According to a recent article in BioSpace, young children and infants who have been diagnosed with primary hyperoxaluria type 1 (PH1) are often faced with the use of gastrostomy feeding tubes enabling direct nutrition into the stomach.
Children with advanced disorders often undergo dialysis and organ transplantation.
About Primary Hyperoxaluria Type 1 (PH1)
This disease is classified as ultra-rare. Overproduction of oxalate results in calcium oxalate crystals that form in the urinary tract and kidneys. This leads to painful, recurrent kidney stones and a disorder that causes calcium deposits in the kidneys called nephrocalcinosis. It is common in premature babies.
Excess oxalate can no longer be excreted effectively resulting in crystallization in various parts of the body. Renal damage occurs. The result is severe illness leading to eventual death.
Limited Treatment Options
Treatment options are limited to dialysis or organ transplantation. A combined organ transplant of liver and kidney carries high morbidity with limitations due to the availability of these organs.
Currently, there are no pharmaceutical therapies available for PH1.
The Phase III Study (NCT03905694)
Alnylam Pharmaceuticals, headquartered in Cambridge, Massachusetts, now reports positive results from its Phase III study evaluating the efficacy and safety of lumasiran for PH1. Lumasiran is a new class of drug and is being studied in adults as well as infants and children under six.
Lumasiran, an investigational RNAi therapeutic, showed a significant decrease in urinary oxalate levels compared to baseline levels.
The company’s vice president commented that lumasiran’s safety results in the latest study compare favorably with those reported in the ILLUMINATE-A study (NCT03681184) that involved children over age six.
About Lumasiran and RNAi
RNA interference (RNAi) gene silencing is considered a major breakthrough that occurs only once in each decade. The therapeutic platform was recognized with a Novel Prize in 2006.
Alnylam’s RNAi is a revolutionary approach that harnesses the natural process of RNAi. This process affects cells by silencing the genetic precursors that encode for the disease-causing proteins. In that way, the proteins cannot be produced.
ILLUMINATE-B Study Results (NCT03905694)
The ILLUMINATE-B trial is a single-arm Phase 3 trial with both health providers and patients aware of the treatment (open-label). Eighteen patients with PH1 under the age of six participated at nine sites throughout five countries.
The dosage of lumasiran was distributed according to weight. At the six month interval in relation to baseline, the drug showed a significant reduction in urinary oxalate/creatinine ratio.
Lumasiran met the primary endpoint in the three bodyweight categories. No serious adverse events were reported. Tolerability and safety results were consistent with the ILLUMINATE-A trial results.
About the Oxalate Molecule
PH1 occurs due to the overproduction of oxalate which, after being filtered through the kidneys, is excreted in the urine. Oxalate is a molecule that is not a nutritional requirement but it is found in humans and plants. Abnormally high levels of oxalate in the urine can result in hyperoxaluria.
When it is excreted, oxalate may combine with calcium forming calcium oxalate, the main substance in bladder, and kidney stones. These deposits may damage the kidneys or other organs leading to hematuria (blood in the urine), infections in the urinary tract, and end-stage renal disease (ESRD).
Alnylam is conducting the ILLUMINATE-C trial which is a global Phase III study of lumasiran involving PH1 patients. This study will include patients of all ages who have advanced renal disease. It will also include patients on dialysis. The results are anticipated in 2021.
FDA and EU Approval
Lumasiran has received various designations from the FDA and European Union including the EMA’s PRIME, Orphan Drug, Rare Pediatric Disease, and Breakthrough Therapy.
The FDA has set a date in December 2020 for a priority review of Alnylam’s lumasiran.
The director of the Oxalosis & Hyperoxaluria Foundation expressed its gratitude to Alnylam for its commitment to designing a study addressing the needs of such a vulnerable group of babies and young children.
She said that it is their belief that reducing urinary oxalate will have a favorable impact on the management and disease progression in these young patients.