Alnylam announces new positive results from Phase 1/2 study of lumasiran in patients with PH1

Alnylam Pharmaceuticals, Inc., the leading RNAi therapeutics company, announced today new positive results from its Phase 1/2 study with lumasiran, an investigational RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of Primary Hyperoxaluria Type 1 (PH1). Results were presented at the OxalEurope, European Hyperoxaluria Consortium, taking place on June 8, 2018 in Naples, Italy.

Updated interim data were from Part B of the Phase 1/2 study and were as of the data cut-off date of March 29, 2018. Part B is a randomized (3:1 drug:placebo), single-blind, placebo-controlled evaluation of lumasiran in patients with PH1. Cohorts 1 and 2 received three monthly doses of lumasiran at 1 mg/kg or 3 mg/kg, respectively; Cohort 3 received two quarterly doses at 3 mg/kg. An additional eight patients received open-label lumasiran in expansions of each of the first two cohorts, totaling 20 patients enrolled. Patients randomized to the placebo group also received subsequent subcutaneous administration of lumasiran following administration of placebo. 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 percent in patients enrolled in Cohorts 1-3 (N=12). All lumasiran-treated patients experienced 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. On day 85, patients receiving lumasiran (N=9) maintained a mean reduction in urinary oxalate of 63 percent (range: 49-73 percent). Alnylam believes the potent and durable reductions in urinary oxalate support a once quarterly, subcutaneous dose regimen. Further, these results continue to support the hypothesis that GO inhibition has the potential to reduce and possibly normalize levels of hepatic oxalate production, thus potentially halting PH1 disease progression. Dosing in Part B of the Phase 1/2 study is ongoing and eligible patients are transitioning into an open-label extension (OLE) study. The Company expects to present additional data from all cohorts as well as from the OLE study in late 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. 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," said Pritesh J. Gandhi, PharmD., Vice President and General Manager, Lumasiran program at Alnylam. "Based upon our recent discussions with the 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."

"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," said Prof. Bernd Hoppe, M.D., Head of the Division of Pediatric Nephrology, Department of Pediatrics, University of Bonn, Germany and an investigator in the lumasiran study. "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."

Lumasiran was generally well tolerated in all patients in the Phase 1/2 study (N=20). Fifteen (75 percent) of patients treated with lumasiran experienced an adverse event (AE); the majority of AEs were mild or moderate in severity and unrelated to study drug. AEs occurring in three or more patients included abdominal pain, headache, nasopharyngitis, pyrexia, and vomiting. Two patients reported injection site reactions, both of which were mild and transient. Two patients reported severe AEs; one patient had pyelonephritis during placebo dosing and one patient had a kidney stone with renal colic after lumasiran dosing. One patient receiving placebo and three patients receiving lumasiran reported serious adverse events (SAEs); none were assessed as related to study drug. The placebo patient experienced kidney stones and pyelonephritis. The lumasiran patients with SAEs included one patient with kidney stones, one patient with fever and abdominal pain, and one patient with gastroenteritis. Lumasiran has not been associated with any clinically significant adverse laboratory findings, and there were no study discontinuations due to AEs through the data cut-off date.

Alnylam recently announced alignment with the U.S. Food and Drug Administration (FDA) on a pivotal study design for lumasiran, including a primary endpoint at six months based on reduction of urinary oxalate, and a study size of approximately 25 patients with PH1. The Company has guided its intention to initiate the Phase 3 trial in mid-2018. Lumasiran has received Breakthrough Therapy Designation from the FDA and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA).

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