Secukinumab long-term efficacy and safety in psoriasis through to year 5 of treatment: results of a randomized extension of the phase III ERASURE and FIXTURE trials.

BACKGROUND: In the long-term extension study of the ERASURE and FIXTURE trials, the efficacy of secukinumab (a fully human anti-interleukin-17A monoclonal antibody) was demonstrated to have been maintained through to year 3 of treatment in moderate-to-severe plaque psoriasis. OBJECTIVES: To assess the efficacy and safety of secukinumab through to year 5 of treatment in moderate-to-severe plaque psoriasis. METHODS: Responders with ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) from two core trials - ERASURE and FIXTURE - were randomized 2 : 1 at year 1 (end of core trials) to either the same dose (300 or 150 mg, continuous treatment) or placebo (treatment withdrawal) every 4 weeks, until year 3 or relapse (> 50% reduction in maximal PASI from core study baseline). Partial responders (achieving PASI 50 but not PASI 75) at year 1 continued at the same dose as in the core trials. At year 3, all patients received open-label secukinumab treatment, with those on secukinumab 300 mg continuing on their dose, while those on secukinumab 150 mg or placebo received secukinumab 150 or 300 mg based on the physician's discretion. The study is registered on ClinicalTrials.gov with the identifier NCT01544595. RESULTS: Most patients randomized to placebo at year 1 relapsed, but the response was rapidly recaptured upon reinitiation of treatment. PASI responses were sustained with secukinumab through to year 5. The PASI responses for the 300 mg responders + partial responders group at year 1 (PASI 75/90/100: 86.8%/72.8%/45.9%) trended downwards until year 3 (PASI 75/90/100: 82.3%/58.4%/32.7%) and then remained stable through year 4 (PASI 75/90/100: 83.3%/60.1%/32.2%) until year 5 (PASI 75/90/100: 81.1%/62.8%/35.1%). Dermatology Life Quality Index showed sustained benefit up to year 5. Absolute PASI responses were maintained throughout the study. The most common adverse events (AEs) were infections and infestations, nasopharyngitis, and upper respiratory tract infections (URTIs). The overall exposure-adjusted incidence rate (EAIR; with 95% confidence interval) for all AEs was 139.9 (130.3-149.9). EAIRs for Crohn's disease and neutropenia were 0.1 (0.0-0.3) and 0.5 (0.3-0.8), respectively. CONCLUSIONS: The 4-year extension of two pivotal phase III trials demonstrated that secukinumab treatment was effective through to year 5 and improved quality of life in patients with moderate-to-severe plaque psoriasis. The most common AEs were infections and infestations, nasopharyngitis, and URTIs. The safety profile was consistent with that in the secukinumab phase II/III clinical development programme.

Secukinumab dosing every 2 weeks demonstrated superior efficacy compared with dosing every 4 weeks in patients with psoriasis weighing 90 kg or more: results of a randomized controlled trial.

