VUTRISIRAN INJ,SOLN

Clinical Criteria Summary

Sensorimotor or autonomic neuropathy without also having a diagnosis of hATTR amyloidosis
Primary amyloidosis
Leptomeningeal amyloidosis
Currently receiving another therapy for hATTR amyloidosis (e.g., diflunisal, tafamidis, patisiran)
Prior liver transplant
New York Heart Association (NYHA) Class III or IV heart failure
Known pregnancy

Provider is a VA or VA Community Care neurologist or locally designated hATTR amyloidosis provider
Diagnosis of polyneuropathy of hATTR amyloidosis including clinical symptoms and genetic testing confirming a variant in TTR
Documented baseline Neuropathy Impairment Score (NIS) of 5 to 130, Polyneuropathy Disability Score (PND) I to IIIb, or Familial Amyloid Polyneuropathy (FAP) stage 1 or 2
Age 18-85 years
Anticipated survival > 2 years
Supplementation of the recommended daily allowance of vitamin A planned to start upon approval
Discussion with patient/caregiver/family member regarding realistic treatment expectations and discontinuation documented

Continuation assessed at 9 months and periodically throughout treatment
Therapy continued only if patient demonstrates positive clinical response (e.g., improved motor function, quality of life, ambulation, or decreased neurological impairment)
Refer to eye clinic if ocular symptoms suggestive of vitamin A deficiency develop (e.g., night blindness)

For females who can become pregnant: Counseling provided on potential risks vs benefits of treatment, including risk that vutrisiran can decrease serum vitamin A levels
Must be administered by a healthcare professional

Diagnosis of wild type or hereditary TTR genotype ATTR-CM based on endomyocardial biopsy OR echo/MRI suggestive of amyloidosis confirmed with radionuclide imaging (e.g., technetium pyrophosphate [Tc99-PYP] scintigraphy)
Assessment of monoclonal protein screen for and exclusion of light chain (AL) amyloidosis
History of symptomatic heart failure (at least one hospitalization for heart failure OR clinical evidence of heart failure manifested by signs and symptoms of volume overload or elevated intracardiac pressures)

Provider must be a VA or VA Community Care cardiologist or locally designated ATTR-CM provider
Discussion with patient/caregiver/family member regarding realistic treatment expectations and discontinuation should be documented

Supplementation of the recommended daily allowance of vitamin A is advised
Referral to eye clinic if ocular symptoms suggestive of vitamin A deficiency develop (e.g., night blindness)
Combination disease modifying ATTR-CM therapy has not been specifically studied or determined to be superior to single agent therapy

Females who can become pregnant: Counseling provided on potential risks vs benefits of treatment

Treatment of cardiomyopathy of hereditary or wild-type TTR-mediated amyloidosis (ATTR-CM)
Indicated to reduce cardiovascular (CV) death, CV hospitalization, and urgent heart failure visits
Also indicated for treatment of polyneuropathy (PN) in hereditary ATTR

25 mg subcutaneous injection once every 3 months into abdomen, thighs, or upper arms
Administered by healthcare professional
Supplied as 25 mg per 0.5 mL solution for injection in a single dose, prefilled 1 mL syringe; stored under at room temperature

Adults with diagnosis of ATTR-CM (wild-type or variant) and clinical heart failure
ATTR-CM diagnosis based on tissue biopsy or validated scintigraphy-based diagnosis in absence of monoclonal gammopathy; evidence of cardiac involvement by echo and end diastolic interventricular septal wall thickness >12 mm
Clinical heart failure determined by ≥1 prior HF hospitalization, signs/symptoms of volume overload, or HF requiring diuretic treatment
6MWD ≥150 m
NT-proBNP >300 pg/mL and <8,500 pg/mL

NYHA class IV (or NYHA class III with Amyloidosis Disease Stage 3)
CM not due to ATTR amyloidosis
eGFR <30 mL/min per 1.73 m²
Polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires assistance to walk or wheelchair bound) at screening
Elevated transaminases >1.5x ULN or total bilirubin >1.5x ULN
Recent ACS or unstable angina

Primary endpoint: composite of all-cause death and recurrent CV events (CV hospitalization or urgent visits for HF)
Superior to placebo in overall population and monotherapy population for primary composite endpoint
Associated with less decline from baseline in 6MWD and health status (KCCQ-OS) vs placebo
Significantly lower all-cause death at 42 months in open label extension vs placebo

No boxed warnings or contraindications
Causes reduced serum vitamin A levels; supplementation of recommended daily allowance advised
Refer to ophthalmologist if ocular symptoms of vitamin A deficiency occur
Adverse event rates similar to placebo (99% vs 98%); discontinuations due to AEs similar (3% vs 4%)
No clinically relevant changes in laboratory measures, vital signs, or electrocardiograms
Not expected to cause drug interactions via enzyme induction or modulating drug transporters

RNA silencer approved for ATTR-CM; alternative disease modifying treatments include TTR stabilizers (tafamidis, acoramidis)
ICER determined high certainty of substantial net benefit vs no treatment or in addition to tafamidis
Insufficient evidence to compare net health benefits among the three agents