AMYLOIDOSIS
Amyloidosis is a progressive, degenerative, multisystemic, life-threatening disease in which insoluble fibril proteins (amyloid deposits) accumulate in various organs of the body, including the central nervous system, nerves, gastrointestinal tract, and heart. Transthyretin (TTR) is a protein that is produced in the liver that normally functions to transport thyroid hormone and retinol (vitamin A). There are a few types of amyloidosis, but this section will only discuss transthyretin amyloidosis (ATTR amyloidosis), a condition where TTR misfolds and forms an insoluble fibril protein that deposits itself in various organs of the body. ATTR amyloidosis can be divided into two subtypes:
- Hereditary transthyretin-mediated (hATTR) amyloidosis is caused by a pathogenic variation in the TTR protein. To date, over 120 TTR variants have been identified as a cause of hATTR. The most common being the p.Val30Met mutation found in hATTR with polyneuropathy and Val122Ile mutation found in hATTR with cardiomyopathy.
- Wild-type amyloidosis (wtATTR amyloidosis) is caused by the deposition of misfolded wild-type (normal) TTR. The mechanism of normal TTR causing amyloidosis is unclear.
The majority of TTR mutations cause a “neuropathic” or a “mixed” phenotype; yet, some variants typically manifest with a predominant or isolated cardiomyopathy (Luigetti et al., 2020). Polyneuropathy and cardiomyopathy are progressive and life-threatening, with survival approximately 2 to 15 years after onset of neuropathy and 2 to 5 years after onset of cardiomyopathy.
POLYNEUROPATHY OF HEREDITARY TRANSTHYRETIN-MEDIATED (HATTR) AMYLOIDOSIS
Symptoms commonly develop in the third to fifth decade of life and depend on several factors, including location of the deposits. Examples of symptoms associated with motor, sensory, and autonomic neuropathy include neuropathic pain, carpal tunnel syndrome, muscle weakness that affects daily living, orthostatic hypotension, recurrent urinary tract infections, diarrhea, nausea, vomiting, vision disorders (e.g., vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance), cardiac conduction blocks, and arrhythmias. Symptoms of hATTR can cause severe decreased ambulation, decline in daily function due to pain or discomfort, and anxiety or depression.
WILD-TYPE OR HEREDITARY TRANSTHYRETIN AMYLOIDOSIS WITH CARDIOMYOPATHY (ATTR-CM) Symptoms commonly develop in individuals at least 60 years of age and older (more commonly in those over 70 years of age). Examples of symptoms associated with cardiac amyloidosis include dyspnea, lower extremity edema, elevated jugular venous pressure, hepatic congestion, ascites, and syncope or presyncope. Additionally, autonomic or peripheral nerve disease can develop.
U.S. FOOD AND DRUG ADMINISTRATION (FDA)
Patisiran (Onpattro) was the first pharmacologic treatment approved by the US Food and Drug Administration (FDA) for the treatment of adults with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. Prior to its approval, treatment options consisted of orthotopic liver transplant or a TTR tetramer stabilizer, such as diflunisal (as an off-label indication). Since its approval, other treatments have been approved by the FDA (e.g., inotersen [Tegsedi], vutrisiran [Amvuttra]).
Additionally, vutrisiran (Amvuttra) was approved by the FDA for cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR) in 2025.
Patisiran (Onpattro) and vutrisiran (Amvuttra) represent a class of drugs called double-stranded small interfering ribonucleic acid (siRNA) treatment that controls gene expression by silencing or interfering with a targeted portion of RNA to reduce the amount of disease-causing TTR, causing a reduction in the amount of amyloid deposits in the body. Patisiran (Onpattro) is administered by intravenous infusion every 3 weeks. Vutrisiran (Amvuttra) is administered by a professional provider by subcutaneous injection once every 3 months.
