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
Guselkumab, an anti‐interleukin‐23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials.
Objectives
To evaluate the efficacy and safety of ...guselkumab in patients with moderate‐to‐severe plaque psoriasis who had an inadequate response to ustekinumab.
Methods
In this phase III, randomized, double‐blind study, 871 patients received open‐label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab Investigator's Global Assessment (IGA) ≥ 2 were randomized (double‐blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open‐label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two‐grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed.
Results
The mean number of visits at which patients achieved IGA 0/1 and at least a two‐grade improvemen (week 28–40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1·5 vs. 0·7; P < 0·001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two‐grade improvement at week 28 (31·1% vs. 14·3%; P = 0·001) and week 52 (36·3% vs. 17·3%; P < 0·001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64·4% of patients in the guselkumab group and 55·6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the ustekinumab group.
Conclusions
Patients treated with ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab.
What's already known about this topic?
Interleukin (IL)‐23/IL‐17 is the major pathway that drives the chronic inflammation underlying the pathophysiology of psoriasis.
Ustekinumab is a monoclonal antibody targeting IL‐12 and IL‐23 and is currently approved for patients with plaque psoriasis.
Guselkumab is a novel anti‐IL‐23 monoclonal antibody and has demonstrated high efficacy in patients with plaque psoriasis in two recent phase III trials.
What does this study add?
Guselkumab demonstrated greater efficacy compared with ustekinumab among patients who failed to achieve an Investigator's Global Assessment score of 0 or 1 with ustekinumab therapy.
The types of adverse events (AEs) with guselkumab and ustekinumab were similar, with infections being the most common.
A slightly higher incidence of AEs was reported in the guselkumab group, primarily driven by AEs of back pain, psoriatic arthropathy and mild injection site reactions.
Linked Comment: Albrecht and Gerdes. Br J Dermatol 2018; 178:20.
Plain language summary available online
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
Long‐term evaluation is required to confirm the safety profile of newer biologic agents.
Objectives
To report on pooled safety data from the ongoing VOYAGE 1 (NCT02207231) and ...VOYAGE 2 (NCT02207244) trials through 100 weeks of follow‐up.
Methods
Patients were randomized to either guselkumab 100 mg at weeks 0 and 4 and every 8 weeks thereafter; placebo at weeks 0, 4, 12 followed by guselkumab 100 mg at weeks 16 and 20 and every 8 weeks thereafter; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every 2 weeks thereafter. Patients who received adalimumab crossed over to guselkumab at week 52 (VOYAGE 1) and at/after week 28 based on clinical response (VOYAGE 2). Open‐label extensions, in which all patients received guselkumab, started at week 52 (VOYAGE 1) and week 76 (VOYAGE 2). Rates of adverse events (AEs) per 100 patient‐years (PYs) are presented through 100 weeks of follow‐up.
Results
Through week 52, observed rates for guselkumab‐ and adalimumab‐treated patients, respectively, were 262·45 per 100 PYs and 328·28 per 100 PYs for AEs, 6·20 per 100 PYs and 7·77 per 100 PYs for serious AEs (SAEs), 1·22 per 100 PYs and 1·79 per 100 PYs for serious infections (SIs), 0·28 per 100 PYs and 0·40 per 100 PYs for malignancies other than nonmelanoma skin cancers (NMSCs), 0·56 per 100 PYs and 0·40 per 100 PYs for NMSCs, and 0·47 per 100 PYs and 0·40 per 100 PYs for major adverse cardiovascular events (MACEs). Rates among patients treated with guselkumab through week 52 and week 100, respectively, were 262·45 per 100 PYs and 210·41 per 100 PYs for AEs, 6·20 and 6·29 per 100 PYs, for SAEs, 1·22 per 100 PYs and 1·06 per 100 PYs for SIs, 0·28 per 100 PYs and 0·38 per 100 PYs for malignancies, 0·56 per 100 PYs and 0·39 per 100 PYs for NMSCs, and 0·47 per 100 PYs and 0·38 per 100 PYs for MACEs. Among patients treated with adalimumab, rates of AEs, SAEs, SIs, malignancies, NMSCs, and MACEs showed some variability before and after crossover to guselkumab, although no new safety signals were noted after crossover.
Conclusions
The safety profile for guselkumab remains favourable through 100 weeks of treatment in patients with moderate‐to‐severe psoriasis.
What's already known about this topic?
Low rates of adverse events of interest for biologic agents (including serious infections, malignancies and major adverse cardiovascular events) have been demonstrated for guselkumab through 1 year of follow‐up in the phase III VOYAGE 1 and VOYAGE 2 studies.
