RESUMEN
BACKGROUND AND HYPOTHESIS: Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. METHODS: In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n = 56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n = 77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. RESULTS: Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p < 0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and + 4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. CONCLUSION: Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855.
RESUMEN
Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib's safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies).Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose.Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable.Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database.Trial registration: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at https://clinicaltrials.gov/.
