Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND: PF-04965842 is an oral Janus kinase 1 inhibitor being investigated for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate-to-severe plaque psoriasis. METHODS: Patients in this phase II, placebo-controlled study (NCT02201524) were randomized to receive placebo, 200 mg once daily (OD), 400 mg OD or 200 mg twice daily (TD) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. RESULTS: Fifty-nine patients were randomized and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active -placebo PASI change from baseline) and 90% confidence interval at week 4 was -5·1 (-9·2 to -1·0), -5·6 (-9·6 to -1·6) and -10·0 (-14·2 to -5·8) for the 200 mg OD, 400 mg OD and 200 mg TD groups, respectively. At week 4, the proportion of patients achieving PASI 75 was 17% for the placebo and 200 mg OD groups, 50% for the 400 mg OD group and 60% for the 200 mg TD group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg TD group compared with the OD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. CONCLUSIONS: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.

Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXaI16L ).

Essentials FXaI16L is a recombinant zymogen-like variant of activated coagulation factor X (FXa). A phase 1 dose escalation clinical trial of FXaI16L was conducted in healthy adults. FXaI16L was safe and tolerated at doses up to 5 µg/kg; no dose-limiting toxicity was observed. Data support further development of FXaI16L for patients with acute hemorrhagic conditions. SUMMARY: Background FXaI16L (PF-05230907) is a zymogen-like variant of activated factor X (FXa). It shows enhanced resistance to inactivation by endogenous inhibitors as compared with wild-type FXa, and restores hemostatic activity in non-clinical models of various bleeding conditions. Objectives To evaluate the safety, pharmacokinetics and pharmacodynamics of FXaI16L by performing a phase 1, first-in-human, dose-escalation clinical trial in healthy adult volunteers. Methods Participants were assigned to one of six ascending single-dose cohorts (0.1, 0.3, 1, 2, 3 or 5 µg kg-1 ), each planned to comprise six volunteers treated with FXaI16L and two treated with placebo. Assessments included safety monitoring, pharmacokinetic and pharmacodynamic (PD) analyses, and immunogenicity testing. Results The trial enrolled 49 male volunteers. Administration of a single intravenous bolus dose of FXaI16L was safe and tolerated at all dose levels tested, with no dose-limiting toxicity or serious adverse events. FXaI16L plasma levels appeared to increase dose-proportionally, with a half-life of ~ 4 min. Treatment-related PD changes were observed for activated partial thromboplastin time, thrombin generation assay, thrombin-antithrombin complexes, prothrombin fragment 1 + 2, and D-dimer. One volunteer had a weak and transient non-neutralizing antidrug antibody response, which did not cross-react with native FX or native FXa. Conclusions FXaI16L was safe and tolerated, and showed a pharmacologic effect in healthy adults when administered at doses up to 5 µg kg-1 . The safety profile, pharmacokinetics and pharmacodynamics observed in this clinical trial support the further development of FXaI16L for hemostatic treatment in individuals with acute hemorrhagic conditions.