Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study

G.J. Schmieder,1 Z.D. Draelos,2 D.M. Pariser,3 C. Banfield,4 L. Cox,4 M. Hodge,4 E. Kieras,4 D. Parsons-Rich,4 S. Menon,4 M. Salganik,4 K. Page4 and E. Peeva4

Summary

Background PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for 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 2, placebo-controlled study (NCT02201524) were randomised to receive placebo, 200 mg once-daily (QD), 400 mg QD, or 200 mg twice-daily (BID) 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 randomised and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active-placebo PASI change from baseline) and 90% CI at Week 4 was –5·1 (–9·2, –1·0), –5·6 (–9·6, –1·6) and –10·0 (–14·2, –5·8) for the 200 mg QD, 400 mg QD and 200 mg BID groups, respectively. At Week 4, the proportion of patients achieving PASI75 was 17% for the placebo and 200 mg QD groups, 50% for the 400 mg QD group and 60% for the 200 mg BID group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg BID group vs the QD 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.

Key words: JAK inhibitor, PF-04965842, plaque psoriasis, efficacy, safety

Introduction

Chronic plaque psoriasis (psoriasis vulgaris), a common immune-mediated skin disorder affecting up to 4% of the population in Western countries, is associated with a high psychological and morbidity burden and has a negative impact on quality of life.1-3 Key cytokines implicated in the pathophysiology of psoriasis require JAK1 for signal transduction, suggesting that JAK1 inhibition could be effective for the treatment of chronic plaque psoriasis.4-7 This concept is supported by data from phase 2 trials of two oral JAK1-selective inhibitors, GSK2586184 and INCB039110, which have demonstrated clinical improvement in patients’ psoriasis.8,9
PF-04965842 is a Janus Kinase (JAK) 1 inhibitor that is being evaluated for the treatment of inflammatory diseases. PF-04965842 exhibits a selective inhibition profile for JAK1 versus other JAK family enzymes. Kinase activity assays (performed at 1mM ATP) determined an IC50 of 29 nM for JAK1 and IC50 of 803 nM, >10,000 nM and 1250 nM for JAK2, JAK3 and TYK2, respectively (Pfizer data on file). A phase 1, dose-escalation study in healthy subjects (ClinicalTrials.gov, NCT01835197) has been completed. The aim of this study was to evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate to severe chronic plaque psoriasis. Enrolment for the study was discontinued on 25 June 2015 due to changes in the sponsor’s development priorities and not due to reasons of safety and/or efficacy.

Patients and methods

Study design

This was a phase 2, placebo-controlled, parallel-group, proof-of-concept study in patients with moderate to severe chronic plaque psoriasis who were candidates for systemic treatment or phototherapy (ClinicalTrials.gov Identifier: NCT02201524). It was conducted at 32 centres in the United States of America and Canada. All patients signed an informed consent form. The study was approved by local Institutional Review Boards and Independent Ethics Committees and was conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice Guidelines.
Eligible patients were initially stratified by an agreement to participate in a biopsy substudy, with 2:2:1:1 randomization to 200 mg twice daily (BID) PF-04965842:400 mg once daily (QD) PF-04965842:200 mg QD PF-04965842:placebo for strata with biopsy, and 1:1:1:1 randomization without biopsy. The data were pooled over strata (see Fig. 1) according to the statistical analysis plan. The number of patients in the biopsy strata was small due to early trial termination. PF-04965842 and placebo were provided by the sponsor as 100 mg tablets in numbered containers and patients took four tablets BID to maintain the blind. Study treatments were identical in packaging, labelling and appearance and were dispensed by qualified study staff. Patients, investigators, and sponsors were blinded to treatment from randomization to database freeze. The central randomisation used block sizes of 6 (biopsy strata) and 8 (strata without biopsy), was computer generated, and was implemented by the interactive response technology system. Four weeks of treatment were followed by a 4-week follow-up period.
The primary efficacy endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at Week 4. Secondary objectives included safety and tolerability assessments and the following additional efficacy endpoints over time: actual and percent change from baseline in PASI scores; proportions of patients achieving 50%, 75% and 90% reduction from baseline PASI (PASI50, PASI75 and PASI90, respectively); and proportions of patients with Physician’s Global Assessment (PGA) of ‘clear’ or ‘almost clear’.
Pharmacokinetic (PK) and pharmacodynamic (PD) data were also collected. Exploratory endpoints included change from baseline in body surface area (BSA) and patient-reported outcomes such as dermatology life quality index (DLQI), itch severity score (ISS) and Patient’s Global Assessment (PtGA).

