Hereditary Transthyretin Amyloidosis (hATTR

Management Update

Data integration of pharmacy and medical benefit claims will allow payers to determine the total cost of care and promote steps that will facilitate treatment decisions.

Simone Ndujiuba, Pharm.D., BCOP Director, Clinical Strategy and Innovation, Oncology Magellan Rx Management The nomenclature has changed with familial forms of transthyretin amyloidosis (ATTR). Previously known as familial amyloid polyneuropathy (FAP) or familial amyloid cardiomyopathy (FAC), it is now called hereditary ATTR (hATTR).1 hATTR is a rare, heterogenous disease resulting from a deposition of soluble and insoluble amyloid fibrils or aggregates in the beta sheets of various organs, including peripheral nerves, heart, kidney, and ocular vitreous.2, 3 Amyloid deposits result when autosomal-dominant mutation in the transthyretin (TTR) gene leads to TTR protein misfolds. The wild-type transthyretin-mediated amyloidosis (ATTRwt), previously known as senile cardiac amyloidosis, is caused by an instability of the natural TTR protein, which is predominantly made in the liver and transports thyroxine and retinol (vitamin A) throughout the body.2

Due to signs and symptoms that overlap with a variety of other conditions, hATTR is not readily diagnosed, which makes it difficult to quantify the number of patients currently living with hATTR. Based on current data, it is estimated that 10,000 to 15,000 people live with hATTR in the U.S., with approximately 50,000 individuals with varying phenotypic presentation of the disease worldwide.4. 5 Over the years, advancements in imaging and increased genetic testing have enhanced timely diagnosis. As a result, the number of patients diagnosed with hATTR is projected to increase.6

More than 130 TTR variants have been identified, many with regional clusters around the world. The V30M mutation accounts for an estimated 50% of the world’s variants and is the predominant form in endemic regions. The ATTR V30M is found in parts of Europe and Japan; ATTR V122I is identified in 3-4% of African Americans; and ATTR T60A, the most identified variant in the United Kingdom, has higher rates in people of Irish descent.6

HATTR | Continued

The therapeutic goal for hATTR is reduction in symptom severity and establishment of a long-term treatment plan.

hATTR primarily presents as a somatic and autonomic nervous system impairment, polyneuropathy (hATTR-PN) seen in early adulthood, and cardiomyopathy (hATTR-CM) seen later in life. If the TTR gene sequence does not have a mutation, it is designated as a wild-type (ATTRwt) and leads to cardiomyopathy. Most patients show signs of a combination of peripheral nervous system and cardiac impairment. By their second decade of life, most patients present with initial neurologic symptoms. As patients near their third and fifth decades, hATTR-PN progresses with signs and symptoms that include sensorymotor polyneuropathy with autonomic involvement, postural hypotension, and bladder and erectile dysfunction, to name a few. hATTR-CM commonly occurs by age 60 or older, with a greater incidence in men than women.4 Hypertrophic cardiomyopathy, even if usually latent, is identifiable in at least 50% of the patients.2 Patients with variants such as Val122Ile, Leu111Met, Ile68Leu, and ATTRwt develop cardiac impairment with preserved ejection fraction. Clinical presentation includes unexplained left ventricular hypertrophy, which results in restrictive cardiomyopathy, heart failure, atrial fibrillation, and conduction abnormalities. Predominant cardiomyopathy with heart failure routinely shows preserved ejection in men older than 60.6 The estimated survival for patients with neurologic dominant hATTR is 5 to 15 years; this estimate is reduced 2.5 to 4 years for patients with cardiac-dominant disease. Overall, if hATTR is left untreated, death may occur within 10 years.7