BACKGROUND: Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment. OBJECTIVES: To investigate the efficacy, safety and tolerability of secukinumab 300 mg every 2 weeks (Q2W) vs. secukinumab 300 mg every 4 weeks (Q4W) in patients with a higher bodyweight. METHODS: In this multicentre, double-blind, parallel-group trial, 331 patients with moderate-to-severe chronic plaque psoriasis weighing ≥ 90 kg were randomized to receive secukinumab 300 mg Q2W or secukinumab 300 mg Q4W. Patients who did not achieve Psoriasis Area and Severity Index (PASI) 90 at week 16 on the Q4W regimen were reallocated to remain on the Q4W regimen or uptitrate to Q2W. RESULTS: At week 16, Q2W dosing (n = 165) led to significantly higher PASI 90 responses vs. Q4W [n = 166; 73.2% vs. 55.5%, one-sided P-value = 0.0003, odds ratio estimate (95% confidence intervals): 2.3 (1.4-3.8)]. At week 52, higher efficacy responses were maintained in the Q2W arm (n = 165) vs. Q4W (n = 83); PASI 75: 88.9% vs. 74.8%; PASI 90: 76.4% vs. 52.4%; PASI 100: 46.7% vs. 27.3%; Investigator's Global Assessment 0/1: 75.9% vs. 55.6% and Dermatology Life Quality Index 0/1: 66.1% vs. 48.8%. PASI 90 nonresponders at week 16 who uptitrated to Q2W (n = 31) showed higher efficacy responses at week 32 (16 weeks post-uptitration, PASI 90: 38.7% vs. 16.5%) vs. those who remained on Q4W (n = 40). Safety results were comparable across treatment arms and consistent with the established secukinumab safety profile. CONCLUSIONS: Secukinumab 300 mg Q2W demonstrated superior and sustained efficacy compared with Q4W in patients with moderate-to-severe plaque psoriasis weighing ≥ 90 kg. PASI 90 nonresponders derived additional benefits from uptitration to a Q2W regimen (ClinicalTrials.gov identifier: NCT03504852). What is already known about this topic? Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment. Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin-17A in the treatment of moderate-to-severe plaque psoriasis. Subgroup analyses of previous study results and pharmacokinetic/pharmacodynamic modelling data suggest that heavier patients may benefit from higher exposure to secukinumab through an increased dosing frequency [300 mg every 2 weeks (Q2W) vs. every 4 weeks (Q4W)]. What does this study add? Over 52 weeks, secukinumab 300 mg Q2W demonstrated superior efficacy compared with secukinumab 300 mg Q4W in patients with moderate-to-severe plaque psoriasis weighing ≥90 kg, with comparable safety results, consistent with the established secukinumab safety profile. In patients who did not achieve PASI 90 at week 16 on the Q4W regimen, uptitration to the Q2W regimen at week 16 resulted in improved efficacy responses through week 52 after switching.

Efficacy, tolerability, patient usability, and satisfaction with a 2 mL pre-filled syringe containing secukinumab 300 mg in patients with moderate to severe plaque psoriasis: results from the phase 3 randomized, double-blind, placebo-controlled ALLURE study.

BACKGROUND: Evidence shows good tolerability in patients for subcutaneous injection volumes up to 3 mL. OBJECTIVES: We investigated efficacy, pharmacokinetics, and tolerability of secukinumab 300 mg/2 mL pre-filled syringe (PFS) in patients with moderate to severe plaque psoriasis. METHODS: ALLURE was a 52-week, multicenter, randomized (1:1:1), double-blind, placebo-controlled, parallel-group study. Co-primary endpoints were secukinumab Psoriasis Area Severity Index (PASI) 75 and Investigator's Global Assessment modified 2011 0/1 (IGA mod 2011 0 or 1) responses at week 12 versus placebo. Other endpoints included the Self-Injection Assessment Questionnaire (SIAQ), and the ability to follow the instructions for use (IFU). RESULTS: Overall, 214 patients were randomized. The secukinumab 300 mg/2 mL PFS showed superiority over placebo for both PASI 75 (88.9% versus 1.7%; p<.0001) and IGA mod 2011 0 or 1 (76.4% versus 1.4%; p<.0001) responses at week 12. All secondary efficacy endpoints were met. The SIAQ scores were similar across groups and improved similarly over 12 weeks. All patients completed critical steps in the IFU at week 1. CONCLUSIONS: The secukinumab 300 mg/2 mL PFS groups showed superiority versus placebo, and it was a safe, effective, and convenient option for patients with psoriasis. NCT02748863.

Investigation of the effect of the dual orexin receptor antagonist almorexant on ophthalmological, spermatogenic, and hormonal variables in healthy male subjects.

BACKGROUND/AIMS: The aim of this single-center, double-blind study was to investigate the effect of a 4-week once daily administration of 200 mg almorexant on tear film break-up time, spermatogenesis, hormone levels, and pancreatic elastase in stool in healthy male subjects. METHODS: Almorexant 200 mg or matching placebo was administered in the evening for 4 weeks once daily to 56 healthy male subjects. Changes in ophthalmological variables, sperm composition, hormone levels, and pancreatic elastase levels in stool were evaluated periodically up to 8 weeks after discontinuation of drug administration. Blood samples for pharmacokinetic measurements were taken after 4 weeks to confirm compliance to study drug intake. RESULTS: The results of this study revealed no treatment effects of almorexant, neither on tear film break-up time nor on other ophthalmological variables investigated during this study. Furthermore, spermatogenesis, hormones of the hypothalamic-pituitary-adrenal and -gonadal axes, and endocrine pancreatic secretion were shown to be not affected by a 4-week once daily administration of almorexant. CONCLUSION: Almorexant was well tolerated and had no effect on the spectrum of pharmacodynamic variables assessed. Ophthalmology and testicular findings detected in preclinical studies were not observed in this clinical study. Therefore, these preclinical findings appear not to be relevant for humans and do not prevent from conducting larger clinical trials with either healthy subjects or patients.

