Lumasiran shows therapeutic potential for primary hyperoxaluria type 1

The RNAi* therapeutic agent lumasiran demonstrated favourable clinical outcomes for primary hyperoxaluria type 1 (PH1) in both paediatric and adult patients, according to the results of the phase III ILLUMINATE-A and ILLUMINATE-B trials presented at PAS 2021.

“[Our findings] demonstrated encouraging early results … PH1 patients treated with lumasiran had reduced urinary oxalate excretion, stable eGFR**, and improved [renal stone event (RSE)] rates and nephrocalcinosis (NC) severity, with a very reassuring safety profile,” said Dr David Sas from the Mayo Clinic, Rochester, Minnesota, US, during his presentation.

PH1 involves overproduction of oxalates that may lead to the formation of kidney stones, NC, progressive kidney disease, and multiorgan damage which may eventually require liver and kidney transplants, said Sas. The procedures and hospitalizations associated with stone removal are a primary cause of morbidity in PH1. [Clin J Am Soc Nephrol 2020;15:1056-1065l]

Evidence has shown that lumasiran, an FDA-approved RNAi for PH1, significantly reduced urinary oxalate excretion relative to placebo in patients aged 4 months to 60 years, with an acceptable safety profile. [Nephrol Dial Transplant 2020;35:suppl 3; ASN 2020, abstracts PO2637 and PO1624] Lumasiran also reduces hepatic oxalate production by inhibiting glycolate oxidase production which, according to Sas, “is a critical step along the oxalate metabolic pathway”.

ILLUMINATE-A randomized 39 participants ≥6 years of age (eGFR ≥30 mL/min/1.73 m²) 2:1 to receive SC lumasiran or placebo for 6 months. Following which, 13 placebo recipients crossed over to lumasiran for another 6 months. The single-arm, open-label ILLUMINATE-B trial enrolled 18 participants <6 years of age (eGFR >45 mL/min/1.73 m² [≥12 months old]; normal serum creatinine [<12 months old]) to receive lumasiran for 6 months. The studies looked into NC grade and RSE and eGFR rates. [PAS 2021, abstract 1940; N Engl J Med 2021;384:1216-1226]

ILLUMINATE-A

At 6 months, NC grade improved in four lumasiran recipients (one bilateral, three unilateral) vs none in the placebo arm. NC grade worsening was seen in one participant in each treatment arm. The number of participants whose NC grades remained stable were 29 and 11 in the respective lumasiran and placebo arms.

At 12 months, NC grade improved in 11 (eight bilateral, three unilateral) and worsened in three patients (one bilateral, two unilateral).

Among those with available ultrasounds at 6 (n=27) and 12 months (n=14), improvements were seen in four and 11 participants, respectively. Of these, eight patients had improvements in both kidneys at 12 months.

Compared with the previous 12-month results, among those who received lumasiran at baseline, RSE rates dropped during the first 6 months of lumasiran treatment (from 3.19 to 1.09/person-year), and was sustained at 12 months (0.85/person-year). For those who crossed over from placebo, a drop in RSE rate was evident at month 12 (from 0.54 to 0.17/person-year).

ILLUMINATE-B

At 6 months, eight participants had NC grade improvements (three bilateral, five unilateral). NC grades remained stable in 10 individuals. No worsening was observed. The RSE rate from the previous 12 months was sustained through month 6 (0.24 per person/year).

Important improvements

Both studies also reflected stable eGFRs with lumasiran through month 12 (ILLUMINATE-A) and month 6 (ILLUMINATE-B).

“Due to the causal role of urinary oxalate in kidney stone formation, NC, and kidney function decline, a substantial reduction in urinary oxalate levels is expected to confer clinical benefit in patients with PH1 … [Moreover, the NC] improvements are important as there is evidence that the presence of NC is a risk factor for progression of chronic kidney disease in PH1,” explained Sas.

The 54-month extension phase of both trials is anticipated to reflect more data on the effect of lumasiran on kidney function, RSEs, and NC.