FC010: Multicentric Experience with RNA Interference Medication (OXLUMO®) in Patients with Primary Hyperoxaluria Type 1

Abstract

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of the glyoxylate metabolism in the liver inducing severe endogenous oxalate overproduction. Massive hyperoxaluria leads to recurrent urolithiasis and/or nephrocalcinosis and often early end-stage kidney failure. Current treatment options were scarce until the first RNA interference drug, Oxlumo® (Lumasiran, Alnylam Pharmaceuticals, USA) can now be prescribed. Oxlumo® targets the mRNA of glycolate oxidase and, thus, prevents its translation. This reduces production of glyoxylate (i.e. the precursor to oxalate) and thus oxalate production. However, glycolate production increases. METHOD We herein report our current clinical experience with s.c. administration of Oxlumo adhering to provide dosage recommendation. A total of 25 PH1 patients were included. Seven patients were on haemodialysis, 1 patient on peritoneal dialysis and 17 were on stable kidney function at start of Oxlumo medication (eGFR > 30 and <55 mL/min in 2 patients and >70 mL/min in all others). The male: female ratio was 15:10, and the age range was 1–62 years of age at start of treatment. In both groups plasma oxalate (Pox) and glycolate (Pglyc) were determined before the first and every next Oxlumo dosage. In non-dialysis patients, urinary oxalate (Uox) and urinary glycolate in 24 h urines were analysed at same interval plus monthly collection until month 6 of treatment and thereafter in 6 weeks’ intervals, if Uox did not reach near normalisation, or had increased again at end of dosing interval (3 monthly). Oxalate and glycolate were determined using ion chromatography/mass spectrometry in the same lab. RESULTS We now report data of those patients, who have received at least four dosages of Oxlumo (n = 15). Non-dialysis patients: Uox was normal (<0.5 mmol/1.73 m2/d) in two patients, in five patients it was near normal (1.5 times the upper limit, <0.75) and in three patients Uox was above 0.75 mmol/1.73 m2/d. Pox was normal in seven and above 7.4 µmol/L in three patients. In seven patients data were available at fifth to seventh dosage interval. Here, one patient had a normal Uox; in all other patients Uox was above 0.75 mmol/1.73 m2/d before next dosage. In the seven dialysis patients median Pox did not really decline over time (median of 45.1 at baseline, n = 7; and 39.9 post fourth dosage, n = 5), as was median Pglyc (86.05/71.1). Patient-specific follow-up differed and must also be related to co-medication with B6. For example, one dialysis patient remained stable with Pglyc below 2 µmol/L (under B6) and another patient experienced Pglyc > 1 mmol/L (without B6). CONCLUSION Oxlumo® has reduced Uox in 7/10 patients after the fourth dosage. However, adjustment of dosage intervals or dosage per se are necessary in the majority of patients to reach the goal of treatment, e.g. at least near normalisation of urinary oxalate excretion. In dialysis patients lack of reduction of Pox maybe because patients dissolve systemic oxalate deposits. However, specific imaging (bone MRI) in three of the dialysis patients did not show improvement of oxalate osteopathy over 6 and 9 months, respectively.