Continuing Education Activity
Patisiran, givosiran, lumasiran, and inclisiran are FDA-approved for managing rare metabolic ailments. All four agents are small interfering RNA (siRNA) based therapies that exert their effects by RNA interference (RNAi) of their target mRNA. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to interprofessional team members in managing adult patients with hereditary transthyretin amyloidosis (hATTR), acute hepatic porphyria (AHP), primary hyperoxaluria type 1 (PH1), and lowering of low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD).
Objectives:
Review the appropriate monitoring for patients receiving small interfering RNA (siRNA) based therapies.
Identify the mechanism of action of small interfering RNA (siRNA) based therapies.
Describe the potential adverse effects of small interfering RNA (siRNA) based therapies.
Summarize interprofessional team strategies for improving care coordination and communication to advance small interfering RNA (siRNA) based therapies in treating patients with hereditary transthyretin amyloidosis (hATTR), acute hepatic porphyria (AHP), primary hyperoxaluria type 1 (PH1), and lowering of low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD).
Indications
Small interfering ribonucleic acid (siRNA) based therapies have been developing for 20 years. The first siRNA agent, patisiran, received US Food Drug Administration (FDA) approval in 2018. To date, FDA has approved four siRNA agents: patisiran, givosiran, lumasiran, and inclisiran.
Patisiran was the first siRNA agent to receive approval by the FDA onAugust 10, 2018. It is indicated in adult subjects withpolyneuropathy due to hereditary transthyretin amyloidosis (hATTR). A year later, givosiran was the secondsiRNA agent to receive approval by the FDA. It was indicated in adult subjects with acute hepatic porphyria (AHP).Lumasiranwas the thirdsiRNA agent to receive approval by the FDA on November 23, 2020. It was to be used in pediatric and adult subjects with primary hyperoxaluria type 1 (PH1) and reduced urinary oxalate levels.The latest siRNA agent to receive FDA approval on December21, 2021, was inclisiran. The agent is indicated in adult subjects with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD). It lowers the levels ofLDL-C.
Six other siRNA-based therapies are currently being evaluated in clinical trials (vutrisiran, nedosiran, fitusiran, teprasiran, cosdosiran, and tivanisiran). Similar to patisiran, vutrisiran isunder evaluation for the treatment of hATTR, and clinicalstudiesare underway comparing both agents. Nedosiran is currently being studiedfor the management of PH1 similarlyto lumasiran but differs in itsmechanism of action. Nedosiran exerts its effects by acting on the hepatic enzyme lactate dehydrogenase, whereas lumasiran acts on the hepatic enzyme glyoxylate oxidase.
Other ailmentscurrently being evaluated for management with siRNA based therapies include hemophilia A and hemophilia B (fitusiran), prophylactic therapy for acute kidney injury (AKI) in patients undergoing transplantation or following cardiovascular surgery (teprasiran), nonarteritic anterior ischemic optic neuropathy, and primary angle glaucoma (cosdosiran), ocular pain and dry eye disease (tivanisiran).[1]
Mechanism of Action
The siRNAs are identified as small double-stranded RNAs that exert their effects by dividing into single strands and binding to their distinct target messenger RNA (mRNA) sequences. This action catalyzes a string of activities that yield the target mRNA to break and degrade, further halting translation and inducing gene suppression by the short RNA strands. It is also known as RNA interference (RNAi).[1][2]
The siRNA agents initiate their RNAi action in the cytoplasm with the help of an enzyme, endoribonuclease dicer, also known as helicase, with an RNase motif. It cleaves the double-stranded RNA and yields a siRNA.