What does this study add?
Pooled data from the VOYAGE 1 and VOYAGE 2 studies show no new safety concerns for guselkumab through 100 weeks of follow‐up.
Analysis of safety data in adalimumab‐treated patients after crossover to guselkumab suggests a consistent safety profile for guselkumab and supports a safe transition from adalimumab to guselkumab.
Linked Comment: Lee and Wu. Br J Dermatol 2019; 180:977–978.
Plain language summary available online
Respond to this article
Summary
Background
Significant advances have been made in the treatment of moderate‐to‐severe plaque psoriasis with biological therapies; however, these agents may not work equally in all ...populations.
Objectives
To evaluate the efficacy of guselkumab in patient subgroups with moderate‐to‐severe psoriasis from the pooled guselkumab VOYAGE 1 and VOYAGE 2 phase III studies.
Methods
Using data from the pooled VOYAGE 1 and VOYAGE 2 psoriasis studies, analyses were performed to evaluate the consistency of efficacy Investigator's Global Assessment (IGA) 0/1 (cleared or minimal psoriasis) and IGA 0 (cleared) across subpopulations defined by demographics, baseline disease characteristics and previous psoriasis treatment.
Results
A total of 1829 patients were randomized. Baseline demographics, disease characteristics and previous psoriasis treatment were comparable across treatment groups in the pooled population. Guselkumab, an anti‐interleukin (IL)‐23 monoclonal antibody that binds to the p19 subunit of IL‐23, provided substantial benefit across almost all subpopulations, with greater proportions of patients achieving IGA 0/1 vs. placebo at week 16, and vs. adalimumab (an antitumour necrosis factor monoclonal antibody) at week 24. Patients treated with guselkumab achieved greater efficacy (IGA 0/1 and IGA 0) compared with adalimumab at week 24 across all weight quartiles, most notably among patients weighing ≥ 100 kg.
Conclusions
This analysis demonstrates a high degree of efficacy with guselkumab treatment compared with placebo at week 16 and with adalimumab at week 24 among broad subpopulations of patients with varying baseline demographics, disease characteristics and previous psoriasis treatments.
What's already known about this topic?
Efficacy of biologics may vary among psoriasis subpopulations.
What does this study add?
Guselkumab achieved superior efficacy vs. adalimumab across all subgroups of patients with psoriasis.
Linked Comment: Feldman. Br J Dermatol 2018; 178:22.
Respond to this article
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.
Background
Anxiety and depression are clinically significant comorbidities associated with psoriasis. Improvements in psoriasis are known to decrease anxiety and depression. Guselkumab, an ...anti‐interleukin‐23 monoclonal antibody, has demonstrated efficacy and safety for the treatment of moderate‐to‐severe psoriasis.
Objective
Assess improvements in anxiety and depression with guselkumab vs. placebo and adalimumab using the Hospital Anxiety and Depression Scale (HADS).
Methods
In VOYAGE 2, a Phase 3, randomized, double‐blind, placebo‐ and adalimumab‐controlled study, patients received placebo (through week 16 followed by crossover to guselkumab), guselkumab, or adalimumab through week 24. HADS consists of two subscales measuring anxiety (HADS‐A) and depression (HADS‐D), with scores ranging from 0 to 21 and higher scores indicating more severe symptoms. Scores ≥8 indicate instrument‐defined anxiety or depression. Severity of psoriasis was assessed using the Psoriasis Area and Severity Index (PASI).
Results
Among 989 patients randomized (with baseline HADS measurements), mean HADS‐A and HADS‐D scores were 6.8 ± 4.2 and 5.3 ± 4.2, respectively; 38.6% of patients reported HADS‐A ≥8 and 27.7% HADS‐D ≥8 at baseline. At week 16, a significantly greater proportion of guselkumab patients with baseline HADS‐A or HADS‐D ≥8 reported HADS‐A <8 (51.4% vs. 25.9%; P < 0.001) or HADS‐D <8 (59.2% vs. 27.0%; P < 0.001) vs. placebo patients. At week 24, a greater proportion of guselkumab patients with baseline HADS‐A or HADS‐D ≥8 reported HADS‐A <8 (58.4% vs. 42.9%; P = 0.028) or HADS‐D <8 (59.8% vs. 46.4%; P = 0.079) vs. adalimumab patients. PASI improvements correlated with improvement in anxiety (r = 0.27; P < 0.0001) and depression (r = 0.25; P < 0.0001) scores in patients with baseline HADS‐A or HADS‐D ≥8. Greater improvements in HADS were also observed at week 16 in guselkumab‐treated patients vs. placebo using a more stringent cut‐off of HADS ≥11.
