Understanding the Pharmacology and Clinical Application of siRNA Therapies

Health care professionals are urged in a StatPearls publication to understand the complex pharmacology of small interfering ribonucleic acid (siRNA) to deliver precise therapeutic interventions, empowering them to integrate advanced strategies into patient care and enhance outcomes in the dynamic field of medical science.

Six siRNA-based agents are approved by the FDA including patisiran, givosiran, lumasiran, inclisiran, nedosiran, and vutisiran. Patisiran was the first siRNA agent approved by the FDA in 2018 for polyneuropathy due hereditary transthyretin amyloidosis (hATTR), followed by givosiran for acute hepatic porphyria and lumasiran for primary hyperoxaluria type 1. In 2021, inclisiran received FDA approval for heterozygous familial hypercholesterolemia (HeFH)/clinical atherosclerotic cardiovascular disease (ASCVD) and can be considered in patients with high LDL-C levels not managed by other therapies. Other siRNA-based therapies such as fitusiran, teprasiran, cosdosiran, and tivanisiran are currently undergoing evaluation in clinical trials for various conditions like hemophilia, acute kidney injury, and ocular diseases.
SiRNAs are small double-stranded RNAs that act by binding to specific mRNA sequences, causing degradation and gene suppression. The enzyme responsible for this process is known as RNA interference (RNAi). The siRNAs are cleaved by the enzyme dicer in the cytoplasm before integrating with a protein complex and targeting the mRNA. Various pharmaceutical agents, such as patisiran, givosiran, lumasiran, inclisiran, nedosiran, and vutrisiran, utilize RNAi to degrade specific mRNA targets and treat various conditions.

Common side effects of siRNA agents are upper respiratory tract infections, nausea, and injection site reactions. Patisiran is linked to side effects such as dyspepsia, muscle spasms, and bronchitis, while givosiran may cause rash, fatigue, and elevated liver transaminases. lumasiran is known for injection site reactions and abdominal pain, while inclisiran may lead to arthralgia and urinary tract infections. Lastly, vutrisiran has been connected to pain in extremities, dyspnea, and rare cases of atrioventricular block.

Patients receiving therapy with patisiran should be monitored for infusion-related adverse responses such as hypersensitivity reactions and anaphylaxis, with treatment delayed or interrupted as needed. Infusion can be gradually resumed once adverse manifestations are resolved, but in cases of critical adverse responses, therapy should be discontinued. Patients should also have routine monitoring of vitamin A levels and be initiated on vitamin A supplementation if necessary. Liver function tests should be routinely monitored in patients receiving givosiran, with special attention to ALT levels, and homocysteine levels should also be checked regularly. Additionally, immunogenicity with all siRNA agents should be considered, although the development of anti-drug antibodies did not impact the effectiveness or safety of the treatment in clinical trials.

Givosiran clinical trials showed hepatic and renal toxicity, with 15% of subjects experiencing ALT elevations and serum creatinine level increases. The severity of symptoms should determine whether to continue therapy. Patisiran and lumasiran therapy during pregnancy may affect vitamin A levels crucial for fetal development, while givosiran animal studies showed adverse effects on fetal development, necessitating evaluation during pregnancy. It is recommended to discontinue inclisiran therapy during pregnancy due to potential harm to the developing fetus.

The health care team for patients with rare metabolic ailments should consist of primary care physicians, hematologists, nephrologists, cardiologists, physician assistants, nurse practitioners, clinical geneticists, nurses, and pharmacists. Prior to initiating siRNA-based therapies, the team should conduct a comprehensive clinical examination and monitor laboratory values, such as renal and liver function, lipid levels, and vitamin A levels at baseline and regularly. Precautions such as administering premedications before infusion and monitoring for adverse effects during infusion are essential to managing potential reactions effectively and ensuring patient safety. Lastly, educating patients on possible adverse effects, monitoring vitamin A levels, evaluating pregnancy risks, and promoting effective communication among health care professionals can help optimize patient outcomes and quality of life when using siRNA-based therapies.

Reference
Padda IS, Mahtani AU, Patel P, et al. Small Interfering RNA (siRNA) Therapy. StatPearls. Published January, 2024. https://www.ncbi.nlm.nih.gov/books/NBK580472/