PATISIRAN (ONPATTRO)
Peer-Reviewed Literature
Summary
Polyneuropathy of Hereditary Transthyretin-mediated (hATTR) amyloidosis
APOLLO was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that evaluated the safety and effectiveness of patisiran (Onpattro) in 225 adults with hATTR amyloidosis. Participants were required to have a documented pathogenic variant in TTR, a Neuropathy Impairment Score (NIS) of 5 to 130 (range, 0–244, with higher scores indicating more impairment) and a polyneuropathy disability score of IIIb or lower (with higher scores indicating more impaired walking ability). Participants were randomly assigned (2:1) to either patisiran (Onpattro), 0.3 mg/kg, or placebo via intravenous infusion once every 3 weeks for 18 months. The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The study resulted in a reduction in TTR level by 81% in those treated with patisiran (Onpattro). There was a statistically significant improvement in polyneuropathy (mNIS+7 score) in those treated with patisiran (Onpattro) compared to placebo. At 18 months, 56% of participants treated with patisiran (Onpattro) had improvement in mNIS+7, compared with 4% treated with placebo.
The following secondary endpoints showed statistically significant improvement in those treated with patisiran (Onpattro): quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN] questionnaire), motor strength (NIS-weakness); disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-meter walk test), nutritional status (modified body mass index [BMI]), patient-reported autonomic symptoms (Composite Autonomic Symptom Score). Exploratory endpoints were evaluated in a predefined cardiac subpopulation that showed improvement in echocardiographic measures of cardiac structure and function and a reduction in N-terminal pro–brain natriuretic peptide (NT-proBNP) levels (a measure of cardiac stress that is an independent predictor of death in individuals with transthyretin cardiac amyloidosis) in those treated with patisiran (Onpattro). The frequency of severe adverse events and serious adverse events were similar between the two groups.
VUTRISIRAN (AMVUTTRA)
Peer-Reviewed Literature
Summary
Wild-Type or Hereditary Transthyretin amyloidosis with cardiomyopathy (ATTR-CM)
HELIOS-B was a Phase 3, global, multicenter, double-blind, randomized, placebo-controlled study that evaluated the safety and effectiveness of vutrisiran (Amvuttra) in 655 adults with ATTR-CM (either hereditary ATTRv [v for variant] or wild-type ATTR [ATTRwt]), defined as the presence of TTR amyloid deposits in a tissue-biopsy specimen or fulfillment of validated scintigraphy-based diagnostic criteria for ATTR-CM in the absence of monoclonal gammopathy; and evidence of cardiac involvement as assessed with transthoracic echocardiography, with an end-diastolic interventricular septal wall thickness exceeding 12 mm. Participants had a clinical history of heart failure, with at least one previous hospitalization for heart failure or clinical evidence of heart failure, with signs and symptoms of volume overload or elevated intracardiac pressures warranting diuretic treatment. At baseline, participants were either receiving tafamidis or were not receiving tafamidis, with no active plan to start tafamidis during the first 12 months after randomization. Those who were not receiving tafamidis at baseline could receive it after enrollment, if necessary. Additional inclusion criteria were an NT-proBNP level of more than 300 pg per milliliter and less than 8500 pg per milliliter (or >600 pg per milliliter and <8500 pg per milliliter for patients with atrial fibrillation) and the ability to cover a distance of at least 150 m on the 6-minute walk test. Key exclusion criteria were a New York Heart Association (NYHA) class of IV, or a NYHA class of III with a National Amyloidosis Centre ATTR stage of 3 (defined as an NT-proBNP level of >3000 pg per milliliter and an estimated glomerular filtration rate [eGFR] of <45 ml per minute per 1.73 m2 of body-surface area); a polyneuropathy disability score of IIIa, IIIb, or IV (indicating that a cane or stick is needed to walk or that the patient is wheelchair-bound); cardiomyopathy that was not associated with ATTR amyloidosis; and an eGFR of less than 30 ml per minute per 1.73 m2. Participants were randomly assigned (1:1) to treatment with vutrisiran (Amvuttra) 25 mg SC or placebo SC every 12 weeks for up to 36 months. All the end points were assessed separately in the overall population and in the monotherapy population (those who were not receiving tafamidis at baseline), resulting in 10 prespecified end points for analysis (2 primary and 8 secondary). The primary end point was a composite of death from any cause and recurrent cardiovascular (CV) events (defined as hospitalizations for CV causes or urgent visits for heart failure) during the double-blind period (up to 36 months). Treatment with vutrisiran (Amvuttra) led to a statistically significant reduction in the risk of death from any cause and recurrent CV events compared to placebo in the overall and monotherapy population of 28% and 33%, respectively (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02). Vutrisiran (Amvuttra) also preserved functional capacity and quality of life and prevented worsening of heart failure symptoms. These effects were consistent across all prespecified subgroups, including individuals who were receiving background tafamidis. The incidence of adverse events was similar between the groups.
