Effective Date

Date of Origin   

04-01-2025           

07-01-2019

Attruby™

(acoramidis)

Tablet

Treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization

11

Tegsedi®

(inotersen)

Subcutaneous injection

Treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults

1

Vyndamax®

(tafamidis)

Capsule

Treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization

2

Vyndaqel®

(tafamidis meglumine)

Capsule

Treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization

2

WAINUA™

(eplontersen)

Subcutaneous injection

Treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults

9

Amyloidosis

Amyloidosis is a protein disorder in which proteins misfold, then bind together to form amyloid fibrils. These fibrils deposit systemically into tissues and organs.(3,8) Transthyretin (TTR) is one of more than 30 proteins that can cause amyloidosis. TTR is primarily synthesized in the liver and carries thyroxine and retinol-binding protein throughout the body.(3,4) TTR is amyloidogenic in both wild-type (ATTRwt) and hereditary (hATTR, ATTRm) forms causing progressive disease associated with increased morbidity and mortality.(4,8) hATTR is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. ATTRwt is not inherited but instead develops with age and mainly affects the heart.(3,5)

Neuropathy

Formally known as Familial Amyloids Polyneuropathy(FAP), hATTR with PN (hATTR-PN) usually presents as adult-onset, autosomal-dominant disease with a range of sensory and motor impairments.(7) Early in the disease course, the pathologic process typically involves small-fiber damage. Initial sensory symptoms vary but can include sensory symptoms such as pain, altered sensation (i.e., decreased pain sensation), numbness and tingling; autonomic dysfunction such as digestive disorders, orthostatic hypotension, bladder, and erectile dysfunction; and general symptoms including fatigue, weight loss, and plantar ulcers.(5,7,10) Advanced disease can involve loss of reflexes, reduced motor skills, and muscle weakness.(10)

Diagnosis of hATTR-PN can be challenging without positive family history as clinical presentation may mimic various peripheral neuropathies. In patients with PN of otherwise undetermined etiology, early search for associated clinical features, especially cardiac involvement can help reveal amyloidosis. Diagnosis can be confirmed by TTR gene sequencing looking for TTR gene amyloidogenic variants and amyloid detection through tissue biopsy or bone scintigraphy with diphosphono-1,2,propanodicarboxylic acid (DPD, hydroxymethylene diphosphonate (HMDP), or pyrophosphate (PYP).(7,10)

Assessment of the spread of disease is a multidisciplinary approach by a neurologist, cardiologist, ophthalmologist, gastroenterologist, and nephrologist due to the systemic involvement of other organs that can be latent but potentially major consequences for patients.(7,10) Measuring disease progression should include the polyneuropathy disability (PND) scoring system and the Neuropathy Impairment Score +7 (NIS+7 along with other markers to determine progression in other organ systems.(5,7,10)

Cardiomyopathy

Cardiomyopathy (CM) is a manifestation of ATTR amyloidosis in which fibrils deposit in the myocardium, leading to CM and symptoms of heart failure. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a late-onset disease; symptoms are predominately manifested in male patients 60 years of age or older.(6) ATTR-CM can be inherited (hATTR-CM) or by deposition of wild-type (ATTRwt-CM). There are more than 120 pathogenic mutations in TTR that result in a variable phenotypic presentation. The most prevalent TTR variants that manifest predominantly as CM include Val122Ile and late-onset Val30Met cases.(8) The prevalence of ATTRwt is uncertain, some studies have reported a prevalence of 13% among patients with heart failure with a preserved ejection fraction, 16% among patients undergoing transcatheter aortic-valve replacement for severe aortic stenosis, and 5% among patients with presumed hypertrophic cardiomyopathy.(6)