Treatment

The therapeutic goal for hATTR is reduction in symptom severity and establishment of a long-term treatment plan. In the 1990s, liver transplant to eliminate amyloid protein production was the preferred treatment of choice. However, transplant led to cardiovascular complications, which led to death in 22% of patients and a 20-year survival rate of 55.3%. With increased diagnosis and treatment advancements, therapeutic options have expanded.2 Currently, medication is indicated for treatment of polyneuropathy or cardiomyopathy but not for all types of hATTR. Reduction in cardiovascular mortality and cardiovascularrelated hospitalization is a key goal, so the FDA approval of two oral selective stabilizers of the TTR tetramer, Vyndaqel® (tafamidis meglumine) and Vyndamax™ (tafamidis), with indications for the treatment of the cardiomyopathy of wild-type or hATTR amyloidosis, will help to accomplish this goal.8-9 hATTR-PN parenteral therapy

options that inhibit TTR hepatic production, such as Onpattro® (patisiran), Tegsedi® (inotersen), and Amvuttra™ (vutrisiran), have also been FDA-approved. Multiple agents are in development to target various stages of ATTR pathogenesis.2, 10-12

AMVUTTRA™ (vutrisiran)

In June 2022, the Food and Drug Administration (FDA) approved Amvuttra (vutrisiran) for polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Vutrisiran is supplied as a single-dose prefilled syringe administered by a healthcare professional once every three months (for four doses per year). In the HELIOS-A phase 3 study, vutrisiran (n=122) was compared to active therapy infusion (external placebo) patisiran (N=42).15 The primary end point was change from baseline in neuropathy impairment using the modified Neuropathy Impairment Score +7 (mNIS+7) versus external placebo at month 9. The study was an intention-to-treat, with patients receiving one or more doses of vutrisiran or placebo. At nine months, vutrisiran quickly attained a decrease in serum TTR level, demonstrating a significant improvement in multiple end points when evaluated against the external placebo. The primary end point was achieved: Vutrisiran significantly improved mNIS+7 versus external placebo (LS mean [±SE] change from baseline: −2.2±1.4 [vutrisiran]; +14.8±2.0 [placebo]; difference −17.0; p=3.5×10−12). Vutrisiran also significantly improved quality of life, gait speed, nutritional status, and disability compared to the external placebo. Vutrisiran was well tolerated with mild to moderate adverse effects and no drug discontinuation or death.13

Payment Management Strategies

In 2020, a retrospective trial analyzed claims data for newly diagnosed hATTR. The study determined that the annual mean total cost to treat each patient was $64,066.14 Inpatient care was the greatest expense ($34,461), with outpatient ($23,853) and pharmacy ($5,752) adding to overall expenditure. The highest utilization occurred during the first quarter post-diagnosis, then decreased in following quarters. Insurance type varied; preferred provider organization/point of service plans (65.9%) were most

The complexity of this disease and its intersection with other conditions creates gaps in payers’ ability to identify affected patients.

utilized, followed by comprehensive (12.4%) and consumerdirected health plan/high-deductible health plans (11.4%).14

In a recent meeting of healthcare decision-makers, a group of payers discussed their role in supporting the identification, management, and consideration of medical and pharmacy benefits for patients with rare disease, particularly hATTR.15 The complexity of this disease and its intersection with other conditions creates gaps in payers’ ability to identify affected patients. With the breadth of complications associated with this rare disease, payers recognized the need for collaboration with case management, health plans, and health systems to create a patient-centered program.15 When medication coverage was addressed, payers agreed that identification of actionable mutations makes it easier to justify high-cost medications.15 In addition, test results help to determine if family members also require screening and early intervention. Ultimately, the payers preferred medications processed through the pharmacy benefit. Traditionally, pharmacy claims decrease drug cost variability. With medical claims, the risk for variable cost increases, especially as costs associated with specialists and centers of excellence come into play. Data integration of pharmacy and medical benefit claims will allow payers to determine the total cost of care and promote steps that will facilitate treatment decisions.15

Three phase 3 trials, one for vutrisiran in hATTR-CM and two for eplontersen on cardiomyopathy and polyneuropathy in hATTR, demonstrate continued treatment advancements for this rare disease.16

