Inotersen

Mechanism of Action

Structurally consisting of a heterodimer surrounded by monomers, the transthyretin protein (TTR) transports both thyroxine and retinol-binding protein (RBP) to retinol in the plasma of healthy individuals.[4][5] In patients affected by hATTR, a heterogeneous mutation in TTR results in abnormal extracellular deposition of TTR in various organ systems, negatively affecting their typical functions. These organ systems include the lungs, eyes, heart, kidneys, and nerves.[1][6] This deposition consequently results in a polyneuropathy characteristic of hATTR, which clinicians may administer inotersen to treat.

Interventions for managing hATTR and its multi-organ manifestations are currently limited to antisense oligonucleotide therapeutics, RNA interference therapeutics, orthotopic liver transplant (OLT), and emerging therapies such as immunotherapy. Other medications that may be administered to treat hATTR include kinetic stabilizer natural products (eg, curcumin, xanthones), FDA-approved molecules (eg, tolcapone, diflunisal), and their iodo-derivatives.

Inotersen is an antisense oligonucleotide that targets the TTR protein, reducing TTR tissue deposition in patients with hATTR. Inotersen is a 2′-O-methoxyethyl-modified RNA molecule that binds TTR messenger ribonucleic acid (mRNA), inhibiting the expression of TTR protein via ribonuclease H (RNase H) degradation.[3][7]

This process reduces circulating TTR levels, alleviating the neuropathic symptoms of the disease. Due to its non-specificity to TTR mRNA, inotersen targets both wild-type and mutant TTR, reducing the circulating and deposited TTR proteins. Therefore, inotersen therapy may theoretically impair retinol transport, which can be mitigated by vitamin A (retinol) supplementation.[8]

Benson et al conducted a 15-month randomized, double-blind, placebo-controlled, phase 3 trial involving 112 adults with stage 1 or stage 2 hATTR polyneuropathy receiving inotersen; these patients demonstrated an improved disease course and quality of life. Six percent of the patients in the study developed thrombocytopenia or glomerulonephritis; 1 patient died due to complications of grade 4 thrombocytopenia. All other patients who developed adverse reactions were monitored closely to ensure survival.[9]

During a continuation of the 15-month trial, Brannagan et al further demonstrated the effectiveness of inotersen in reducing the progression of the deleterious consequences of hATTR polyneuropathy. The authors reported the relative safety of inotersen for up to 5 years of uninterrupted therapy. However, to ensure the relative safety of inotersen treatment, the authors recommend that providers closely monitor platelet levels and renal function to mitigate the potential risk of severe thrombocytopenia and glomerulonephritis in patients undergoing long-term inotersen therapy.[10]

Administration

Available Dosage Forms and Strengths 

Inotersen is available as a colorless to pale yellow, transparent solution in a prefilled 1.5 mL syringe (TEGSEDI). The medication is administered subcutaneously in the upper thigh, outer arm, or abdominal regions, rotating sites with each weekly dose. If the injection administration is desired to be in the upper arm, it should be administered by someone other than the patient. Injections should be avoided at the waistline and other areas where clothing might cause pressure or friction. Inotersen should not be injected into areas with skin disease, injury, tattoos, or scars.

The solution should be allowed to reach room temperature before administration. If previously stored in a refrigerator, the vial should be allowed to come to room temperature by keeping it at room temperature for up to 30 minutes. Other methods should not be used to warm up the injection.

Adult Dosage

The recommended dose of inotersen is 284 mg once weekly. Initial doses should be administered by a patient or caregiver under the guidance of a qualified healthcare professional. If a dose is missed, patients should be advised to take it as soon as possible unless the next dose is due within the next 2 days. In that case, they should skip the missed dose and resume their regular schedule with the next dose.

Appropriate bloodwork should be obtained before, during, and after inotersen therapy. Parameters measured before and during treatment include platelet counts, serum creatinine levels, glomerular filtration rate, urine protein-to-creatinine ratio, alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels. These levels should be monitored for up to 8 weeks after discontinuing therapy, in addition to a complete urinalysis.

As described below, the following adjustments to a patient's dosing schedule should be made based on platelet count (PLT).

PLT: ≥100,000/μL

• Monitoring frequency: Weekly
• Dosing recommendation: Weekly

PLT: 75,000 to 100,000/μL

• Monitoring frequency: Weekly
• Dosing recommendation: Hold until the platelet count is above 100,000/μL.

