Key Data: Treatment Algorithm, Disease-Modifying Agents, Vyndaqel

ATTR-CA Treatment Algorithm

japan

Treatment of ATTRwt-CM involves both (i) disease modifying agents to treat the underlying condition and (ii) supportive care to manage cardiovascular complications [1,2]

Algorithm modified from Kittleson MM, et al. Circulation. 2021 and Kitaoka H, et al. Circ J. 2020

Notes: ACE = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blockers; ARNI = angiotensin receptor blocker-–neprilysin inhibitor; BB = β-blocker; CA = cardiac amyloidosis; CM = cardiomyopathy; CRT = cardiac resynchronization therapy; DOAC = direct oral anticoagulant; HF = Heart failure; ICD = implantable cardiac defibrillator; PPM = permanent pacemaker; SCD = sudden cardiac death; VKA = vitamin K antagonist; VT = ventricular tachycardia

Notes: * Bioavailable loop diuretics are used for decongestion, although they may compromise renal function or systemic perfusion in patients with advanced restrictive disease because diminishing preload may compromise an already fixed stroke volume, leading to low cardiac output. Aldosterone antagonists may be used alone or in conjunction with loop diuretics in patients with adequate blood pressure and renal function.1

Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J, Ruberg FL; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1. Erratum in: Circulation. 2021 Jul 6;144(1):e11. PMID: 32476490.
Kitaoka H, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020. 84(9), 1610-1671. https://doi.org/10.1253/circj.CJ-20-0110.
Inomata, T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.

Overview of Disease-Modifiying Agents for ATTR

Overview of existing ATTR therapies and those in development [1-6]

*Stabilize the TTR tetramer, prevent its dissociation, and thereby remove the amoloidogenic source [1-3]
**Silence or knockdown TTR mRNA and block protein synthesis3; have not received regulatory approval for use in ATTR-CM amyloidosis without PN [1]

Notes: ^ According to the most recent figures of the worldwide “Familial World Transplant Registry” (http://fapwtr.org), approximately 120 patients with ATTRv receive a liver transplant per year. This therapeutic option is associated with a 10-year survival rate of 21–85% depending on the underlying mutation. Independent factors for a favorable outcome are a higher body mass index, an early onset of the disease (age < 50 years), a short disease duration, and the presence of a Val30Met mutation. Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3.

ALXN: Acoramidis for the Treatment of ATTR-CM: Training Deck. November 22, 2021. 34_Acoradmidis Training Deck_22Nov21 FINAL. Citing: Yamamato H, Yokochi T. ESC Heart Fail. 2019;6:1128-1139 & Sekijima Y, et al. Orphanet J Rare Dis. 2018;13:6.
Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
ALXN: Acoramidis for the Treatment of ATTR-CM: Training Deck. November 22, 2021. 34_Acoradmidis Training Deck_22Nov21 FINAL. Citing: Sekijima Y, et al. Orphanet J Rare Dis. 2018;13:6; Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891 & Kitaoka H, et al. Circ J. 2020;84:1610-1671.
Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J, Ruberg FL; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1. Erratum in: Circulation. 2021 Jul 6;144(1):e11. PMID: 32476490.
ALXN: ATTR Dx Summary. 09_ATTR Dx Summary_06_16_2021.
According to the most recent figures of the worldwide “Familial World Transplant Registry” (http://fapwtr.org), approximately 120 patients with ATTRv receive a liver transplant per year. This therapeutic option is associated with a 10-year survival rate of 21–85% depending on the underlying mutation. Independent factors for a favorable outcome are a higher body mass index, an early onset of the disease (age < 50 years), a short disease duration, and the presence of a Val30Met mutation. Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3.

Current Disease-Modifying Agents

Notes: ACE = angiotensin converting enzyme; AE = adverse event; A-fib = Atrial fibrillation; ARB = angiotensin receptor blockers; HF = Heart failure; ICD = implantable cardiac defibrillator; NSAID = Non-steroidal anti-inflammatory drug; OL = off label; siRNA = small interfering RNA

Notes: *Cardiac amyloid regression has been decribed by CMR. ALXN2060 TPP & SVP Evolution. June 24, 2021. 10_SVP-TPP AG10_10 21 20 (003) (1).