The short double-strand RNA fragments integrate with a cluster of essential proteins known as the RNA-induced silencing complex (RISC) and are then split into two single RNA strands recognized as sense and antisense. The single antisense strand further targets its mRNA arrangement while the sense strand is dismissed from the complex.The essential enzymes in the RISC complex, such as the Ago-2 endonucleases, cleave their target mRNA sequence once affixed.[1][2][3]
Patisiran
Patisiran exerts its mechanism of action through RNAi, resulting in cleavage and breakdown of all types (mutant and wild-type) of transthyretin (TTR) mRNA. The agent is adouble-stranded siRNAformulated as a lipid nanoparticle (LNP) taken up by hepatocytes once bound to apolipoprotein E (APOE)receptors. The RNAi of the TTR mRNA decreases the production of TTR protein in circulation and its deposition in tissues and organs.[4][5]
Givosiran
Givosiran exerts its mechanism of action through RNAi, resulting in the cleavage and breakdown of its target, aminolevulinate synthase 1 (ALAS1) mRNA, which is found in the liver. The agent is a double-stranded siRNA conjugatedwith N-acetylgalactosamine (GalNAc) ligand for intake by hepatocytes. Once taken up by hepatocytes and degrading its target mRNA, it decreases aminolevulinic acid (ALA) and porphobilinogen (PBG) levels in the blood, further limiting AHP disease characteristics.[6][7]
Lumasiran
Lumasiran exerts its mechanism of action through RNAi in the liver resulting in cleavage and breakdown of its target, hydroxy acid oxidase 1 (HAO1) mRNA. The agent is a double-stranded siRNA conjugatedwith GalNAcligandfor effective uptake by hepatocytes.HAO1 produces glycolate oxidase (GO), an enzyme responsible for producing glyoxylate, a substrate for the further synthesis of oxalate. The inhibition of the GO enzyme results in decreased oxalate precursor levels which in turn reduces the production of the enzyme alanine glyoxylate aminotransferase (AGT) that is mutated in PH1.[1][8][6]
Inclisiran
Inclisiran exerts its mechanism of action through RNAi in the liver and orchestrates hepatic mRNA degradation of proprotein convertase subtilisin/kexin type 9 (PCSK9). The sense strand of the siRNA is bound with GalNAcligand, allowing hepatocytes to efficiently uptake the siRNA agent and target PCSK9. PCSK9 internalizes and breaks down the hepatic LDL receptors once attached. Inclisiran inhibits this action of PCSK9, further promoting the expression of LDL-C receptors on the cell's surface and facilitating receptor cycling. Once LDL-C is bound to its receptor, it is subject to degradation by lysosomal enzymes and recycled back to the cell's surface. This results in a raised uptake of LDL-C and reduces its levels in the blood.[9]
Administration
Patisiran
Patisiran is availableand distributed as a single-dose vial of 10 mg/5 mL (2 mg/mL). It is a lipid complex injection that should be filtered and diluted before administering. The correctdosage should be calculated and adjusted according to the patient's body weight and administered as an intervenous infusion by a healthcare professional.
Indication: polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
0.3 mg/kg once every three weeks (weight less than 100 kg)
30 mg once every three weeks (weigh100 kg or more)
Patisiran should be administered immediately if anearlier dose was missed. Patients who are givena dose within the three days from a missed dosage are recommended tofollow their original regime. If the patient has missed a dose
Patients receivingtreatment with patisiran are advised to receivepremedication therapy 60 minutes beforeadministration of the IV infusion to decrease the occurrence of infusion-related reactions (IRRs). Premedication therapies consist ofcorticosteroid (IV), acetaminophen (oral), H1 blocker (IV), andH2 blocker (IV).
Givosiran
Givosiran is available and distributed as a single-dose vial of189 mg/mL for subcutaneous injection.
Indication: acute hepatic porphyria in adults.
2.5 mg/kg once monthly
Givosiran should be administered immediately if a prior dosage was missed and continued monthly thereafter. Patients who have critical elevations in liver transaminases are recommended to decrease their dosage to1.25 mg/kg every month. Dosingcan be increased to 2.5 mg/kg in subjects who do not show a recurring increase intransaminases while receiving therapy at 1.25 mg/kg.
Lumasiran
Lumasiranis available and distributed as a single-dose vialof94.5 mg/0.5 mL for subcutaneous injection.Lumasiran is administered asloading doses accompanied bymaintenance doses calculated and adjusted according to the patient's body weight.
Indication: PH1 adult and pediatric subjects.
