Data from the French Daily-Luma cohort suggest predictors of a lumasiran response

Introduction Primary Hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disorder with genotype/phenotype correlation. The RNA interfering therapy lumasiran has revolutionized its prognosis but with heterogeneous response amongst patients. Here, we assessed a possible association between genotype and lumasiran response. Methods In the ongoing French DAILY-LUMA cohort evaluating real-life efficacy and safety of lumasiran, we collected data at treatment initiation and at months three, six and 12 of treatment. The main outcomes were composite criteria, namely normalization and/or reduction over 30% from baseline in the urinary ratio of oxalate and creatinine (UOx/Creat) or in blood oxalate levels (POx) in patients with estimated glomerular filtration rate (eGFR) over or under 30 mL/min/1.73 m 2 , respectively. The primary endpoint was the proportion of patients reaching this criterion at three months, and secondary endpoints were the same analysis at six and 12 months. Genotype was classified into three groups depending on the vitamin B6 response: resistance, sensitivity, uncertain response (Ile244Thr variant of alanine-glyoxylate aminotransferase). Results In total, 76 patients (54 children) were included, at a median (inter quartile range) age at lumasiran initiation of 13 (4-33) years with 24 patients on dialysis. After three months treatment, 73 % of patients met the primary endpoint (% calculated on available data). There was no significant association between the underlying genotype and lumasiran response, albeit with a trend towards a lesser response in vitamin B6- sensitive forms. The only significant determinants found to be associated with the primary outcome were age at diagnosis and age at lumasiran initiation, the best response being observed in pediatric patients. Conclusion Our study suggests a better response to lumasiran in children independent of the underlying genotype. In patients with pyridoxine sensitivity, we suggest continuing or initiating pyridoxine even after lumasiran initiation. After lumasiran initiation, a close follow-up and re-evaluation should be systematically performed.