Paul J. Healey

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Tofacitinib, an oral, small‐molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS We conducted three phase 3, randomized, double‐blind, placebo‐controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5‐mg tofacitinib group and 40.6% in the 10‐mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763, NCT01458951, and NCT01458574, respectively.)

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Objective Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohns disease (CD). Design We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. Results 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. Conclusions Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. Trial registration numbers NCT01393626 and NCT01393899.

Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes.

BackgroundTofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs).MethodsEligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey.ResultsAt Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission.ConclusionsShort-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).

Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial

Objectives This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE). Methods Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses. Results 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea. Conclusions PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings. Trial registration number NCT01405196; Pre-results.

Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis

Objectives: A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib. Methods: Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI). Results: Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival (PFS), axitinib was superior compared with placebo (HR = 0.25, 95% CrI: 0.17 – 0.38), sorafenib (HR = 0.46, 95% CrI: 0.32 – 0.68) and pazopanib (HR = 0.47, 95% CrI: 0.26 – 0.85). An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib. Conclusion: Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy.

Economic analysis of triptan therapy for acute migraine : A medicaid perspective

Study Objective. To compare triptan therapies for migraine in terms of the cost to treat 100 migraine attacks and the cost per successfully treated patient (cost/success), by analyzing utilization and reimbursement data from state Medicaid programs.

Ulcerative Colitis Treatment Patterns and Cost of Care

OBJECTIVES To examine treatment patterns, dosing, health care resource utilization, and cost of tumor necrosis factor inhibitors (TNFi), adalimumab (ADA) and infliximab (IFX), among patients enrolled in US Humana insurance plans who have been diagnosed with ulcerative colitis (UC). METHODS This retrospective cohort study identified the first pharmacy or medical claim for ADA or IFX (from January 1, 2007, to December 31, 2014) in patients with continuous enrollment for 6 months or more preindex and 12 months or more postindex, with one or more UC diagnosis claim 6 months pre- or postindex. TNFi discontinuation was defined as a therapy gap of 56 days or more for ADA and 112 days or more for IFX. TNFi switch was defined as nonindex TNFi initiation. Health care resource utilization and costs were characterized quarterly according to treatment patterns. RESULTS The study population comprised 295 patients: mean age 50.9 years, 50.5% females, and 61.7% in southern United States. At the index date, 17% of patients received ADA and 83% received IFX. Treatment discontinuation was observed in 52% of ADA and 45% of IFX users through 12 months postindex (mean time 19 and 22 weeks, respectively). Among discontinuers, 46% of ADA and 68% of IFX users did not restart/switch TNFi. ADA and IFX showed mean times to switch of 18 and 30 weeks, respectively. TNFi discontinuers had the lowest mean quarterly total health care cost (

OP0185 Significant Clinical Improvement and Reduction of Severe Flares Following Administration of an IL-6 Monoclonal Antibody in Systemic Lupus Erythematosus (SLE) Subjects with High Disease Activity

3,935) versus patients who initiated/switched TNFi (

Economic and patient-reported outcomes of oral triptans in the treatment of migraine

15,004). Nevertheless, discontinuers had higher UC-related hospitalization versus patients receiving therapy. CONCLUSIONS Approximately half of ADA and IFX users discontinued, with approximately half of discontinuers not restarting/switching therapies. Further investigation of treatment patterns and outcomes after TNFi discontinuation is required.

DOP075 Tofacitinib in active ulcerative colitis: Analysis of efficacy based on patient-reported outcomes

Background PF-04236921 is a fully human monoclonal antibody (mAb) that binds to circulating IL-6 and neutralizes its activity. This may be beneficial in reducing the disease manifestations of active SLE. Objectives To assess the efficacy, safety, and tolerability of PF-04236921 in subjects with active SLE. Methods 183 subjects with active SLE (SLEDAI ≥6 and ≥1 BILAG 2004 A or ≥2 Bs) received 3 doses of PF-04236921 (10, 50, or 200mg) or placebo given subcutaneously every 8 wks. The primary endpoint was the proportion of SLE Responder Index 4 (SRI-4) responders at Wk 24 using a generalized linear mixed model. The BILAG-based Combined Lupus Assessment (BICLA), frequency of severe flares, and SF-36 were also evaluated. Results The majority of subjects were female (91.8%), mean age 40.4, with musculoskeletal and mucocutaneous organ system involvement. Baseline demographics were similar across groups. At Wk 24, there were more responders in the 10mg group vs placebo for the SRI (p=0.076) and BICLA (p=0.026). Improvement in the SF-36 PCS domain was also noted for the 10mg group vs placebo (p=0.092). For the 50mg group there were no significant differences vs placebo for the SRI (p=0.528) or BICLA (p=0.1). A post-hoc subgroup analysis was completed in subjects with high baseline disease activity [SLEDAI ≥10, detectable anti-dsDNA, low complement, or prednisone >7.5 mg/day (enriched population)]. In this subgroup, a significant effect size was observed for the SRI, BICLA, and SF-36 PCS domain for the 10mg group vs placebo. There was also a significant reduction in the frequency of severe SELENA-SLEDAI Flare Index (SFI) flares for the combined 10 and 50mg groups vs placebo for both the broad (p=0.004) and enriched populations (p=0.004). Adverse events (AEs), infectious AEs, and discontinuations due to AEs were comparable across groups. The rate of SAEs was highest in the placebo and 200mg groups and the rate of serious infections was highest in the 200mg group. There were 4 deaths; 3 in 200mg [cardiorespiratory arrest, urosepsis with pulmonary embolism (PE), and disseminated tuberculosis] and 1 in 10mg (suspected PE); further dosing of 200mg was subsequently terminated. Conclusions An efficacy signal was apparent in the broad population following administration of an IL-6 mAb notably with regard to severe flare reduction. Greater efficacy was observed across several key parameters for the 10mg group in the enriched population compared to the broad population. The safety profile with 10 and 50mg doses appeared acceptable for both the broad and enriched population; dosing with 200mg was terminated due to safety concerns. Disclosure of Interest J. Smolen Grant/research support from: Abbvie, Janssen, MSD, Pfizer Inc, Roche, UCB, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, GSK, Janssen, Eli-Lilly, Medimmune, MSD, Novartis-Sandoz, Novo-Nordisk, Pfizer Inc, Roche, Samsung, Sanofi-Aventis, UCB, S. Popa: None declared, I. Szombati: None declared, D. Wallace: None declared, M. Petri Consultant for: Pfizer Inc., P. Lipsky Consultant for: Pfizer Inc., J. Merrill Consultant for: Pfizer Inc., V. Strand Consultant for: Abbvie, Amgen, Anthera, Astra-Zeneca, Biogen Idec, Bristol-Myers Squibb, Genentech, GSK, Janssen, Merck Serono, Novartis, Pfizer Inc, Sanofi-Aventis, Takeda, UCB, P. Healey Employee of: Pfizer Inc., C. Li Employee of: Pfizer Inc., J. Christensen Employee of: Pfizer Inc., A. Diehl Employee of: Pfizer Inc., J. Beebe Employee of: Pfizer Inc., M. Vincent Employee of: Pfizer Inc., J. Wajdula Employee of: Pfizer Inc., S. Sridharan Employee of: Pfizer Inc.