Alnylam Pharmaceuticals, Inc. announced new positive results from the six-month primary analysis period of the ILLUMINATE-C Phase 3 open-label study of lumasiran, an RNAi therapeutic targeting hydroxyacid oxidase 1– the gene encoding glycolate oxidase (GO) – that is being investigated for the treatment of patients of all ages with advanced primary hyperoxaluria type 1. As previously reported, treatment with lumasiran resulted in substantial reductions in plasma oxalate at six months. Results from new exploratory analyses provide evidence that lumasiran treatment resulted in improvements in cardiac measures, nephrocalcinosis and kidney stone events. In addition, some patients treated with lumasiran experienced improvements in their most burdensome symptoms (as assessed by the investigator), including fatigue, nausea, and bone pain, with no patients reporting worsening of those symptoms. These data were presented at the European Renal Association-European Dialysis and Transplant Association International Congress being held both in Paris, France, and as a virtual event on May 19-22.

ILLUMINATE-C enrolled a total of 21 patients, including six who were not on dialysis at study start (Cohort A) and 15 who were on hemodialysis (Cohort B). As previously presented at the American Society of Nephrology (ASN) Kidney Week Meeting in 2021, in Cohorts A and B, respectively, treatment with lumasiran led to 33% and 42% mean reductions in POx from baseline to Month 6. Additionally, treatment with lumasiran led to 35 µmol/L (Cohort A) and 48 µmol/L (Cohort B) mean absolute reductions in POx from baseline to Month 6. In new exploratory analyses, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured to assess the impact of lumasiran on the cardiac manifestations of systemic oxalosis. Among patients with abnormal LVEFi at baseline across Cohort A (N=1) and Cohort B (N=4), the patient in Cohort A and two of four patients in Cohort B experienced a = 5% improvement following six months of treatment with lumasiran.

Among patients with abnormal GLSii at baseline across Cohort A (N=1) and Cohort B (N=3), all four patients showed a =2% improvement at Month 6. In patients with medullary nephrocalcinosis at baseline in Cohort A (N=5), two patients remained stable, three improved (two unilateral and one bilateral improvement) and none worsened following six months of treatment with lumasiran. In Cohort A, one patient did not have nephrocalcinosis at baseline and had bilateral worsening at six months. In patients with nephrocalcinosis at baseline in Cohort B (N=2), both improved (one unilateral and one bilateral improvement) following six months of treatment with lumasiran.

In Cohort A, the rate of kidney stone events per person-year decreased from 3.2 (95% CI: 2, 5.2) in the 12 months prior to consent to 1.5 (95% CI: 0.6, 3.9) during the first six months of treatment with lumasiran. As expected, given patients in Cohort B are on hemodialysis, the rate of kidney stone events was low: 0.07 (95% CI: 0.01, 0.71) in the 12 months prior to consent and 0.0 (95% CI: 0.0, 0.53) during the first six months of treatment with lumasiran. For patients in both cohorts, the most burdensome symptoms at baseline (as assessed by the investigator), including fatigue, nausea/decreased appetite, bone pain and decreased mobility, improved or remained stable following six months of treatment with lumasiran; none of the symptoms worsened.

The most common adverse event related to lumasiran was injection-site reaction (ISR) reported in 5 of 21 patients (24%). All ISRs were mild and transient, and the most common symptoms included erythema, discoloration, and hematoma. A separate analysis presented at ERA-EDTA demonstrated that the recommended weight-based dosing regimens of lumasiran showed equivalent efficacy in patients of all ages and degrees of kidney function, including patients on hemodialysis.