Patients with ATTR-CM often show common signs and symptoms of heart failure, such as dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, fatigue, exercise intolerance, dizziness/syncope, palpitations, electrical conduction abnormalities, and arrhythmias. Therefore, ATTR-CM is sometimes mistakenly diagnosed as hypertrophic cardiomyopathy or as generic, undifferentiated heart failure with preserved ejection fraction rather than amyloidosis.(6,8) In addition, because of the age-dependent development of ATTR-CM, comorbid conditions including hypertension, diabetes, and ischemic heart disease, a high degree of clinical suspicion is required to identify ATTR-CM.(8) Patients with suspected ATTR-CM should include testing for monoclonal protein followed by scintigraphy or biopsy. Nuclear imaging can also be performed for additive information. In some cases, endomyocardial biopsy is necessary for a definitive diagnosis. If no monoclonal protein is detected and a diagnosis of light chain amyloidosis (AL) has been ruled out, scintigraphy alone can definitively diagnose ATTR-CM. If ATTR-CM is identified, TTR genotyping should be performed.(8)

Efficacy

Attruby (acoramidis) is a transthyretin stabilizer that binds to TTR at the thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process. Efficacy was demonstrated in a multicenter, international, randomized, double-blind, placebo-controlled study (NCT03860935) in 611 adult patients with wild-type or variant (hereditary) ATTR-CM. Patients were randomized  in a 2:1 ratio to receive either Attruby 712 mg (409 patients) or placebo (202 patients), for 30 months. Primary endpoint was the the impact on the hierarchical combination of All-Cause mortality (ACM), cumulative frequency of cardiovascular-related hospitalizations (CVH), change from baseline in NT-ProBNP, and change from baseline in 6MWT over a 30-min fixed treatment duration. The endpoint was analyzed using the Finkelstein-Schoenfeld (F-S) method. The F-S test showed a statistically significant reduction in ACM and cumulative frequency of CVH in the Attruby arm versus the placebo arm. ACM was reported in 19% and 26% of participants in the Attruby and placebo groups, respectively. The majority (79%) of the deaths were cardiovascular. CVH was reported in 27% and 43% of participants in the Attruby and placebo groups, respectively. The mean number of CVH events was 0.3 vs 0.6 per year. The majority (59%) of CVH were heart failure hospitalizations reported in 13% and 26% of the participants in the Attruby and placebo groups, respectively. The treatment effect of Attruby on functional capacity and health status was assessed by the 6MWD and the Kansas City Cardiomyopathy Questionnaire-Overall Summary score (KCCQ-OS) respectively. At month 30, the LS mean difference (95% CI) in change from baseline in 6MWD was 40 [21, 58] meters (p<0.0001) and change from baseline in KCCQ-OS was 10 [6, 14] points (p<0.0001).(11)

Tegsedi (inotersen) is an antisense oligonucleotide (ASO) that causes degradation of mutant and wild-type transthyretin (TTR) mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. The efficacy of Tegsedi was demonstrated in the NEURO-TTR trial, a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients with polyneuropathy cause by hATTR amyloidsis (Study 1; NCT 01737398) Patients were randomized  in a 2:1 ratio to receive either Tegsedi (113 patients) or placebo (60 patients), as a subcutaneous injection once per week for 65 weeks. Seventy seven percent of Tegsedi-treated patients and 87% of patients on placebo completed 66 weeks. Patients were FAP stage 1 or 2 (ambulatory or ambulatory with assistance, respectively) and had no prior liver transplant or anticipated liver transplant within 1 year of screening. Primary endpoints were the change in the mNIS+7 score and the change in the Norfolk QoL-DN score. At 66 weeks, both primary efficacy assessments favored inotersen. The least squares mean change from baseline was -19.7 points (95% CI, -26.4 to -13.0; p<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QoL-DN score.(1)

Vyndeqel (tafamidis) is a selective stabilizer of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process. Efficacy was demonstrated in a multicenter, international, randomized, double-blind, placebo-controlled study (NCT01994889) in 441 patients with wild-type or hereditary ATTR-cardiomyopathy (ATTR-CM), with no prior liver or heart transplantation. Patients were randomized in a 1:2:2 ratio to receive Vyndaqel 20 mg (88 patients), Vyndaqel 80 mg (176 patients), or placebo (177 patients) once daily for 30 months, in addition to standard of care (e.g., diuretics). Treatment assignment was stratified by the presence or absence of a variant TTR genotype as well as baseline disease severity (NYHA Class I-III, Class IV was excluded). The primary analysis points were all-cause mortality and frequency of cardiovascular-related hospitalizations. The analysis demonstrated a significant reduction in all-cause mortality and frequency of cardiovascular-related hospitalizations in the pooled Vyndaqel group versus placebo.(2)

