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Objective: Using the modified Rodnan skin score (mRSS) as a surrogate for disease activity, a phase 2a study in patients with systemic sclerosis (SSc) measured efficacy of the autotaxin inhibitor ziritaxestat. Mathematical modeling of mRSS was used to predict disease progression, examine candidate trial designs, and predict the probability of successfully discriminating treatment effect. Methods: Patients with SSc receiving 600 mg of ziritaxestat or placebo for 24 weeks were included, in addition to data up to week 52 of the open‐label extension (OLE). Longitudinal mRSS data were described using a disease progression model; drug effect was a binary variable. Parameters used to predict the OLE mRSS outcome were estimated using data from the 24‐week double‐blind phase and validated with observed data. Three trial designs were simulated to identify which had the highest probability of detecting a treatment effect. Power to detect a treatment effect was quantified using the simulations. Results: Maximum decreases from baseline in mRSS were 50.4% (ziritaxestat) and 34.7% (placebo). Study designs based on 300 patients randomized 2:1 or 1:1 to 600 mg of ziritaxestat or placebo had similar probabilities of detecting a significant treatment effect. Power to detect a treatment effect was >80% for all simulations. Conclusion: Disease progression and drug effect could be predicted beyond the range of observed data. This modeling and simulation approach may inform future trial design, including study duration, and predict the probability of success. [ABSTRACT FROM AUTHOR]

Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion–positive non–small cell lung cancer (NSCLC). Pooled safety analysis of two studies included patients with NSCLC (N = 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events [TEAEs]) in the RP2D population; characterization of GI and skin-related events in 114 PPP from a phase 1/2 study (NCT02716116); and clinical activity in PPP with and without dose reductions due to TEAEs. In the RP2D population (N = 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N = 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n = 29) or without (n = 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively. GI and skin-related events are common with mobocertinib; minimizing dose reductions with proactive management may improve clinical outcomes. NCT02716116; NCT03807778 Mobocertinib is a treatment for patients with a certain type of lung cancer. We analyzed the safety of mobocertinib in 257 patients with lung cancer. The most common side effects with mobocertinib were diarrhea, nausea, vomiting, and skin rash. In 114 patients with lung cancer who were treated in the past with chemotherapy that included platinum-based drugs, diarrhea started after about 5 days of mobocertinib treatment and went away in about 2 days. Skin-related side effects started after about 9 days and went away in about 2.5 months. One-fifth of patients who had to receive a smaller amount of mobocertinib because of side effects responded to treatment compared with one-third of patients who received the recommended mobocertinib amount. Managing side effects quickly can better help patients with lung cancer who are treated with mobocertinib. [ABSTRACT FROM AUTHOR]

The BCR‐ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model‐based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration–time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed‐effects modeling. Ponatinib pharmacokinetics were described by a 2‐compartment model with first‐order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19‐85 years), race, body weight (40.7‐152.0 kg), total bilirubin (0.1‐3.16 mg/dL), alanine aminotransferase (6‐188 U/L), albumin (23.0‐52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady‐state average concentrations that are in the pharmacological range for BCR‐ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805 [ABSTRACT FROM AUTHOR]

Risankizumab, an anti‐interleukin‐23 monoclonal antibody, achieved significantly (P < 0.001) greater Psoriasis Area and Severity Index (PASI) and static Physician Global Assessment (sPGA) clear or almost clear (0/1) responses than adalimumab in a phase III trial in patients with moderate‐to‐severe psoriasis. Meta‐analyses of the PASI 50, PASI 75, PASI 90, PASI 100, and sPGA0/1 responses after 16 weeks of treatment from eight (three for risankizumab and five for adalimumab) randomized, placebo‐controlled trials were conducted to estimate the efficacy difference between risankizumab and adalimumab. For PASI 75, PASI 90, PASI 100, and sPGA0/1 responses, the estimated effect differences (95% confidence interval) between risankizumab and adalimumab were 15.2% (10.1%, 20.4%), 23.7% (15.7%, 31.2%), 20.8% (13.0%, 28.7%), and 20.1% (13.7%, 26.1%), respectively. These results were consistent with the observed efficacy difference from the head‐to‐head phase III trial, which was not included in the meta‐analyses, providing independent, confirmatory evidence of the superior efficacy of risankizumab compared with adalimumab for treatment of moderate‐to‐severe psoriasis. [ABSTRACT FROM AUTHOR]

Model‐informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)‐based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib‐based combinations, phase III dose for maintenance treatment), regulatory review (model‐informed QT analysis, benefit–risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient‐centric therapeutic optimization during the development of ixazomib. [ABSTRACT FROM AUTHOR]