Lumasiran reduces plasma oxalate in advanced PH1

Treatment with the RNAi therapeutic lumasiran led to a significant reduction in plasma oxalate and pre-dialysis oxalate levels in patients with advanced primary hyperoxaluria type 1 (PH1), according to the 6-month primary analysis of phase III ILLUMINATE-C trial presented at ASN Kidney Week 2021.

PH 1 is a rare genetic disease marked by progressive kidney failure and multi-organ dysfunction.

“Elevated plasma oxalate levels are responsible for much of the morbidity associated with advanced PH1,” said study investigator Dr Mini Michael, a paediatric nephrologist at Texas Children’s Hospital in Texas, US. “It can result in oxalosis, leading to bone  fractures, cardiomyopathy, vision loss, skin ulcers, and other serious manifestations.” 

Excess oxalosis can result in recurrent kidney stones, nephrocalcinosis, progressive kidney disease, and ultimately, kidney failure, Michael continued. “Patients who progress to, or present with kidney failure, require intensive haemodialysis and liver or combined liver-kidney transplants.”

The ILLUMINATE-C study included 21 patients with confirmed PH 1 diagnosis– six with stage 3b to 5 chronic kidney disease (CKD) but did not require dialysis and 15 patients on haemodialysis. They had confirmed PH1 diagnosis, an eGFR of 45 mL/min/1.73m² or less, if they were >1 year of age (stages 3b–5 CKD), or elevated serum creatinine if age is <12 months. All patients had a plasma oxalate level of 20 μmol/L or higher at baseline.  [ASN Kidney Week 2021, abstract FR-OR64]

The primary efficacy endpoint was the percent change in plasma oxalate and pre-dialysis plasma oxalate from baseline to 6 months, averaged across months 3–6. Patients’ median age was 8; 43 percent were female. Median dialysis sessions were 6 per week among those on dialysis.

Treatment with lumasiran led to a 33-percent reduction in plasma oxalate and a 42-percent reduction in pre-dialysis plasma oxalate from baseline to month 6. “The reduction in plasma oxalate was evident by month 1 and persisted through the end of 6 months,” reported Michael.  

“This reduction was marked by a 10.56-percent change in 24-hour urinary oxalate from baseline to month 6, as well as an almost 40-percent change in spot urinary oxalate-to-creatinine ratio during the treatment period,” she added.

Treatment with lumasiran was safe and generally well-tolerated, with the adverse events (AEs) being mild or moderate. Pyrexia and injection-site reactions (29 percent and 24 percent, respectively) were the most common AEs reported.  No patients withdrew from the study or discontinued treatment early. There were no severe adverse events reported, nor deaths.

“Changes in plasma oxalate of the magnitude seen in this study are encouraging and may positively impact long-term clinical outcomes, including those related to systemic oxalosis,” Michael said. “A 54-month extension period is now underway.”

Lumasiran is US-FDA approved for paediatric and adult patients with PH1 to lower urinary oxalate levels.  The drug is administered subcutaneously at three monthly starting doses, followed by monthly or quarterly doses.