Deep Dive

Compare TTR silencers & stabilizers

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Kitaoka H, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020. 84(9), 1610-1671. https://doi.org/10.1253/circj.CJ-20-0110.
Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J, Ruberg FL; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1. Erratum in: Circulation. 2021 Jul 6;144(1):e11. PMID: 32476490.
Sekijima Y, et al. Orphanet J Rare Dis. 2018;13:6.
Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-67.
Plante-Bordeneuve V. Transthyretin familial amyloid polyneuropathy: an update. J Neurol. 2018;265(4):976-83.
Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29 Suppl 1:S14-26.
Rezk, T. and Gillmore, J.D., 2021. Amyloid heart disease module 2: Management. BJC.
ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier.
Muchtar E, et al. J Intern Med. 2021;289:268-292.

The ATTR-ACT Trial for ATTR Showed a 30% Reduction in Risk of Death

Vyndaqel (tafamidis), the only disease-modifying ATTRwt Tx approved in Japan, demonstrated a 30% reduction in risk of death [1]

In the Ph3 ATTR-ACT study, patients receiving tafamidis for 30 months had reductions in all-cause mortality, with a 30% reduction in risk of death

However, it took >1.5 years from the start of tafamidis Tx to observe a decrease in mortality, and it could not be confirmed to be effective in NYHA Class III patients at baseline with CV-related hospitalization, suggesting the importance of early administration [1]

Versus the placebo groups, tafamidis groups also had:
- Lower rates of cardiovascular hospitalizations,
  - Relative reduction in frequency of CV-related hospitalization of 32%
- A slower rate of decline in 6MW, and
- Improved healthcare QoL [2*]
AE profiles were similar between the tafamidis and placebo groups
Moreover, additional long-term (60 mo.) safety and efficacy of tafamidis were confirmed in an OLE study in patients with ATTR-CM [1]

ATTR- ACT Study*

(n = 441 ATTR-CM patients [75% ATTRwt, 25% ATTRv])

*Only ATTR-ACT has been reported as a randomized controlled trial for ATTR-CM; thus, JCS guidelines note the following:

NYHA Class IV patients were excluded; thus, efficacy and safety have not been confirmed
The efficacy and safety in the excluded population was not confirmed
Given that it took >1 year after administration to confirm effectiveness, it should be carefully considered in cases with a life expectancy not >1 year [1]

Notes: 6MW = 6-minute walk; AE = adverse event; CV = cardiovascular; JCS = Japanese Circulation Society; NYHA = New York Heart Association; OLE = open-label extension

Notes: * In the secondary study end points, a decline in functional capacity as measured by 6-min walking test distance was alleviated in the tafamidis group, and a decline in QOL as evaluated by the Kansas City Cardiomyopathy Questionnaire-Overall Summary score was also improved.

Notes: **Tafamidis increases survival by 23% at 30 months in the ph. 3 ATTR-ACT study (70% with Vyndaqel/Vyndamax vs. 57% with placebo). ALXN2060 TPP & SVP Evolution. June 24, 2021. 10_SVP-TPP AG10_10 21 20 (003) (1).

Notes: Pfizer press release (Nov. 12, 2020): Results from the analysis of the Phase 3 Tafamidis in Transthyretin Amyloid Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension study, which were published in the European Journal of Heart Failure, demonstrated a 30% relative reduction in the risk of death (p=0.0374) among patients with ATTR-CM initially treated with VYNDAQEL 80 mg and subsequently transitioned to VYNDAMAX 61 mg, versus patients initially treated with VYNDAQEL 20 mg and transitioned to VYNDAMAX 61 mg. https://www.pfizer.com/news/press-release/press-release-detail/analysis-phase-3-attr-act-and-its-long-term-extension-study

Kitaoka H, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020. 84(9), 1610-1671. https://doi.org/10.1253/circj.CJ-20-0110.
Muchtar E, et al. J Intern Med. 2021;289:268-292.

Access to Vyndagel in Japan

japan

In Japan, eligible patients with ATTR-CM can receive an initial prescription for Vyndaqel (tafamidis) only if the criterion of both the site and the physician being certified by the JCS is met [1,2]

In addition, patients may be granted a Medical Care Recipient Certificate if they have a definite diagnosis per the JCS disease criteria for ATTRwt-CM

In Japan, treatment costs for patients with a definite diagnosis are eligible for medical expense deductions

Notes: HF = heart failure; JCS = Japanese Circulation Society

Kitaoka H, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020. 84(9), 1610-1671. https://doi.org/10.1253/circj.CJ-20-0110.
Inomata, T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.
Teng C, et al. Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy. Clin Cardiol. 2020;43:1223–1231. DOI: 10.1002/clc.23434.

