100-mg Arm Research Articles

Integrated Safety Analysis of Abrocitinib in 635 Adolescent Patients With Moderate-To-Severe Atopic Dermatitis With Over 1000 Patient-Years of Exposure

Introduction: Abrocitinib, an oral, once-daily, Janus kinase 1–selective inhibitor, was efficacious and well tolerated in adolescent patients with moderate-to-severe atopic dermatitis (AD) exposed for approximately 1 year of treatment. Here, we describe the updated long-term integrated safety profile of abrocitinib in adolescent patients in the JADE clinical program.Methods: A total of 635 adolescent patients (12 to <18 years; exposure: 1011.4 patient-years [PY]) were pooled for safety analysis from the phase 3 JADE clinical trials MONO-1 (NCT03349060), MONO-2 (NCT03575871), TEEN (NCT03796676), and REGIMEN (NCT03627767) and subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND (NCT03422822; data cutoff: September 25, 2021). Incidence rates (IRs; number of unique patients with events/100 PY) of severe adverse events (SAEs) and AEs of special interest were assessed.Results: Of the total 635 adolescents, 490 received the same abrocitinib dose throughout exposure (730.6 PY); 289 received abrocitinib 200 mg (424.5 PY) and 201 received abrocitinib 100 mg (306.1 PY). Duration of exposure was ≥96 weeks in 38% and 37%, and ≥144 weeks in 8% and 4% of patients who received abrocitinib 200 mg or 100 mg, respectively. In the 200-mg and 100-mg arms, AEs occurred in 243 (84%) and 153 (76%) patients; 8% (IR [95% CI], 5.87 [3.76-8.74]) and 9% (5.87 [3.48-9.27]) experienced SAEs, and 10% (6.96 [4.69-9.93]) and 8% (5.13 [2.93-8.33]) discontinued the study due to AEs, respectively. IRs of AEs of special interest were 1.84 (95% CI, 0.79-3.62) and 1.28 (0.35-3.27) for serious infection, 2.11 (0.97-4.01) and 1.62 (0.53-3.77) for all herpes zoster (HZ) infections, and 0.69 (0.14-2.03) and 0.32 (0.01-1.77) for opportunistic HZ infections in the 200-mg and 100-mg arms, respectively. One patient (aged 16 years) in the 200-mg arm had a nonfatal venous thromboembolism event (pulmonary embolism; IR, 0.23 [95% CI, 0.01-1.28]); patient had a family history of pulmonary embolism. There were no events of nonmelanoma skin cancer or other malignancies, tuberculosis, or other opportunistic infections (excluding HZ), major adverse cardiovascular events, or deaths.Conclusions: In this integrated safety analysis using the September 2021 data cut from the ongoing JADE EXTEND trial, abrocitinib had an acceptable long-term safety profile in adolescents with moderate-to-severe AD.

383 Integrated safety analysis of abrocitinib in 635 adolescent patients with moderate-to-severe atopic dermatitis with over 1000 patient-years of exposure

