12 November 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has initiated ILLUMINATE-C, a new global Phase 3 study of lumasiran, an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of primary hyperoxaluria type 1, the company said.
The study will enroll patients of all ages with advanced renal disease, and the primary study endpoint is the percent reduction in plasma oxalate from baseline to six months.
Alnylam expects to report initial ILLUMINATE-C results in late 2020.
The company also announced new positive efficacy results from the ongoing Phase 2 open-label extension study of lumasiran, which were presented at the American Society of Nephrology 2019 annual meeting on Saturday, November 9 in Washington, DC.
The Phase 2 OLE results were reported as of the data cut-off date of September 12, 2019 and demonstrated a 76% mean maximal reduction (range: 43-91%) in urinary oxalate excretion relative to Phase 1/2 baseline values in all cohorts.
In the study, all patients achieved a urinary oxalate level at or below 1.5 times the upper limit of normal (less than or equal to 0.69 mmoL/24hr/1.73m2), and 68% of patients achieved a urinary oxalate level within the normal range (less than or equal to 0.46 mmol/24hr/1.73m2).
Patients also experienced an 82% mean maximal reduction in urinary oxalate: creatinine ratio (range: 62-94%) after lumasiran dosing across all cohorts.
The Phase 2 OLE safety results were based on a median study duration of 10.4 months (range: 7-17 months) since the first dose administered in the OLE study.
As of the data cut-off date, there were no discontinuations from treatment.
A single patient (1/20; 5%) reported two serious adverse events of traumatic brain injury and bone contusion sustained in a car accident; neither was assessed as related to study drug.
There were no other reported SAEs in the OLE study. Adverse events were reported in 19/20 (95%) patients; most were mild in severity and assessed as unrelated to study drug by the investigators.
Injection site reactions, which were reported in 4/20 (20%) patients, were mild and did not affect dosing. Other AEs reported in more than one patient were: headache, oropharyngeal pain; gastroenteritis, viral gastroenteritis, pyrexia, and vomiting.
There were no clinically significant laboratory changes.
The ILLUMINATE-C Phase 3 trial is a single-arm, open-label, global, multicenter study to evaluate the efficacy and safety of lumasiran in approximately 16 patients with a documented diagnosis of PH1.
Cohort A will enroll patients with advanced disease who do not yet require dialysis and Cohort B will enroll patients who are dialysis-dependent.
During the six-month primary analysis period patients will receive three monthly doses of lumasiran followed by monthly or quarterly maintenance doses. The primary endpoint is the percentage change in plasma oxalate from baseline to six months.
Key secondary endpoints will evaluate additional measures of plasma oxalate and changes in: urinary oxalate, renal function, nephrocalcinosis, frequency and mode of dialysis, frequency of renal stone events, and measures of systemic oxalosis.
Lumasiran is an investigational, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 in development for the treatment of primary hyperoxaluria type 1. 
HAO1 encodes glycolate oxidase. Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced Stabilization Chemistry -GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
Lumasiran has received both US and EU Orphan Drug Designations, a Breakthrough Therapy Designation from the US Food and Drug Administration, and a Priority Medicines (PRIME) designation from the European Medicines Agency.
The safety and efficacy of lumasiran have not been evaluated by the FDA, EMA or any other health authority.