Long-term Etanercept Response for Patients with Radiographic Axial Spondyloarthritis Based on Achievement of Early, Intermediate, or Late Responses During Index Studies.

INTRODUCTION: Short-term placebo (PBO)- or active-controlled clinical studies have demonstrated that etanercept (ETN) is effective and well tolerated in patients with radiographic axial spondyloarthritis (r-axSpA) with long-term efficacy and safety continuing for up to 7 years after treatment start. Short-term randomized controlled trials (RCTs) have shown the efficacy of ETN after 12-24 weeks, with statistically significant improvements as early as week 2. This post hoc analysis investigated the timeframe (i.e., temporal responses) in which patients with r-axSpA achieved their first clinical response with ETN and how patients responded over a longer period according to different temporal responses in index studies. METHODS: Data were analyzed from three phase 3/4 PBO- or sulfasalazine-controlled RCTs of ETN for the treatment of r-axSpA (index studies). Long-term open-label extension (OLE) studies assessed how patients responded over a longer period according to different temporal responses ("Early," "Intermediate," "Late," or "Non-response") in their corresponding index studies. RESULTS: Within each index study, patient responses differed significantly between ETN and control arms for achievement of Assessment in SpondyloArthritis international Society (ASAS) 20 and other measures of treatment response. In general, the proportion of responders in the OLE studies was high for those with "Early" and "Intermediate" responses as defined in the index studies. Despite patients being considered non-responders in the index studies, a large proportion achieved response on continued treatment in the OLE studies over the longer term, including through 48 weeks. CONCLUSIONS: Response in the index studies was maintained in the long term, and continued treatment was warranted in a large proportion of patients despite initial non-response. Absence of an early response in index studies did not predict non-response over the long term, and early response to treatment was not always a predictor for later response. TRIAL REGISTRATION: NCT00421915; NCT00247962; NCT00356356; NCT00421980; NCT00410046.

Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. METHODS: Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. RESULTS: The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild-moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. CONCLUSION: CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.

The incidence of Clostridium difficile infection in the tofacitinib ulcerative colitis clinical program was evaluated. C. difficile infection among patients with ulcerative colitis receiving tofacitinib were infrequent; cases were mild­moderate in severity, and most resolved with treatment.

Major Adverse Cardiovascular Events by Baseline Cardiovascular Risk in Patients with Ulcerative Colitis Treated with Tofacitinib: Data from the OCTAVE Clinical Programme.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease have increased risk of atherosclerotic cardiovascular [CV] disease [ASCVD]. Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis [UC]. We report major adverse CV events [MACE] in the UC OCTAVE programme, stratified by baseline CV risk. METHODS: Rates of MACE were analysed by baseline [first tofacitinib exposure] CV risk profile: prior ASCVD, or 10-year ASCVD risk categories [low, borderline, intermediate, high]. RESULTS: Of 1157 patients [2814.4 patient-years of exposure; ≤7.8 years' tofacitinib treatment], 4% had prior ASCVD and 83% had no prior ASCVD and low-borderline baseline 10-year ASCVD risk. Eight [0.7%] patients developed MACE; one had prior ASCVD. Incidence rates [unique patients with events/100 patient-years of exposure; 95% confidence intervals] for MACE were: 0.95 [0.02-5.27] in patients with prior ASCVD; and 1.81 [0.05-10.07], 1.54 [0.42-3.95], 0.00 [0.00-2.85], and 0.09 [0.01-0.32] in patients without prior ASCVD and with high, intermediate, -borderline, and low baseline 10-year ASCVD risk, respectively. For the 5/7 patients with MACE and without prior ASCVD, 10-year ASCVD risk scores were numerically higher [>1%] prior to MACE versus at baseline, primarily due to increasing age. CONCLUSIONS: Most patients receiving tofacitinib in the UC OCTAVE programme had low baseline 10-year ASCVD risk. MACE were more frequent in patients with prior ASCVD and higher baseline CV risk. This analysis demonstrates potential associations between baseline CV risk and MACE in patients with UC, suggesting CV risk should be assessed individually in clinical practice. CLINICALTRIALS.GOV: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.

A retrospective, pooled data analysis of the safety of pegaptanib sodium in the treatment of age-related macular degeneration in subjects with or without diabetes mellitus.

