Givosiran - Indications, Dosage, Warnings, And Mechanism of Action

Overview

Givosiran belongs to a promising novel class of small interfering ribonucleic acid (siRNA) therapeutics developed to treat hereditary disorders by inducing genetic modifications. These siRNAs are a group of oligonucleotides that are designed to work at the RNA (ribonucleic acid) level inside the cell. On November 20, 2019, the FDA (U.S. Food and Drug Administration) approved Givosiran for treating acute hepatic porphyria in adult patients. Acute hepatic porphyria (AHP) is a spectrum of genetic disorders that affect heme biosynthesis (production) in the liver, causing various neurological and related problems. Givosiran inhibits aminolevulinic acid synthase 1 (ALAS1), which is a key enzyme in heme metabolism. The efficacy of Givosiran was well documented in reducing the rates of acute hepatic porphyria attacks during clinical trials. Also, it offers a better therapeutic option that is more convenient to administer and well tolerated.

Indications

Following phase I clinical trials, the use of Givosiran is indicated in the following conditions:

• For reducing the attacks of acute hepatic porphyria (AHP) in adult patients.

• For treating acute hepatic porphyria in adolescent patients of 12 years and above.

• To treat patients with acute intermittent porphyria which is the most common type of AHP.

• For patients developing recurrent AHP attacks.

Contraindications

The use of Givosiran is contraindicated under the following conditions:

• In known cases of developing hypersensitivity to Givosiran.

• Prone to anaphylactic reactions.

Dosage Forms and Available Strengths

• Available Form - Givosiran is available as a preservative-free, sterile, clear (colorless to yellow) 1 mL solution containing 189 mg Gvosiran as a single-dose vial.

• It is supplied as a ready-to-use solution in a glass vial (2-mL type 1) that has a Teflon-coated stopper along with a flip-off aluminum seal.

• Dosage Strength - 189 mg per 1 mL Givosiran solution for subcutaneous injection use.

Dosage and Administration

• Route of Administration - Subcutaneously injected only by a trained healthcare professional.

• Recommended Dosage - The dosing of Givosiran is calculated according to the actual body weight of the individual.

• The recommended dose of Givosiran is 2.5 mg per kg body weight administered once a month.

• Missed Dose - If a scheduled dose is missed, Givosiran should be given at the earliest following the missed dose. The regular schedule of dosage administration should be continued at monthly intervals after administering the missed dose.

• Dose Modifications - Dosage is modified on the occurrence of adverse side effects (abnormal elevation of liver enzymes or renal impairment).

• In patients showing severe or clinically significant adverse reactions, the Givosiran dose is interrupted and reduced to 1.25 mg per kg body weight and administered once a month.

• The recommended dose is resumed if the adverse reactions disappear and normalcy is established.

• Instructions for Administering - Givosiran vial is thoroughly checked for the presence of particulate impurities and visible discoloration before subcutaneous administration.

• Aseptic precautions are followed before withdrawing the solution from the vial.

• Depending on the body weight of the patient, the required volume of Givosiran is calculated to ensure weight-dependent dosage.

• A 21-gauge or a larger needle is used for withdrawing the Givosiran solution which is replaced by a 25-gauge to 27-gauge needle before subcutaneous injection.

• Injection Site - The needle is injected into the subcutaneous space of the abdomen, side or back of the upper arm, or the thigh region. The same injection sites are not preferred for subsequent injections as the rotation of injection sites is the recommended protocol.

• Scar tissues and areas of swelling or inflammation are not considered for injecting Givosiran solution.

• An area of five centimeters in diameter around the navel is avoided as an injection site if the abdomen is preferred.

• In case of more than one injection, the injection sites should be no closer than a distance of two centimeters.

Storage and Handling

Givosiran is stored at a temperature ranging from 2 degrees to 25 degrees Celcius in the original ready-for-use container. Reconstitution or dilution is not needed, and transferring the solution to other containers for storage purposes is avoided. The unused portion of the solution is discarded after subcutaneous injection and should not be preserved for following injections.

Warnings and Precautions

• Risk of developing anaphylactic reactions during Givosran treatment.

• Increased chance of hepatotoxicity resulting in elevated transaminase levels.

• Occurrence of renal toxicity causing decreased glomerular filtration rate and renal efficiency.

• Risk of developing injection site reactions such as pain, erythema, rash, pruritus, discoloration, and swelling around the area of the injection site.

