In late November, RNAi therapeutics company Alnylam Pharmaceuticals (“Alnylam”) announced that its therapy OXLUMO (Lumasiran) received approval from the European Commission (EC) for both pediatric and adult patients with primary hyperoxaluria type 1 (PH1). By receiving this marketing authorization, Alnylam is moving forward in their goal of treating patients with rare conditions using RNA interference therapies. Currently, OXLUMO is the first approved therapy for patients with PH1.
Before this approval, no therapies were approved in Europe to treat patients with PH1. Now, Alnylam has marketing authorization for OXLUMO (Lumasiran). This RNA interference (RNAi) therapy directly targets hydroxyacid oxidase 1 (HAO1), which plays a role in raising oxalate levels and contributes to the development of PH1. The UMass Medical School’s RNA Therapeutics Institute describes RNAi as:
a cellular mechanism that use the gene’s own DNA sequence of gene to turn it off, a process that researchers call silencing. During RNAi, long double-stranded RNA (dsRNA) is cut or “diced” into small fragments ~21 nucleotides long [siRNA, which] bind to proteins from a special family: the Argonaute proteins.
Once siRNA binds to Argonaute proteins, it begins to remove some of the dsRNA. By using RNAi therapies, researchers are able to silence genes, learn how specific genes function, and treat genetic conditions. With OXLUMO, the therapy inhibits oxalate production.
In the ILLUMINATE-A clinical trial, OXLUMO reduced urinary oxalate levels; it was also shown to be safe, effective, and relatively well-tolerated in the Phase 3 ILLUMINATE-B trial. In some patients, the therapy reduced oxalate levels to normal or near-normal levels. OXLUMO is administered subcutaneously. While there were some side effects, they were relatively mild and included abdominal pain or discomfort and injection site reactions. In addition to receiving Orphan Drug and Priority Medicines designations in Europe, OXLUMO is currently under Priority Review in the United States.
Primary Hyperoxaluria Type 1 (PH1)
Resulting from AGXT gene mutations, primary hyperoxaluria type 1 (PH1) is a rare kidney disorder. Normally, AGXT tells the body to make alanine-glyoxylate aminotransferase, a type of enzyme. Usually, this enzyme breaks down glyoxylate. However, gene mutations prevent this breakdown from occurring. As a result, oxalate, normally filtered through the kidneys and removed through urine, accumulates in the urinary tract and kidneys. When it combines with calcium, it forms the foundation for bladder and kidney stones. Up to 10% of patients experience PH1 symptoms as infants.
- Kidney and bladder stones
- Bloody urine
- Failure to thrive
- Painful urination
- High levels of calcium in the urine (for pediatric patients)
- Abdominal pain
- Frequent urinary tract infections (UTIs)
- Kidney damage and renal failure
Early diagnosis and treatment improve patient outcomes. Currently, OXLUMO is the first approved treatment for PH1. Prior to OXLUMO, treatments included dietary supplements, fluid intake, dialysis, and organ transplants.