Nedosiran for Primary Hyperoxaluria Type 1 - An Overview

Overview:

Nedosiran, an RNA (ribonucleic acid)-targeted drug, is a therapeutic drug used to treat excessive oxalate production in a genetic condition called primary hyperoxaluria type 1. It is given to adults and children more than nine years of age. Nedosiran, a double-stranded small interfering RNA (siRNA), aims to reduce hepatic glyoxylate production by inhibiting the enzyme lactate dehydrogenase. By addressing the root cause of primary hyperoxaluria type 1, Nedosiran shows potential in mitigating oxalate accumulation, thereby offering a novel approach to managing this challenging condition. The United States Food and Drug Administration (USFDA) approved the usage of Nedosiran for primary hyperoxaluria type 1 on October 2, 2023.

Dosage and Route of Administration:

Nedosiran is given as a subcutaneous injection. The dosages vary depending on the age and body weight of the individual.

Adults (12 Years and Older):

• If the body weight is more than 110 pounds (50 kilograms), the administered dose is 160 milligrams (mg).

• If the weight of the individual is less than 110 pounds (50 kilograms), 128 mg of Nedosiran is given.

Children (Nine to 11 years):

• For a body weight of more than 50 kilograms or 110 pounds, 160 mg is given.

• If the body weighs less than 50 kilograms or 110 pounds, 3.3 mg/kg (milligrams per kilogram) should be given. However, the dosage should not exceed 128 mg.

The prescribed doses are given once a month through the subcutaneous route. Nedosiran is available as single-dose vials or prefilled syringes.

For Patients:

What Is Primary Hyperoxaluria Type 1?

Primary hyperoxaluria type 1 is a rare genetic disorder with excessive production of oxalate (a substance that is filtered and excreted by kidneys through urine). This happens because a mutation causes a deficiency of an enzyme, alanine-glyoxylate aminotransferase (AGT), which is responsible for converting glyoxylate into a less harmful substance. As a result, the amount of glyoxylate accumulates in the body, and this causes excessive production of oxalate. These high amounts of deposited oxalates create crystals and can result in the incidence of kidney stones, nephrocalcinosis (deposition of calcium oxalate in the kidneys), and, ultimately, progressive kidney damage.

What Are the Symptoms of Primary Hyperoxaluria Type 1?

• Pain while urinating (This is because there is a formation of calcium oxalate stones in the kidney).

• Blood in urine (hematuria).

• Increased frequency of urinating.

• Urge to urinate.

• Burning type of pain while urinating.

• Pain and discomfort in the abdomen.

When investigations are performed, kidney stones and significant amounts of kidney damage can be elicited. Untreated primary hyperoxaluria type 1 can cause significant amounts of renal damage due to oxalate deposition. This further exacerbates systemic oxalosis and can result in life-threatening situations like arrhythmias or neuropathy.

Why Is Nedosiran Prescribed for Primary Hyperoxaluria Type 1?

Nedosiran is given to people with primary hyperoxaluria Type 1 (PH1) because it reduces a substance called hepatic lactate dehydrogenase (LDH) in the liver. This reduction happens by breaking down LDHA (lactate dehydrogenase-A) by messenger ribonucleic acid (mRNA) in liver cells using a process called RNA interference (a process where the translation of proteins is stopped).

Lactate dehydrogenase (LDH) does not directly produce oxalate. However, it plays a role in the metabolic pathway that contributes to oxalate formation. LDH is an enzyme involved in the conversion of lactate to pyruvate in various cells, including hepatocytes (liver cells) in the liver. The pyruvate produced by LDH can enter the glyoxylate pathway, where it is eventually converted into glyoxylate. Excessive glyoxylate can lead to the overproduction of oxalate. In the context of primary hyperoxaluria Type 1 (PH1), a genetic mutation results in the deficiency of alanine-glyoxylate aminotransferase that is responsible for converting glyoxylate into a less harmful substance. The accumulation of glyoxylate due to this deficiency, along with the involvement of LDH in the metabolic pathway, contributes to elevated oxalate levels.

