Alnylam presents positive results from ILLUMINATE-B phase III study of lumasiran in pediatric patients with primary hyperoxaluria type 1 at the American Society of Nephrology Kidney Week.

Results were presented from ILLUMINATE-B, as well as new 12-month results from the ILLUMINATE-A pivotal Phase III study and the ongoing Phase II open-label extension (OLE) study, at the American Society of Nephrology (ASN) Kidney Week 2020 held as a virtual event on October 22-25. “Pathologic overproduction of oxalate by the liver is the root cause of morbidity and mortality associated with PH1. There is strong evidence in the literature to suggest that levels of urinary oxalate correlate with clinical outcomes in patients with this ultra-rare disease. With that in mind, I am pleased to see the reduction in urinary oxalate levels in response to lumasiran in all three studies presented at this year’s meeting. More broadly, I am encouraged by the promise that these findings hold for my patients living with this condition,” said Jeffrey M. Saland, M.D., Professor and Chief, Pediatric Nephrology and Hypertension, Jack and Lucy Clark Department of Pediatrics, Mount Sinai Kravis Children’s Hospital, New York City, and Investigator on the ILLUMINATE-A trial. “With the sustained reductions in urinary oxalate during long-term treatment and the exploratory renal stone and nephrocalcinosis data presented, I am hopeful about the potential of lumasiran to have a positive impact on the severe clinical manifestations that individuals with PH1 suffer.” ILLUMINATE-B 6-Month Results : Alnylam presented positive efficacy and safety results from the 6-month primary analysis (N=18) of the ILLUMINATE-B Phase III study of lumasiran in infants and children under the age of 6, with the youngest patient enrolled at 3 months of age. The efficacy results and safety profile of lumasiran were found to be similar to those observed in adults and children 6 years or older in the ILLUMINATE-A study. Treatment with lumasiran in ILLUMINATE-B led to a 72 percent mean reduction in spot urinary oxalate:creatinine ratio from baseline to Month 6, averaged across months 3 to 6 – the primary endpoint of the study. Lumasiran also demonstrated positive results across secondary endpoints, including proportion of patients (9/18 or 50 percent) achieving urinary oxalate levels at or below 1.5 times ULNa. Preliminary analysis of exploratory endpoints indicated improvements in nephrocalcinosis in 8 out of 18 patients (44 percent), while estimated glomerular filtration rates (eGFR) remained stable. At baseline, 14 of 18 patients had nephrocalcinosis. After 6 months of lumasiran treatment, no patients worsened, 10 remained stable, and eight showed bilateral (3 out of 8) or unilateral (5 out of 8) improvements in nephrocalcinosis. As expected, given the 6-month duration of the study, there was no change in the rate of renal stone events (RSEs). . Lumasiran had an acceptable safety profile in infants and young children under the age of six. There were no deaths, severe adverse events, discontinuations of treatment or withdrawals from the study. One patient had a serious adverse event (SAE) of viral infection that was considered not related to lumasiran by the study investigator. The most common drug-related adverse events (AEs) were mild and transient injection site reactions (ISRs) reported in 3 of 18 (17 percent) patients. No clinically relevant changes in laboratory measures (including liver function tests), vital signs, or electrocardiograms related to lumasiran were observed. ILLUMINATE-A 12-Month Results : As of the data cut-off date of May 1, 2020, results from the extension period of the ILLUMINATE-A Phase III study showed that patients initially randomized to lumasiran in the 6-month double-blind (DB) period who continued treatment with lumasiran through Month 12 (“lumasiran/lumasiran”; N=24) maintained their reduction in 24-hour urinary oxalate excretion, with a 64 percent mean reduction relative to baseline. The majority (88 percent) of patients in this group reached normal or near-normal levels (at or below 1.5x ULN)a of urinary oxalate. In patients who were originally randomized to placebo in the DB period but crossed over to lumasiran (“placebo/lumasiran”; N=13), treatment with lumasiran led to a 57 percent mean reduction in 24-hour urinary oxalate excretion after six months of treatment; 77 percent of these patients reached urinary oxalate levels at or below 1.5 x ULN.In an exploratory analysis, reductions in oxalate levels were associated with lower rates of RSEb in lumasiran treated patients in both lumasiran/lumasiran and placebo/lumasiran groups. The safety profile of lumasiran remained consistent with ongoing dosing (233 doses) and 9.9 months of mean exposure (range 2.8-15.1 months). There were no deaths, SAEs, treatment interruptions or discontinuations related to lumasiran. One patient had an SAE of urosepsis that was not related to study drug. Mild ISRs were the most common drug-related AE reported in at least 10 percent of patients. Most common ISR symptoms included erythema, pain, pruritus, or swelling at the injection site. No clinically relevant changes in laboratory measures (including liver function tests), vital signs, and electrocardiograms related to lumasiran were observed. Phase II OLE Results : Additional positive data were also presented from the ongoing Phase II OLE study of lumasiran demonstrating the long-term efficacy and safety of lumasiran with up to 22 months of exposure (range: 11-22 months; median: 15 months). As of January 30, 2020, data cut-off date, patients continued to experience sustained reductions in urinary oxalate excretion, with similar responses across dosage regimens. Specifically, ongoing treatment with lumasiran resulted in 74 percent (range: 35.7–88.3 percent) mean maximal reduction in urinary oxalate relative to Phase 1/II baseline (N=17), and 17/18 (94 percent) of patients achieved normal or near-normal levels of urinary oxalate. Mean eGFR levels remained stable over time. Lumasiran had an acceptable safety profile. There were no deaths, severe AEs, or AEs leading to discontinuation of treatment. There were no drug-related SAEs. The most common drug-related AEs were mild ISRs. No clinically significant laboratory changes related to lumasiran were reported. Post-hoc analysis of renal stones showed that long-term treatment with lumasiran resulted in a decline in the number of patients experiencing renal stones. In the 12 months prior to study entry, 6/20 patients (30 percent) reported renal stones . In the Phase 1/II Part B study where renal stones were captured as AEs, 4/20 patients (20 percent) reported AEs of renal stones during the initial 5-month period, and no patients (0/20) reported AEs of renal stones during the Phase II OLE with up to 22 months of treatment. Additional findings on real-world disease manifestations and healthcare resource use among patients with PH1 were also presented based on a retrospective multinational study of physician chart reviews. The Company is also conducting ILLUMINATE-C – a global open-label Phase III study of lumasiran in PH1 patients of all ages with advanced renal disease, including patients on dialysis, with topline results expected in 2021.