Vyndaqel is the Most Expensive Cardiovascular Drug

With a list price of $225,000 per year in the US, Vyndaqel is the most expensive cardiovascular drug on the market, resulting in a number of (potential) negative impacts on patients

USA

The Vyndaqel (tafamidis) $225K/year list price raises several key issues, e.g.: [2]

Cost of comparative trials:
- Vyndaqel should be the standard for future ATTR-CM comparative trials, but costs for Vyndaqel alone in such a trial could reach $100 million [2]
Delayed care
- A recent study by Masri, et al., showed how the length of time it takes to get approval and financial assistance for Vyndaqel has led to a significant and potentially devastating delay in care for many patients [3]
Concerns about long-term access—and whether the cost is justified [4]
- A recent study used a calculated cost-effectiveness ratio and annual budget impact as primary outcomes to determine the cost-effectiveness of tafamidis [5]
  - At the current price, Vyndaqel was found to be cost-effective in 0% of 10,000 probabilistic simulations
  - Based on the model, it would take a 92.6% reduction in price to $16,563 to make Vyndaqel cost-effective

Other drugs that are being investigated in the treatment of ATTR-CA also have extremely high-price points, such as inotersen and patisiran, which are listed at $450,000 annually [2]

“As cardiac ATTR amyloidosis is considered to be a common disease in the elderly, improvement in the diagnostic rate and an appropriate drug price are desired in the near future.” [1]

japan

Topic for PsV workshop discussions: do HCPs encounter any cost-related difficulties / hurdles in getting patients access to Vyndaqel?

In January 2020, the JCS provided conditions for reimbursement of the treatment cost of ATTR-CA using Vyndaqel, which was noted to have an expected cost >$250,000 per year [1]*

* NOTE:

•Vyndaqel was approved for ATTRv-PN by the JMHLW in 2013 at a 20-mg QD; the daily drug price is ~¥57,000

•The recommended dose of Vyndaqel for ATTR-CM is 80 mg/day. Endo, et al. noted it was expected to cost ~ ¥83,500,000 per year (which would be ~$733K USD)1

NICE rejected regular NHS funding for Pfizer’s Vyndaqel (tafamidis) for ATTR-CM, although it left the door open for negotiations if the Pfizer decides to drop its price [6]

NICE rejected funding because there is not enough evidence to back Pfizer’s claim that Vyndaqel could reduce delays in diagnosis and avoid healthcare costs and anxiety caused.
The cost-effectiveness body added that there is uncertainty about how long the benefit from the drug lasts after it is stopped in its final guidance

Note: NICE = National Institute for Health and Care Excellence

Endo J, et al. A Statement on the Appropriate Administration of Tafamidis in Patients With Transthyretin Cardiac Amyloidosis. Circ J. 2020; 84: 15–17. doi:10.1253/circj.CJ-19-0811.
Capustin M & Frishman W. Transthyretin Cardiac Amyloidosis and Novel Therapies to Treat This Not-so-rare Cause of Cardiomyopathy. Cardiology in Review. 2021;29: 263-273. DOI: 10.1097/CRD.0000000000000387.
Masri A, Chen H, Wong C, et al. Initial experience prescribing commercial tafamidis, the most expensive cardiac medication in history. JAMA Cardiol. 2020;5:1066–1067
Gurwitz JH, Maurer MS. Tafamidis—A pricey therapy for a not-so-rare condition. JAMA Cardiol. 2020;5:247–248.
Kazi DS, Bellows BK, Baron SJ, et al. Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy. Circulation. 2020;141:1214–1224.
Staines R. NICE says ‘no’ to Pfizer’s Vyndaqel for rare heart condition. pharmaphorum. May 12, 2021. Available at https://pharmaphorum.com/news/nice-says-no-to-pfizers-vyndaqel-for-rare-heart-condition/. Accessed January 19, 2022.

KOLs Have Criticized Vyndaqel Pricing

usa

Several heart failure physicians, specifically those who treat patients with ATTR-CM, are calling attention to the extraordinarily high price of Vyndaqel (tafamidis)

Tafamidis and tafamidis meglumine (Vyndamax and Vyndaqel; Pfizer) both received orphan drug designation and were approved by the US FDA in 2019.