WAINUA (eplontersen) is a transthyretin-directed ASO that 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. The efficacy of WAINUA was demonstrated in a randomized, open-label, multicenter trial and adult patients with polyneuropathy caused by hATTR amyloidosis (Study 1; NCT04136184). Patients were randomized in a 6:1 ratio to receive subcutaneous injections of either 45mg of WAINUA once every 4 weeks (144 patients), or 284mg of inotersen once weekly (24 patients), respectively. Efficacy assessments were based on a comparison of the WAINUA arm of Study 1 with an external placebo group (60 patients) from another study (NCT01737398) of a comparable population of adult patients with the same indication. Endpoint was change from baseline to week 35 in the mNIS+7 composite score and change from baseline to week 35 in the QoL-DN total score. Treatment with WAINUA resulted in statistically significant improvements in the mNIS+7 and Norfolk QoL-DH total scores compared to placebo control (p<0.001) at week 35. The least squares mean change from baseline was -9.0 points (95% CI, -13.5 to -4.5; p<0.001) for the mNIS+7 and -11.8 points (95% CI, -16.5 to -6.8; P<0.001) for the Norfolk QoL-DN score.(9)

Safety

Attruby has no FDA labeled contraindications for use.(11)

Tegsedi has the following boxed warnings:(1)

• Thrombocytopenia: Tegsedi causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. Tegsedi is contraindicated in patients with a platelet count below 100 x 10^9/L. Prior to starting Tegsedi, obtain a platelet count. During treatment, monitor platelet counts weekly if values are 75 x 10^9/L or greater, and more frequently if values are less than 75 x 10^9/L. If the patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional Tegsedi unless a platelet count is determined to be interpretable and acceptable by a medical professional. Following discontinuation of treatment for any reason, continue to monitor the platelet count for 8 weeks, or longer if platelet counts are less than 100 x 10^9/L, to verify that platelet counts remain above 75 x 10^9/L.
• Glomerulonephritis: Tegsedi can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. Tegsedi should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Prior to starting Tegsedi, measure serum creatinine, estimated glomerular filtration rate (eGFR), UPCR, and perform a urinalysis. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every two weeks. Tegsedi should not be given to patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m^2, pending further evaluation of the cause. If a dose is held, once eGFR increases to greater than or equal to 45 mL/minute/1.73 m^2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, Tegsedi should be permanently discontinued. 
• Tegsedi REMS Program: Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, Tegsedi is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS).

Tegsedi is contraindicated in patients with:(1)

• Platelet count below 100 x 10^9/L
• History of acute glomerulonephritis caused by Tegsedi
• History of a hypersensitivity reaction to Tegsedi

Vyndaqel and Vyndamax have no FDA labeled contraindications for use.(2)

WAINUA has no FDA labeled contraindications for use.(9)

1

Tegsedi prescribing information. Akcea Pharmaceuticals, Inc. January 2024.

2

Vyndaqel and Vyndamax prescribing information. Pfizer Laboratories Div Pfizer Inc. October 2023.

3

Amyloidosis Research Consortium. About Amyloidosis. Updated August 3, 2023. https://arci.org/about-amyloidosis/.

4

Kapoor M, Rossor AM, Laura M, Reilly MM. Clinical presentation, diagnosis and treatment of TTR amyloidosis. Journal of Neuromuscular Diseases. 2019;6(2):189-199. doi:10.3233/jnd-180371

5

Dyck PJB, González-Duarte A, Obici L, et al. Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7. Journal of the Neurological Sciences. 2019;405:116424. doi:10.1016/j.jns.2019.116424

6

Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. New England Journal of Medicine. 2018;379(11):1007-1016. doi:10.1056/nejmoa1805689

7

Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care. Therapeutics and Clinical Risk Management. 2020;Volume 16:109-123. doi:10.2147/tcrm.s219979

8

Maurer MS, Bokhari S, Damy T, et al. Expert Consensus Recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circulation Heart Failure. 2019;12(9). doi:10.1161/circheartfailure.119.006075

9

WAINUA prescribing information. AstraZeneca Pharmaceuticals LP. December 2023. 