• The risks of Givosiran therapy in pregnant women are not yet documented. However, the potential risk of adverse effects on the fetus is considered while prescribing Givosiran to pregnant women.

For Patients

What Causes Acute Hepatic Porphyria?

Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by defective heme biosynthesis. In these conditions, the liver cannot produce normal heme molecules (an essential part of hemoglobin). Subsequently, byproducts such as substrates and enzymes that are involved in the production of heme get accumulated in the body, induce toxic effects, and get deposited in various organs and tissues. This leads to severe clinical symptoms in the form of acute attacks such as vomiting, abdominal pain, and neurological disorders.

The clinical presentation of acute hepatic porphyria occurs in episodes of acute attacks characterized by neurovisceral (involving the central, autonomous, and peripheral nervous systems) manifestations such as cutaneous photosensitivity, severe abdominal pain, abdominal distention, nausea, constipation, and headaches. Hypertension, respiratory dysfunction, tachycardia, severe arrhythmias, and motor neuropathy leading to paralysis are some of its life-threatening complications. These recurrent acute attacks result in devastating consequences for the quality of an individual’s life.

How Is Acute Hepatic Porphyria Treated?

The accumulation of the heme precursors (starting substrates) and byproducts of the heme metabolic pathway, such as 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), is responsible for acute hepatic porphyria attacks. The following are the treatment strategies for managing acute hepatic porphyria attacks.

• Eliminating triggering factors like medications that induce porphyria production (porphyrinogenic).

• Hospitalization is necessary during attacks. Symptomatic treatment by administering analgesia, laxatives, anxiolytics, and hypnotics is carried out.

• Carbohydrate administration.

• Hemin therapy reduces heme biosynthesis and decreases the accumulation of precursors.

• Liver transplantation.

How Is Givosiran Effective in Treating Acute Hepatic Porphyria?

New discoveries in molecular technology have led to the development of RNA (ribonucleic acid) therapeutics that are designed for treating genetic disorders. Givosiran is a small interfering ribonucleic acid (siRNA) agent that is recently used for the therapeutic intervention of acute hepatic porphyria (AHP). It is also known as an orphan medicine since it is used to treat rare diseases. Givosiran is effective in treating AHP in the following ways:

• Givosiran works at the RNA level by silencing the production of abnormal precursors of heme metabolism.

• Givosiran is designed to target and interfere specifically with the production of abnormal proteins that occur due to genetic defects.

• Givosiran treatment causes a rapid dose-dependent reduction of the abnormal protein (aminolevulinic acid (ALA) and porphobilinogen-PBG) levels in AHP patients and thereby preventing its accumulation in the tissues.

• Once-in-a-month dosing results in a greater and more consistent reduction in ALA and PBG levels which eventually decreases recurrent acute attacks of acute hepatic porphyria.

What Are the Adverse Reactions That Occur With Givosiran Treatment?

The most common adverse side effects of Givosiran therapy are due to allergic reactions or overdoing. Some of the clinical symptoms of adverse reactions are listed below:

• Nausea.

• Injection site reactions.

• Rash.

• Increased levels of serum creatinine.

• Elevated levels of liver enzymes such as transaminases.

• Fatigue (feeling of persistent tiredness and weakness).

• Pruritus (itching sensation on the skin).

• Eczema (inflamed, dry, itchy, and cracked skin patches).

• Erythema (redness of the skin and mucous membrane).

• Urticaria (allergic skin rashes).

• Affects renal functioning such as decreased glomerular filtration rate.

• Chronic kidney disease.

• Anaphylactic reactions.

• Hypersensitivity.

What Are the Precautions to Be Followed During Givosiran Treatment?

Patients are advised about the potential risks of Givosiran treatment during patient counseling sessions, and necessary precautionary measures are recommended. Some of the precautions to be followed during the therapy are as follows:

• Any known allergy to Givosiran or any other drugs should be informed to the doctor prior to the initiation of the therapy.

• Any use of medications should be informed to avoid drug interactions.

• Any sign of developing adverse side effects should be reported immediately to the healthcare professional.

• It should be injected only by a healthcare professional as self-injection is prohibited.

• The vials should be properly stored as per storage recommendations and should be kept out of the reach of children.

• In case of an overdose, medical care is needed immediately.

• Missed doses should be reported immediately and should be taken after consulting the doctor.

• The vials should be visually inspected for the presence of impurities or color changes. If sediments are present or discoloration is noticed, the vial should be immediately discarded.