Initial loading dose: 6 mg/kg administeredonce a month for three doses (weight below 10 kg)
Maintenance dose: 3 mg/kg administered once a month (weight below 10 kg)
Initial loading dose: 6 mg/kg administered once a monthfor three doses (10 kg to below20 kg)
Maintenance dose:6 mg/kg administered once every three months quarterly(10 kg to below 20 kg)
Initial loading dose: 3 mg/kg administered once a month for three doses (20 kg and greater)
Maintenance dose: 3 mg/kg administered once every three months (20 kg and greater)
Lumasiran should be administered immediately if a prior dosage was missed and continued monthly thereafter.
Inclisiran
Inclisiran is available and distributed as a prefilled single-dose vial of 284 mg/1.5 mL (189 mg/mL) for subcutaneous injection.
Indication: reducing LDL-C in subjects with HeFH or ASCVDadjunctive to diet and statin therapy tolerated at a maximum dose.
284 mg (initial dose)
284 mg (at three months)
284 mg (every six months thereafter)
Inclisiran should be administered immediately if a prior dosage was missed. Patients who are givena dosage within three months of a missed dosage are recommended tofollow their original regime. If a dosehas been missed formore than three months, therapyshould be initiated at three monthsfollowing administration of the missed dosage and every six months thereafter.
Adverse Effects
Adverse events are listed by agent below.[9]
Patisiran
Upper respiratory tract infections (URTI) (28%)
Infusion-related reactions (19%)
Dyspepsia(8%)
Dyspnea(8%)
Muscle spasms(8%)
Arthralgia(7%)
Erythema (7%)
Bronchitis (7%)
Vertigo(5%)
Givosiran
Nausea (27%)
Injection site reactions (25%)
Rash (17%)
Serum creatinine increase (15%)
Elevated liver transaminases (13%)
Fatigue (10%)
Lumasiran
Injection site reactions (38%)
Abdominal pain/discomfort (15%)
Inclisiran
Arthralgia (4%)
Urinary tract infection (3.6%)
Diarrhea (3.5%)
Bronchitis (2.7%)
Pain in extremity(2.6%)
Dyspnea (2.6%)
Injection site reaction (1.8%)
Contraindications
No labeled contraindications have been reported for patisiran, lumasiran, and inclisiran. Hypersensitivity to givosiran is an absolute contraindication to therapy. Anaphylaxis was reported in<1% of subjects during clinical trials with givosiran.
Monitoring
Patients receiving therapy with patisiran should be monitored for infusion-related adverse responses such as hypersensitivity reaction and anaphylaxis. Treatment with patisiran should be delayed or interrupted, and appropriate management should be initiated as clinically required. Infusion should be resumed gradually once there is a resolution of adverse manifestations. In the event of critical infusion-related adverse responses, therapy should not be continued.Patients receiving treatment with patisiran should also have their vitamin A levels monitored routinely as therapy decreases its levels. Patients should be initiated on vitamin A supplementation not exceeding recommended daily dosage and monitored for clinical manifestations of vitamin A deficiency.[10]
Liver function tests (LFTs) should be monitored at baseline and routinely thereafter in patients receiving treatment with givosiran as an increase in alanine transaminase (ALT) was observed during clinical trials. Elevation in liver function is reported to occur around 3 to 5 months from the initiation of therapy. Recommendations are to measure LFTs every month for the first six months of givosiran. Treatment should be discontinued in patients with severe elevations in ALT.Along with LFTs, patients should also have their estimated glomerular filtration rate (eGFR) and serum creatinine levels monitored at baseline and routinely while receiving givosiran. Alterations in eGFR and creatinine were reported during clinical trials.
Patients receiving givosiran should also have their hom*ocysteine levels measured at baseline and routinely thereafter. Elevations in hom*ocysteine levels in the blood were reported in 16% of subjects during clinical trials. Patients with evidence of hom*ocysteine elevations should have their vitamin B9, vitamin B12, and B6 levels assessed and consider initiating vitamin B6 supplementation.
