Pivotal phase 3 trial of lumasiran in PH1 meets primary end point

The pivotal phase 3 ILLUMINATE-C trial of lumasiran (Oxlumo) in patients of all ages with advanced primary hyperoxaluria type 1 (PH1) or PH1 associated with progressive decline in renal function has met its primary endpoint, according to Alnylam Pharmaceuticals, the developer of the RNA interference agent.1

Results of the 6-month primary analysis from the open-label, single arm ILLUMINATE-C trial (NCT04152200) showed that in both dialysis-independent and -dependent patients, lumasiran induced a substantial reduction in plasma oxalate. The treatment also met several key secondary end points, including additional measures of plasma oxalate and measures of urinary oxalate.

Alnylam reported in a release that the actual data from the ILLUMINATE-C trial would be shared at a medical conference by the end of the year. The company also plans to submit the data to regulatory authorities in the United States and the European Union.

"Through the ILLUMINATE clinical program, we are hoping to establish that lumasiran may be a therapeutic option for PH1 patients regardless of age or disease severity, including patients on hemodialysis," Jeroen Valkenburg, general manager, Lumasiran program at Alnylam, stated in the release.

Patients with the rare metabolic disorder PH1 produce excess oxalate, which, when combined with calcium, can cause kidney stones and loss of kidney function. Lumasiran works by inhibiting the production of oxalate.

In November 2020, the FDA approved lumasiran as the first drug for the treatment of patients with PH1.2 The drug was approved for both adult and pediatric patients. The approval of lumasiran was supported by data from the phase 3 ILLUMINATE-A and ILLUMINATE-B studies.

The phase 3 open-label ILLUMINATE-A trial (NCT03681184) included 39 patients aged ≥6 years with PH1. Overall, 26 patients were randomized to lumasiran and 13 were randomized to placebo.

In the treatment arm, patients received subcutaneous lumasiran monthly for 3 months followed by quarterly maintenance doses at 3 mg/kg. The primary outcome measure was percent change in 24-hour urinary oxalate excretion from baseline to month 6.

Among patients in the lumasiran arm, there was a 65% average reduction of oxalate in the urine compared with an average reduction of 12% in the placebo arm. Over half (52%) of patients receiving lumasiran achieved a normal 24-hour urinary oxalate level at 6 months, compared with no patients in the placebo group.

Regarding safety, investigators determined the drug to be safe and tolerable. No severe or serious adverse events (AEs) were reported and there were no patient deaths.3 All AEs were mild to moderate. The most common AE was injection site reactions, which occurred in 35% of patients.

The open-label, single-arm phase 3 ILLUMINATE-B trial (NCT03905694) evaluated lumasiran in patients aged under 6 years with PH1. Among 16 evaluable pediatric patients, lumasiran treatment led to an average decrease of 71% in urinary oxalate at the 6-month point of the study.

The investigators reported that lumasiran had an acceptable safety profile in the pediatric population.4 No patients discontinued treatment or withdrew from the study, and no severe AEs or patient deaths occurred. The most common AE was mild injection-site reactions, which occurred in 3 patients. Also, there were no clinically relevant changes in laboratory measures, vital signs, or electrocardiograms.

According to the FDA, approximately 80% of all PH cases are PH1, and the rare disease affects an estimated 1 to 3 people per million in North America and Europe.

Lumasiran is also approved in the European Union for the treatment of PH1 in both pediatric and adult patients.

References

1. Alnylam Reports Positive Results From Phase 3 Study Of Lumasiran In Primary Hyperoxaluria Type 1. Published online July 29, 2021. Accessed July 29, 2021. https://bit.ly/3fabWNf.

2. FDA Approves First Drug to Treat Rare Metabolic Disorder. Published online November 23, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-rare-metabolic-disorder. Accessed July 29, 2021

3. ILLUMINATE-A Phase 3 Results for Lumasiran Presented at ERA-EDTA. Published online June 7, 2020. https://www.alnylam.com/2020/06/07/era-edta-2020. Accessed July 29, 2021

4. ILLUMINATE-B Phase 3 Results for Lumasiran Presented at ASN. Published online October 22, 2020. https://www.alnylam.com/2020/10/22/asn-2020. Accessed July 29, 2021.