When LDH levels go down, the liver produces less oxalate, which is essential for individuals with primary hyperoxaluria, as excessive oxalate can lead to kidney stone formation. Essentially, Nedosiran targets a specific process in the body to cut down on oxalate production, aiming to ease symptoms and protect the kidneys in people with primary hyperoxaluria type 1.

How Should Nedosiran Be Used?

Nedosiran is given as an injection subcutaneously (under the skin). It is used for primary hyperoxaluria type 1, wherein the symptoms develop at any time during childhood to adulthood. Thus, the administration dosage varies widely depending on the age and weight of the patients. The medication is administered in three dosages: 80, 128, and 160 milligrams. The injection is received once a month by a certified healthcare professional.

The common sites used for this injection are the stomach region (two inches away from the belly button) and the upper portion of the thighs.

What Are the Side Effects of Taking Nedosiran?

Since this is a subcutaneous injection, the most common side effects seen are reactive lesions at the injection sites. This manifests as:

• Redness.

• The erythematous halo surrounding the injection site.

• Swelling.

• Burning sensation.

• Bleeding spots.

• Bruising.

• Formation of rash.

• A feeling of pressure building at the site of injection.

• Hives.

• Skin discoloration.

• Hypersensitivity response.

However, all these side effects are considered minimal, and no life-threatening complications were noted after administering Nedosiran.

What Are the Warnings and Precautions Regarding Nedosiran Treatment?

• Nedosiran injections should be taken at the right time to prevent any renal complications that can be life-threatening.

• Continuous monitoring of the renal and liver function tests is essential to look out for any abnormalities following the injection.

• In case a scheduled dose of Nedosiran is missed, it should be administered as soon as possible. If the planned dose of Nedosiran is missed by more than seven days, the individual should promptly receive the missed dose and resume the monthly dosing schedule based on the latest administered dose.

For Doctors:

Clinical Pharmacology:

Nedosiran is a double-stranded small interfering RNA and operates as an RNA-targeted therapeutic specifically designed for individuals with primary hyperoxaluria Type 1 (PH1). By employing RNA interference, Nedosiran acts on hepatic lactate dehydrogenase (LDH), leading to the degradation of LDHA messenger ribonucleic acid (mRNA) in hepatocytes. This targeted mechanism aims to reduce the hepatic production of glyoxylate, a precursor to oxalate. Through the inhibition of LDH, Nedosiran plays a crucial role in disrupting the metabolic pathway that contributes to oxalate overproduction, addressing the genetic basis of PH1.

Half-Life:

The half-life of Nedosiran is estimated to be 15 hours.

Drug Ingredients:

• Active Ingredient: Nedosiran (double-stranded RNA with GalNAc amino sugar residues).

• Inactive Ingredients: Sodium hydroxide or hydrochloric acid, water.

Indications:

• Primary hyperoxaluria type 1, and in individuals with a good level of kidney function and glomerular filtration rate greater than 30 mL/min/ (milliliters per minute)1.73 square meters.

• The drug is given only to individuals more than nine years of age.

Contraindications:

• People with hypersensitivity to any of the ingredients or components of Nedosiran drug.

• Children less than nine years old are not indicated for treatment with Nedosiran.

Pharmacokinetics:

• Absorption: After subcutaneous injection, Nedosiran is absorbed into the circulatory system, and the peak is reached within six hours.

• Metabolism: Nedosiran is converted to smaller oligonucleotides by the action of exonuclease and endonuclease.

• Distribution: The drug reaches the hepatocytes to complete the intended action. The GalNAc-conjugated sugars present in Nedosiran facilitate its delivery to hepatocytes by binding to asialoglycoprotein receptors (ASGPR).

• Elimination: Within the first day or 24 hours, approximately 27 percent of the given dose will be excreted unchanged through the renal route.

How Should Nedosiran Be Administered?

Drug Storage:

Nedosiran should be refrigerated and maintained at a temperature between two to eight degrees Celsius until used. It should be ensured that the drug is not exposed to any kind of direct heat or light.

Drug Administration:

The dosages available for administration of Nedosiran are 80 mg, 128 mg, and 160 mg. They are available as single vial doses or prefilled syringes.

The total volume available for such dosages are:

• Single Dose Vial - 0.5 milliliters (mL) containing 80 mg of Nedosiran.

