Sustained efficacy and safety of guselkumab in patients with palmoplantar pustulosis through 1.5 years in a randomized phase 3 study.

The safety and efficacy of guselkumab for palmoplantar pustulosis (PPP) have been established through week (W)52; however, no sufficient information is available beyond 1 year. This study was conducted to assess the efficacy and safety of guselkumab through W84, and to explore factors associated with the sustainability of its efficacy in Japanese PPP patients. Patients received guselkumab 100 or 200 mg at W0, W4, W12, and every 8 weeks (q8w) until W60, or placebo at W0, W4, and W12. At W16, patients receiving placebo were re-randomized to receive guselkumab 100/200 mg at W16, W20, and q8w until W60. Efficacy end-points included PPP Area and Severity Index (PPPASI), PPP Severity Index (PPSI), Physician's Global Assessment scores, and patient reported outcomes (PRO) (Dermatology Life Quality Index, EuroQoL-5 Dimensions, and 36-item Short Form Health Survey). Post-hoc comparison of patient characteristics was performed between PPPASI-75/90 responders and non-responders at W60, and sustained responders and non-responders at W84. Safety was evaluated through W84. A total of 45, 43, 21, and 24 patients from the guselkumab 100 mg, guselkumab 200 mg, placebo→guselkumab 100 mg, and placebo→guselkumab 200 mg groups, respectively, completed the study through W84. Overall, the mean improvement in the guselkumab groups from baseline in the PPPASI and PPSI total scores at W84 was ~79% and ~66%, respectively. All PRO improved through W84. The proportion of responders through W60 was higher in patients who had not received prior phototherapy and non-biologic systemic therapy for PPP. Non-smokers and patients with no prior non-biologic systemic treatment tended numerically towards sustained efficacy through W84. The majority of treatment-emergent adverse events (TEAE) were mild to moderate (~88%) with low incidence of serious TEAE (7.6%). Overall, guselkumab showed sustained efficacy and safety with improvement in the health-related quality of life through W84 in Japanese PPP patients.

Efficacy and Safety of Guselkumab in Japanese Patients With Palmoplantar Pustulosis: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Palmoplantar pustulosis (PPP) causes erythematous, scaly plaques with recurrent sterile pustules refractory to treatment and with few randomized clinical trials conducted. Evidence points to involvement of interleukin 23 in the pathogenesis of PPP. OBJECTIVE: To determine the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized clinical trial was conducted from December 15, 2015, to December 12, 2017. A total of 159 enrolled patients (aged ≥20 years) had an inadequate response to conventional therapies, with a diagnosis of PPP for 24 or more weeks before screening. Intention-to-treat analysis was performed. INTERVENTIONS: Subcutaneous injections of guselkumab, 100 or 200 mg, at weeks 0, 4, and 12, and every 8 weeks thereafter were administered; placebo was given at weeks 0, 4, and 12. MAIN OUTCOMES AND MEASURES: Changes from baseline in PPP Area and Severity Index (PPPASI) score (possible score range, 0-72, with higher scores indicating greater area and severity), PPP severity index (PPSI) score (possible score range, 0-12, with higher scores indicating greater severity), and proportion of PPPASI-50 (≥50% reduction) responders at weeks 16 and 52 were assessed. Safety was monitored through week 52. RESULTS: A total of 159 patients (mean [SD] age at diagnosis, 46.8 [11.9] years; 126 women [79.2%]) were enrolled. Treatment groups comprised guselkumab, 100 mg (n = 54), guselkumab, 200 mg (n = 52), or placebo (n = 53). Both guselkumab groups demonstrated significant improvement in least-squares mean changes in PPPASI score compared with placebo: -15.3 and -11.7 in the guselkumab 100-mg and 200-mg groups, respectively, and -7.6 in the placebo group (difference [SE] vs placebo: -7.7 [1.7] in the 100-mg group, P < .001; 95% CI, -11.00 to -4.38; and -4.1 [1.7] in the 200-mg group, P < .017; 95% CI, -7.47 to -0.75]). Least-squares mean changes in PPSI score showed significant improvement in both guselkumab groups (100 mg: -2.0 [0.5]; P < .001; 95% CI, -2.96 to -0.95; 200 mg: -1.0 [0.5; P = .04; 95% CI, -2.06 to -0.03). A significantly higher proportion of patients in the guselkumab 100-mg group (31 [57.4%]) achieved a PPPASI-50 response at week 16 vs placebo (18 [34.0%]; P = .02); however, the result was not significant for the guselkumab 200-mg group (19 [36.5%]) vs placebo; P = .78). Each efficacy end point improved consistently through week 52. Health-related quality of life improved significantly as indicated by a reduction in the Dermatology Life Quality Index score (100 mg: -2.6; 95% CI, -4.0 to -1.2; P < .001; 200 mg: -1.6; 95% CI, -3.1 to -0.2; P = .03). Serious treatment-emergent adverse events were observed in 8 patients (placebo group, 2 of 53 [3.8%]; combined guselkumab group, 6/157≠10.5%). No serious infections were reported. CONCLUSIONS AND RELEVANCE: Targeting interleukin 23 with guselkumab may be an effective and safe treatment option for a recalcitrant disease such as PPP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02641730.

Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study.

Previous global studies of guselkumab have demonstrated clinical benefits in patients with psoriasis. The aim of this 52-week, phase 3 study was to evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaque-type psoriasis. Patients randomly received guselkumab 50 mg or 100 mg at weeks 0, 4 and every 8 weeks, or placebo with cross-over to guselkumab 50 mg or 100 mg at week 16. Co-primary end-points were the proportion of patients achieving Investigator's Global Assessment (IGA) cleared/minimal (0/1) and 90% or more improvement in Psoriasis Area and Severity Index (PASI-90) at week 16. Overall, 192 patients were randomized to placebo, guselkumab 50 mg or 100 mg. At week 16, patients in the placebo group were crossed over to guselkumab 50 mg or 100 mg. At week 16, a significantly (P < 0.001) higher proportion of patients receiving guselkumab 50 mg and 100 mg versus placebo achieved IGA 0/1 (92.3% and 88.9% vs 7.8%) and PASI-90 (70.8% and 69.8% vs 0%). Patients in guselkumab 50 mg and 100 mg groups achieved significant improvement versus placebo in PASI-75 (89.2% and 84.1% vs 6.3%, P < 0.001) at week 16; improvement was maintained through week 52. Incidences of treatment-emergent adverse events were comparable among the groups through week 16; the most commonly reported was nasopharyngitis. No new safety concerns were observed until week 52. In conclusion, guselkumab treatment demonstrated superior efficacy over placebo and was well tolerated in Japanese patients with moderate to severe plaque-type psoriasis.

Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study.

Generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP) are the rare and severe subtypes of psoriasis, which are often difficult to treat. The aim of this phase 3, open-label study was to evaluate efficacy and safety of guselkumab, a human interleukin-23 monoclonal antibody, in Japanese patients with GPP and EP. Guselkumab 50 mg was administrated to GPP (n = 10) and EP (n = 11) patients at weeks 0, 4 and thereafter every 8 weeks (q8w). Beginning at week 20, patients were escalated to 100 mg q8w if they met the dose escalation criteria. The primary end-point was the proportion of patients achieving treatment success (Clinical Global Impression score of "very much improved", "much improved" or "minimally improved") at week 16. Safety evaluations included assessment of treatment-emergent adverse events (TEAE) through week 52. At week 16, the proportions of GPP and EP patients achieving treatment success were 77.8% (7/9) and 90.9% (10/11), respectively. Furthermore, guselkumab treatment consistently showed improvement in responses of secondary end-points such as Psoriasis Area and Severity Index, Investigator's Global Assessment, Japanese Dermatological Association severity index and improvement in body surface area involvement. Improvements in quality of life, as assessed by the Dermatology Life Quality Index, were also observed through week 52. The most commonly reported TEAE was nasopharyngitis (28.6%, 6/21). Safety findings were consistent with those observed previously in other studies. In conclusion, guselkumab treatment demonstrated efficacy and showed no safety concerns in Japanese patients with GPP and EP through week 52.

Transmitochondrial mito-miceΔ and mtDNA mutator mice, but not aged mice, share the same spectrum of musculoskeletal disorders.

The spectra of phenotypes associated with aging and mitochondrial diseases sometimes appear to overlap with each other. We used aged mice and a mouse model of mitochondrial diseases (transmitochondrial mito-miceΔ with deleted mtDNA) to study whether premature aging phenotypes observed in mtDNA mutator mice are associated with aging or mitochondrial diseases. Here, we provide convincing evidence that all the mice examined had musculoskeletal disorders of osteoporosis and muscle atrophy, which correspond to phenotypes prevalently observed in the elderly. However, precise investigation of musculoskeletal disorders revealed that the spectra of osteoporosis and muscle atrophy phenotypes in mtDNA mutator mice were very close to those in mito-miceΔ, but different from those of aged mice. Therefore, mtDNA mutator mice and mito-miceΔ, but not aged mice, share the spectra of musculoskeletal disorders.