Lumasiran - Uses, Dosage, and Pharmacology

Overview

On November 23, 2020, the U.S. Food and Drug Administration approved Lumasiran for treating primary hyperoxaluria type 1 (PH1), a rare genetic disorder. This approval is a combined effort of expert scientists and community members coordinated by the Oxalosis & Hyperoxaluria Foundation and the Kidney Health Initiative. Primary hyperoxaluria (PH) is caused by excess oxalate (a substance used in food and produced by the body). Primary hyperoxaluria type 1 (PH1) is the most common and severe. PH1 affects approximately one to three individuals per million in North America and Europe and accounts for approximately 80 percent of PH cases.

Patients with PH1 produce excessive amounts of oxalate, which, combined with calcium, can cause kidney stones and deposits in the kidneys. Patients might suffer from progressive kidney damage, which can further lead to kidney failure and require dialysis (a procedure that purifies the blood). As kidney function worsens, oxalate can build up and damage other organs, including the heart, bones, and eyes. In this article, one will understand Lumasiran, its mechanism of action, clinical trials, and the potential impact on patients' lives.

Dosage and Administration:

Recommended Dosage:

The recommended dosing regimen of Lumasiran consists of loading doses after the maintenance dose is administered subcutaneously. Dosing is based on actual body weight.

Weight-Based Dosing Regimen:

1. Less Than 10 kg:

• Loading Dose - 6 milligrams/kilograms (mg/kg) once monthly for three doses.

• Maintenance Dose (Start One Month After the Last Loading Dose) - 3 mg/kg once monthly.

2. 10 kg to Less Than 20 kg:

• Loading Dose - 6 mg/kg once monthly for three doses.

• Maintenance Dose (Start One Month After the Last Loading Dose)- 6 mg/kg once every three months (quarterly).

3. 20 kg and Above:

• Loading Dose - 3 mg/kg once monthly for three doses.

• Maintenance Dose (Start One Month After the Last Loading Dose) - 3 mg/kg once every three months (quarterly).

For Patients

What Is Primary Hyperoxaluria Type 1 (PH1)?

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that causes the overproduction of oxalate, resulting in the formation of kidney stones and can damage various organs. PH1 is an inherited metabolic disorder seen as a result of a mutation in the AGXT (Alanine--Glyoxylate Aminotransferase) gene, resulting in the liver's inability to break down glyoxylate entirely into harmless byproducts. The glyoxylate is converted to oxalate, leading to its accumulation in the kidneys and other organs. The excess oxalate can crystallize, forming kidney stones and contributing to the development of nephrocalcinosis and chronic kidney disease.

Patients with PH1 often complain about recurrent kidney stones, abdominal pain, and urinary tract infections. Over the years, progressive damage to the kidneys can lead to renal failure, posing a great threat to the patient's overall health and quality of life. Managing PH1 has been difficult, emphasizing the immediate need for innovative treatment options.

Why Is Lumasiran Prescribed?

Lumasiran is prescribed mainly for treating primary hyperoxaluria type 1 (PH1). PH1 is a rare genetic disorder caused by the overproduction of oxalate, resulting in the formation of kidney stones and can damage various organs, especially the kidneys. Lumasiran addresses the primary reason for PH1 and provides a targeted therapeutic approach to lower oxalate levels in the body.

Lumasiran is prescribed for the following reasons:

• Targeted Gene Therapy: Lumasiran is an RNA (ribonucleic acid) interference therapeutic that acts on the liver's hydroxy acid oxidase 1 (HAO1) gene. By inhibiting the expression of HAO1, Lumasiran lowers the production of the enzyme glycolate oxidase (GO), an enzyme that plays a vital role in converting glycolate to glyoxylate. This mechanism directly affects the genetic basis of PH1, resulting in a reduction in the levels of glyoxylate and, subsequently, oxalate.

• Reduction of Oxalate Levels: The primary goal of prescribing Lumasiran is to decrease excessive oxalate production in individuals with PH1. By reducing oxalate levels, Lumasiran helps stop the formation of kidney stones and reduce the risk of nephrocalcinosis (deposition of calcium in the kidneys) and chronic kidney disease associated with PH1.

