These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.

Administration of JNJ-41443532 resulted in modest improvement in glycaemic parameters compared with placebo, and was generally well tolerated in patients with T2DM.

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Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves indices of β-cell function estimated based on circulating C-peptide and glucose concentrations (e.g., Homeostasis Model Assessment [HOMA2-%B], meal tolerance test-based indices). However, use of these β-cell function indices assumes C-peptide kinetics are not altered by canagliflozin. This 2-period crossover study assessed the effect of a single canagliflozin 300-mg dose on C-peptide kinetics in 10 healthy participants. Two hours after receiving canagliflozin or placebo, participants received intravenous somatostatin infusion to suppress endogenous C-peptide secretion and 1 hour later received a bolus injection of synthetic human C-peptide 150 µg. Serum C-peptide was measured over 3 hours and urinary glucose and C-peptide excretion were measured. C-peptide kinetic parameters, including total clearance (CLtotal ) and renal clearance (CLrenal ), were calculated. Serum C-peptide profiles were similar following canagliflozin or placebo treatment. C-peptide CLtotal was slightly lower with canagliflozin versus placebo (mean (SD) of 190 (37) vs. 197 (30) mL/min; canagliflozin/placebo ratio [90% CI] = 96.1% [93.0%; 99.3%]). Other kinetic parameters, including CLrenal , were generally similar between treatments. Results indicate canagliflozin 300 mg does not meaningfully alter C-peptide clearance or other kinetic parameters; therefore, C-peptide-based measurements of insulin secretion are appropriate for assessing β-cell function in canagliflozin-treated participants.

treatment for locally advanced or metastatic disease, history of leptomeningeal disease, interstitial lung disease, and prior treatment with an EGFR TKI. Approximately 1000 patients will be randomly assigned 2:2:1 to receive amivantamab + lazertinib (nw400), osimertinib (nw400), or lazertinib (nw200). Randomization will be stratified by mutation type (Exon19del vs L858R), race (Asian vs non-Asian), and history of brain metastases (present vs absent). Patients in the combination arm will receive open-label treatment with amivantamab (1050 mg [1400 mg, patients 80 kg] intravenously once weekly for the first 4 weeks, every 2 weeks thereafter) + lazertinib (240 mg oral daily). Patients in the single-agent osimertinib and lazertinib arms will receive double-blind treatment (80 mg or 240 mg oral daily, respectively). The primary endpoint of the study is progression-free survival (PFS) based on blinded independent central review according to RECIST v1.1. To assess the contribution of amivantamab to the efficacy of the combination, comparison of the combination and monotherapy lazertinib arms will also be performed. Secondary endpoints include overall survival, objective response rate, duration of response, PFS after first subsequent therapy, time to symptomatic progression, and intracranial PFS. Safety assessments will include monitoring adverse events and laboratory abnormalities.