 mg of toreforant once daily through week 24 and followed for 4 weeks. The primary end point was change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16. Secondary end points included change from baseline at week 16 in postbronchodilator percent-predicted forced expiratory volume in 1 second, Asthma Control Questionnaire scores, weekly averages of Daytime and Nighttime Asthma Diary Symptom Scores, and weekly average of number of puffs in a day that rescue medication was used.

There was no significant difference between groups in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16 (difference in least-square means -0.19%; 95% confidence interval -3.01 to 2.64; P = .90). Similarly, there were no significant differences between groups at week 16 in changes from baseline in the secondary end points (P ≥ .30). Toreforant was generally well tolerated. No deaths or serious adverse events were reported at any time point.

Toreforant, at the dose tested, failed to provide therapeutic benefit in this population of patients with uncontrolled, eosinophilic, persistent asthma.

ClinicalTrials.gov, NCT01823016.

Toreforant is a selective histamine H4 receptor antagonist. H4 receptor activation may play a role in immune-mediated inflammation in psoriasis.

To evaluate Toreforant efficacy and safety in patients with moderate-to-severe psoriasis.

Biologic-naïve patients were to be treated (30, 60, or 3 mg Toreforant or placebo) for 12 weeks and followed through week 16. In this adaptive-design study, assignments were guided by interim analyses. Primary and major secondary efficacy endpoints, evaluated using Bayesian analyses, were the proportions of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline and achieving Investigator's Global Assessment (IGA) of cleared (0) or minimal (1), respectively, at week 12.

Per interim analyses results, patients were randomized to 30 (n = 30) or 60 mg (n = 26) Toreforant or placebo (n = 6). The estimated mean difference in the PASI 75 response rate at week 12 from the posterior distributions compared to placebo was 14.1% (95% credible interval [CI], -0.1% to 30.9%) and 8.9% (95% CI, -5.0% to 24.3%) with 30 and 60 mg Toreforant, respectively. The posterior probabilities of 30 and 60 mg Toreforant inducing a greater response rate than placebo were 97.4% and 90.3%, respectively; neither met the 97.5% predefined success criterion. Results for the IGA 0/1 endpoint were similar. Toreforant was generally safe and well tolerated. No deaths, serious or opportunistic infections, active tuberculosis, or malignancies were reported.

Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion. J Drugs Dermatol. 2018;17(8):873-879.