Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), announced on 5/3/18 that the Company has reached alignment with the U.S. Food and Drug Administration (FDA) on a pivotal study design for lumasiran, an investigational RNAi therapeutic for the treatment of primary hyperoxaluria type 1 (PH1). The Company and the FDA have aligned on a primary endpoint for the pivotal study based on reduction of urinary oxalate at six months, a biomarker directly linked to the pathophysiology of PH1 and known to be well correlated with disease progression. In addition, Alnylam and the FDA have aligned on a study size of approximately 25 patients with PH1. Based on the discussions with the FDA, the Company is on track to start the Phase 3 study in mid-2018 and is now guiding that it expects to report topline results in 2019 and, if positive, to submit an NDA in early 2020. Lumasiran was recently granted Breakthrough Therapy Designation from the FDA and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA).
“Given the preliminary results reported to date, we believe that investigational lumasiran has the potential to prevent excessive oxalate production implicated in the pathophysiology and morbidity associated with PH1, an ultra-rare, life-threatening disease. We are very pleased with the FDA’s shared sense of urgency to evaluate the efficacy and safety of lumasiran as a potential therapeutic option for patients as rapidly as possible,” said Pritesh Gandhi, PharmD., Vice President and General Manager, Lumasiran program at Alnylam. “Indeed, we have now reached alignment with the FDA on a six-month primary endpoint based on reduction of urinary oxalate and a pivotal study sample size of approximately 25 patients. Based on this pivotal study design, and assuming positive results, we now expect to be in a position to submit an NDA in early 2020, which represents a significant acceleration in our efforts to bring this promising investigational medicine to patients.”
Lumasiran (formerly known as ALN-GO1) is an investigational RNAi therapeutic targeting glycolate oxidase (GO) in development for the treatment of Primary Hyperoxaluria Type 1 (PH1). Lumasiran is designed to reduce the hepatic levels of the GO enzyme, thereby depleting the substrate necessary for oxalate production, which directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Lumasiran has received both U.S. and EU Orphan Drug Designations, a Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA), and a Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). The safety and efficacy of lumasiran have not been evaluated by the FDA, EMA or any other health authority.
PH1 is an ultra-orphan disease in which excessive oxalate production results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones or nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. About 50 percent of patients will have kidney failure by age 15, and about 80 percent will have end stage renal disease by age 30. Current treatment options for advanced disease are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidneys, a procedure with high morbidity that is limited due to organ availability. Although a small minority of patients respond to Vitamin B6 supplementation, there are no approved pharmaceutical therapies for PH1.
Primary hyperoxaluria is estimated to affect 1 in 58,000 individuals worldwide. Type 1 is the most common form, accounting for approximately 80 percent of cases.