Patients with moderate-to-severe ulcerative colitis were randomly assigned to receive placebo or induction doses of ustekinumab. Patients who had a response to induction therapy underwent a second ...randomization to maintenance therapy with ustekinumab or placebo. Ustekinumab was more effective than placebo for inducing and maintaining remission.
Summary Background Long‐term safety evaluations of biologics are needed to inform patient management decisions.
Objectives To evaluate the safety of ustekinumab in patients with moderate‐to‐severe ...psoriasis treated for up to 5 years.
Methods Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE) per 100 patient‐years (PY) of follow‐up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow‐up (years 1–5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population.
Results Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥ 4 years (including 838 patients ≥ 5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year‐to‐year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population.
Conclusions No dose‐related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate‐to‐severe psoriasis.
What’s already known about this topic?
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Short‐term studies of ustekinumab in patients with moderate‐to‐severe psoriasis indicated a favourable benefit–risk profile. Long‐term safety evaluations are needed to inform patient management decisions.
What does this study add?
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This report evaluated the largest psoriasis clinical trial cohort to date with the longest duration of follow‐up. Safety outcomes after 5 years of ustekinumab treatment are consistent with shorter‐term reports and are generally comparable with observations from studies of other biologics in patients with psoriasis.
Summary
Background
Evaluation of the dosing flexibility and long‐term efficacy of biological agents is limited.
Objectives
To evaluate the long‐term efficacy and safety of ustekinumab with and ...without dosing adjustment in the 5‐year PHOENIX 2 study.
Methods
Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed‐over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long‐term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively.
Results
In the overall population, 70% (849 of 1212) of ustekinumab‐treated patients completed treatment through week 244, with high proportions of patients responding to the 45‐mg and 90‐mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment.
Conclusions
Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.
What's already known about this topic?
Data regarding dosing adjustment from PHOENIX 1 are limited. Protocol‐defined dose‐interval adjustment was permitted only early in the study based on clinical response.
What does this study add?
PHOENIX 2 evaluated both protocol‐defined and investigator‐initiated dose and/or dose‐interval adjustment.
Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify the actual incremental benefits.
Some patients may desire treatment goals beyond 75% improvement in Psoriasis Area and Severity Index.
Summary
Background An unmet need remains for safe and effective long‐term treatments of psoriasis.
Objectives To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial.
...Methods Patients (n = 766) with moderate‐to‐severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders ≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40 were re‐randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50–74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician’s Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures.
Results Overall, 79·8% of the ustekinumab‐treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity.
Conclusions Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.
Background Ongoing evaluation of biological agents in patients with moderate‐to‐severe psoriasis is needed to support their long‐term use.
Objective To evaluate long‐term efficacy and safety of ...ustekinumab through 5 years in the PHOENIX 1 study.
Methods Patients were randomized to placebo or ustekinumab (45 mg or 90 mg) at Weeks 0, 4 and every‐12‐weeks thereafter; placebo patients crossed‐over to ustekinumab at Week 12. Clinical response through Week 244 was evaluated using the Psoriasis Area and Severity Index (PASI) in the Overall Population (i.e. patients receiving ≥1 dose of ustekinumab), Initial Responders (i.e. PASI 75 responders Weeks 28/40 re‐randomized at Week 40 to continue every‐12‐week maintenance) and Partial Responders (i.e. <PASI 75 responders adjusted to every‐8‐week maintenance at Weeks 28 or 40). Safety endpoints were evaluated through Week 264 for the Overall Population.
Results Overall, 68.7% (517/753) of ustekinumab‐treated patients completed treatment through Week 244. Initial clinical responses were generally maintained through Week 244 (PASI 75: 63.4% and 72.0%; PASI 90: 39.7% and 49.0%; PASI 100: 21.6% and 26.4%) for patients receiving 45 mg and 90 mg, respectively. Similarly, PASI 75 responses were generally maintained among Initial Responders 79.1% (45 mg) and 80.8% (90 mg) and Partial Responders 57.6% (45 mg) and 55.1% (90 mg). With 3104 patient‐years of follow‐up, rates of overall adverse events (AEs), serious AEs, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses.
