Hereditary transthyretin-mediated (hATTR) 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. hATTR amyloidosis is caused by a variation in the transthyretin (TTR) protein, a protein that is produced in the liver. Pathogenic variation(s) of TTR causes the protein to misfold and form an insoluble fibril protein that deposits itself in various organs of the body. To date, over 120 TTR variants have been identified as a cause of hATTR, the most common being the p.Val30Met mutation. Symptoms commonly develop in the third to fifth decade of life and depend on several factors, including location of the deposits. 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. 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.
Patisiran (Onpattro) is the first pharmacologic treatment approved by the US Food and Drug Administration (FDA) for the treatment of adults with polyneuropathy associated with hATTR 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: inotersen (Tegsedi) and vutrisiran (Amvuttra).
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.
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 to 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 NIS+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 with 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). More randomized, double-blind studies will be needed to assess efficacy in those with hATTR who have cardiac manifestations. The frequency of severe adverse events and serious adverse events were similar between the two groups.
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 QOL-DN, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified BMI, and R-ODS (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.
There 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.