Pipeline: hATTR19

Drug

Manufacturer Route of Administration Mechanism of Action Indication

Vutrisiran (AMVUTTRA™) Alnylam Pharmaceuticals SC injection

Eplontersen (AKCEA-TTR-LRx) Ionis Pharmaceuticals Inc. SC injection RNAi

ligand-conjugated antisense cardiomyopathy

cardiomyopathy; polyneuropathy Status

phase 3

phase 3

HATTR | Continued

References

1. Benson, M. D., et al. “Diagnosis and Screening of Patients with Hereditary Transthyretin Amyloidosis (hATTR): Current Strategies and Guidelines.” Therapeutics and Clinical Risk Management, 14 Aug. 2020, https://doi.org/10.2147/tcrm.s185677. 2. Luigetti, Marco, et al. “Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care.” Therapeutics and Clinical

Risk Management, 21 Feb. 2020, https://doi.org/10.2147/tcrm. s219979. 3. Ruberg, Frederick L., and Matthew S. Maurer. “Expert Analysis and Opinion—Understanding Cardiac Amyloidosis.” American College of

Cardiology, 14 Apr. 2021, https://www.acc.org/latest-in-cardiology/ articles/2021/04/14/17/11/understanding-cardiac-amyloidosis. 4. Gertz, Morie A. “Hereditary ATTR Amyloidosis: Burden of Illness and Diagnostic Challenges.” American Journal of Managed Care, Supplements and Featured Publications, 13 June 2017, https:// www.ajmc.com/view/hereditary-attr-amyloidosis-burden-of-illnessand-diagnostic-challenges-article. 5. Lovley, Andrew, et al. “Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being.” Journal of Patient-Reported Outcomes, 7 Jan. 2021, https://doi.org/10.1186/ s41687-020-00273-y. 6. Obi, Chukwuemeka A., et al. “ATTR Epidemiology, Genetics, and Prognostic Factors.” Methodist DeBakey Cardiovascular Journal, 14 March 2022, https://doi.org/10.14797/mdcvj.1066. 7. Walker, Scot. “New Medications in the Treatment of Hereditary Transthyretin Amyloidosis,” Hospital Pharmacy, 4 June 2018, https://doi.org/10.1177/0018578718779757. 8. Vyndamax [package insert]. NY, NY; Pfizer; April 2020. 9. Vyndaqel [package insert]. NY, NY; Pfizer; April 2020. 10. Opattro [package insert]. Cambridge, MA; Alnylam; July 2022. 11. Tegsedi [package insert]. Waltham, MA; Akcea; May 2021. 12. Amvuttra [package insert]. Cambridge, MA; June 2022. 13. Gonzalez-Duarte, Alejandra, et al. “HELIOS-A: Results from the phase 3 study of vutrisiran in patients with hereditary transthyretinmediated amyloidosis with polyneuropathy.” Journal of the

American College of Cardiology, March 2022, https://www.jacc.org/ doi/10.1016/S0735-1097%2822%2901293-1. 14. Reddy, Sheila R., et al. “The Clinical and Economic Burden of Newly Diagnosed Hereditary Transthyretin (ATTRv) Amyloidosis: A Retrospective Analysis of Claims Data.” Neurology and Therapy, U.S. National Library of Medicine, 25 May 2020, https://pubmed.ncbi. nlm.nih.gov/32451849/ 15. “Rare Disease: Access, Reimbursement, and Disease Management A Stakeholder Interchange Report.” American Journal of Managed

Care Supplements and Featured Publications, MJH Life Sciences, 3 Feb. 2022, https://www.ajmc.com/view/rare-disease-accessreimbursement-and-disease-management-a-stakeholderinterchange-report. 16. U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/ home. 17. “Hereditary Transthyretin Amyloidosis.” IPD Analytics, https:// ipdanalytics.com.