Lumasiran Effects in Rare Disease Seen Despite Kidney Status

Nancy A. Melville

November 09, 2021

Lumasiran has shown benefit in reducing plasma oxalate in patients with primary hyperoxaluria type 1 (PH1) and severely impaired kidney function, according to new research. 

Lumasiran (Oxlumo, Alnylam Pharmaceuticals), an RNA interference (RNAi) therapeutic agent, was recently approved in the United States as the first drug to treat PH1, a rare genetic disorder. 

"So far, the effects [of lumasiran in reducing oxalate generation] have been fairly dramatic in patients with preserved kidney function," study co-investigator John C. Lieske, MD, director of the O'Brien Urology Research Center at the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

"The Illuminate-C study now suggests that the effect on oxalate generation is significant enough to reduce plasma oxalate in patients with chronic kidney disease (CKD)," he said.

Commenting on the study, David S. Goldfarb, MD, said the treatment's clinical implications could be profound.

"Reductions in plasma oxalate are very important to patients with [PH1 and] CKD, and especially those on dialysis, since they are associated with oxalosis," he said.

"Lowering it by giving what appears to be a safe therapy is an amazing scientific breakthrough," added Goldfarb, clinical chief of nephrology at NYU Langone Health, New York City.

The findings were presented by first author Mini Michael, MD, of the Division of Nephrology, Department of Pediatrics, Texas Children's Hospital/Baylor College of Medicine, in Houston, at the virtual Kidney Week 2021.

A Potentially Life-Threatening Disorder

PH1, a potentially life-threatening progressive disorder, is characterized by the hepatic overproduction of the metabolite oxalate, which acts as a toxic driver of progressive kidney disease, systemic oxalosis, and ultimately, organ damage.

Patients often present with kidney stones, however, the rare condition can go misdiagnosed for years, and in advanced disease, patients require intensive dialysis, often as a bridge to a dual kidney/liver transplant.

Lumasiran, administered subcutaneously, inhibits the production of oxalate, and in the recent phase 3 double-blind ILLUMINATE-A clinical trial, published in April 2021, the therapy was shown to lead to significant reductions in urine and plasma oxalate excretion levels in children and adults as early as 1 month of treatment, with most patients (84%) showing normal or near-normal levels after 6 months.

The current ILLUMINATE-C trial was designed to further investigate the drug's effects among people with advanced renal disease, including those on dialysis.

The 21 participants had a genetically confirmed PH1 and included children and adults. Patients had CKD stages 3b to 5, with an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73m2 or lower and plasma oxalate levels of at least 20 μmol/L, well above the upper limit of normal (12 μmol/L).

Patients were stratified into cohorts of those not requiring dialysis or kidney transplantation at baseline (n = 6; median age 9 [0-40]) and those on stable hemodialysis prior to screening (n = 15; median age 6 [1-59]).

Mean baseline levels of plasma oxalate in the nondialysis and dialysis groups were 64.7 μmol/L and 108.4 μmol/L, respectively. All patients completed the 6-month primary analysis period, consisting of monthly weight-based injections of lumasiran for 3 months.

Results Not Surprising but Important to Demonstrate

For the primary endpoint of change in plasma oxalate levels from baseline to month 6, the reduction was substantial in both groups, with a 33.3% mean reduction among those not requiring dialysis and a 42.4% mean reduction among those who did require dialysis.

Reductions in plasma oxalate were observed by month 1 in both cohorts and persisted through the end of the 6-month primary analysis period. All patients who were not on dialysis maintained their renal function.

Treatment with lumasiran was also associated with reductions in urinary oxalate among those not requiring dialysis.

Plasma glycolate levels, evaluated as an exploratory endpoint, showed initial increases followed by a plateau in both cohorts, consistent with a reduction in hepatic glycolate oxidase activity driven by lumasiran.

No serious or severe adverse events relating to lumasiran treatment were reported, with the most common adverse events involving mild injection-site reactions and pyrexia. No treatment discontinuations or study withdrawals were reported.

"Similar magnitudes of plasma glycolate increases in (both cohorts) and previously completed studies in patients with relatively preserved kidney function suggest similar pharmacodynamics of lumasiran regardless of kidney function," Michael said when presenting the findings.

Lieske noted that, given the positive results of ILLUMINATE-A, the current results were not surprising, "however, it was important to demonstrate that, in a relatively short time frame, the effect of lumasiran was enough to significantly reduce plasma oxalate levels," he said.

"The effect size seen in this study should reduce the risk of oxalosis," he said, but cautioned that "the time frame of the current data is not long enough to know for sure that this will be the case or what the magnitude of risk reduction for oxalosis might be over the long term."

Key questions that remain include the drug's effects in various genotypes, the effect on those required to remain on longer-term hemodialysis, and the long-term safety profile, Lieske added.

Goldfarb added that more data are needed to determine the effects on the avoidance of oxalosis and other factors, however, the results nevertheless appear encouraging.

"Ultimately, we would hope that these treatments will preclude the development of kidney failure, but until then, this is likely to be a clinically meaningful effect," he said.

The study was funded by Alnylam Pharmaceuticals. Lieske has reported receiving research grants from and consulting for Alnylam. Goldfarb was a member of the data safety monitoring board for Alnylam's ILLUMINATE studies.

Kidney Week 2021. Presented November 5, 2021.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.