KOLs criticized the current system, noting that the US government is unable to set drug prices for Medicare patients and is suffering the consequences for it.

“I think it’s a little bit ludicrous—I love my patients and I think they should get the drug—but to spend a quarter of a million dollars every year on patients who are 80 years of age? Not to be disrespectful to them, but it’s not sustainable.” - Maurer, MD, Columbia*

Researchers say Pfizer is “gouging” payers, noting that elderly patients have out-of-pocket costs of $1,000 to $2,000 a month.***

One patient with ATTR-CM, ran the numbers and weighed the financial impact with his current symptoms, and despite his life-threatening, progressive condition ultimately decided against Vyndaqel.

“He went out and bought himself a brand-new pickup truck, because he said that’s the drug cost for the first 2 years, and he might as well enjoy himself.” – Falk, MD, Brigham & Women’s Hospital*, discussing a patient

KOLs argue it’s an orphan drug price for a non-rare disease**

“It’s much more common than we recognized a decade ago,” said Falk. “Every single major amyloid center has seen an enormous surge in TTR amyloid, particularly wild-type TTR amyloidosis. Many people believe it’s responsible for about 5% to 10% of older patients with heart failure with preserved ejection fraction, which is an awful lot of patients.”**

“It was priced like a drug is typically priced for a truly rare disease, which this simply isn’t.” - Witteles, MD, Stanford*

A Pfizer spokesperson said the company believes the price of Vyndaqel is in line with the value the drug brings to patients and society and noted that the list price is not what patients pay.

However, Pfizer also agreed that it’s difficult to measure the true prevalence of ATTR-CM.

“While physicians may be more likely to diagnose ATTR-CM now that there is an approved treatment, it remains to be seen at what rate this will continue in the coming months and years,” the statement reads. “As part of our commitment to the ATTR-CM community, we intend to conduct two epidemiology studies to help improve our understanding of the prevalence of the disease. If it turns out this is not a rare disease, we will reevaluate the price accordingly.”

Notes: * Mathew Maurer, MD (Columbia University Irving Medical Center, New York, NY), who published his views along with Jerry Gurwitz, MD (University of Massachusetts Medical School, Worcester), January 8, 2020, in JAMA Cardiology; Rodney Falk, MD (Brigham and Women’s Hospital, Boston, MA), who runs a specialized cardiac amyloidosis program; Ronald Witteles, MD (Stanford University Medical Center, CA), who is co-director of the amyloid program at his institution

Notes: ** Pfizer estimates the prevalence of ATTR-CM to be approximately 100,000 people in the United States and that approximately 4 to 5% of people are diagnosed, but Maurer and Gurwitz highlight one study suggesting a prevalence of 13% among patients with heart failure with preserved ejection fraction (HFpEF) and increased wall thickness.

Notes: *** OOP costs for most patients are difficult to pin down given rebates and subsidies, but researchers estimate patients pay roughly $1,000 to $2,000 per month if they don’t receive additional financial support.” – Maurer, MD

Notes: In cardiology, the makers of the PCSK9 inhibitors faced significant backlash when they initially priced alirocumab (Praluent; Sanofi/Regeneron) and evolocumab (Repatha; Amgen) at nearly $15,000 per year, although that drug class is for a much more common disease affecting a significantly larger number of patients. The companies eventually cut their prices—slashing the costs by roughly 60%—when uptake stalled.

Notes: ^ Two agents, inotersen (Tegsedi; Akcea) and patisiran (Onpattro; Alnylam), both of which are approved as orphan agents for the treatment of the much-rarer hereditary amyloidosis, a disease the primarily affects the nervous system, will be tested in patients with ATTR-CM. Patisiran currently has a list price of $350,000 per year, while inotersen costs $450,000. The author notes AG10 is an investigational small molecule TTR therapy being developed for and tested in cardiomyopathy and polyneuropathy, and it has already been designated an orphan drug by the FDA

O’Riordan, Michale. ‘Outrageous’ $225,000 per Year List Price for Tafamidis Draws Outcry. TCTMD.com. January 10, 2020. https://www.tctmd.com/news/outrageous-225000-year-list-price-tafamidis-draws-outcry

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