Description
Patisiran (Onpattro^TM) is an RNA interference (RNAi) therapeutic targeting transthyretin for the treatment of hereditary transthyretin amyloidosis (TTR amyloidosis, hATTR or ATTR). RNAi is a cellular process of gene silencing. Patisiran (Onpattro) silences specific messenger RNA, blocking the production of transthyretin protein. This enables the clearance of TTR amyloid deposits from and restores function in peripheral tissues.

Inotersen (Tegsedi^TM) is an antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) protein synthesis indicated for the treatment of hereditary transthyretin amyloidosis (TTR amyloidosis, hATTR or ATTR). Inotersen (Tegsedi) causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

Background
Amvuttra is also a siRNA targeting transthyretin mRNA to reduce serum TTR and TTR deposits in tissues. Unlike Onpattro, Amvuttra is administered via SC injection once every 3 months by a healthcare professional. The recommended dosage is 25 mg every 3 months regardless of the patient’s weight. 

Treatment with patisiran (Onpattro) or inotersen (Tegsedi) typically leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised. Higher doses than the recommended daily allowance should not be given to try to achieve normal serum vitamin A levels during treatment, as serum vitamin A levels do not reflect the total vitamin A in the body. Individuals should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Hereditary transthyretin amyloidosis is a slowly progressive condition characterized by the buildup of abnormal deposits of amyloid protein in the body’s organs and tissues. It is caused by mutations in the TTR gene. The TTR gene provides instructions for producing a protein called transthyretin, which transports vitamin A and thyroxine throughout the body. Transthyretin is produced primarily in the liver. A small amount is produced in the choroid plexus of the brain and in the retina. In TTR amyloidosis, transthyretin builds up as amyloid fibrils in tissues (primarily liver), interfering with the normal function of these tissues. The ideal setting for evaluation of the individual with hereditary transthyretin amyloidosis is a multi-disciplinary Amyloid Program.

Policy

Patisiran (Onpattro)/ Amvuttra may be considered MEDICALLY NECESSARY for the treatment of individuals 18 years of age and older with a diagnosis of hereditary TTR amyloidosis when ALL of the following criteria are met:

• Prescribed by or in consultation with a neurologist or physician who specializes in the treatment of amyloidosis
• Diagnosis of polyneuropathy associate with hereditary TTR amyloidosis
• Documented mutation in TTR gene as confirmed by genetic testing
• A complete neurologic examination has been performed, showing clinical signs and symptoms of the disease (e.g., peripheral/autonomic neuropathy, motor disability, carpel tunnel, etc.)
• Patisiran (Onpattro)/ Amvuttra  is not being used for sensorimotor or autonomic neuropathy unrelated to hATTR amyloidosis
• Documentation of baseline functional ambulation performance (FAP) stage of 1 or 2
• Peripheral neuropathy impairment score (NIS) of 10 or greater or polyneuropathy disability (PND) score of IIIb or lower
• Individual is not simultaneously utilizing other gene targeted therapy for polyneuropathy of hATTR
• Patient has not had a liver transplant

Inotersen (Tegsedi) may be considered MEDICALLY NECESSARY for the treatment of individuals 18 years of age and older with a diagnosis of hereditary TTR amyloidosis when ALL of the following criteria are met:

• Prescribed by or in consultation with a neurologist or physician who specializes in the treatment of amyloidosis who is also certified within the Tegsedi Prescribing Program
• Diagnosis of polyneuropathy associated with hereditary TTR amyloidosis

• Documented mutation in TTR gene as confirmed by genetic testing
• A complete neurologic examination has been performed, showing clinical signs and symptoms of the disease (e.g., peripheral/autonomic neuropathy, motor disability, carpel tunnel, etc.)
• Inotersen (Tegsedi) is not being used for sensorimotor or autonomic neuropathy unrelated to hATTR amyloidosis
• Individual and prescriber are both enrolled in the Tegsedi REMS program
• Individual has normal liver function tests
• Documentation of baseline FAP stage of 1 or 2
• Has documentation of ANY of the following:
  • Peripheral NIS of ten (10) or greater
  • PND score of IIIb or lower
• Has not had a prior or scheduled liver transplant
• Individual is not simultaneously utilizing other gene-targeted therapy for polyneuropathy of hATTR

The use of patisiran (Onpattro) is considered INVESTIGATIONAL and, therefore, noncovered for all other indications.

Dose is based on actual body weight as follows: 

• For patients weighing less than 100 kg, the dosage is 0.3 mg/kg once every 3 weeks. 
• For patients weighing 100 kg or more, the dosage is 30 mg once every 3 weeks.

Note: Clinical description of PND score

• Score 0 = No symptoms
• Score I = Sensory disturbances but preserved walking capability 
• Score II = Impaired walking capacity but ability to walk without a stick or crutches 
• Score IIIA = Walking with the help of one stick or crutch 
• Score IIIB = Walking with the help of two sticks or crutches 
• Score IV = Confined to a wheelchair or bedridden 

Note: Clinical description of FAP stage 

• Stage 0 = No symptoms 
• Stage 1 = Unimpaired ambulation
• Stage 2 = Assistance with ambulation required
• Stage 3 = Wheelchair-bound or bedridden  

Rationale 
Onpattro™ (patisiran)
Fair quality evidence from the Phase 2 and APOLLO studies showed that patisiran 0.3 mg/kg intravenously (IV) every three weeks (Q3W) is effective in reducing transthyretin (TTR levels) and improving their modified neuropathy impairment scale+7 (mNIS+7) score, respectively, in adults diagnosed with hereditary transthyretin amyloidosis (hATTR) and neuropathy. The 0.3 mg/kg IV Q3W dosing regimen demonstrated the highest maximum TTR knockdown (KD) and TTR KD at nadir for both dose 1 (94.2% and 83.8%) and dose 2 (96.0% and 86.7%) compared to other dosing regimens (0.01, 0.05, 0.15, and 0.3 mg/kg every four weeks [Q4W]). Patisiran showed significant improvement in patients’ change in mNIS+7 scores from baseline compared to placebo (-6.03 vs. 27.96), suggesting improvement in autonomic function. This is further proven in the Phase 2 open-label extension (OLE) trial, where patients were on patisiran for 24 months and had a change in mNIS+7 from baseline of -7.0. Secondary endpoints in the APOLLO trial saw improved scores as well, most notably in assessing quality of life using the Norfolk quality of life-diabetic neuropathy (QoL-DN) scale (-6.7 vs. 14.4).

