Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics.

Ritlecitinib is a selective, covalent, irreversible inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases. Pharmacokinetics and safety of ritlecitinib in participants with hepatic (Study 1) or renal (Study 2) impairment were to be characterized from two phase I studies. Due to a study pause caused by the COVID-19 pandemic, the study 2 healthy participant (HP) cohort was not recruited; however, the demography of the severe renal impairment cohort closely matched the study 1 HP cohort. We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and an in silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairment vs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating the latter approach. When applied to study 2, both the statistical and POPPK simulation approaches demonstrated that patients with renal impairment would not require ritlecitinib dose modification. In both phase I studies, ritlecitinib was generally safe and well tolerated. These analyses represent a new methodology for generating reference HP cohorts in special population studies for drugs in development with well-characterized pharmacokinetics in HPs and adequate POPPK models. TRIAL REGISTRATION: ClinicalTrials.gov NCT04037865 , NCT04016077 , NCT02309827 , NCT02684760 , and NCT02969044 .

Comparing abrocitinib and dupilumab in the treatment of atopic dermatitis: a plain language summary.

Atopic dermatitis (AD, also called atopic eczema) is a long-term skin disease that causes intensely itchy, red skin. Healthcare providers can prescribe medicated creams and ointments to reduce the signs and symptoms of AD. However, these treatments are not always enough to provide relief. A new medicine called abrocitinib, which is taken every day as a tablet, reduces part of the body's immune response that happens in AD. The clinical study described in this plain language summary, called JADE COMPARE, investigated how well and how safely 16 weeks of treatment with abrocitinib worked in adults with AD compared to placebo ('dummy treatment') and a medicine that is already approved for AD, called dupilumab. The study showed that abrocitinib was better than placebo in improving the signs and symptoms of AD after 16 weeks. In addition, patients who were taking abrocitinib 200 mg for 2 weeks experienced greater relief from itch than patients who were taking abrocitinib 100 mg, placebo, or dupilumab. More people who took abrocitinib 200 mg reported side effects than those taking abrocitinib 100 mg, placebo, or dupilumab, but most of these side effects were mild or moderate. ClinicalTrials.gov NCT number: NCT03720470.

Pregabalin as adjunctive therapy in adult and pediatric patients with generalized tonic-clonic seizures: A randomized, placebo-controlled trial.

OBJECTIVE: Generalized tonic-clonic (GTC) seizures are the most common type of generalized seizure and more common in children than adults. This phase 3 study evaluated the efficacy and safety of pregabalin for GTC seizures in adults and children with epilepsy. METHODS: This randomized, double-blind, multicenter study evaluated pregabalin (5 mg/kg/day or 10 mg/kg/day) vs placebo as adjunctive therapy for 10 weeks (following a 2-week dose escalation), in pediatric and adult patients (aged 5-65 years) with GTC seizures. Primary endpoint was change in log-transformed 28-day seizure rate during active treatment. Secondary endpoints included responder rates, defined as proportion of patients with ≥50% reduction in 28-day GTC seizure rate from baseline. Safety was monitored throughout. RESULTS: Of 219 patients, 75, 72, and 72 were randomized to adjunctive pregabalin 5 mg/kg/day, 10 mg/kg/day, and placebo, respectively. Fifteen, 11, and 6 patients discontinued from the 5 mg/kg/day, 10 mg/kg/day, and placebo arms, respectively, most commonly due to adverse events (AEs; 10.7%, 6.9%, and 5.6%, respectively). A nonsignificant change in log-transformed mean 28-day seizure rate was seen with pregabalin 10 mg/kg/day vs placebo (least-squares [LS] mean difference -0.01 [95% confidence interval (CI) -0.19 to 0.16]; P = .8889) and with pregabalin 5 mg/kg/day vs placebo (LS mean difference 0.02 [CI -0.15 to 0.19]; P = .8121). Similar observations were noted for adults and children. No significant differences were seen for secondary endpoints with pregabalin vs placebo, including responder rate. The most common AEs (≥10%) were dizziness, headache, and somnolence. Most were of mild/moderate intensity. Seven patients had serious AEs, with one death in the placebo arm (sudden unexpected death in epilepsy). SIGNIFICANCE: Adjunctive pregabalin treatment did not change GTC seizure rate in adults or children. The safety profile of pregabalin was similar to that known; treatment was well tolerated with few discontinuations due to AEs.

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis.

BACKGROUND: The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited. METHODS: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16. RESULTS: A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively. CONCLUSIONS: In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).

