Phase 1/2 Study of PH1 Treatment, Lumasiran, Yields Positive Results

Positive data regarding phase 1/2 study for lumasiran, an investigational RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1), yielded positive results.

In an update presented at the OxalEurope, European Hyperoxaluria Consortium today, June 8, 2018, in Naples, Italy, Alnylam Pharmaceuticals announced positive data regarding its phase 1/2 study for lumasiran (formerly known as ALN-GO1), an investigational RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1). They included all data collected prior March 29, 2018.

“PH1 is an ultra-orphan disease, with a generally pediatric onset and an immediate need for an effective intervention. Today, patients with advanced disease have no choice but to undergo intensive dialysis and, ultimately, a dual liver/kidney transplant, with no other approved treatment alternatives in place,” stated Prof Bernd Hoppe, MD, head of the division of Pediatric Nephrology, Department of Pediatrics at the University of Bonn, Germany and an investigator in the lumasiran study, in a recent statement. “The data presented on lumasiran provide evidence for oxalate reduction, highlighting the potential of this investigational medicine as an innovative approach for the treatment of patients with PH1.”

In expansions of each of the first 2 cohorts, 8 patients were administered open-label lumasiran, which amounted to 20 enrolled patients. Subjects randomized to the placebo group were also administered subsequent subcutaneous lumasiran following placebo administration. Patients had a mean age of 14.9 years (range: 6-43) and a mean estimated glomerular filtration rate (eGFR) of 77 mL/min/1.73m2 (range: 42-131).

Lumasiran demonstrated a mean maximal reduction in urinary oxalate of 64% in patients enrolled in Cohorts 1-3 (N=12). A lowering in urinary oxalate below 0.7 mmol/24 hrs/1.73m2, a threshold level associated with a reduced rate of progression to end-stage renal disease, was experienced by all lumasiran-treated patients. In addition, patients administered lumasiran (N=9) maintained a mean reduction in urinary oxalate of 63% (range: 49% to 73%) on day 85. The hypothesis that GO inhibition has the potential to reduce and possibly normalize levels of hepatic oxalate production, thus potentially halting PH1 disease progression, is further supported by the trial’s updated results.

Part B of the phase 1/2 study is ongoing, and eligible patients are transitioning into an open-label extension (OLE) study.

“Based upon our recent discussions with the US Food and Drug Administration (FDA), we are on track to advance this program into phase 3 development at mid-year, with the goal of bringing lumasiran to patients around the world as rapidly as possible. The reported data will be from part B of the phase 1/2 study, which is a randomized (3:1 drug:placebo), single-blind, placebo-controlled evaluation of lumasiran in patients with PH1. Respectively, 3 monthly doses of lumasiran at 1 mg/kg or 3 mg/kg were administered to cohorts 1 and 2 while 2 quarterly doses at 3 mg/kg were administered to cohort 3.”

Previously, lumasiran has received Breakthrough Therapy Designation from the FDA and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). A phase 3 trial is planned to commence in mid-2018.

“We are pleased to present data that signal hope to patients with PH1, an ultra-rare, life-threatening disease, with a profound unmet need,” added Pritesh J. Gandhi, PharmD., Vice President and General Manager, Lumasiran program at Alnylam. “Given the encouraging results, we believe that lumasiran has the potential to alleviate the pathologic overproduction of oxalate, the metabolite that causes the severe, systemic manifestations of PH1. Furthermore, we believe these results validate our approach of targeting GO, a key liver enzyme involved in the excessive oxalate output in patients with PH1.”