Conclusion
Guselkumab treatment was associated with greater improvements in symptoms of anxiety and depression scores in patients with psoriasis compared with placebo and adalimumab.
Summary
Background
Most patients with psoriasis have nail changes, and treating nail psoriasis is challenging.
Objectives
To assess improvement in fingernail psoriasis with ustekinumab treatment in ...the PHOENIX 1 trial.
Methods
Patients received ustekinumab 45 mg or 90 mg, or placebo at weeks 0 and 4. Ustekinumab‐randomized patients continued maintenance dosing every 12 weeks, while patients receiving placebo crossed over to receive ustekinumab 45 mg or 90 mg at weeks 12/16 followed by dosing every 12 weeks. At week 40, initial responders those with ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) were rerandomized either to continue maintenance dosing or to withdraw from treatment. Nail involvement was evaluated using the Nail Psoriasis Severity Index (NAPSI) on a target fingernail, Nail Physician's Global Assessment (Nail PGA) and mean number of nails involved.
Results
Of 766 randomized patients, 545 (71·1%) had nail psoriasis. At week 24, the percentage improvement from baseline NAPSI score was 46·5% (ustekinumab 45 mg) and 48·7% (ustekinumab 90 mg). Percentage improvements in NAPSI ranged from 29·7% (PASI < 50) to 57·3% (PASI ≥ 90). Mean NAPSI scores improved from 4·5 at baseline to 2·4 at week 24 (45 mg) and from 4·4 to 2·2 (90 mg). Nail PGA scores and the mean number of psoriatic nails improved by week 24. Further improvement was observed for all end points among initial responders continuing maintenance treatment through week 52.
Conclusions
Ustekinumab significantly improves nail psoriasis, and improvements continue over time until up to 1 year of treatment in those receiving maintenance treatment.
What's already known about this topic?
The majority of patients with moderate‐to‐severe psoriasis have nail manifestations, for which limited therapies are available.
What does this study add?
Beyond the recognized benefit to the skin in psoriasis, ustekinumab significantly improves nail psoriasis over time.
Both nail and skin manifestations of psoriasis should be considered when choosing treatment.
Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)‐12/23 p40 to treat psoriasis. The IL‐12 pathway is also important in regulating immunity to Mycobacterium ...tuberculosis.
Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in ustekinumab‐treated patients with psoriasis.
Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON®‐TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis.
Results At baseline, 101/2898 (3·5%) non‐Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and ustekinumab‐treated patients, as well as between ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and ustekinumab‐treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and ustekinumab groups through week 12. The rate of INH‐related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline.
Conclusions Across five trials of ustekinumab‐treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.
See also the Commentary by Shear
Background
How patients experience the symptoms/signs of psoriasis is highly relevant for assessing treatment response.
Objectives
Compare outcomes with guselkumab, placebo and adalimumab utilizing ...the novel, validated Psoriasis Symptoms and Signs Diary (PSSD).
Methods
VOYAGE 1 is an ongoing, phase III, double‐blinded, controlled trial of patients with moderate‐to‐severe psoriasis. Patients were randomized to guselkumab 100 mg every 8 weeks; placebo‐to‐guselkumab 100 mg every 8 weeks; or adalimumab 40 mg every 2 weeks. The PSSD was self‐administered to assess symptoms (i.e. itch, skin tightness, burning, stinging and pain) and signs (i.e. dryness, cracking, scaling, shedding/flaking, redness and bleeding) of psoriasis (0–10 absent‐to‐worst‐imaginable) every 24 h. Symptom and sign summary scores were derived (0–100) based on average scores of the individual symptoms and signs. Proportions of patients with clinically meaningful improvements and symptom‐ and sign‐free scores of 0 were evaluated across treatment groups at weeks 16, 24 and 48.
Results
At baseline, 652 of 837 randomized patients had PSSD scores. The proportion of patients achieving clinically meaningful improvements in PSSD summary scores was significantly higher in the guselkumab group compared with the placebo group at week 16 (P < 0.001) and compared with the adalimumab group at weeks 24 (P = 0.002) and 48 (P < 0.001). The proportions of patients achieving PSSD symptom and sign summary scores of 0 (i.e. symptom‐ and sign‐free) were significantly higher for guselkumab vs. placebo at week 16 and vs. adalimumab at weeks 24 and 48 (all P < 0.001).
Conclusions
Based on PSSD scores, greater improvements in symptoms and signs of psoriasis were reported by patients treated with guselkumab compared with placebo at week 16 or adalimumab through 48 weeks.
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