ESPN 51th Annual Meeting

ESPN 2018


 
A Phase 1/2 Trial of Lumasiran (ALN-GO1), an Investigational RNA Interference (RNAi) Therapeutic for Primary Hyperoxaluria Type 1
YAACOV FRISHBERG 1 PIERRE COCHAT 2 WILLIAM VANT HOFF 3 SALLY HULTON 4 TRACY L. MCGREGOR 5 PATRICK HASLETT 5 DAVID V. ERBE 5 GEORGES DESCHêNES 6

1- SHAARE ZEDEK MEDICAL CENTER, JERUSALEM, ISRAEL
2- HôPITAL FEMME MèRE ENFANT, LYON, FRANCE
3- GREAT ORMOND STREET HOSPITAL, LONDON, UNITED KINGDOM
4- BIRMINGHAM CHILDRENS HOSPITAL, BIRMINGHAM, UNITED KINGDOM
5- ALNYLAM PHARMACEUTICALS, CAMBRIDGE, MA, USA
6- HOSPITAL ROBERT DEBRE, PARIS, FRANCE
 
Introduction:

In Primary Hyperoxaluria Type 1 (PH1), alanine-glyoxylate aminotransferase deficiency leads to excessive hepatic oxalate production, resulting in progressive renal impairment and multi-organ damage from systemic oxalosis. Lumasiran is an investigational RNAi therapeutic which suppresses hepatic glycolate oxidase, decreasing the conversion of glycolate to glyoxylate, a required substrate for oxalate production. In healthy adult volunteers, single-dose lumasiran was well tolerated with dose-dependent elevations in plasma glycolate. Here we report updated data from patients with PH1 in the ongoing Phase 2 ALN-GO1-001 study.

Material and methods:

ALN-GO1-001 is a randomized, placebo-controlled, single-blind, multicenter trial, in which the Phase 2 includes patients with PH1 with urinary oxalate (UOx) ≥0.7 mmol/24h/1.73m2 and eGFR >45 ml/min/1.73m2. One of four patients in each cohort is randomized to receive 3 doses of placebo prior to lumasiran dosing. The first cohort received 1 mg/kg lumasiran subcutaneously every 28 days x3 doses; the second cohort received 3 mg/kg lumasiran every 28 days x3 doses. The primary endpoint is safety, and secondary endpoints include change in 24-hour UOx from baseline.

Results:

Lumasiran has demonstrated acceptable preliminary safety and tolerability with no treatment related serious adverse events or discontinuations from study; majority of adverse events were mild/moderate and unrelated to study drug. Initial results showed patients randomized to lumasiran in first cohort dosed with 1 mg/kg monthly of lumasiran experienced >50% decrease in UOx from baseline. All patients in this cohort experienced a lowering of UOx below 1.1 mmol/24hrs/1.73m2 – a threshold associated with reduced progression to end-stage renal disease. Data from patients in the 1 mg/kg monthly and 3 mg/kg monthly cohorts will be presented. 

Conclusions:

Initial data show acceptable safety data and promising clinical activity in lowering UOx in patients with PH1 and support the continued development of lumasiran as a potential therapeutic to alleviate pathologic overproduction of oxalate in this devastating disease.