Kenneth Kwok

Analysis of Infections and All-Cause Mortality in Phase II, Phase III, and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis†

To determine the rate of infection and all‐cause mortality across tofacitinib phase II, phase III, and long‐term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).

Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme. Methods Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies. Results Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. Conclusions The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis

Objectives To evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib. Methods Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05). Results We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15–161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)). Conclusions Within the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.

Fixed combination of latanoprost and timolol vs individual components for primary open-angle glaucoma or ocular hypertension: a randomized, double-masked study.

OBJECTIVE To assess the efficacy and safety of fixed-combination latanoprost-timolol (FCLT) vs latanoprost or timolol monotherapy. METHODS This 12-week, randomized, double-masked, parallel-group study included patients with open-angle glaucoma or ocular hypertension treated with a beta-blocker and with baseline intraocular pressure (IOP) of 26 through 36 mm Hg. Following washout, eligible patients were randomized to once-daily FCLT in the evening, latanoprost in the evening, or timolol in the morning. MAIN OUTCOME MEASURES Postbaseline IOP assessments at 8 am, 10 am, and 4 pm at weeks 2, 6, and 12; statistical superiority of FCLT for the 18 pairwise comparisons between FCLT and the 2 monotherapies, using analysis of variance. RESULTS All therapies resulted in significant IOP reductions from baseline. Pairwise comparisons favored FCLT at all time points. When the 18 comparisons were tested simultaneously, FCLT was statistically superior to latanoprost at 7 of 9 time points and at all 9 time points when compared with timolol. In addition, FCLT was associated with greater percentage reductions in diurnal IOP levels and a greater likelihood of achieving lower mean diurnal IOP levels. Diurnal IOP reductions of 30% or more from baseline to week 12 were achieved by 73.5%, 57.5%, and 32.8% of those treated with FCLT, latanoprost, and timolol, respectively (P = .007 for FCLT vs timolol; P < .001 for FCLT vs latanoprost). All therapies were well tolerated. CONCLUSIONS Fixed-combination latanoprost-timolol therapy is as safe and effective in lowering IOP in patients with either ocular hypertension or glaucoma as monotherapy with latanoprost or timolol. Combination therapy can be used to treat patients for whom monotherapy does not provide sufficient IOP reduction. APPLICATION TO CLINICAL PRACTICE The simplicity, efficacy, and tolerability of FCLT contribute to its utility in clinical practice. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00277498.

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs

Objectives Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Methods Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. Results 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Conclusions Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. Trial registration numbers (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).

THU0179 Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis: Safety and Efficacy in Open-label, Long-term Extension up to 6 Years

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To report tofacitinib safety, tolerability, and durability of response up to 72 months (mo) in long-term extension (LTE) studies. Methods Data were from 2, open-label studies: A3921024 (NCT00413699 [ongoing; database unlocked as of April 2014 data cut-off]) and A3921041 (NCT00661661). Patients (pts) had RA and participated in randomised Phases (P)1/2/3 tofacitinib studies. Treatment was initiated with tofacitinib 5 or 10 mg BID as monotherapy or with background DMARDs; data for both doses ± background DMARDs were pooled. Primary endpoints: AEs and laboratory safety. Confirmed data are reported for decreased haemoglobin (HgB), neutrophil, and lymphocyte counts, and increases >50% from baseline (BL) in creatinine. Secondary endpoints: ACR responses, DAS28-4(ESR), and HAQ-DI. Safety data were included over 84 mo and efficacy up to Mo 72 (n≤29 pts, post-Mo 72). Results 4858 pts were treated (mean [max] duration: 918 [2535] days). BL data were from index studies for 91% of pts. Total tofacitinib exposure was 12 359 pt-years (py). In total, 1747 pts (36.0%) discontinued (AEs: 882 [18.2%]; insufficient clinical response: 133 [2.7%]). Most common classes of AEs: infections and infestations (63.4%), musculoskeletal/connective tissue disorders (33.9%), and GI disorders (29.9%). Most frequently reported AEs: nasopharyngitis (16.3%), upper respiratory tract infection (14.5%), and urinary tract infection (10.3%). SAEs occurred in 23.0% of pts (incidence rate [IR] 9.9/100 py [95% confidence interval [CI]; 9.4, 10.5]) and serious infections in 7.2% (IR 2.9/100 py [95% CI; 2.6, 3.2]). Malignancies (excluding NMSC) were reported in 2.5% of pts (IR 1.0/100 py [95% CI; 0.8, 1.2]). IRs for SAEs, serious infections, and malignancies up to Mo 84 did not increase vs previously reported data (Mo 72).1 Decreased Hgb (>2g/dL change from BL or Hgb <8 g/dL) occurred in 6.1% of pts and increased aminotransferases (>3× ULN) in 1.6% (ALT) and <1.0% (AST) of pts. Moderate to severe neutropenia (absolute neutrophil count [ANC] 0.5–1.5×103/mm3) was reported in 1.3% of pts. No pts had ANC <0.5×103/mm3. Absolute lymphocyte counts <0.5×103/mm3 were reported in 1.1% of pts. Increases >50% from BL in creatinine occurred in 3.1% of pts. ACR20, ACR50 and ACR70 response rates for tofacitinib were sustained to Mo 72 (80.8%, 61.5% and 35.9%). Mean DAS28-4(ESR) was 6.29 at BL, 3.74 at LTE Mo 1 and 3.32 at Mo 72. Mean HAQ-DI score was 1.42 at BL, 0.81 at LTE Mo 1 and 0.77 at Mo 72. Conclusions A consistent safety profile and sustained efficacy up to 72 mo was observed in pts with RA receiving tofacitinib 5 or 10 mg BID in LTE studies. References Wollenhaupt J et al. J Rheumatol 2014; 41: 837-852 Acknowledgements Previously presented (Wollenhaupt J et al. Arthritis Rheum 2014; 66 (11): S375 abs 849) and reproduced with permission from Arthritis and Rheumatism. All aspects of this study were funded by Pfizer Inc. Editorial support was provided by Claire Cridland of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest J. Wollenhaupt Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc (speaker fees), J. Silverfield Grant/research support from: Pfizer Inc, Speakers bureau: Pfizer Inc (speaker fees), E. B. Lee Consultant for: Pfizer Inc, S. P. Wood Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Terry Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Nakamura Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Anisfeld Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Nduaka Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor.