PLT: 50,000 to 75,000/μL

• Monitoring frequency: Twice weekly until 3 successive values above 75,000/μL; then weekly monitoring.
• Dosing recommendation: Stop inotersen treatment. Do not restart inotersen in patients with thrombocytopenia until 3 successive values above 100,000/μL and the benefit of inotersen outweighs the risk of thrombocytopenia and potential bleeding.

PLT: 25,000 to 50,000/μL

• Monitoring frequency: Twice weekly until 3 successive values above 75,000/μL; then weekly monitoring. Consider more frequent monitoring if additional risk factors for bleeding are present (eg, prior history of major bleeding events, receiving anticoagulant or antiplatelet medicinal products, or older than 60)
• Dosing recommendation: Stop inotersen treatment. Do not restart inotersen in patients with thrombocytopenia until 3 successive values above 100,000/μL and the benefit of inotersen outweighs the risk of potential bleeding or thrombocytopenia. Corticosteroids are recommended. Consider stopping any antiplatelet agents or anticoagulants.

PLT: <25,000/μL

• Monitoring frequency: Daily until 2 successive values above 25,000/μL. Then, monitor twice weekly until 3 successive values above 75,000/μL. Then, monitor weekly until stable.
• Dosing recommendation: Stop inotersen treatment. Corticosteroids are recommended. Consider stopping antiplatelet agents or anticoagulants.

Unless the patient has a medical contraindication to receiving glucocorticoids, they receive glucocorticoid therapy to reverse the platelet decline. Patients who discontinue therapy with inotersen because their platelet count falls below 25,000/μL should not reinitiate therapy.

Specific Patient Populations

Renal impairment: No dose adjustment is recommended for patients with eGFR 30 to 90 mL/min/1.73 m² (mild to moderate impairment). Inotersen has not been studied in patients with severe renal impairment or end-stage renal disease.

Hepatic impairment: No dose adjustment is recommended for patients with mild hepatic impairment, and inotersen has not been studied in patients with other degrees of hepatic impairment.

Pregnancy considerations: A pregnancy exposure registry monitors pregnancy outcomes in women exposed to inotersen during pregnancy. Healthcare providers and pregnant women are encouraged to register patients by emailing tegsedipregnancy@ubc.com, calling 1-877-465-7510, or visiting  www.tegsedipregnancystudy.com. There is no data on inotersen use and developmental risk. Inotersen treatment reduces serum vitamin A levels; hence, vitamin A supplementation is recommended for patients taking inotersen. Vitamin A is vital for normal embryofetal development; however, excessive amounts of vitamin A are associated with adverse developmental effects. The effects of a reduction in maternal serum TTR caused by inotersen and vitamin A supplementation on the fetus are unknown. Perform risk-benefit analysis for pregnant women and fetuses for treatment with inotersen.

Breastfeeding considerations: There is no data regarding the presence of inotersen in human milk, milk production, or the effects on the breastfed infant. However, a study in lactating mice has shown that inotersen is excreted in milk. Perform a risk-benefit analysis for lactating women and infants treated with inotersen.

Pediatric patients: The safety and effectiveness of inotersen are not established in pediatric patients.

Older patients: Various clinical studies of inotersen included 69 patients (45%) aged 65 and older. No differences in effectiveness or pharmacokinetics were observed between these and younger patients. Adults 65 years and older may be at higher risk of specific adverse reactions, such as chills, myalgia, congestive heart failure, and extremity pain.

Adverse Effects

Adverse effects most commonly reported with subcutaneous administration of inotersen include:

• Fatigue
• Fever
• Headache
• Injection site reaction
• Nausea
• Thrombocytopenia

Severe adverse effects reported with subcutaneous administration of inotersen include:

• Hypersensitivity reaction
• Stroke and cervicocephalic arterial dissection
• Inflammatory and immune effects
• Liver function impairment
• Glomerulonephritis and renal toxicity

Contraindications

Inotersen therapy is contraindicated for patients with the following:

• A platelet count below 100,000/μL
• A history of acute glomerulonephritis occurring during inotersen therapy
• A history of hypersensitivity reactions to inotersen

Box Warnings

Inotersen packaging includes the following black box warnings:

• Thrombocytopenia
• Glomerulonephritis

Additionally, inotersen treatment may reduce vitamin A serum levels due to its non-selective inhibition of TTR proteins. Patients undergoing inotersen treatment should be given vitamin A supplementation to maintain adequate vitamin A status. Patients should be cognizant of vitamin A deficiency symptoms, such as night blindness, so that they may report them to their healthcare provider.[10]

Warnings and Precautions

Renal test: Inotersen should generally not be prescribed to patients with a urine protein-to-creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor estimated glomerular filtration rate (eGFR), serum creatinine, UPCR, and urinalysis every 2 weeks during therapy with inotersen.