• Improvement in Patient Outcomes: Lumasiran has been associated with improving the overall well-being of individuals with PH1. Patients in clinical trials reported decreased frequency and severity of kidney stone episodes, leading to an enhanced quality of life.

• Potential to Prevent Complications: By decreasing oxalate levels, Lumasiran can avoid complications associated with PH1, including progressive kidney damage that could lead to renal failure. Early intervention with Lumasiran can help manage the condition and improve long-term outcomes for patients with PH1.

Missed Dose:

Lumasiran must be administered immediately if a dose is delayed or missed. Continue taking the prescribed monthly or quarterly dose from the most recent dose administered.

Dosage:

Injection:

94.5 mg/0.5 mL clear, colorless-to-yellow solution in a single-dose vial.

Contraindications:

There are no contraindications for the patient's use of this medication.

For Doctors

Lumasiran belongs to a new class of drugs known as RNA interference (RNAi) therapeutics. This revolutionary approach helps the body's natural RNA silencing process to target and inhibit the expression of specific genes. In the case of Lumasiran, the target is the hydroxy acid oxidase 1 (HAO1) gene, the gene responsible for producing the enzyme glycolate oxidase (GO).

GO plays a significant role in converting glycolate to glyoxylate in the liver. By inhibiting the expression of HAO1, Lumasiran effectively reduces the production of GO, thereby decreasing the levels of glyoxylate and subsequent oxalate formation. This mechanism of action directly deals with the root cause of PH1, showing a promising therapeutic avenue.

Indications:

1. Primary Hyperoxaluria Type 1 (PH1): Lumasiran is specifically approved for treating individuals diagnosed with PH1, a rare inherited metabolic disorder caused by a mutation in the AGXT gene. In PH1, the liver's inability to properly break down glyoxylate leads to the overproduction of oxalate, resulting in kidney stones and potential damage to the kidneys and other organs.

2. Reduction of Urinary Oxalate Levels: Lumasiran is designed to lower urinary oxalate levels, addressing the underlying metabolic imbalance associated with PH1. By inhibiting the expression of the hydroxy acid oxidase 1 (HAO1) gene in the liver, Lumasiran reduces the production of the enzyme glycolate oxidase (GO), further reducing the glyoxylate and oxalate levels.

3. Prevention of Kidney Stone Formation: One of the primary goals of Lumasiran therapy is to inhibit the formation of kidney stones, a common and agonizing symptom of PH1. Lumasiran aims to mitigate the risk of kidney stone episodes and related complications by lowering urinary oxalate levels.

Administration:

• Divide injection volumes of more than 1.5 milliliters (mL) equally into multiple syringes.

• A sterile 0.3 mL syringe can be used for less than 0.3 mL volumes.

• Administer subcutaneous injection into the abdomen, the side or back of the upper arms or thigh.

• Do not inject around the navel when injecting into the abdomen.

• Keep rotating injection sites.

• Avoid injecting into scar tissue or inflamed, reddened, or swollen areas.

• If more than one injection is required for a single dose of Lumasiran, the injection sites must be separated by a distance of at least two centimeters.

• Discard unused portions of the drug.

Instructions:

• Lumasiran is used subcutaneously and should be administered by a healthcare professional.

• Inspect the drug product solution properly. Avoid using it if it contains particulate matter or if it is discolored.

• Lumasiran is a preservative-free, clear, sterile, and colorless-to-yellow solution.

• It is available as a single-dose vial, a ready-to-use solution that does not require additional reconstitution or dilution before administration.

Pharmacology:

Lumasiran is an innovative RNA interference (RNAi) therapeutic designed to deal with the underlying genetic cause of primary hyperoxaluria type 1 (PH1). The drug targets a specific gene involved in the overproduction of oxalate, providing a unique mechanism to reduce urinary oxalate levels.