Secukinumab demonstrates high efficacy and a favorable safety profile over 52 weeks in Chinese patients with moderate to severe plaque psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease, affecting about 0.6% of the Chinese population. Many patients are not well controlled by conventional treatments, thus there is need for new treatment regimens. In this study, we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis. METHODS: This study was a 52-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 trial. A sub-population of study participants (≥18 years) of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab, or placebo. The co-primary endpoints were psoriasis area severity index (PASI) 75 and Investigator's Global Assessment (IGA) 0/1 at Week 12. RESULTS: A total of 441 Chinese patients were enrolled in this study. Co-primary outcomes were achieved; 300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75 (97.7% and 87.2% vs. 3.7%, respectively; P < 0.001), and IGA 0/1 (82.3% and 69.7% vs. 2.7%; P < 0.001) at Week 12. Treatment efficacy was maintained until Week 52. There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period. CONCLUSION: Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03066609; https://clinicaltrials.gov/ct2/show/record/NCT03066609.

Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different delivery systems in healthy volunteers and in psoriasis patients.

AIMS: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. METHODS: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration-time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1-mL prefilled syringe or 1 × 2-mL prefilled syringe. RESULTS: Mean serum concentration-time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1-year phase 3 study in patients confirmed PK results observed in the phase 1 study. CONCLUSION: Collective evidence from both studies demonstrated that 2-mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.

Dual Orexin Receptor Antagonist, Almorexant, in Elderly Patients With Primary Insomnia: A Randomized, Controlled Study.

Objective: Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with primary chronic insomnia. Methods: Patients aged ≥65 years with primary insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. Results: 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, -39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, -12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [-15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Conclusions: Two-night oral administration of almorexant was effective and well tolerated in treating primary insomnia in elderly patients.

Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection.

Cadazolid, a novel fluoroquinolone-oxazolidinone antibiotic, exhibits potent in vitro activity against Clostridium difficile, including the epidemic BI/NAP1/027 strain. This multicenter, randomized, double-blind, active reference group, phase 2 study evaluated the efficacy and safety of oral cadazolid in treatment of adult patients with C. difficile infection (CDI). Eligible patients with first occurrence/first recurrence of CDI were randomized 1:1:1:1 to 250, 500, or 1,000 mg cadazolid twice daily (BID) or oral 125 mg vancomycin four times daily (QID) for 10 days. The primary endpoint was clinical cure at test of cure (48 ± 24 h after the end of treatment; modified intent-to-treat population), defined as resolution of diarrhea with no further CDI treatment required. Secondary endpoints included recurrence rate, sustained clinical response (clinical cure without recurrence), and time to diarrhea resolution. Of 84 patients enrolled, 20, 22, 20, and 22 received 250, 500, or 1,000 mg cadazolid BID or 125 mg vancomycin QID, respectively. The primary endpoint was achieved in 76.5% (80% confidence interval [CI], 58.4, 89.3), 80.0% (63.9, 91.0), 68.4% (51.1, 82.5), and 68.2% (52.3, 81.3) of patients, respectively. There was no evidence of a cadazolid dosage-dependent response. Each dosage of cadazolid resulted in a lower recurrence rate than with vancomycin (18.2 to 25.0% versus 50%). Consequently, higher sustained clinical response rates were observed with cadazolid (46.7 to 60.0%) than with vancomycin (33.3%). The times to diarrhea resolution were similar for cadazolid and vancomycin. Cadazolid was well tolerated, with no safety signal observed. The results of this phase 2 study support further clinical development of cadazolid. (This study has been registered in the United States at ClinicalTrials.gov under registration no. NCT01222702 and in Europe with the European Medicines Agency under registration no. EUDRA-CT 2010-020941-29.).