Lb002illuminate-A, a Phase 3 Study of Lumasiran, an Investigational Rnai Therapeutic, in Children and Adults With Primary Hyperoxaluria Type 1 (Ph1)

Abstract

Background and Aims PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1. Method Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6). Results Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions. Conclusion Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.

Therapeutic RNA Delivery for COVID and Other Diseases

“…[ 36 ] Scientists showed that lumasiran achieved >50% silencing of urinary oxalate levels, leading to improvements in secondary endpoints such as plasma oxalate levels and preventing kidney failure and eventual multiorgan damage from systemic oxalosis, and resulting in an FDA‐approved drug treating primary hyperoxaluria type 1 (PH1). [ 38 ] Alnylam has two late‐stage drugs under development for amyloidosis and hemophilia as well as multiple early‐stage programs for alpha‐1 liver disease, hepatitis B infection, and complement‐mediated diseases, all of which utilize their enhanced stabilization chemistry (ESC)‐GalNAc platform. [ 39 ] Fitusiran, which works by targeting the antithrombin gene SERPINC1, has resulted in increased thrombin levels in patients with hemophilia A or B similar to levels found in healthy patients.…”

Therapeutic RNA interference: A novel approach to the treatment of primary hyperoxaluria

“…[140][141][142][143][144] This 2). 145,146 Glycolate is excreted by the kidneys but is highly soluble and not associated with a renal phenotype in GO-deficient (Hao1 knockout) mouse models. 147 Rare human cases of biallelic loss of function variants in HAO1 have also been characterized to have high serum and urine glycolate levels without a disease phenotype, endorsing the safety of an RNAi approach to GO.…”

“…146 Lumasiran effected a 53.5% reduction in 24 hour urine oxalate levels (95% confidence interval 62.3-44.8%) compared to placebo (mean reduction 11.8%) and 85% of patients achieved a urine oxalate excretion within 150% of the upper limit of the normal range 146. Furthermore, no serious adverse events were reported.…”

Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives

“…Indeed, preliminary results from Illuminate-A trial (Table 1) showed a 65% reduction of UOx after 6 months of treatment. 18 Consequently, prolonged treatment might be necessary before reaching a nearly normalized situation. Another important consequence could be that the systemic involvement of oxalate, especially in patients on chronic dialysis, could take longer time to be cleared with this medication compared to liver transplantation.…”

“…Developing better tools to evaluate the systemic oxalate burden will help delineate the best timing for kidney transplantation to avoid oxalate deposition recurrence in the kidney allograft. Questions regarding these new treatments and the outcome of kidney allograft, Innovative treatments involved in clinical trials NCT03681184 -Main inclusion criteria : ≥ 6 years, eGFR ≥30 mL/min -Preliminary results: 65.4% reduction of 24 hr UOx at month 6; no serious adverse event reported 18 . Estimated completion date: May 2024…”