Clinical outcomes in Phase 3 studies of lumasiran in pediatric and adult patients with primary hyperoxaluria type 1
David Sas, DO1, Yaacov Frishberg, MD2, Sander Garrelfs, MD3, Mini Michael, MD, FRACP, MMed4, Jeffrey Saland, MD, MSCR5, Taylor Ngo, MPH6, John Gansner, MD, PhD6, Tracy McGregor, MD6, John Lieske, MD1, Jeron Stokes, PharmD6.
1Mayo Clinic, Rochester, MN, USA, 2Shaare Zedek Medical Center, Jerusalem, Israel, 3Emma Children’s Hospital, University of Amsterdam, Amsterdam, Netherlands, 4Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA, 5Icahn School of Medicine at Mount Sinai, New York, NY, USA, 6Alnylam Pharmaceuticals, Cambridge, MA, USA.
BACKGROUND: Lumasiran is a subcutaneously administered RNAi therapeutic indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. In the Phase 3 studies ILLUMINATE-A and ILLUMINATE-B, lumasiran treatment resulted in substantial reductions in urinary oxalate, with an acceptable safety profile in patients aged 4 months to 60 years. METHODS: ILLUMINATE-A enrolled 39 patients with PH1 ≥6 years of age with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2. The trial has a 6-month, randomized, double-blind, placebo-controlled period and an extension period (EP). In the EP, the 13 patients initially randomized to placebo crossed over to lumasiran treatment. ILLUMINATE-B, a single-arm, open-label trial in which all participants received lumasiran, enrolled 18 patients with PH1 <6 years of age with an eGFR >45 mL/min/1.73 m2 if ≥12 months old or normal serum creatine if <12 months old. In both studies, change in eGFR was a descriptive secondary endpoint, and changes in medullary nephrocalcinosis (NC) grade and renal stone event (RSE) rates were exploratory endpoints. Here, we report on clinical outcomes from both studies. RESULTS: In patients from ILLUMINATE-A who had renal ultrasounds at baseline and Month 6, NC grade improved in 3/22 patients (1 bilateral, 2 unilateral) in the lumasiran group vs. 0/12 in the placebo group. NC grade worsened in 1/12 patients in the placebo group vs. 0/22 in the lumasiran group. The available NC data from Month 12 of ILLUMINATE-A will be presented. In the same study, RSE rates decreased during the first 6 months of lumasiran treatment in both the patients initially randomized to lumasiran and the patients who crossed over from placebo to lumasiran, relative to the 12 months prior to consent (Table 1). This reduction was maintained after an additional 6 months of treatment in the patients initially randomized to lumasiran. After 6 months of lumasiran treatment in ILLUMINATE-B, NC grade improved in 8/18 patients (3 bilateral, 5 unilateral) and remained stable in 10/18 patients; no patient worsened. In ILLUMINATE-B, RSE rates remained stable from 12 months prior to consent through the end of the 6-month treatment period at 0.24 per person-year (95% confidence interval 0.09, 0.63 and 0.06, 0.96, respectively). eGFR remained stable in both studies.CONCLUSION: Lumasiran demonstrated a positive effect on clinical outcomes in both pediatric and adults with PH1. Data continue to be collected in the extension periods of both studies.
Table 1: Renal Stone Event Rates per Person-Year (95% Confidence Interval) in ILLUMINATE-A
| Month 6 | Month 12 | ||
| 12 Months Prior to Consent | Lumasiran | Lumasiran | |
| Patients initially randomized to lumasiran | 3.19 (2.57, 3.96) | 1.09 (0.63, 1.88)* | 0.85 (0.46, 1.58) |
| 12 Months Prior to Consent | Placebo | Lumasiran | |
| Patients initially randomized to placebo | 0.54 (0.26, 1.13) | 0.66 (0.25, 1.76) | 0.17 (0.02, 1.18)* |
| *First 6 months of lumasiran treatment | |||
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