Inotersen

Mechanism of Action

The transthyretin (TTR) protein is one of several proteins normally found in human plasma. Structurally consisting of a heterodimer surrounded by monomers, TTR functions to transport both thyroxine and retinol-binding protein (RBP) to retinol in healthy individuals.[4][5] In patients affected by hATTR, a heterogeneous mutation in the TTR gene results in abnormal extracellular deposition of TTR proteins in various organ systems, negatively affecting their typical functions. These predominantly include the lung, eyes, heart, kidney, and nerves.[1][6] Such deposition consequently results in a classic polyneuropathy of hATTR, which clinicians may employ inotersen to treat. 

Currently, medications for managing hATTR and its multi-organ manifestations are limited to antisense oligonucleotide therapeutics, RNA interference therapeutics, orthotopic liver transplant (OLT), and emerging therapies such as immunotherapy. Similarly, other medications sometimes used for the disease include kinetic stabilizer natural products, including curcumin and xanthones, FDA-approved molecules, such as tolcapone and diflunisal, and their iodo-derivatives.

Specifically, inotersen is an antisense oligonucleotide that targets the TTR protein, subsequently reducing TTR tissue deposition in patients with hATTR. Notably, inotersen is a 2′-O-methoxyethyl-modified RNA molecule that exerts its mechanism of action by binding TTR messenger ribonucleic acid (mRNA), thus inhibiting the expression of TTR protein via Ribonuclease H (RNAseH) degradation.[3][7]

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

In a 15-month randomized, double-blind, placebo-controlled, phase 3 trial in 112 adults with stage 1 or stage 2 hATTR polyneuropathy receiving inotersen, Benson et al. demonstrated an improved disease course and quality of life in those receiving the drug. It should be noted that 6% of the patients in the study developed either thrombocytopenia or glomerulonephritis, one of which died as a result of grade 4 thrombocytopenia. All other patients with either complication were given close monitoring to ensure survival.[9]

Additionally, in 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. Notably, the authors reported the relative safety of inotersen in patients with up to 5 years of continuous use. Further, the authors noted in order to ensure the relatively safe use of inotersen, healthcare providers should administer routine platelet and renal monitoring to mitigate the potential risk of severe thrombocytopenia and glomerulonephritis in patients undergoing inotersen therapy long term. [10]

Administration

Inotersen is prepared in an injection form, with a recommended dose of 284 milligrams once weekly. Initial doses should be given by a caregiver, and patients and/or additional caregivers may be trained under qualified health professionals if self-administration is desired for subsequent dosing. The medication is administered subcutaneously in the upper thigh, outer arm, or abdominal regions, rotating sites with each weekly dose. Additionally, the medication solution should be allowed to reach room temperature prior to dosing. As such, providers should allow cooling for up to 30 minutes if previously stored in a refrigerator.

Further, appropriate bloodwork parameters should be assessed before, during, and after inotersen therapy. Parameters measured prior to 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. The previously mentioned parameters should be monitored for up to 8 weeks upon discontinuation with the addition of a complete urinalysis.

Adverse Effects

Common Adverse Effects

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

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

Serious Adverse Effects

Less common, serious 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 

Black Box Warning

Subcutaneous Inotersen administration includes the following black box warnings:

• Thrombocytopenia
• Glomerulonephritis

Additionally, due to its non-selective inhibition of TTR proteins, it should be noted that inotersen treatment may lead to reduced vitamin A serum levels. As such, patients who are undergoing inotersen treatment should be given vitamin A supplementation in order to maintain adequate vitamin A status. It should also be noted that patients should be cognizant of vitamin A deficiency symptoms such as night blindness so that they may report them to their healthcare provider.[10]

Contraindications

Inotersen therapy is contraindicated under the following conditions:

• Patients with a platelet count below 100 x 10^9/L
• Patients with a history of acute glomerulonephritis caused by previous use of inotersen
• Patients with a history of hypersensitivity reactions to inotersen

Monitoring

In order to safely undergo inotersen therapy, several blood and organ function parameters must be initially assessed, as well as monitored before and after treatment with the drug for safety assurance. Further, it is not recommended to initiate or continue therapy if patients are unable to undergo monitoring before, after, or during inotersen therapy. The following recommended monitoring for before, during, and after therapy may be found listed below. 

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

Additionally, with the exception of previously described rare occurrences, current data supports inotersen use for up to 5 years without significant toxicity concerns, so as long as bloodwork is monitored accordingly and contraindications are avoided.[10] Further, there is paucity in the literature regarding acute inotersen toxicity and antidotes in such circumstances. Should patients undergoing inotersen therapy experience major 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 used in patients with a platelet count below 100 x 10^9/L, history of glomerulonephritis with previous inotersen use, or history of hypersensitivity reactions to inotersen.

Additionally, patients should be assessed prior to treatment to ensure that eGFR, UPCR, AST, and bilirubin are within appropriate ranges. Further, 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 suffering from the neuropathic manifestations of hATTR for at least five years.[10][13] [Level 1]