Among the participants in the monotherapy population, 44 out of 196 (22%) in the vutrisiran (Amvuttra) group and 41 out of 199 (21%) in the placebo group began tafamidis treatment after randomization. The study lacks stratified data to assess outcomes specifically for individuals who did not receive tafamidis at baseline and did not start tafamidis after randomization (i.e., there is no explicit and individualized outcome data for individuals who only received vutrisiran (Amvuttra) throughout the study), nor is there stratified data available for individuals who received Amvuttra and started tafamidis after randomization. The peer-reviewed published data have been reported in an overall manner at this point. The authors reported data stratified by baseline tafamidis use in the overall population even though a portion of individuals not receiving tafamidis at baseline did in fact go on to receive tafamidis at some point during the study. Among participants in the overall population, those given vutrisiran (Amvuttra) who were not receiving tafamidis at baseline had a 33% lower risk of death from any cause and recurrent cardiovascular events compared to placebo (hazard ratio = 0.67; 95% CI, 0.49 to 0.93), whereas, those given vutrisiran (Amvuttra) who were receiving tafamidis at baseline had a 21% lower risk of the composite endpoint compared to placebo (hazard ratio = 0.79; 95% CI, 0.51 to 1.21). Since the current seminal work does not have results reported in a stratified manner (including participants that may have had vutrisiran (Amvuttra) only throughout the trial), additional data would be needed to assess the effectiveness and/or additional clinical value that may result from tafamidis + vutrisiran (Amvuttra) combination therapy. Concurrent use of Amvuttra with other medications indicated for the treatment of hereditary transthyretin-mediated amyloidosis or transthyretin-mediated amyloidosis-cardiomyopathy have yet to be studied.
Polyneuropathy of Hereditary Transthyretin-mediated (hATTR) amyloidosis
HELIOS-A was a Phase 3, global, multicenter, randomized, open-label study that evaluated the safety and effectiveness of vutrisiran (Amvuttra) in 160 adults with hereditary transthyretin (ATTRv; v for variant) amyloidosis (also known as hATTR amyloidosis). Participants were required to have a documented pathogenic variant in TTR, a NIS of 5 to 130, a polyneuropathy disability (PND) score of IIIb or less, a Karnofsky Performance Status score of 60% or greater, and adequate liver and renal function. Participants were randomly assigned (3:1) to treatment with vutrisiran (Amvuttra) 25 mg SC every 3 months or patisiran (Onpattro) 0.3 mg/kg IV every 3 weeks for 18 months or external placebo group from the APOLLO study. The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7) compared with the placebo group of the APOLLO study (external placebo group) at Month 9. The study resulted in with vutrisiran (Amvuttra) meeting the primary endpoint, resulting in statistically significant improvement in mNIS+7 at Month 9 versus the external placebo group. At Month 9, 50.4% of participants treated with vutrisiran (Amvuttra) had an improvement in mNIS+7 versus 18.2% in the external placebo group. Vutrisiran (Amvuttra) met all of its secondary efficacy endpoints: significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran (Amvuttra) every 3 months was noninferior to within-study patisiran (Onpattro) every 3 weeks. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. All secondary endpoints resulted in significant improvements with vutrisiran (Amvuttra) treatment compared with the external placebo group.
OFF-LABEL INDICATIONSThere may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