• If any residual drug is remaining in the vial, it should not be stored or reused. It should be discarded.

For Doctors

Clinical Pharmacology

Pharmacodynamics

Givosiran belongs to the new class of RNA interference therapeutics effective in gene silencing defective double-stranded RNA molecules. It is an aminolevulinic acid synthase 1 (ALAS 1) directed small interfering RNA (siRNA) that is covalently linked to a lipophilic ligand containing three N-acetylgalactosamine (GalNAc) residues for facilitated delivery of the siRNA molecules into the hepatocytes. It reduces the toxic precursors that are generated in the liver during heme biosynthesis in AHP patients. This prevents their accumulation and deposition in tissues and subsequent neurotoxicities and gastro toxicities. Givosiran functions at the RNA transcriptional level. Patients receiving Givosiran therapy are regularly monitored for the proper functioning of the liver and kidneys to prevent toxic side effects. There is no data available on the chemical taxonomy of this drug.

Mechanism of Action

• Heme is a structural component of various essential hemoproteins.

• Its biosynthesis starts within the hepatocytes under the regulatory control of 5-aminolevulinic acid synthase (ALAS1 and ALAS2) enzymes to form 5-aminolevulinic acid (ALA), a heme precursor.

• Due to genetic defects of acute hepatic porphyria, heme synthesis is dysregulated leading to the accumulation of byproducts.

• Givosiran is a double-stranded small interfering RNA (siRNA) agent that is targeted to degrade aminolevulinate synthase 1 (ALAS1) in hepatocytes.

• The antisense RNA strand of Givosiranintegrates into the RNA-induced silencing enzyme complex where it selectively cleaves the mRNA sequence of the ALAS1 resulting in the degrading and preventing the ALAS1 enzyme synthesis.

• Through RNA interference, Givosiran silences the mRNA of ALAS1 by blocking its transcription.

• Downregulation of ALAS1 decreases the circulating levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) which are neurotoxic.

• These neurotoxic intermediates associated with AHP attacks are clinically reduced.

Pharmacokinetics

• Following subcutaneous injection, Givosiran is rapidly absorbed from the injection site reaching the peak plasma concentrations within 0.5 to five hours of administration.

• Its active metabolite is AS(N-1)3′ Givosiran and its maximum plasma levels are reached within 1.5 to 12 hours.

• On Absorption - Givosiran primarily reaches the liver and shows a rapid dose-dependent reduction of ALA and PBG levels in urine, and the maximum reduction is found to be 95 percent in a 2.5 mg/kg once-a-month dose.

• Distribution - The average central volume of distribution is found to be 10.4 L with a protein binding of 90 percent.

• The half-life of Givosiran is six hours and is metabolized by nuclease enzymes to shorter oligonucleotides.

• No accumulation of Givosiran and its metabolite AS(N-1)3′ Givosiran is observed in subsequent multiple dosing.

• Givosiran is mainly eliminated in urine through the kidneys.

Toxicities

Givosiran is safe and well-tolerated. However, certain dose-related toxicities are reported. Some of the toxic effects of Givosiran include the following:

• Pyrexia.

• Chronic kidney disease.

• Abnormal liver functioning such as plasma aminotransferase elevated levels.

• Increased serum creatinine is indicative of renal toxicity.

• Deep venous thrombosis.

• Hemorrhagic pancreatitis.

• Pulmonary thromboembolism.

• Heart failure.

• Risk of inducing anaphylaxis.

• Renal damage.

• Hypersensitivity.

Drug Interactions

Although Givosiran does not interfere with drugs metabolized by liver cytochrome enzymes, it could increase the sensitivity of such drugs. Some of its drug interactions are as follows:

• Concomitant use of Givosiran is avoided with cytochrome (CYP1A2 and CYP2D6) substrates to prevent increased sensitivity and life-threatening toxic side effects.

• Givosiran increases caffeine (sensitive CYP1A2 substrate) plasma concentrations by 3.1 fold.

• Plasma levels of Dextromethorphan and Losartan are increased in concomitant use with Givosiran.

• Omeprazole (sensitive CYP2C19 substrate) shows increased plasma levels when administered with Givosiran.

• Givosiran does not have a direct effect on cytochrome (CYP) enzymes. However, it reduces the activity of these enzymes due to the pharmacological action on the hepatic biosynthesis of the heme pathway.