Conclusions Through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response and a safety profile consistent with previous reports.
Summary
Background Patients with psoriasis are believed to be at an increased risk of cardiovascular (CV) morbidity, and the effect of biological agents on CV safety is not fully understood.
...Objectives To evaluate the effect of ustekinumab on CV events using detailed analyses of pooled data from the phase II/III clinical studies of its use in moderate to severe psoriasis.
Methods The incidence of major adverse CV events MACE: myocardial infarction (MI), stroke or CV death is reported. Meta‐analyses using risk difference and odds ratio estimates are presented based on data collected during the placebo‐controlled period of ustekinumab trials. The cumulative numbers of events and rates of MIs and strokes over time were compared with those expected in the psoriasis and/or general populations.
Results During the placebo‐controlled period (12/20 weeks), five MACE were reported in 1582 ustekinumab‐treated patients 0·3%; 95% confidence interval (CI) 0·1–0·7% compared with no events in 732 placebo‐treated patients (0·0%; 95% CI 0·0–0·5%). MACE rates were stable over time during both the controlled and uncontrolled study periods, with 19 of 3117 ustekinumab‐treated patients (0·6%) experiencing 21 events for a combined event rate per 100 patient‐years of follow‐up of 0·44 (95% CI 0·27–0·67) through up to 3 years. Standardized incidence ratios for comparison of ustekinumab clinical data with external data sources ranged from 0·34 to 0·52, suggesting no increased risk of MI or stroke in ustekinumab‐treated patients compared with the general U.S. and psoriasis populations.
Conclusions The totality of available clinical data suggests neither a detrimental nor a beneficial effect of ustekinumab on serious CV events. Additional data are needed to define the net effect of ustekinumab on CV events.
Background Ustekinumab, a human anti‐interleukin‐12/23 monoclonal antibody, has been shown to effectively treat moderate‐to‐severe psoriasis which significantly affects health‐related quality of ...life (HRQoL), including patients’ sexual lives.
Objectives The aim of this study was to determine if sexual difficulties associated with psoriasis are related to disease severity and whether sexual difficulties improve with skin disease during ustekinumab treatment.
Methods In phase III PHOENIX 1 and 2 trials, psoriasis patients were randomized to ustekinumab (n = 1334) at weeks 0 and 4 and q12 weeks thereafter or placebo (n = 662) at weeks 0 and 4 with crossover to ustekinumab at week 12. Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) were used to assess psoriasis severity and patient‐reported HRQoL respectively. Based on DLQI Question #9, impaired sexual function was defined as ‘very much’ or ‘a lot’ of sexual difficulties.
Results At baseline, mean DLQI was 12.0, indicating a very large negative effect on patients’ lives. Impaired sexual function was reported by 22.6% (women = 27.1%; men = 20.8%) and was significantly associated with increased psoriasis severity. At week 12, ustekinumab‐treated patients had a greater mean improvement in DLQI (−9.13 vs. −0.53 with placebo, P < 0.001) and the proportion of patients with impaired sexual function decreased from 22.4% to 2.7% compared with no change with placebo (P < 0.001). Patients with greater PASI improvement experienced a greater reduction of sexual difficulties due to psoriasis. A similar pattern of improved sexual function was observed at weeks 24–28 in placebo crossover patients.
Conclusions Ustekinumab treatment is associated with significant improvement in HRQoL and sexual difficulties due to psoriasis.
OBJECTIVE—The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic ...patients with metabolic syndrome (MetSyn).
METHODS AND RESULTS—Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance.
CONCLUSIONS—In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.
Elevated serum trigylcerides and low high-density lipoprotein (HDL) cholesterol are part of a metabolic syndrome that is increasingly being recognized as an important risk factor for cardiovascular ...disease. Several classes of pharmacological agents including fibrates, niacin and statins, can modify the triglyceride–HDL axis. Fibrates in particular have recently been shown in clinical trials not only to increase HDL, but also to reduce cardiovascular mortality in secondary prevention. More research is needed to further define the role of fibrates when used alone and in combination with statins in high-risk individuals.
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