Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).

A strategy for risk management of drug-induced phospholipidosis.

Drug-induced phospholipidosis (PL) is an excessive accumulation of phospholipids and drug in lysosomes. Phospholipidosis signals a change in cell membrane integrity and accumulation of intracellular drug or metabolite in tissues. The sensitivity and susceptibility of preclinical models to detect PL vary with therapeutic agents, and PL is expected to be reversible after discontinuation of drug treatment. The prevailing scientific opinion is that PL by itself is not adverse; however, some regulatory authorities consider PL to be adverse because a small number of chemicals are able to cause PL and concurrent organ toxicity. Until a greater understanding of PL emerges, a well-thought-out risk management strategy for PL will increase confidence in safety and improve selection and development of new drugs. This paper provides a tiered approach to risk management of drug-induced PL. It begins with use of in silico and in vitro tools to design and select compounds with reduced potential to produce PL. Early in vivo studies in two species are used to better characterize potential for toxicity and PL. Finally, routine risk management tools (i.e., translational biomarkers, assessment of reversibility) are used to support confidence in safety of compounds that induce PL in animals.

Assessments of suicidality in double-blind, placebo-controlled trials of ziprasidone.

OBJECTIVE: A pooled analysis was conducted to identify possibly suicide-related adverse events in Pfizer-sponsored, phases 2-4, placebo-controlled, double-blind, adult and pediatric completed randomized controlled trials of ziprasidone and to evaluate the risk of suicidality with ziprasidone versus placebo. METHOD: The trials included were initiated as early as June 1992, and the cutoff date for selection of the placebo-controlled trials in the Pfizer database was October 2, 2009. The US Food and Drug Administration (FDA)-defined search methodology was used to identify possibly suicide-related adverse events, and the Columbia Classification Algorithm of Suicide Assessment (primary outcome measure) was used to categorize them. The incidences of possibly suicide-related adverse events were calculated for individual classifications and for the predefined combined categories of suicidality (comprising classification codes 1-4) and suicidal behavior (comprising classification codes 1-3), along with the ziprasidone versus placebo relative risks and corresponding 95% CIs. Exact binomial 95% CIs were calculated for the individual treatment group incidences. RESULTS: Suicidality events were identified in 52 among 5,123 subjects treated with either ziprasidone or placebo in 22 trials. No cases of completed suicide occurred in this analysis. There were no statistically significant differences between ziprasidone and placebo in any of the individual classification categories, combined suicidal behavior category (ziprasidone vs placebo relative risk = 0.67; 95% CI, 0.206-2.201), or combined suicidality risk category (ziprasidone vs placebo relative risk = 0.90; 95% CI, 0.514-1.563). CONCLUSIONS: Results of our analyses, performed in accordance with the FDA-specified search strategy, reveal no significant differences in treatment-emergent suicidality risk in ziprasidone versus placebo subjects treated in controlled clinical trials.