Initial Treatment - Hereditary Transthyretin-Mediated Amyloidosis Polyneuropathy

Patisiran and vutrisiran are considered medically necessary for individuals if they meet criteria 1 through 5:

1. 18 years of age or older.

2. Confirmatory diagnosis of hATTR by a genetic test OR tissue biopsy showing amyloid deposition.

3. Presence of clinical signs and symptoms of polyneuropathy characterized by any one of the following:

    i. Baseline polyneuropathy disability (PND) IIIb or lower (see Table 1 in background section)

    ii. Baseline familial amyloid polyneuropathy (FAP) Stage 1 or 2 (see Table 1 in background section).

4. Does not have ANY of the following:

    i. New York Heart Association (NYHA) class III or IV heart failure

    ii. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonalgammopathy, autoimmune disease, etc.)

5. Does not have any U.S. Food and Drug Administration (FDA) labeled contraindications to the requestedagent and is intended to be used consistently with the FDA approved label (see policy guidelines).

Initial authorization period is for 12 months.

Continuation of Treatment - Hereditary Transthyretin-Mediated Amyloidosis Polyneuropathy

Incremental reauthorization of patisiran and vutrisiran are considered medically necessary for individuals if they meet criteria 1 through 2:

1. Continues to meet the initial treatment criteria cited above.

2. Documentation of stabilization OR improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or 5 EQ-5D.

Reauthorization period is for 12 months.

Patisiran and vutrisiran are considered Incremental reauthorization of patisiran, vutrisiran, and eplontersen are considered investigational when the above criteria are not met.

BACKGROUND

Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, progressive, and fatal autosomal dominantgenetic disease with variable penetrance. Transthyretin is a transporter protein that carries thyroxine andretinol (vitamin A) and is primarily synthesized in the liver (95%) but also choroid plexus. The gene for transthyretin is located on chromosome 18. Variance in the transthyretin gene results in the production of misfolded transthyretin protein. More than 120 variants have been described, including single variants, compound heterozygotes, and deletions. The valine-to-methionine substitution at position 30 (V30M) is the most common variant observed worldwide, while valine-to-isoleucine substitution at position 122 (V122I) is the most common variant in the U.S. The misfolded protein generated because of a variant in the transthyretingene is insoluble and accumulates as amyloid fibrils (i.e., amyloidosis) in multiple organs of the body, such asthe liver, nerves, heart, and kidneys causing disruption of organ tissue structure and function.

Historically, hATTR was classified into 2 distinct syndromes—amyloidosis with polyneuropathy (previouslyknown as familial amyloid polyneuropathy or FAP) and amyloidosis with cardiomyopathy (previously known asfamilial amyloid cardiomyopathy).^1. While hATTR patients may show predominance of polyneuropathy or cardiomyopathy, it is now recognized that most patients manifest signs and symptoms of both syndromes over the course of their disease and, therefore, the current clinical approach treats FAP and familial amyloidcardiomyopathy as 1 hereditary disease with a spectrum of clinical manifestations.², The first symptoms ofhATTR amyloidosis typically appear between the mid-20s and the mid-60s, involving multiple tissues and organs and often seem unrelated. Neurologic symptoms include severe sensorimotor disturbances (loss of sensation, pain, muscle weakness and loss of ambulation) and autonomic dysfunction resulting in orthostatic hypotension, diarrhea, impotence, and bladder disturbances.³, While the neurologic symptoms of hATTR are among the most physically disabling, cardiac manifestations are the most predictive of early death. Cardiac manifestations include arrhythmias, conduction disorders, cardiomegaly, and heart failure. If the disease is untreated, the median survival for patients with predominantly neuropathic symptoms is 5 to 15 years, while patients with predominantly cardiomyopathic symptoms have a median survival of 2.5 to 6 years.^4,5,

The FAP stage system and the polyneuropathy disability score are the 2 most used clinical staging systemsand are summarized in Table 1. Higher scores on each of the staging systems are indicative of greater disease severity

Table 1. Clinical Staging in Hereditary Transthyretin-Mediated Amyloidosis

Diagnosis

Diagnosis of hATTR based on clinical signs and symptoms is difficult because of heterogeneity in clinical manifestations and the nonspecific nature of signs and symptoms that may mimic other conditions. Furthermore, the age of onset and rate of progression are highly variable from patient to patient^2.