Mild to moderate adverse events (AEs) were common in patisiran. Most AEs were infused-related reactions (IRRs), which occurred in 10.3% of patients in the Phase 2 trial and 18.9% of subjects in the patisiran group from the APOLLO trial. The Phase 2 OLE trial demonstrated similar results as well, with 22.2% of subjects experiencing IRRs. Researchers attempted to prevent IRRs by pre-medicating patients with dexamethasone, acetaminophen, an H1 blocker, and an H2 blocker. As a result, pill burden may play a role in adherence and managing AEs. Another common AE was peripheral edema (29.7% in patisiran vs. 22.1% in placebo) which decreased over time with no patient needing to discontinue treatment. The Phase 2 trial reported one patient experiencing a urinary tract infection (UTI), sepsis, nausea, and vomiting. Another patient reported cellulitis, nausea, and vomiting. Because one patient experienced these symptoms, it is difficult to associate patisiran with these serious adverse events (SAEs). The APOLLO study had 36.5% of the patisiran group experience an SAE. The most common SAE found was diarrhea in 5.4% of patients. No increase in observed frequency of events for patisiran compared to placebo group by SOC.

Tegsedi™ (inotersen)
In the Phase III trial NEURO-TTR trial, inotersen treatment slowed the progression of polyneuropathy relative to placebo and stabilized neuropathy-related quality of life (QOL). The statistically significant treatment difference in mNIS+7 reflected progression in the placebo group and delayed progression in the inotersen group, though many inotersen patients reported improved neuropathy scores. Open-label extension (OLE) data suggest sustained delay of progression of polyneuropathy, though neuropathy-related QOL gain may not be durable. Cardiac endpoints did not differ statistically between the inotersen group and placebo group after 15 months of intervention; however, the trial was not powered to detect differences in cardiac outcomes. A small single-arm open label study shows minimal worsening of left ventricular mass.

Five deaths were reported during the study, all of which occurred in the inotersen group, through 15 months of treatment. Four deaths were considered related to disease progression and one death was considered possibly inotersen-related. Safety data show two key concerns with inotersen treatment: thrombocytopenia and glomerulonephritis. Frequent platelet and renal monitoring implemented during the Phase III NEURO-TTR trial suggests thrombocytopenia and decreased renal function may be manageable through enhanced monitoring. Adverse events considered related to treatment were more frequently reported by inotersen patients compared to placebo patients. Anti-inotersen antibodies were reported in 30.4% of NEURO-TTR patients. These antibodies typically develop after a median of 200 days of treatment and did not appear to affect drug efficacy, but patients with such antibodies reported more injection site reactions.

Amvuttra
The efficacy of Amvuttra was evaluated in a randomized, open-label clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis. Patients were randomized 3:1 to receive 25 mg of Amvuttra subcutaneously once every 3 months (n = 122) or 0.3 mg/kg Onpattro intravenously every 3 weeks (n = 42) as a reference group. Efficacy assessments were based on a comparison of the Amvuttra arm of this study with an external placebo group in another study composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis. The primary efficacy endpoint was the change from baseline to Month 9 in modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified+7 composite scores. In the version of the mNIS+7 used in the trial,
the NIS objectively measures deficits in cranial nerve function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The mNIS+7 has a total score range from 0 to 304 points, with higher scores representing a greater severity of disease. Treatment with Amvuttra in this study resulted in statistically significant improvements in the mNIS+7 at Month 9 compared to placebo in the external study (p < 0.001) with a change from baseline of -2.2 in the Amvuttra group and 14.8 in the placebo group.

References 

1. Onpattro™ (patisiran) prescribing information. Alnylam Pharmaceuticals, Inc.; Cambridge, MA. August 2018.
2. Tegsedi™ (inotersen) prescribing information. Akcea Therapeutics, Inc. October 2018.
3. What Is Hereditary ATTR Amyloidosis (hATTR)? hATTR Amyloidosis. https://www.hattrguide.com/about-hattr-amyloidosis/Accessed March 2019.
4. NIS-Neurological Impairment Scale. King's College London. https://www.kcl.ac.uk/nursing/departments/cicelysaunders/resources/tools/nis.aspx Published April 2013. Accessed March 2019.
5. Gertz M. Hereditary ATTR Amyloidosis: Burden of Illness and Diagnostic Challenges. American Journal of Managed Care. 2017;23.
6. ICER. Institute for Clinical and Economic Review. Inotersen and Patisiran for Hereditary Transthyretin Amyloidosis: Effectiveness and Value. Published October 4, 2018. Available at: https://icerreview.org/wpcontent/uploads/2018/02/ICER_Amyloidosis_Final_Evidence_Report_101718.pdf . Accessed March 2019.
7. Amvuttra [package insert]. Alnylam Pharmaceuticals, Inc., Cambridge, MA. Updated June 2022.
8. Amvuttra (vutrisiran) New Drug Review. IPD Analytics. June 2022.

Coding Section

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This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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