Mechanism of Action:

• RNA Interference (RNAi) Technology: Lumasiran utilizes RNAi, a natural cellular process that manipulates gene expression by silencing specific messenger RNA (mRNA) molecules. RNAi involves the introduction of small interfering RNA (siRNA) molecules into the cell. These siRNA molecules are designed to match the sequence of the target gene.

• Target Gene Selection: The target gene for Lumasiran is hydroxy acid oxidase 1 (HAO1). HAO1 encodes the enzyme glycolate oxidase (GO), which is crucial in converting glycolate to glyoxylate in the liver.

• Inhibition of Glycolate Oxidase (GO): Lumasiran particularly inhibits the expression of the HAO1 gene in the liver cells. This helps Lumasiran to reduce the production of GO, the enzyme responsible for converting glycolate to glyoxylate.

• Reduction of Glyoxylate and Oxalate Production: With lowered GO activity, there is a subsequent decrease in the conversion of glycolate to glyoxylate. Glyoxylate is a precursor to oxalate, and by lowering glyoxylate levels, Lumasiran effectively decreases the overall production of oxalate in the liver.

Clinical Trials and Efficacy:

The development of Lumasiran has undergone thorough testing by undergoing a series of clinical trials. The pivotal Phase 3 trial, called the ILLUMINATE-A study, documents the efficacy and safety of Lumasiran in a diverse group of patients with PH1. The trial included all ages ranging from pediatric to adults, highlighting the broad spectrum of individuals affected by this rare genetic disorder.

Results from the ILLUMINATE-A study demonstrated a remarkable decrease in urinary oxalate levels among Lumasiran-treated patients compared to those administered with a placebo. The study's primary endpoint, the percent change in 24-hour urinary oxalate excretion, revealed a statistically essential reduction, proving Lumasiran's potential to address the metabolic imbalance in individuals with PH1. Further, Lumasiran has shown a favorable safety profile, with most adverse events from mild to moderate severity. The positive results of the clinical trials have proved that Lumasiran is a frontrunner in the race to provide a transformative treatment for PH1.

Specific Considerations:

• Pregnancy Risk Summary: There is no data available on the usage of in pregnant women to evaluate major birth defects, drug-associated risk of miscarriage, or adverse maternal or fetal outcomes. No adverse effects on pregnancy or embryo-fetal development related to Lumasiran were observed in rats at 45 times and in rabbits at 90 times the maximum human dosage in women recommended. The risk of major birth defects and miscarriage in the pregnant population is an area that remains unclear. All pregnancies have a risk of birth defects, child loss, or other adverse effects. In the United States, the risk of miscarriage and major birth defects in clinically recognized pregnancies is 15 to 20 percent and 2 to 4 percent, respectively.

• Lactation Risk Summary: No relevant data is available on the presence of human milk, the effects on the breastfed child, or the effects of the drug on milk production. The growth and health benefits of breastfeeding should be kept in mind, along with the mother’s need for any adverse effects on the breastfed child from Lumasiran or the underlying maternal problems.

• Pediatric Use: Lumasiran's safety and effectiveness have been studied and established in pediatric patients.

• Geriatric Use: No sufficient clinical studies of Lumasiran have been performed on patients aged 65 and over to understand whether they respond differently from younger patients.

• Hepatic Impairment: No dose adjustment is advised for patients with mild or moderate hepatic impairment. Lumasiran has not been studied in patients with severe hepatic impairment.

• Renal Impairment: No dose adjustment is required for patients with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2. Lumasiran has not been studied in patients with an eGFR of less than 30 mL/min/1.73 m2 or patients on dialysis.

Conclusion:

Lumasiran is a testament to the significant progress made in rare genetic disorders. With its unique mechanism of action, supported by robust clinical trial data, Lumasiran offers renewed hope for individuals battling primary hyperoxaluria type 1. As this innovative RNAi therapeutic makes its way into clinical practice, the landscape of PH1 treatment is set to undergo a transformative shift, paving the way for improved patient outcomes and a brighter future for those affected by this challenging condition.