10

Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. Journal of Neurology. 2020;268(6):2109-2122. doi:10.1007/s00415-019-09688-0

11

Attruby prescribing information. BridgeBio Pharma, Inc. November 2024. 

Attruby

acoramidis hcl tab pack

356 MG

M ; N ; O ; Y

N

Wainua

eplontersen sodium subcutaneous soln auto-inj

45 MG/0.8ML

M ; N ; O ; Y

N

Tegsedi

inotersen sod subcutaneous pref syr

284 MG/1.5ML

M ; N ; O ; Y

N

Vyndamax

tafamidis cap

61 MG

M ; N ; O ; Y

N

Vyndaqel

tafamidis meglumine (cardiac) cap

20 MG

M ; N ; O ; Y

N

Attruby

acoramidis hcl tab pack

356 MG

112

Tablets

28

DAYS

Tegsedi

Inotersen Sod Subcutaneous Pref Syr 284 MG/1.5ML (Base Eq)

284 MG/1.5ML

4

Syringes

28

DAYS

Vyndamax

Tafamidis Cap 61 MG

61 MG

30

Capsules

30

DAYS

Vyndaqel

Tafamidis Meglumine (Cardiac) Cap 20 MG

20 MG

120

Capsules

30

DAYS

Wainua

eplontersen sodium subcutaneous soln auto-inj

45 MG/0.8ML

1

Pen

30

DAYS

Attruby

acoramidis hcl tab pack

356 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tegsedi

inotersen sod subcutaneous pref syr

284 MG/1.5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Vyndamax

tafamidis cap

61 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Vyndaqel

tafamidis meglumine (cardiac) cap

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Wainua

eplontersen sodium subcutaneous soln auto-inj

45 MG/0.8ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Attruby

acoramidis hcl tab pack

356 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tegsedi

Inotersen Sod Subcutaneous Pref Syr 284 MG/1.5ML (Base Eq)

284 MG/1.5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Vyndamax

Tafamidis Cap 61 MG

61 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Vyndaqel

Tafamidis Meglumine (Cardiac) Cap 20 MG

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Wainua

eplontersen sodium subcutaneous soln auto-inj

45 MG/0.8ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has ONE of the following:
   1. ALL of the following:
      1. A diagnosis of polyneuropathy of hereditary transthyretin-mediated amyloidosis confirmed by testing (e.g., genetic testing, biopsy) AND
      2. The requested agent is FDA labeled for use in polyneuropathy of hereditary transthyretin-mediated amyloidosis AND
      3. The patient has clinical manifestations of polyneuropathy (e.g., neuropathic pain, altered sensation, numbness, tingling, impaired balance, motor disability) OR
   2. ALL of the following:
      1. A diagnosis of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis confirmed by testing (e.g., stannous pyrophosphate (PYP) scanning, monoclonal antibody studies, biopsy, scintigraphy, genetic testing [TTR genotyping]) AND
      2. The requested agent is FDA labeled for use in cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis AND
      3. The patient has New York Heart Association (NYHA) Functional Class I, II, or III heart failure AND
      4. The patient has clinical manifestations of cardiomyopathy (e.g., dyspnea, fatigue, orthostatic hypotension, syncope, peripheral edema) OR
   3. The patient has another FDA labeled indication for the requested agent and route of administration AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. The patient has NOT received a liver transplant AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, geneticist, neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient will NOT be using the requested agent in combination with another agent targeted in this program, Onpattro (patisiran), OR Amvuttra (vutrisiran), for the requested indication AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The patient has NOT received a liver transplant AND
4. The requested agent is Vyndamax (tafamidis) or Vyndaqel (tafamidis meglumine) AND the patient has New York Heart Association (NYHA) Functional Class I, II, or III heart failure AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, geneticist, neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient will NOT be using the requested agent in combination with another agent targeted in this program, Onpattro (patisiran), OR Amvuttra (vutrisiran), for the requested indication AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval: up to 12 months