Patients

Patients were included if they were between 18 and 65 years of age, had a diagnosis of plaque psoriasis for at least 6 months prior to first study dose, plaque-type psoriasis covering at least 15% of total BSA at Day 1, a PASI score of 12 or greater at Day 1, were candidates for phototherapy or systemic treatment of psoriasis, and had no evidence of acute or chronic infections, including active, latent or inadequately treated tuberculosis.
Exclusion criteria included females of childbearing potential (until confirmation of no adverse effects on reproduction), patients with non-plaque/drug-induced psoriasis, patients who required treatment with prohibited concomitant medication or received any prohibited concomitant medications 4 weeks prior to the first study dose and those who participated in other investigational studies within 30 days or 5 half-lives (whichever was longer). Criteria for treatment discontinuation and withdrawal from study are provided in Table S1. Patients who discontinued treatment due to an AE were permitted to complete the remaining study visits in order to be monitored for safety.

Assessments

Standard methods were used to measure PASI scores,10 BSA11 and DLQI12 over the 4-week treatment period with follow-up to Week 8. PGA and PtGA were scored on a 5-point scale ranging from 0 (clear) to 4 (severe) and the severity of itch was assessed using a 0 (no itching) to 10 (worst possible itching) rating scale. Blood samples were collected and analysed for plasma levels of PF-04965842, PD parameters and standard laboratory tests. All changes in clinical laboratory values, vital signs and electrocardiograms were recorded, as were all adverse and serious adverse events (AEs and SAEs, respectively).

Statistical analysis

Power analysis determined that 196 patients would provide 80% power to detect a treatment effect of 5.6 (SD of PASI change from baseline at week 4 =10, two-sided = 0.1 unadjusted for multiple comparisons). The lower standard deviation compared with the assumed value (7 vs 10, respectively) and adjustment for baseline in longitudinal modeling nearly compensated for the effect of the reduction in the sample size caused by the early study termination.
All randomised patients who received at least one dose of study medication (modified intent-to-treat population, mITT) were included in the efficacy, safety and PD analyses. The PK analysis was conducted in all patients who were treated with PF-04965842. Data were summarised using descriptive statistics.
The primary analysis was based on longitudinal analysis of covariance modelling of the PASI scores.13 The analysis provided estimates and two-sided 90% confidence intervals (CI) for the difference (active – placebo) in the expected values of the PASI change from baseline at multiple visits. Exploratory analyses were summarised using descriptive statistics over time (means and 90% CIs).

Results

Patient disposition and demographics

Patient disposition in the study (conducted from 25 November 2014 to 10 September 2015) is shown in Figure 2. Baseline demographic and disease characteristics were generally similar across the treatment groups (Table 1); however, small differences in some baseline characteristics were observed.