Pregabalin adjunctive therapy for focal onset seizures in children 1 month to <4 years of age: A double-blind, placebo-controlled, video-electroencephalographic trial.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin as adjunctive treatment for children (aged 1 month-<4 years) with focal onset seizures (FOS) using video-electroencephalography (V-EEG). METHODS: This randomized, placebo-controlled, international study included V-EEG seizure monitoring (48-72 hours) at baseline and over the last 3 days of 14-day (5-day dose escalation; 9-day fixed dose) double-blind pregabalin treatment (7 or 14 mg/kg/d in three divided doses). This was followed by a double-blind 1-week taper. The primary efficacy endpoint was log-transformed seizure rate (loge [24-hour seizure rate + 1]) for all FOS recorded during the double-blind V-EEG monitoring, evaluated in subjects who took ≥1 dose of study medication, experienced ≥1 baseline seizure(s), and had a treatment phase V-EEG. Safety and tolerability were assessed by adverse events (AEs), clinical laboratory data, physical/neurological examinations, vital signs, and electrocardiograms. RESULTS: Overall, 175 patients were randomized (mean age = 28.2 months; 59% male, 69% white, 30% Asian) in a 2:1:2 ratio to pregabalin 7 or 14 mg/kg/d (n = 71 or n = 34, respectively), or placebo (n = 70). Pregabalin 14 mg/kg/d (n = 28) resulted in a statistically significant 35% reduction of loge (24-hour seizure rate + 1) versus placebo (n = 53; P = .022), an effect that was not observed with pregabalin 7 mg/kg/d (n = 59; P = .461). The most frequently reported treatment-emergent AEs for pregabalin 7 mg/kg/d, 14 mg/kg/d, and placebo, respectively, were somnolence (11.3%, 17.6%, and 5.7%) and upper respiratory tract infection (7.0%, 11.8%, and 11.4%). All AEs were mild to moderate in severity. SIGNIFICANCE: Pregabalin 14 mg/kg/d (but not 7 mg/kg/d) significantly reduced seizure rate in children with FOS, when assessed using V-EEG, compared with placebo. Both pregabalin dosages were generally safe and well tolerated in children 1 month to <4 years of age with FOS. Safety and tolerability were consistent with the known profile of pregabalin in older children with epilepsy.

Pregabalin as Adjunctive Treatment for Focal Onset Seizures in Pediatric Patients: A Randomized Controlled Trial.

Efficacy and safety of pregabalin as adjunctive treatment for children (aged 4-16 years) with partial-onset seizures, hereafter termed focal onset seizures for this study, was evaluated. This double-blind, randomized, placebo-controlled, international study had 3 phases: 8-week baseline, 12-week double-blind treatment (2-week dose escalation; 10-week fixed dose), and 1-week taper. Selection criteria included experiencing focal onset seizures and receiving a stable regimen of 1 to 3 antiepileptic drugs. Study treatments were pregabalin 2.5 mg/kg/d, 10 mg/kg/d, or placebo; doses were increased to 3.5 or 14 mg/kg/d for subjects weighing <30 kg. The key endpoints were change in loge(28-day seizure rate), achieving a ≥50% seizure responder rate, safety, and tolerability during double-blind treatment. Subjects (n = 295; mean age 10.2 years, 55% male, 69% white) were randomized to pregabalin 2.5 mg/kg/d (n = 104), 10 mg/kg/d (n = 97), or placebo (n = 94). A statistically significant reduction in loge(28-day seizure rate) was demonstrated with pregabalin 10 mg/kg/d (a 19.9% improvement over placebo; P = .0185). Seizure frequency was numerically improved (statistically nonsignificant) with pregabalin 2.5 mg/kg/d ( P = .2577). Responder rate significantly favored pregabalin 10 mg/kg/d (40.6%, P = .0068) compared with placebo (22.6%) and was numerically improved with pregabalin 2.5 mg/kg/d (29.1%, P = .2600). Common adverse events (≥10% of any group) in 10 mg/kg/d, 2.5 mg/kg/d, and placebo groups, respectively, included somnolence (25.8%, 17.3%, 13.8%), increased weight (13.4%, 3.8%, 4.3%), and increased appetite (10.3%, 6.7%, 4.3%). Pregabalin 10 mg/kg/d demonstrated efficacy in seizure frequency reduction in children with focal onset seizures compared with placebo, and both pregabalin doses were generally safe and well tolerated. www.clinicialtrials.gov identifier NCT01389596; EudraCT #2010-020852-79.