As a result, many patients are misdiagnosed or their diagnosis is delayed, and patients often see physicians acrossmultiple specialties before receiving an accurate diagnosis 2

To confirm the diagnosis, proven amyloid deposition in biopsy specimens and identification of a pathogenic variant in the transthyretin gene are necessary.⁶, Amyloid deposition in the biopsied tissues can be confirmed by using Congo red staining and, ideally, immunohistochemical study as well as laser capture tandem mass spectrometry. However, mass spectrometry can only demonstrate a mass difference between wild-type and transthyretin protein variants in serum. It does not specify the site and kind of amino acid substitution in a number of disease-related transthyretin variants; thus, DNA sequencing is usually required. Sequence analysis of the transthyretin gene, the only gene in which mutation is known to cause hATTR, detects more than 99% of pathogenic variants.⁶,

There are currently 2 genetic test programs that offer no-cost, confidential genetic testing and genetic counseling services sponsored by the manufacturer of patisiran. It is summarized in Table 2.

Table 2. Characteristics of Genetic Testing Program Offered by Manufacturers in the U.S.

Epidemiology

It is estimated that the neuropathy-predominant form of hATTR affects at least 10,000 people worldwide,⁸, and roughly 3,000-3,500 people in the United States (U.S.).⁹, Due to under-diagnosis and a lack of population-based data, these numbers may underestimate the actual prevalence.¹⁰, According to unpublished data from Alnylam, there may be 10,000 to 15,000 individuals with the neuropathy-predominant form of hATTR [AMCPdossier].

The prevalence of the cardiomyopathy form of hATTR is also problematic to estimate. About 50,000 people worldwide may have hATTR amyloidosis.⁸,⁹, In the U.S. general population, the prevalence of V122I variant (which is the most common variant seen in the U.S.) is 3.4%.¹¹, However, phenotypic penetrance resulting in overt clinical cardiac disease depends on age and varies widely from 7% to 80%.¹², Higher estimates of clinical prevalence were reported in studies with very small samples of carriers. Characteristics of hATTR in the U.S. by different variants are summarized in Table 3.

Table 3. Characteristics of hATTR in the U.S. by Variants

Treatment

Prior to the approval of patisiran and inotersen in 2018, there was no U.S. Food and Drug Administration (FDA) approved treatment available in the U.S. for the treatment of hATTR. As of September 27, 2024, inotersen (Tegsedi) was discontinued in the United States due to low utilization.¹⁴,

Management approaches included the use of pharmacotherapy with tetramer stabilizers (such as diflunisal and tafamidis) and surgery (orthotopic liver transplant).

Diflunisal, a generic nonsteroidal anti-inflammatory drug, is not approved by the FDA for the treatment of hATTR but is available in the U.S. as a generic and has been used off-label for treatment. Diflunisal has been shown to stabilize transthyretin tetramers in a phase I study,¹⁵, and significantly reduced the progression of neurologic impairment and preserved the quality of life in a randomized controlled trial.¹⁶, Although the results of the randomized controlled trial were positive, multiple limitations with long-term use of diflunisal such as gastrointestinal bleeding, worsening of renal insufficiency, and cardiovascular events (e.g., MI, stroke)preclude its long-term use. Furthermore, diflunisal does not reverse neurologic or cardiac impairment.

Tafamidis received FDA approval in 2019 for treatment of hATTR patients with cardiomyopathy.

As transthyretin is primarily formed in the liver, orthotopic liver transplantation has been the disease-modifying treatment available to most patients with hATTR. This procedure can remove approximately 95% of the production of variant transthyretin. However, limited organ availability, exclusion of older patients and those with advanced disease, the high costs of transplantation, the risks of lifelong immunosuppression, and reports of disease progression following liver transplantation limits it use. Furthermore, orthotopic liver transplantation is not recommended for patients with cardiac involvement due to the observed post-transplant progression of cardiac; making a considerable proportion of patients in the U.S. who will develop cardiomyopathy ineligible for transplantation.¹⁷, As such the procedure is not commonly performed in the U.S.

Mechanism of Action

The function of small interfering ribonucleic acid (RNA) is to regulate gene expression, or how much protein will be made from a particular gene. Patisiran and vutrisiran are small interfering RNA that are designed to selectively target variant and wild-type transthyretin messenger RNA through RNA interference, which results in a reduction of serum transthyretin and transthyretin deposits in tissues. Eplontersen is an antisenseoligonucleotide that causes degradation of variant and wild-type transthyretin messenger RNA through binding to the transthyretin messenger RNA, which results in a reduction of serum transthyretin and transthyretindeposits in tissues.

Regulatory Status

In August 2018, patisiran (Onpattro, Alnylam Pharmaceuticals, Inc.) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

In June 2022, vutrisiran (Amvuttra, Alnylam Pharmaceuticals, Inc.) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

In December 2023, eplontersen (Wainua, AstraZeneca Pharmaceuticals, LP) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

In May 2019, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) capsules were approved by the FDA for the treatment of heart disease (cardiomyopathy) caused by transthyretin mediated amyloidosis in adults.