Efficacy

At Week 4, the mean (90% CI) PASI scores were 13·2 (9·3, 17·0), 8·5 (6·0, 10·9), 6·5 (3·6, 9·4) and 3·0 (0·9, 5·1) for the placebo, 200 mg QD, 400 mg QD and 200 mg BID groups, respectively (Fig. 3a). The Week 4 mean change from baseline (90% CI) in PASI was 6.6 1·6) for the 400 mg QD group and –10·0 (–14·2, –5·8) for the 200 mg BID group (P = 0·042, P = 0·023, and P  0·001, respectively, all significant at two-sided  = 0·1 significance level). Sensitivity analyses supported the robustness of estimates; estimates from longitudinal analysis unadjusted for baseline values were –5.2 (–10.1, –0.4) for 200 mg QD, –5.2 (–9.9, – 0.4) for 400 mg QD and –9.1 (–14·1, –4·1) for 200 mg BID.
The mean PASI scores decreased in all active treatment groups from Week 1 through to Week 4. The magnitude of the change from baseline was greater in the 200 mg BID group than in the 200 mg QD and 400 mg QD groups, and the treatment-related reduction in PASI persisted up to Week 8 (4 weeks after the end of the treatment period) in the 200 mg BID group. Additionally at Week 4, the proportion of patients achieving PASI75 (Fig, 3b) was 17% for the placebo and 200 mg QD groups, 50% for the 400 mg QD group and 60% for the 200 mg BID group. The 200 mg BID group consistently had a greater proportion of patients achieving PASI50 (Fig. S1a) and PASI90 (Fig. S1b) compared with placebo.
At Week 4, all PF-04965842 treatment groups had a higher proportion of patients with a PGA response of ‘clear’ or ‘almost clear’ (200 mg QD, 42%; 400 mg QD, 58%; 200 mg BID, 70%) compared with placebo (17%), and the PGA response remained higher in all the PF- 04965842-treated patients compared with the placebo-treated patients through to Week 8 (Fig. 3c). By the end of the treatment period (Week 4), BSA had decreased in all PF- 04965842 treatment groups (data not shown), there was a higher proportion of patients with a PtGA response of ‘clear’ or ‘almost clear’ in the 400 mg QD and 200 mg BID groups (50% for both) compared with the 200 mg QD and placebo groups (8% and 0%, respectively; Fig. S1c), and ISS and DLQI had decreased in all PF-04965842 treatment groups (Figs. 3d and S1d, respectively).

Pharmacokinetics

Predose plasma concentrations were higher following 200 mg BID dosing than 400 mg QD dosing throughout the 4-week treatment period; the 200 mg QD group showed the lowest predose levels. Approximate Cmax values (on Day 28) were highest for the 400 mg QD dose and lower, but of similar magnitude, following treatment with 200 mg QD and 200 mg BID.

Pharmacodynamics

There were reductions in circulating interferon gamma-induced protein 10 (IP-10, a disease- relevant biomarker for inhibition of IFN signalling via JAK1 inhibition) and high sensitivity C- reactive protein (hsCRP, a mechanism-specific biomarker for inhibition of IL-6 signalling via JAK1 inhibition) that generally persisted throughout the treatment period. The magnitude of reduction was dose dependent, with the greatest reduction observed in the 200 mg BID treatment group. All reductions generally normalized to baseline by Week 8.
Increases from baseline in absolute lymphocyte counts (ALCs) were observed in the active treatment groups at Week 1 followed by reductions at Week 2 and a trend towards normalisation on continued treatment (Fig. 4a). PF-04965842 treatment also resulted in reduced numbers of circulating NK and CD8+ T cells, and an increase in B cell numbers that was not dose dependent. In the 200 mg BID cohort, there was a rapid decrease in absolute neutrophil counts (ANCs), with the largest mean change from baseline (2·0 x 103 mm3) occurring at Week 1 (Fig. 4b), but recovering to near baseline 4 weeks after drug discontinuation. ANC changes in the 400 mg QD and 200 mg QD groups were small and similar to the changes observed in the placebo group. Reductions in reticulocyte (Fig. 4c) and platelet counts (Fig. 4d) were also observed in all PF-04965842 groups during the treatment period.