Abstract Abrocitinib is an oral, once-daily, Janus kinase 1–selective inhibitor approved for the treatment of moderate-to-severe atopic dermatitis (AD). Recently, the US Food and Drug Administration expanded the indication of abrocitinib in adolescent patients with moderate-to-severe AD aged 12 to <18 years. Abrocitinib was efficacious and well tolerated in adolescent patients exposed for approximately 1 year of treatment in the JADE clinical program. This study aims to describe the updated long-term integrated safety profile of abrocitinib in adolescent patients treated in the JADE clinical program. This interim integrated safety analysis assessed data from patients aged 12 to <18 years who participated in the phase 3 JADE clinical trials MONO-1 (NCT03349060), MONO-2 (NCT03575871), TEEN (NCT03796676) and REGIMEN (NCT03627767) and subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND (NCT03422822; data cutoff: September 25, 2021). Data were pooled in two cohorts. The consistent-dose cohort comprised patients who received the same abrocitinib dose (200 or 100 mg) during the entire exposure time in the qualifying JADE trials, MONO-1, MONO-2 and TEEN and/or in JADE EXTEND. This cohort also included patients who did not meet the inclusion criteria for the maintenance period of JADE REGIMEN after abrocitinib 200 mg induction in the open-label period and subsequently received abrocitinib 200 mg in JADE EXTEND. The variable-dose cohort included patients who were randomly assigned to the maintenance period of JADE REGIMEN after induction and, hence, received different abrocitinib doses throughout exposure time in JADE REGIMEN, and subsequently entered in JADE EXTEND. Incidence rates (IRs) along with 95% CIs are presented as numbers of patients with events per 100 patient-years (PY). The analysis included 635 adolescent patients (exposure: 1011.4 PY). The consistent-dose cohort comprised 490 adolescents (730.6 PY): 289 received abrocitinib 200 mg (424.5 PY) and 201 received abrocitinib 100 mg (306.1 PY). Duration of exposure was ≥96 weeks in 38% and 37%, and ≥144 weeks in 8% and 4% of patients who received abrocitinib 200 or 100 mg, respectively. In the 200- and 100-mg arms, adverse events (AEs) occurred in 243 (84%) and 153 (76%) patients; 8% (IR [95% CI], 5.87 [3.76–8.74]) and 9% (5.87 [3.48–9.27]) experienced severe AEs and 10% (6.96 [4.69–9.93]) and 8% (5.13 [2.93–8.33]) discontinued the study due to AEs, respectively. The IRs of AEs of special interest were 1.84 (95% CI, 0.79–3.62) and 1.28 (0.35–3.27) for serious infection, 2.11 (0.97–4.01) and 1.62 (0.53–3.77) for all herpes zoster infections, and 0.69 (0.14–2.03) and 0.32 (0.01–1.77) for opportunistic herpes zoster infections in the 200- and 100-mg arms, respectively. One patient (aged 16 years) in the 200-mg arm had a nonfatal venous thromboembolism (VTE) event (pulmonary embolism; IR, 0.23 [95% CI, 0.01–1.28]); patient had a family history of pulmonary embolism. The variable-dose cohort comprised 145 adolescents (exposure: 280.8 PY). Adverse events occurred in 139 patients (96%) exposed to either abrocitinib dose; 10% (IR [95% CI], 5.15 [2.81–8.64]) had severe AEs and 11% (5.66 [3.23–9.19]) discontinued the study due to AEs. The IRs of AEs of special interest were 1.05 (95% CI, 0.22–3.07) for serious infection, 2.17 (0.80–4.72) for all herpes zoster infections and 0.35 (0.01–1.96) for opportunistic herpes zoster infections; no patients had VTE in the variable-dose cohort. In both the consistent-dose and variable-dose cohorts, there were no events of nonmelanoma skin cancer or other malignancies, tuberculosis or other opportunistic infections (excluding herpes zoster), major adverse cardiovascular events or deaths. In this integrated safety analysis using the most recent data cut from the ongoing JADE EXTEND trial, abrocitinib had an acceptable long-term safety profile in adolescents with moderate-to-severe AD.

543. An Integrated Safety Analysis Comparing Once-Daily Doravirine (DOR) to Darunavir+Ritonavir (DRV+r) and Efavirenz (EFV) in HIV-1-Infected, Antiretroviral Therapy (ART)-Naïve Adults

543. An Integrated Safety Analysis Comparing Once-Daily Doravirine (DOR) to Darunavir+Ritonavir (DRV+r) and Efavirenz (EFV) in HIV-1-Infected, Antiretroviral Therapy (ART)-Naïve Adults

Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study.

IntroductionHypogonadism is one of the most common male endocrine problems. Although many treatments are currently available, unmet need exists for new testosterone (T) replacement therapies that are simple to administer and use, are safe, and mimic physiologic T levels.AimThe study aim was to determine the pharmacokinetics (PK), safety, and tolerability of T enanthate (TE) administered via a novel single‐use autoinjector system, which was designed to eject high‐viscosity solutions from a prefilled syringe fitted with a five‐eighths‐inch 27‐gauge needle.MethodsThirty‐nine men with hypogonadism entered this dose‐finding, open‐label, parallel‐group study. Patients were washed out of their topical T regimens and randomized to receive 50 or 100 mg of subcutaneous (SC) TE weekly. The reference group were patients with hypogonadism who were maintained on standard 200‐mg intramuscular (IM) TE.Main Outcome MeasureThe primary outcome measure was the PK profile of SC TE, analyzed in reference to T levels used by the Food and Drug Administration to approve T products. Secondary outcome measures were safety and tolerability assessments.ResultsBoth doses of SC TE achieved normal average concentrations of serum T within a 168‐h dosing interval after injection. Concentration ranges were similar at all time points following 50‐mg SC TE injections and following the third injection in the 100‐mg arm. Mean steady‐state T concentration at week 6 was 422.4 and 895.5 ng/dL for the 50‐ and 100‐mg SC TE arms, respectively. SC TE demonstrated PK dose proportionality. SC TE restored normal serum T with low variation relative to 200‐mg IM without clinically significant adverse events.ConclusionsAdministration of TE via this novel injection system restored T levels to normal range in men with hypogonadism. SC TE dosed weekly demonstrated steady, dose‐proportional measures of exposure and was well‐tolerated. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single‐use autoinjector: A phase II study. Sex Med 2015;3:263–273.

Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.

Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms). These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).

Tolerability of desvenlafaxine 100 mg in women with vasomotor symptoms (VMS) associated with menopause: a pooled analysis of 5 trials

ObjectiveTo assess safety and tolerability of desvenlafaxine 100 mg/d (administered as desvenlafaxine succinate) in women with menopausal VMS.DesignA pooled analysis of all double-blind, randomized, placebo-controlled Phase III clinical desvenlafaxine trials for VMS.Materials and MethodsPostmenopausal women with ≥50 moderate to severe hot flushes/wk (4 studies) or bothersome hot flushes (Greene Climactic Scale total score ≥12 and question 19 score >2,1 study) at baseline received desvenlafaxine or placebo in 5 trials. All studies included a desvenlafaxine 100-mg arm; 2 used dose titration. Pooled data from desvenlafaxine 100 mg/d or placebo groups were analyzed Study durations were 12 (2 studies), 26 (1 study), or 52 (2 studies) weeks.Adverse events (AEs), laboratory evaluations, and vital signs were assessed.ResultsThe safety population included 3323 women (desvenlafaxine, 1711; placebo, 1612).The most common treatment-emergent AEs (TEAEs; >5% and 2x placebo) for desvenlafaxine were nausea, dizziness, constipation, dry mouth, fatigue, and somnolence. During week 1, overall TEAE rates were lower in studies with titration (desvenlafaxine, 42%; placebo, 20%) vs no titration (desvenlafaxine, 80%; placebo, 58%). In all, 589/1711 (34%) desvenlafaxine-treated women discontinued early, 324/1711 (19%) due to AE; rates were 440/1612 (27%) and 155/1612 (10%), respectively, for placebo. Small but statistically significant changes compared with placebo were observed at final on-therapy evaluation for systolic (+3.24 vs +0.92 mm Hg) and diastolic blood pressure (+2.37 vs +1.01 mm Hg) and heart rate (+1.81 vs –0.15 bpm). Laboratory values of potential clinical importance were observed in 42% of the desvenlafaxine group (placebo, 35%).ConclusionDesvenlafaxine 100 mg/d was generally safe and well-tolerated in postmenopausal women with VMS, with an AE profile consistent with other serotonin-norepinephrine reuptake inhibitors. ObjectiveTo assess safety and tolerability of desvenlafaxine 100 mg/d (administered as desvenlafaxine succinate) in women with menopausal VMS. To assess safety and tolerability of desvenlafaxine 100 mg/d (administered as desvenlafaxine succinate) in women with menopausal VMS. DesignA pooled analysis of all double-blind, randomized, placebo-controlled Phase III clinical desvenlafaxine trials for VMS. A pooled analysis of all double-blind, randomized, placebo-controlled Phase III clinical desvenlafaxine trials for VMS. Materials and MethodsPostmenopausal women with ≥50 moderate to severe hot flushes/wk (4 studies) or bothersome hot flushes (Greene Climactic Scale total score ≥12 and question 19 score >2,1 study) at baseline received desvenlafaxine or placebo in 5 trials. All studies included a desvenlafaxine 100-mg arm; 2 used dose titration. Pooled data from desvenlafaxine 100 mg/d or placebo groups were analyzed Study durations were 12 (2 studies), 26 (1 study), or 52 (2 studies) weeks.Adverse events (AEs), laboratory evaluations, and vital signs were assessed. Postmenopausal women with ≥50 moderate to severe hot flushes/wk (4 studies) or bothersome hot flushes (Greene Climactic Scale total score ≥12 and question 19 score >2,1 study) at baseline received desvenlafaxine or placebo in 5 trials. All studies included a desvenlafaxine 100-mg arm; 2 used dose titration. Pooled data from desvenlafaxine 100 mg/d or placebo groups were analyzed Study durations were 12 (2 studies), 26 (1 study), or 52 (2 studies) weeks.Adverse events (AEs), laboratory evaluations, and vital signs were assessed. ResultsThe safety population included 3323 women (desvenlafaxine, 1711; placebo, 1612).The most common treatment-emergent AEs (TEAEs; >5% and 2x placebo) for desvenlafaxine were nausea, dizziness, constipation, dry mouth, fatigue, and somnolence. During week 1, overall TEAE rates were lower in studies with titration (desvenlafaxine, 42%; placebo, 20%) vs no titration (desvenlafaxine, 80%; placebo, 58%). In all, 589/1711 (34%) desvenlafaxine-treated women discontinued early, 324/1711 (19%) due to AE; rates were 440/1612 (27%) and 155/1612 (10%), respectively, for placebo. Small but statistically significant changes compared with placebo were observed at final on-therapy evaluation for systolic (+3.24 vs +0.92 mm Hg) and diastolic blood pressure (+2.37 vs +1.01 mm Hg) and heart rate (+1.81 vs –0.15 bpm). Laboratory values of potential clinical importance were observed in 42% of the desvenlafaxine group (placebo, 35%). The safety population included 3323 women (desvenlafaxine, 1711; placebo, 1612).The most common treatment-emergent AEs (TEAEs; >5% and 2x placebo) for desvenlafaxine were nausea, dizziness, constipation, dry mouth, fatigue, and somnolence. During week 1, overall TEAE rates were lower in studies with titration (desvenlafaxine, 42%; placebo, 20%) vs no titration (desvenlafaxine, 80%; placebo, 58%). In all, 589/1711 (34%) desvenlafaxine-treated women discontinued early, 324/1711 (19%) due to AE; rates were 440/1612 (27%) and 155/1612 (10%), respectively, for placebo. Small but statistically significant changes compared with placebo were observed at final on-therapy evaluation for systolic (+3.24 vs +0.92 mm Hg) and diastolic blood pressure (+2.37 vs +1.01 mm Hg) and heart rate (+1.81 vs –0.15 bpm). Laboratory values of potential clinical importance were observed in 42% of the desvenlafaxine group (placebo, 35%). ConclusionDesvenlafaxine 100 mg/d was generally safe and well-tolerated in postmenopausal women with VMS, with an AE profile consistent with other serotonin-norepinephrine reuptake inhibitors. Desvenlafaxine 100 mg/d was generally safe and well-tolerated in postmenopausal women with VMS, with an AE profile consistent with other serotonin-norepinephrine reuptake inhibitors.