Immunogenicity with all four siRNA agents is possible and may serve as a barrier to therapeutic delivery.An unwanted biological immunogenic response may identify siRNA as viral RNA antigen provoking undesirable adverse responses.During clinical trials, anti-drug antibodies (ADA) developed in 3.6% of subjects receiving patisiran, 6% of subjects receiving lumasiran, 0.9% of subjects receiving givosiran, 1.8% of subjects prior to inclisiran dosing, and 4.9% of subjects at 18 months therapy. ADA did not influence effectiveness or safety in all four siRNA agents, resulting in no clinically significant discrepancies in the pharmaco*kinetics and pharmacodynamics.[11]
Toxicity
Hepatic and renal toxicity was reported during clinical trials with givosiran. 15% of subjects receiving therapy reported ALT elevations three times above the normal range. 15% of subjects reported elevated serum creatinine levels and reductions in eGFR with a median elevation in creatinine of 0.07 mg/dL at three months. Continuing therapy should be determined based on the severity of laboratory alterations and clinical symptoms.
Pregnancy
Data on using patisiran and lumasiran therapy during pregnancy has not been reported. A reduction in vitamin A levels is recognized with patisiran use, which is a crucial component of normal embryo maturation and fetal development. An excess in vitamin A levels correlates with adverse effects on the fetus.
Although givosiran has not been studied in humans during pregnancy, animals reproduction analyses demonstrated unfavorable developmental effects during organogenesis. Givosiran during pregnancy should be assessed, weighing the advantages and dangers to the mother and probable impacts on the developing fetus.Inclisiran therapy is recommended to be discontinued during pregnancy. It is reported that the agent's mechanism of action for decreasing cholesterol and additional potential biologically active substances may result in harm to the developing fetus.[12]
Enhancing Healthcare Team Outcomes
Small interfering ribonucleic acid (siRNA) based therapies are newly approved therapeutics exerting their effects by RNAi on their target mRNA in the liver. To date, four agents (patisiran, givosiran, lumasiran, and inclisiran) are FDA-approved for managing adult patients with hATTR, AHP, reducing LDL-C in subjects with HeFH or ASCVD, and PH1 in adults and pediatric patients. Caring for patients with such rare metabolic ailments demands care coordination from a team of healthcare professionals. The team should include a primary care physician (PCP), a hematologist, a nephrologist, cardiologist, mid-level practitioners, genetic counselor, nurses, and a pharmacist.
The healthcare team should conduct a thorough clinical examination to assess if management with siRNA-based therapies is suitable for the patient. Before prompting treatment, the interprofessional team should determine the patient's laboratory values, such as renal and liver function (givosiran), lipid levels (inclisiran), and vitamin A levels (patisiran) at baseline and routinely thereafter. The PCP should regularly communicate with the other specialists taking care of such patients.
The healthcare team should administer the premedications mentioned above (corticosteroid, acetaminophen, H1 blocker, andH2 blocker) at least 60 minutes before the infusion to prevent an infusion-related reaction. The prescribing and administering clinician should be prepared and equipped for immediate adverse effects such as infusion-related hypersensitivity reactions. The healthcare team should look out for headaches, back pain, abdominal pain, dyspnea, and nausea during infusion. In the event of clinical signs such as hypotension, syncope, and anaphylaxis, the infusion should be discontinued immediately, and appropriate symptomatic management should be initiated.
The interprofessional team should educate their patients thoroughly on the probable adverse effects of siRNA-based therapies and counsel them regarding the appropriate measures in the event of such occurrences. Vitamin A levelsrequire routine monitoring for patients receiving patisiranby the prescribing healthcare provider as the agent is reported to decrease its levels.
Childbearing females considering treatment with siRNA-based therapies during pregnancy should be evaluated to determine the benefits and risks before starting therapy. Although no studies and data involving pregnant women have been reported, pregnancy risksmerit discussion. Patisiran reportedly decreases vitamin A levels and is essential for fetal development. Excess vitamin A levels may also cause adverse developmental consequences. Pregnant patients considering givosiran should be informed about unfavorable fetal developmental outcomes during organogenesis in animal models. Inclisiran should be discontinued during pregnancy. Communication among the primary healthcare team and specialists treating patients with siRNA-based therapies can reduce complications and improve patient outcomes and quality of life.[1][3]
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Disclosure: Inderbir Padda declares no relevant financial relationships with ineligible companies.
Disclosure: Arun Mahtani declares no relevant financial relationships with ineligible companies.
Disclosure: Mayur Parmar declares no relevant financial relationships with ineligible companies.