Safety and tolerability

The majority of AEs were mild or moderate in severity (i.e., did not interfere with usual function or interfered with normal function to some extent, respectively). All causality and treatment-related TEAEs occurring in two or more patients are shown in Table 2. The incidence of treatment-related TEAEs was similar for the placebo (n = 3, 5 events) and 200 mg QD (n = 4, 7 events) groups. A higher incidence of TEAEs was observed in the 400 mg QD (n = 9, 15 events) and 200 mg BID (n = 10, 24 events) groups. The most commonly reported treatment-related TEAEs were nausea (n = 8) and headache (n = 7), and these occurred most frequently in the 400 mg QD group. Other commonly reported treatment- related TEAEs included neutropenia and thrombocytopenia. One patient in the 200 mg BID group experienced three severe AEs of haematological abnormality, which were neutropenia (ANC level decreased to 1·1 x 103 mm3), decreased platelet count and decreased white blood cell (WBC) count (values decreased to 56·0 x 103 mm3 and 2·5 x 103 mm3, respectively).
AEs in the infections and infestations category were considered of special interest and were reported by one patient in the placebo group (1 event; cellulitis), three patients in the 200 mg QD group (5 events; carbuncle, gastroenteritis viral, herpes zoster, upper respiratory tract infection and folliculitis), six patients in the 400 mg QD group (8 events; rhinitis, bronchitis, urinary tract infection, vaginitis, upper respiratory infection, viral upper respiratory infection, tinea cruris and viral gastroenteritis) and three patients in the 200 mg BID group (5 events; urinary tract infection, upper respiratory tract infection, folliculitis, oral candidiasis and viral pharyngitis).
Eight patients discontinued treatment due to AEs, the majority of which were due to cytopenia. Five patients that discontinued treatment due to AEs completed the study while three patients discontinued treatment and the study (two patients in the 200 mg QD group [1 due to a subcutaneous abscess and another due to a decrease in ANC and WBC count] and one patient in the 400 mg QD group [due to nausea]). One SAE, a transient ischaemic attack not related to treatment, was reported in one patient in the placebo group. There were no other reported SAEs and no deaths during the study.
A similar number of patients in each group (8 patients in the placebo group, 9 patients in the 200 mg QD and 200 mg BID groups, and 11 patients in the 400 mg QD group) had laboratory test abnormalities. Laboratory abnormalities of clinical interest included reticulocyte counts, platelet counts, ANCs and ALCs (Figs. 4a–d), WBC counts and low haemoglobin (Fig. S2a). In most cases, a greater mean change from baseline was observed in the 200 mg BID group during the treatment period (Weeks 1 through 4) with results appearing to normalise by Week 8 (4 weeks after the end of the treatment period).
One patient in the 200 mg BID group had ANC levels < 0·5 x 103 mm3. WBC counts < 3 x 103 mm3 occurred in one patient each in the placebo and 200 mg QD groups and in five patients in the 200 mg BID group. ALC < 0·5 x 103 mm3 occurred in one patient each in the 200 mg QD and 200 mg BID groups. One patient in the 400 mg QD and three patients in the 200 mg BID group had platelet counts < 75 x 103 mm–3. No individual haemoglobin results < 10·0 g dL–1 and no serious infections or bleeding events related to neutropenia or thrombocytopenia, respectfully, were reported.
Low-density lipoprotein (LDL), high-density lipoprotein (HDL) and total cholesterol levels increased in all PF-04965842 groups during the treatment period, with the largest magnitude of increase generally occurring in the 200 mg QD and 200 mg BID groups (Figs. S2bd). At Week 8, 4 weeks after the end of the treatment period, all treatment groups returned to near baseline. Normal mean absolute values of LDL, HDL and total cholesterol, as well as the LDL:HDL ratio were maintained during and after the treatment period. No clinically meaningful treatment-related trends in change from baseline in vital signs or ECG results were noted.

