In the past, there have been few effective treatments for patients with primary hyperoxaluria type 1 (PH1), a genetic disorder causing kidney damage and failure. But, according to News Medical, that might soon change. Lumasiran, a RNAi therapy, has shown promising results in its Phase 3 study.
Primary Hyperoxaluria Type 1 (PH1)
Primary hyperoxaluria type 1 (PH1) is a rare, autosomal recessive inherited disorder that impacts kidney function. Autosomal recessive inherited means that patients with PH1 must receive one mutated gene from each parent. In this case, it is the AGXT gene, which stimulates production of an enzyme called alanine-glyoxylate aminotransferase. The mutated gene stops the body from breaking down glyoxylate, leading to a buildup of oxalate. Normally, oxalate is removed from the body through urine. However, excess oxalate and calcium together can lead to organ damage, particularly in the kidneys. In fact, calcium oxalate is a main characteristic of kidney stones.
Symptoms vary in severity. Additionally, onset varies; PH1 can impact people of all ages. The Genetic and Rare Diseases Information Center (GARD) notes that around 19% of people with PH1 experience severe symptoms within a few months of birth; alternately, some cases are so mild that patients aren’t diagnosed until their 40’s or 50’s. However, it most commonly occurs around 5-6 years old. Symptoms include:
- Kidney and bladder stones
- Painful and frequent urination
- Bloody urine
- Fever and chills
- Abdominal pain
- Stunted growth (“failure to thrive”)
- Kidney damage
- Renal failure
- Extreme fatigue, loss of appetite, anemia, pale skin, nausea and vomiting, infrequent urination
Learn more about PH1.
According to Alnylam, the developer, Lumasiran is:
an investigational, subcutaneously administered (under the skin) RNA interference (RNAi) therapeutic targeting glycolate oxidase (GO) in development for the treatment of primary hyperoxaluria type 1 (PH1).
RNA interference (RNAi) works by targeting mRNA and preventing them from creating disease-causing proteins. As a result, RNAi therapies are able to silence or prevent the expression of mutated or disease-causing genes. This therapeutic option could change the future of disease treatment through its ability to specifically target certain genes, making it a customizable solution.
In this case, Lumasiran inhibits the HAO1 gene, thus stopping the liver from producing oxalate.
Prior PH1 Treatments
In the past, those with PH1 did not have many effective, well-tolerated, or accessible treatment options. Those included:
- Drinking 2-3 liters of water per day
- Kidney and liver transplant
- Administration of vitamin B6 or alkali citrate
Most of these treatments look to treat the symptoms of PH1. However, none of them address the underlying cause.
Lumasiran Results as Presented at the ERA-EDTA Congress
Like many events, this year’s ERA-EDTA Congress was moved online because of COVID-19. However, the 4-day event consisted of 100 sessions, 350 presentations, 1800 e-posters, and 200 speakers. During this time, Alnylam shared the results of the Phase 3 study designed to analyze Lumasiran’s safety, tolerability, and efficacy:
- The study was randomized, double-blind, and placebo-controlled.
- Patients were randomly assigned (2:1) into either a treatment group or a control group. Neither the participants nor the doctors knew who was receiving what treatment: Lumasiran or the placebo.
- 39 patients, aged 6 and older, participated
- Patients received either Lumasiran or a placebo once a month for 3 months. Next, they received one dose every 3 months.
- 65.4%: the baseline change in urinary oxalate for patients on Lumasiran
- 11.8%: the baseline change in urinary oxalate for patients on the placebo
- 0%: the amount of placebo-treated patients who achieved normalization or near-normalization
- 52% and 84%: the amount of Lumasiran-treated patients who achieved normalization and near-normalization, respectively
In addition to showing extremely positive results for patients as compared to the placebo, patients taking Lumasiran experienced no serious side effects. The most common side effect was an injection-site reaction. As a result, Lumasiran seems mostly safe and well-tolerated.