20 June 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has achieved full patient enrollment in its ILLUMINATE-A Phase 3 study of lumasiran, an investigational RNAi therapeutic targeting glycolate oxidase for the treatment of adults and children with primary hyperoxaluria type 1, the company said.
This study enrolled patients across 16 sites in eight countries. Alnylam is on track to report topline results from ILLUMINATE-A expected in late 2019 and, if positive, to submit filings for global regulatory approvals starting in early 2020.
The company also announced complete positive results from its Phase 1/2 clinical study and reiterated positive results from its ongoing Phase 2 open-label extension study of lumasiran.
Results will be presented at the 2019 Oxalosis and Hyperoxaluria International Workshop being held in Boston, on June 21-22.
In final Phase 1/2 study results, lumasiran demonstrated a mean maximal reduction in urinary oxalate of 75 % (range: 43-92 %) relative to baseline across all cohorts (1 mg/kg monthly, 3 mg/kg monthly, and 3 mg/kg quarterly; N=20). At 28 days post the last dose, the mean reduction relative to baseline was 66%.
All patients (100%) achieved oxalate lowering to less than 1.5 times upper limit of normal (less than or equal to 0.69 mmol/24hr/1.73m2).
Among patients receiving 3 mg/kg monthly or quarterly doses of lumasiran, 92% achieved urinary oxalate levels within the normal range (less than 0.46 mmol/24hr/1.73m2).
Furthermore, lumasiran-treated patients across all cohorts experienced a mean maximal decrease of 77% (range: 50-95%) in the ratio of urinary oxalate to creatinine an additional measure of oxalate reduction that addresses the variability that is inherent in 24-hour urine collections.
Lumasiran results showed an acceptable safety and tolerability profile, with PH1 patients on study for a median of 9.8 months (range: 5.6 to 15.2 months); there were no study discontinuations. Serious adverse events were reported for one patient (33%) receiving placebo and four patients (20 %) receiving lumasiran; none were related to study drug.
The placebo patient experienced acute pyelonephritis and kidney stones. The lumasiran patients with SAEs included one patient with vomiting, one patient with abdominal pain, fever and vomiting, one patient with gastroenteritis, and one patient with kidney stones.
Adverse events were reported in two (66.7%) patients during placebo dosing and 20 (100%) patients after lumasiran dosing. The majority of AEs were mild or moderate in severity and were assessed as unrelated to study drug.
Severe AEs were reported in one (33%) patient during placebo dosing (acute pyelonephritis) and one (5%) patient after lumasiran dosing (kidney stone); none were considered related to study drug by investigator.
AEs reported in more than three patients receiving lumasiran were pyrexia; vomiting, cough, abdominal pain, headache (N=5 each); and rhinitis and nephrolithiasis (N=4 each).
Self-limiting injection site reactions were reported in three (15 %) patients receiving lumasiran; all mild or moderate and with none affecting dosing.
Lumasiran was not associated with any clinically significant adverse laboratory findings, including liver function tests.
As previously reported, all patients (100 %) who completed Phase 1/2 continue dosing in the ongoing Phase 2 OLE phase of the study. As of February 2019, patients in the Phase 2 OLE study have received lumasiran for a median of four months (range: 0.03–8.36; N=18).
Lumasiran dosing across all evaluable cohorts resulted in mean maximal reduction in urinary oxalate of 72 % (range: 41-90 %) relative to Phase 1/2 baseline levels.
Multiple doses of lumasiran demonstrated an acceptable safety and tolerability profile in patients with PH1, with no drug related SAEs and no discontinuations from study treatment.
The company also recently presented a case study of a healthy human with mutations in the HAO1 gene, a validated target for the treatment of PH1, as well as results from research on the diagnostic journey of PH1 at the 56th Congress of the European Renal Association and European Dialysis and Transplant Association held on June 13-16, 2019 in Budapest, Hungary.
ILLUMINATE-A is a six month randomised, double-blind, placebo-controlled, global, multicenter Phase 3 study to evaluate the efficacy and safety of lumasiran in approximately 30 patients with a documented diagnosis of PH1, followed by a 54 month extension period where all patients will receive lumasiran.
Patients are randomised 2: 1 to receive three monthly doses of lumasiran or placebo at 3 mg/kg followed by quarterly maintenance doses.
The primary endpoint is the % change in 24-hour urinary oxalate excretion from months 3 to 6 relative to baseline in the patients treated with lumasiran as compared to placebo.
Key secondary and exploratory endpoints will evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate, safety and tolerability, and quality of life.
At month six, the patients receiving placebo will cross over to receive lumasiran for long-term follow up. For more information on ILLUMINATE-A (NCT03681184) visit clinicaltrials.gov, email clinicaltrials@alnylam.com or call 877-256-9526 in North America and +31 20 369 7861 in Europe.
Lumasiran (formerly known as ALN-GO1) is an investigational RNAi therapeutic targeting glycolate oxidase in development for the treatment of Primary Hyperoxaluria Type 1.
It is designed to reduce hepatic levels of the GO enzyme, thereby depleting the substrate necessary for the production of oxalate the metabolite that directly contributes to the pathophysiology of PH1.
Lumasiran utilises 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 (FDA), 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.