• Single Dose Prefilled Syringe - 0.8 mL contains 128 mg.

• Single Dose Prefilled Syringe - 1 mL contains 160 mg.

pH of the drug is maintained around 7.2.

The exact dose and concentration of Nedosiran should be calculated before starting the treatment.

Steps for Administration:

• The first step is to disinfect the site of injection by wiping off the region with alcohol and sterile gauze, avoiding any contact or airflow on the cleaned area.

• Prepare the vial by removing the cap and cleaning the gray rubber stopper with a new alcohol wipe. Do not remove the rubber stopper. Then, the needle cap should be removed, taking care not to touch the uncapped needle, and the prescribed dose of Nedosiran should be withdrawn into the syringe.

• If the dose is 0.5 mL or less, put the needle inside the vial, bring it upside down (reversed), and then gently pull back on the plunger rod. For doses of 0.6 mL or more, withdraw the required amount from two vials using separate syringes. This may not be necessary if administered with prefilled syringes.

• Turn the vial and syringe upright, remove the needle, and inject the needle at a 45-degree angle by holding the skin at the injection site.

• Slowly inject the medicine, and after completing the injection, remove the needle without recapping it.

• Dispose of used vials and syringes appropriately, and if there is bleeding noted at the site, light pressure with a cotton ball or gauze can be applied.

Also, if individuals require two injections, it should be ensured that the different injections are given at two different sites. Doctors can also impart this knowledge to the patients for self-administration during their dosing schedule.

Clinical Toxicity:

There are no severe toxic effects seen after administration of Nedosiran. The most common reactions noted are about subcutaneous injections.

• Erythema and inflammation.

• Bruising at the injection site.

• Bleeding.

• Rash formation.

• Formation of dimples at the site.

• Hives.

• Burning sensation.

Monitoring the renal and liver functions is essential after treatment with Nedosiran. No other complications are noted with the Nedosiran administration.

There is no information regarding the carcinogenic or mutagenic potential of Nedosiran.

Drug Interactions:

Nedosiran is not known to cause any kind of drug interactions and hazardous reactions in the body with drugs like vitamin B6 (Pyridoxine) or other cytochrome P450 inducers and inhibitors.

Guidelines for Specific Population:

• Pregnant and Lactating Women: Nedosiran is not extensively studied to guide the dosage for pregnant and lactating women. It is still not known if the drug Nedosiran is eliminated through breast milk. Hence, Nedosiran is generally avoided in such populations.

• Pediatric Population: For children above the age of nine years, Nedosiran is given based on their weight. Nedosiran is not indicated for use in children less than nine years old.

• Geriatric Population: No specific dose modifications are essential in elderly adults more than 65 years of age.

Precautions to Be Followed:

• Any patient receiving Nedosiran should be evaluated thoroughly to determine the drug dosage. Determining the exact drug dosage is essential to ensure adequate pharmacological action of the drug and reduce the risk of any adverse events.

• The glomerular filtration rate should be assessed. Only if the glomerular filtration rate is above 30 milliliters per minute in 1.73 square meters should the drug Nedosiran be given. This means Nedosiran is indicated for individuals with a good level of renal functioning status only.

• If the status of renal function is poor, Nedosiran is avoided. Renal function and liver function tests are taken periodically to ensure that there are no complications arising after treatment with Nedosiran.

Overall, Nedosiran represents a significant advancement in the treatment landscape for individuals with primary hyperoxaluria Type 1 (PH1). This innovative therapeutic is a double-stranded small interfering RNA (siRNA) conjugated with GalNAc amino sugar residues. Administered through subcutaneous injections, the GalNAc-conjugated sugars facilitate targeted delivery to hepatocytes by binding to asialoglycoprotein receptors (ASGPR). Clinical trials have indicated Nedosiran's potential to lower oxalate levels, thereby mitigating kidney-related complications such as stone formation. The subcutaneous administration, combined with the GalNAc conjugation for hepatocyte targeting, enhances the precision and effectiveness of the treatment. While details regarding drug interactions and clinical toxicity are essential considerations, the ongoing research and development of Nedosiran underscore its potential as a transformative therapy for individuals affected by PH1.