Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib in long-term studies.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis). METHODS: In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis. RESULTS: For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n = 269). CONCLUSION: Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661.

Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study.

BACKGROUND: Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA). METHODS: Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators' discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients' average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy. RESULTS: Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained. CONCLUSIONS: Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions. TRIAL REGISTRATION: NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006).

Analysis of non-melanoma skin cancer across the tofacitinib rheumatoid arthritis clinical programme.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the incidence of non-melanoma skin cancer (NMSC) across the tofacitinib RA development programme. METHODS: NMSC events (through August 2013) were identified in patients receiving tofacitinib in two Phase (P)1, eight P2, six P3 and two long-term extension (LTE) studies. In P123 studies, tofacitinib was administered at various doses (1-30 mg twice daily [BID], 20 mg once daily), as monotherapy or with conventional synthetic disease-modifying anti-rheumatic drugs, mainly methotrexate. In LTE studies, patients from qualifying P123 studies received tofacitinib 5 or 10 mg BID. Crude incidence rates (IRs; patients with events/100 patient-years) for first NMSC event were evaluated across doses and over time. RESULTS: In the overall population, comprising data from 18 studies (15,103 patient-years), 83 of 6092 tofacitinib-treated patients had NMSC events. The IR for NMSC (0.55 [95% confidence interval, 0.45-0.69] overall population) was stable up to 84 months of observation. IRs for tofacitinib 5 and 10 mg BID in combined P123 trials were 0.61 (0.34-1.10) and 0.47 (0.24-0.90), respectively. Corresponding IRs for LTE studies were 0.41 (0.26-0.66) and 0.79 (0.60-1.05). CONCLUSIONS: The IR for NMSC across the tofacitinib RA clinical development programme was low and remained stable over time. The IR for NMSC in LTE studies was numerically but not significantly higher with tofacitinib 10 versus 5 mg BID; an inverse dose relationship was observed in P123 trials. Longer follow-up is required to confirm these results.

Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the efficacy and safety of tofacitinib 5 or 10 mg twice daily (BID), in patients with moderate to severe RA, aged ≥65 and <65 years. METHODS: Data were pooled from five Phase 3 trials and, separately, from two open-label long-term extension (LTE) studies (data cut-off April, 2012). Patients received tofacitinib, or placebo (Phase 3 only), with/without conventional synthetic DMARDs (mainly methotrexate). Clinical efficacy outcomes from Phase 3 studies were evaluated at Month 3. Safety evaluations using pooled Phase 3 data (Month 12) and pooled LTE data (Month 24) compared exposure-adjusted incidence rates (IRs; with 95% confidence intervals [CIs]), in older versus younger patients. RESULTS: In Phase 3 and LTE studies, 15.3% (475/3111) and 16.1% (661/4102) of patients, respectively, were aged ≥65 years. Consequently, exposure to tofacitinib was lower in older versus younger patients in Phase 3 (259.2 vs. 1554.9 patient years [pt-yrs]) and LTE (962.1 vs. 5071.7 pt-yrs) studies. Probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 (Month 3) favoured tofacitinib and were similar in older and younger patients, with overlapping CIs. IRs for SAEs and discontinuations due to AEs were generally numerically higher in older versus younger patients, irrespective of treatment. CONCLUSIONS: Older patients receiving tofacitinib 5 or 10 mg BID had a similar probability of ACR20 or ACR50 response and, due to comorbidities, a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients.

Prostaglandin E2 receptor subtype EP-2 is not involved in the induction of non-pregnant guinea pig uterine contractions associated with terminal pregnancy.

Prostaglandin E2 (PGE2) exerts its biological effects through 4 different receptor subtypes, EP-1, EP-2, EP-3, and EP-4. Recently we have demonstrated the importance of the prostaglandin E2 receptor subtype EP-2 in the healing of bone defects and fractures. This discovery led to the identification of CP-533,536, an EP-2 selective agonist, a promising therapeutic alternative for the enhancement of bone healing and the treatment of fractures (J Bone Miner Res 18 (2003) 2033). PGE2 has a myriad of effects throughout the body including the induction of uterine contractions, which results in termination of pregnancies. Our objective in this study was to determine the role of the EP-2 receptor and specifically that of CP-533,536, an EP-2 specific agonist, to induce uterine contractions and terminate pregnancy in guinea pigs, an animal model of human pregnancy. Preliminary experiments confirmed earlier reports that the guinea pig uterus was more sensitive than that of the rat. The guinea pig uterus contains the four PGE2 receptor subtypes, and ex vivo treatment of the uterus with PGE2 as expected causes profound uterine contractions. However, using receptor selective prostaglandin agonists including CP-533,536 we showed that the EP-1 and 3 receptors not the EP-2 receptor is responsible for the induction of uterine contractions of PGE2. Further, CP-533,536 did not antagonize the ability of PGE2 to induce uterine contractions in this model.