Monthly Oral Ibandronate Is Well Tolerated and Efficacious in Postmenopausal Women: Results from the Monthly Oral Pilot Study

Ibandronate, a potent, nitrogen-containing bisphosphonate developed for intermittent administration in postmenopausal osteoporosis, aims to overcome current adherence issues with daily and weekly oral bisphosphonates through once-monthly oral dosing. The purpose of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of once-monthly oral ibandronate. A randomized, 3-month, double-blind, placebo-controlled, phase I study (Monthly Oral Pilot Study) was conducted. The study was conducted at five clinical trial centers in the United Kingdom and Belgium. Subjects were postmenopausal women (age, 55-80 yr; > or =3 yr post menopause; n = 144). Once-monthly oral ibandronate 50, 100, or 150 mg or placebo was used. After the first cycle, the 50-mg arm was split, with participants continuing on either 50 or 100 mg. Primary outcome measures were safety, serum and urinary C-telopeptide (CTX), and serum ibandronate AUC0-infinity. Once-monthly oral ibandronate was well tolerated, with a similar overall and upper gastrointestinal safety profile to placebo. Once-monthly ibandronate was also highly effective in decreasing bone turnover; substantial reductions from baseline in serum CTX (-56.7% and -40.7% in the 150- and 100-mg arms, respectively; P < 0.001 vs. placebo) and urinary CTX (-54.1% and -34.6%, respectively; P < 0.001 vs. placebo) were observed at d 91 (30 d after the final dose). Analysis of the area under the effect curve (d 1-91) for change from baseline (percent x days) in serum CTX and urinary CTX indicated a dose-response relationship. The AUC0-infinity for ibandronate increased with dose but not in a dose-proportional manner. These findings indicate a potential role for once-monthly oral ibandronate in the treatment of postmenopausal osteoporosis.