OBJECTIVES Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated. METHODS Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee. RESULTS Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE). CONCLUSIONS Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

A 12-week, randomized, double-masked study of fixed combination latanoprost/timolol versus latanoprost or timolol monotherapy.

Purpose. To evaluate the efficacy and safety of fixed combination latanoprost/timolol versus latanoprost or timolol monotherapy. Methods. This 12-week, randomized, double-masked study was designed to overcome potential shortcomings of previous trials. We enrolled 788 subjects with open-angle glaucoma or ocular hypertension treated with a beta-blocker for ≥4 weeks before screening. After washout, 500 subjects with a baseline mean intraocular pressure (IOP) ≥26 and <37 mmHg were randomized to fixed combination latanoprost-timolol in the evening (n=170), latanoprost monotherapy in the evening (n=165), or timolol monotherapy in the morning (n=165). At weeks 2, 6, and 12, each subjects IOP level was measured in triplicate at 8 AM (predose), 10 AM, and 4 PM in each eye. Adverse events were monitored throughout. The statistical superiority of the fixed combination for the 18 pairwise comparisons with the 2 monotherapies was evaluated (analysis of variance). Results. The statistical superiority of the fixed combination was demonstrated at 7/9 time points versus latanoprost and 9/9 time points versus timolol. Mean diurnal IOP levels were similar at baseline but significantly lower with the fixed combination than with either monotherapy at weeks 6 and 12 (each p<0.05). Patients treated with the fixed combination were significantly more likely than those treated with either monotherapy to reach prespecified percent IOP reductions at the upper thresholds and to achieve very low target diurnal IOP levels. All therapies were well tolerated. Conclusions. Fixed combination latanoprost/timolol safely reduces IOP levels in patients with glaucoma or ocular hypertension, though only slightly more than does latanoprost monotherapy.

Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies

Objectives. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The aim of this analysis was to characterize changes in haematological parameters following tofacitinib treatment, and to compare changes in haemoglobin with markers of disease activity, fatigue and vitality. Methods. Changes in neutrophil counts, lymphocyte counts and haemoglobin levels were analysed in patients with RA from six phase 3 randomized controlled trials (n = 4271) of tofacitinib 5 or 10 mg bd, placebo or active comparators of up to 24 months’ duration, and two long-term extension (LTE) studies (n = 4858) of tofacitinib of up to 84 months’ duration. Disease activity markers included CRP and ESR. Fatigue and vitality were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Short Form Health Survey-36 vitality domain scores. Results. In phase 3 studies, mean neutrophil and lymphocyte counts decreased and mean haemoglobin levels increased in all tofacitinib treatment groups. Haemoglobin levels and neutrophil counts stabilized in the LTE studies, while lymphocyte count decreases stabilized at approximately month 48. Increased haemoglobin was associated with decreased ESR and CRP levels. Clinically meaningful reductions in haemoglobin levels (⩾3 g/dl from baseline or haemoglobin ⩽7 g/dl) occurred in <1.0% of patients in all treatment groups. FACIT-F and Short Form Health Survey-36 vitality scores were weakly correlated with haemoglobin levels. Conclusion. Small changes in haematological parameters were seen with tofacitinib treatment, which stabilized over time in the LTE studies. Changes in haemoglobin levels, although associated with changes in ESR and CRP, were not associated with fatigue or vitality.

Comparison of Newly Diagnosed Ocular Hypertension and Open-Angle Glaucoma: Ocular Variables, Risk Factors, and Disease Severity

Purpose. To describe the distribution of ocular variables, risk factors, and disease severity in newly diagnosed ocular hypertension (OH) or open-angle glaucoma (OAG). Methods. Eligible subjects underwent a complete history and examination. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) obtained from multiple logistic regression models were used to compare OAG to OH and advanced to early/moderate OAG. Results. 405 subjects were enrolled: 292 (72.1%) with OAG and 113 (27.9%) with OH. 51.7% had early, 27.1% moderate, and 20.9% advanced OAG. The OR for OAG versus OH was 8.19 (P < 0.0001) for disc notch, 5.36 (P < 0.0001) for abnormal visual field, 1.45 (P = 0.001) for worsening mean deviation, 1.91 (P < 0.0001) for increased cupping, 1.03 for increased age (P = 0.030), and 0.36 (P = 0.010) for smoking. Conclusions. Increased age was a risk for OAG, and smoking decreased the risk of OAG compared to OH. Almost half of the OAG subjects had moderate/advanced disease at diagnosis.