The translational safety intelligence portal

The PMDA is currently reviewing the association between atezolizumab (PD-L1 inhibitor) and the risk of cholangitis sclerosing. Regulatory Agency Communication

The FDA has put AstraZeneca’s phase I study of its experimental blood cancer drug AZD5991 (Mcl-1 inhibitor) on hold due to a potential cardiovascular safety concern. The company has reported asymptomatic elevations in cardiovascular laboratory parameters in a patient with relapsed/refractory acute myeloid leukemia administered AZD5991 in combination with venetoclax. The cardiac issue has not been reported with AZD5991 monotherapy.

The EMA has updated the product information of Brilique (ticagrelor; P2Y12 receptor antagonist) to include a warning on central sleep apnea (including Cheyne-Stokes respiration). Regulatory Agency Communication

Study suggesting that administration of azathioprine (amidophosphoribosyltransferase/protein-arginine deiminase type-4 inhibitor; 1.5 mg/kg) to mice impairs pancreatic ductal chloride and bicarbonate secretion by disrupting CFTR plasma membrane tethering. These effects may result in an increased frequency of acute pancreatitis. Ehop-016 (RAC1 inhibitor) showed similar effects on pancreatic ductal secretion. Safety findings from in vitro and ex vivo assays are listed. Congress Alert

The special warnings and precautions for use section of the EMA EPAR for Ozawade indicates that it may cause suicidal ideation in patients with a psychiatric history; gastric disorders; QTc interval prolongation with supra-therapeutic doses; and epilepsy aggravation (reported in 1 epileptic patient). Convulsions were observed in animal models receiving high-dose pitolisant. Pitolisant showed no or very low signal for abuse liability at doses up to 216 mg. [Data from EMA European public assessment report for Ozawade (pitolisant; H3 receptor antagonist/inverse agonist)] Regulatory Agency Communication

Phase II study of AT-527 (HCV NS5B polymerase inhibitor; 550 or 1,100 mg PO bid) in patients with mild/moderate COVID-19. The most common adverse events were gastrointestinal disorders (7% patients with AT-527 550 mg; 17% with AT-527 1,100 mg; 8% with placebo). Mild-to-moderate nausea/vomiting led to drug discontinuation in 17% patients in the AT-527 1,100 mg group and 3% in the placebo group. [Data from an Atea Pharmaceuticals presentation summarizing results from the MOONSONG trial] Company Communication

Phase III trial comparing the fixed-dose combination sulbactam/durlobactam (SUL/DUR) to colistin in 207 patients with Acinetobacter baumannii infections. Nephrotoxicity was noted in 12/91 patients (13.2%) receiving SUL/DUR and in 32/85 (37.6%) on colistin. [Data from a Zai Lab and Entasis therapeutics communication announcing positive topline results from the ATTACK study] Company Communication

Clinical studies evaluating a booster dose of Ad26.COV2.S (Janssen COVID-19 vaccine). Systemic adverse events (AEs) included grade 3 fatigue, headache, myalgia, nausea and fever. Serious AEs considered related to vaccination included asthma, complex regional pain syndrome, post-vaccination syndrome and atrial fibrillation. Other AEs are listed. [Data from FDA Briefing Information (Ad26.COV2.S Vaccine) for the October 14-15, 2021 Meeting of the Vaccines and Related Biological Products Advisory Committee] Regulatory Agency Communication

The special warnings and precautions for use section of the EMA EPAR for Koselugo indicates that it may cause left ventricular ejection fraction reduction; ocular toxicity (including blurred vision, retinal pigment epithelial detachment, central serous chorioretinopathy and retinal vein occlusion); liver enzyme abnormalities (including AST and ALT elevations); and skin and subcutaneous disorders (including skin rash, maculopapular rash, acneiform rash, paronychia, hair changes, pustular rash, hair color changes and dry skin). [Data from EMA European public assessment report for Koselugo (selumetinib; MEK1/2 inhibitor)] Regulatory Agency Communication

The FDA has updated the product information of Agrylin (anagrelide hydrochloride; PDE3A inhibitor) to include cerebral infarction as an adverse reaction identified during postmarketing experience. Regulatory Agency Communication

The most common side effects of Rybrevant (amivantamab; EGFR/Met inhibitor) are rash, infusion-related reactions, nail toxicity, hypoalbuminemia, edema, fatigue, stomatitis, nausea and constipation. [Data from EMA summary of opinion for Rybrevant] Regulatory Agency Communication

The most common side effects of Cibinqo (abrocitinib; JAK1 inhibitor) are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, upper abdominal pain and serious infections. [Data from EMA summary of opinion for Cibinqo] Regulatory Agency Communication