Lumasiran exhibits promising safety, efficacy for primary hyperoxaluria type 1
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Lumasiran, an RNA interference therapeutic that suppresses glycolate oxidase and reduces hepatic oxalate production, exhibited an acceptable safety and efficacy profile in patients with primary hyperoxaluria type 1, according to a study.
“The potential clinical significance of this result is clear in the context of the natural history of the disease,” Yaacov Frishberg, MD, of the division of pediatric nephrology at Shaare Zedek Medical Center in Jerusalem, and colleagues wrote. “Among patients with primary hyperoxaluria without kidney failure at baseline, the degree of hyperoxaluria at diagnosis appears to be associated with the subsequent risk of kidney failure.”
The phase 1/2 randomized study involved two parts. Part A included 32 healthy adults who received a single dose of either subcutaneous lumasiran or placebo in ascending dose groups from 0.3 mg/kg to 6 mg/kg. Part B included 20 adult and pediatric patients with primary hyperoxaluria type 1 who received up to three doses of either lumasiran or placebo in treatment cohorts of 1 mg/kg or 3 mg/kg monthly or 3 mg/kg quarterly. Patients on placebo began lumasiran on day 85. Frishberg and colleagues examined the safety, tolerability and proof of mechanism of lumasiran for the lowering of urinary oxalate.
No serious adverse events were reported in either part A or B. During the first 85 days of part A, 20 mild to moderate adverse events occurred in patients treated with lumasiran and five occurred in the placebo group. The most common adverse events among patients in part A included nasopharyngitis, headache or injection site pain. During the first 85 days in part B, 10 patients who received lumasiran reported adverse events compared with two patients on placebo. The most common adverse events included abdominal pain, headache, rhinitis or nephrolithiasis.
All lumasiran-treated patients in part B achieved a near-normal 24-hour urinary oxalate excretion of at least 1.5 times upper level of normal (0.69 mmol/24 h per 1.73 m²), and 75% of patients were within the normal range (0.46 mmol/24 h per 1.73 m²). Among the 12 patients treated with 3 mg/kg once monthly or once every 3 months, 92% had 24-hour urinary oxalate excretion levels within the normal range.
The responses observed from patients in part A concerning plasma glycolate concentrations, with the lowest dose producing “an appreciable pharmacologic effect,” allowed researchers to select a 1 mg/kg dose for patients in part B. The 3-mg/kg once monthly dose regimen appeared to exhibit a faster and greater reduction of 24-hour urinary oxalate excretion compared with the 1-mg/kg once monthly and 3-mg/kg once every 3 months dosing. Also, patients treated with lumasiran 3 mg/kg once every 3 months saw a sustained effect on urinary oxalate through one dosing period.
“These findings suggest that the profound lowering of urinary oxalate excretion observed following lumasiran treatment may lead to improvements in clinical outcomes, such as kidney stone events, nephrocalcinosis and kidney function,” Frishberg and colleagues wrote.
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