BACKGROUND: To evaluate the safety of pegaptanib sodium 0.3 mg intravitreal injection in the treatment of neovascular age-related macular degeneration in subjects with or without diabetes mellitus. METHODS: A pooled, retrospective, analysis was conducted of data from 9 sponsor-administered, randomized, open-label trials. Subjects who received pegaptanib by randomization or change in dose assignment, crossover design, or protocol amendment, were included. Reports of endophthalmitis, increased intraocular pressure, retinal injury, intraocular hemorrhage, traumatic cataract, hypersensitivity reactions, stroke, myocardial infarction, and other arterial thromboembolic events defined by the Antiplatelet Trialists' Collaboration were identified by Medical Dictionary for Regulatory Activities preferred terms. Adverse events were summarized from the first injection to 42 days after the last injection. The incidence of adverse events was stratified by the presence/absence of diabetes. RESULTS: Of 1,586 subjects enrolled, 165 (10.4%) had a history of diabetes mellitus and 1,421 (89.6%) did not. The 2 populations were similar at baseline. Based on the comparison of prespecified ocular, hypersensitivity, and Antiplatelet Trialists' Collaboration event terms, the safety review did not identify any notable differences between the 2 populations. CONCLUSIONS: This retrospective analysis found no increased safety risk resulting from treatment with pegaptanib 0.3 mg in individuals with neovascular age-related macular degeneration and concomitant diabetes mellitus.

Worldwide post-marketing safety surveillance experience with tofacitinib in ulcerative colitis.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs). AIMS: To report an analysis of PMS case safety reports for tofacitinib in patients with UC METHODS: Worldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate- or extended-release formulations. RESULTS: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders. CONCLUSIONS: The types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non-serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.

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 > or = 4 weeks before screening. After washout, 500 subjects with a baseline mean intraocular pressure (IOP) > or = 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 subject's 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.

Five-year, multicenter safety study of fixed-combination latanoprost/timolol (Xalacom) for open-angle glaucoma and ocular hypertension.

PURPOSE: To evaluate the safety of fixed-combination latanoprost/timolol (Xalacom) in patients requiring additional intraocular pressure (IOP) reduction over 5 years. METHODS: This phase 3b, open-label, multicenter study included prostaglandin-naive participants with open-angle glaucoma or ocular hypertension insufficiently responsive to ß-blockers and requiring additional IOP reduction. Participants were evaluated at eleven 6-month visits. A masked assessor evaluated iris/eyelash changes at baseline and 12, 36, and 60 months. Increased iris pigmentation incidence was compared with a historic control from a similarly designed study evaluating latanoprost. Ocular and systemic adverse events were recorded. RESULTS: Among 828/974 treated participants with assessable iris photographs, 233 (28.1%) developed increased iris pigmentation versus 127/380 (33.4%) in the historic controls. Participants with mixed eye colors exhibited greater susceptibility to overall increased iris pigmentation (85.8% in both studies). In this study, most participants (80.3%) with increased iris pigmentation developed only a weak increase. Eyelash changes were seen in 58.1% of participants and darkening of the eyelids in 5-6%; 14.1% experienced a serious adverse event. Adverse events resulted in treatment withdrawal in 133 (13.7%) participants. Most were nonserious ocular adverse events, about half of them ocular irritation. Only 3 of 13 serious systemic adverse events were considered to be drug related by the investigator. Mean IOP reductions were stable over 5 years. CONCLUSIONS: After 5 years, more than 70% of participants treated with fixed-combination latanoprost/timolol had no increased iris pigmentation. The fixed combination is safe and well tolerated for long-term treatment in patients with open-angle glaucoma or ocular hypertension.

Lack of evidence for a link between latanoprost use and malignant melanoma: an analysis of safety databases and a review of the literature.

AIM: To determine if there is an association between the use of latanoprost ophthalmic solution and malignant melanoma and to assess the evidence of a plausible biological mechanism. METHODS: Two safety databases were reviewed: one representing all latanoprost (n=24) and fixed-combination latanoprost/timolol (n=16) clinical trials conducted from November 1992 through November 2007 and a global safety database of all spontaneous non-trial-related clinical reports spanning 13 and 9 years for latanoprost and for latanoprost/timolol, respectively. A systematic PubMed search for studies evaluating potential mechanisms was conducted. RESULTS: Amongst 12,880 latanoprost-treated subjects in clinical trials, no reported cases of ocular melanoma and three cases of cutaneous melanoma were identified. Of 19,940 cases recorded in the global safety database, 22 reports of ocular/cutaneous neoplasms were identified. Of these neoplasms, 11 were ocular and six were cutaneous melanomas. Possible association with latanoprost use could not be excluded in three ocular and one periorbital report. In vitro and in vivo data were consistent with a mechanism whereby the increased iris pigmentation results from stimulation of melanin synthesis by induction of tyrosinase transcription without increasing mitotic activity. CONCLUSION: There is no evidence at present that establishes a link between latanoprost use and either ocular or cutaneous melanoma.

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.