• Hold on treatment upon developing a UPCR ≥1000 mg/g or an eGFR <45 mL/minute/1.73 m², depending on further case evaluation. If a dose is withheld, once eGFR ≥45 mL/minute/1.73 m², UPCR <1000 mg/g, or the underlying cause of the decreased renal function is corrected, may start weekly dosing.
• In the case of a patient with a UPCR ≥2000 mg/g, further evaluation for acute glomerulonephritis should be performed, as clinically indicated. If acute glomerulonephritis is confirmed, inotersen should be permanently discontinued.

Liver test: Monitor ALT, AST, and total bilirubin monthly during inotersen therapy. Closely monitor patients with liver transplants. Inotersen should be discontinued in patients suspected of developing liver injury.

Monitoring

In order to safely undergo inotersen therapy, several blood and organ function parameters must be initially assessed and monitored before and after treatment with the drug for safety assurance. Initiating or continuing therapy is not recommended if patients cannot undergo monitoring before, after, or during inotersen therapy. The following parameters should be monitored before, during, and after therapy.

Pre-therapy

The following blood, renal, liver, bilirubin, and kidney parameters should be assessed prior to initiating inotersen:

• Estimated glomerular filtration rate (eGFR)
• Urine protein:creatinine ratio (UPCR)
• Aspartate aminotransferase (AST)
• Total bilirubin

Intra-therapy and 8-week Post-therapy Monitoring

The following blood, renal, urine, liver, and bilirubin parameters should be assessed during and up to 8 weeks after discontinuing inotersen:

• Platelet count
• Serum creatinine
• eGFR
• Urinalysis
• UPCR
• ALT
• AST
• Total bilirubin

Toxicity

Inotersen toxicity may cause glomerulonephritis and renal failure in some patients. Additionally, patients with pre-existing renal conditions may experience exacerbated symptoms.[11][12] Inotersen may result in hepatotoxicity, as the liver is an organ where antisense oligonucleotide accumulation may occur. Due to a lack of research in this domain, it is currently unknown whether inotersen is toxic in pregnancy.

Additionally, with the exception of previously described rare occurrences, current data supports inotersen use for up to 5 years without significant toxicity concerns, as long as bloodwork is monitored accordingly and contraindications are avoided.[10] Documentation regarding acute inotersen toxicity and antidotes in such circumstances is scarce. Should patients undergoing inotersen therapy experience severe adverse effects, therapy may be discontinued.

Enhancing Healthcare Team Outcomes

Managing hATRR with inotersen therapy requires qualified healthcare practitioners working as a coordinated interprofessional healthcare team to provide optimal patient care. Healthcare providers should also be cognizant of potential risks of inotersen use, especially in populations with pre-existing conditions such as those patients with renal or liver dysfunction. Inotersen should not be administered to patients with a platelet count below 100,000/μL, a history of glomerulonephritis with previous inotersen use, or hypersensitivity reactions to inotersen.

Prescribers should be aware that TEGSEDI is only available in the USA via a risk evaluation and mitigation strategy (REMS), a restricted distribution channel named "TEGSEDI REMS Program." Clinicians should inform patients of the risks of serious bleeding caused by severe thrombocytopenia and glomerulonephritis. Qualified healthcare professionals can train patients and caregivers on safe administration techniques if self-administration is desired for initial or subsequent dosing. Additionally, clinicians should assess patients before treatment to ensure that eGFR, UPCR, AST, and bilirubin are within appropriate ranges. Close monitoring of platelet count, serum creatinine, eGFR, urinalysis, UPCR, ALT, AST, and total bilirubin is recommended during and up to 8 weeks after therapy to ensure patient safety. Healthcare providers must work in unison to communicate these salient concerns to prevent adverse reactions and poor healthcare outcomes.

Inotersen appears to be a relatively safe drug with a low toxicity profile, which can be used to manage polyneuropathy in patients with hATTR. When used properly, inotersen can effectively and safely manage patients experiencing the neuropathic manifestations of hATTR for at least 5 years.[10][13]