Rare Daily Staff
Alnylam Pharmaceuticals reported positive topline results from the ILLUMINATE-C phase 3 open-label study of lumasiran in patients of all ages with advanced primary hyperoxaluria type 1 associated with progressive decline in renal function.
PH1 is an ultra-rare genetic disease that affects an estimated one to three individuals per million in the United States and Europe. PH1 is characterized by oxalate overproduction in the liver. The excess oxalate results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. PH1 is associated with a progressive decline in kidney function, which exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and deposition of oxalate in bones, eyes, skin, and heart, leading to severe illness and death.
Lumasiran is a subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in development for the treatment of primary hyperoxaluria type 1 (PH1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
Lumasiran has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients and from the European Medicines Agency for the treatment of PH1 in all age groups under the brand name Oxlumo.
ILLUMINATE-C is a single arm, open-label, multinational phase 3 study evaluating the safety and efficacy of lumasiran in PH1 patients of all ages with severe renal impairment and conducted at 13 study sites across 10 countries around the world. Cohort A enrolled six patients with advanced PH1 who do not yet require dialysis, and Cohort B enrolled 15 patients who are hemodialysis dependent. The dosing regimen is based on weight with three monthly starting doses followed by ongoing monthly or quarterly doses.
The primary efficacy endpoint for Cohort A was the percent change in plasma oxalate from baseline to month six, and the primary endpoint for Cohort B was the percent change in pre-dialysis plasma oxalate from baseline to month six. Key secondary endpoints are designed to evaluate additional measures of plasma oxalate and changes in urinary oxalate. Renal function, frequency and mode of dialysis, frequency of renal stone events, and measures of systemic oxalosis, including clinical manifestations, will also be evaluated in the extension period of the study.
At six months, treatment with lumasiran resulted in a substantial reduction in plasma oxalate from baseline in both dialysis-independent and -dependent patients. Lumasiran also demonstrated positive results across key secondary endpoints, including measures of urinary oxalate (for patients in Cohort A) and additional measures of plasma oxalate.
There were no deaths and no drug related serious adverse events among enrolled patients. There were two treatment discontinuations due to adverse events in the extension period of the study, neither of which was drug related. The most common drug-related adverse events (occurring in 10 percent or more of patients) were injection site reactions reported in five patients (23.8 percent), all of which were mild.
Based on these results, the company plans to submit a Supplemental New Drug Application for lumasiran with the U.S. Food and Drug Administration and a Type II Variation with the European Medicines Agency in late 2021.
In November 2020, lumasiran was approved by the FDA for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients and by the EMA for the treatment of PH1 in all age groups. Lumasiran is marketed in the United States and European Union as Oxlumo.
“Patients with PH1 face devastating health challenges, especially those approaching or experiencing kidney failure, and these new results from the ILLUMINATE clinical development program signal hope to some of the sickest and most severely impacted individuals in this patient community,” said Kim Hollander, executive director of the Oxalosis and Hyperoxaluria Foundation.
Photo: Kim Hollander, executive director of the Oxalosis and Hyperoxaluria Foundation.