Discussion

Recognition of the key role of the JAK family in the pathophysiology of inflammatory diseases has increased investigation of JAK inhibitors for the treatment of psoriasis.4,5,14 In spite of the loss of the sensitivity resulting from early termination of this trial (due to changes
in the sponsor’s development priorities), the data demonstrated that treatment with PF- 04965842 for 4 weeks resulted in statistically significant reductions in PASI compared with placebo. The effect of PF-04965842 was dose-dependent, with the 200 mg BID dose producing the largest magnitude of change. Of note, the therapeutic effect of PF-04965842 200 mg BID was seen as early as Week 1 of treatment and persisted to Week 8, 4 weeks after the last treatment with PF-04965842. These results were supported by the increased number of patients achieving PASI50/75/90 and PGA of ‘clear’ or ‘almost clear’, as well as reduced itching, in all the PF-04965842 groups compared with placebo. PF-04965842 was generally well-tolerated; no deaths or SAEs were reported in the PF-04965842 treatment groups and the majority of the reported AEs were mild or moderate. Overall, the rates of TEAEs were higher for PF-04965842 400 mg QD and 200 mg BID compared with placebo and PF-04965842 200 mg QD.
Dose-dependent reduction in psoriasis severity has been reported with two other JAK1 inhibitors. Treatment with INCB039110 resulted in reductions from baseline in static PGA at Day 28 (mean 22·2%–42·4% for 100 mg QD, 200 mg QD, 200 mg BID and 600 mg QD, respectively).8 Similarly, dose-dependent changes from baseline in PASI scores were observed following 12 weeks of treatment with GSK2586184 100 mg BID, 200 mg BID and 400 mg BID.9 Other JAK inhibitors with differential selectivity for JAK1, JAK2 or JAK3 that have also demonstrated clinical improvements in psoriasis severity include tofacitinib, ASP015K and baricitinib.15-17
Increased rates of infections, anaemia, thrombocytopenia and neutropenia are a recognized concern with JAK inhibitors, as is hypercholesterolemia.18,19 In this study, infections occurred more frequently in the PF-04965842 vs placebo groups, but there were no serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively. Infections were also reported more frequently for patients treated with INCB0391108 compared with placebo, but not for those treated with GSK2586184 compared with placebo.9 Recent data from studies of tofacitinib treatment in patients with psoriasis showed that nasopharyngitis and upper tract infections were the most frequent infections and the authors noted increased occurrence of herpes zoster.16
With regard to laboratory assessments, the majority of haematological laboratory abnormalities in this study occurred in the PF-04965842 200 mg BID group. Although PF- 04965842 is a JAK1-selective inhibitor, the decreases observed in reticulocyte, neutrophil and platelet counts in this study suggest there may be some inhibition of erythropoietin/thrombopoietin signalling via PF-04965842-mediated JAK2 inhibition.19 The decrease observed in neutrophil counts may be due to IL-6 signalling inhibition via JAK1.20
In terms of notable AEs reported for other JAK inhibitors, severe thrombocytopenia was reported in a patient who received GSK2586184 100 mg BID; however, there were no statistically significant changes in mean haemoglobin, neutrophils, monocytes, reticulocytes, leucocytes or platelets.9 Minor decreases in platelet counts and elevations in mean lipid values were observed with INCB039110 treatment but these were not considered clinically meaningful.8 Similar to other JAK inhibitors, dose-dependent changes in lipoprotein cholesterol were observed for PF-04965842 in the current study but were not considered clinically relevant. Although the 200 mg BID dose resulted in the greatest treatment effect in this study, the frequency of AEs and cytopenias was higher, suggesting that once-daily PF- 04965842 administration may be preferable in future studies.
In conclusion, these data demonstrated a trend towards improvements in psoriasis severity following treatment with 200 mg QD, 400 mg QD and 200 mg BID doses of PF- 04965842, and the safety and tolerability were comparable with those of other JAK inhibitors in patients with moderate to severe psoriasis.

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