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New treatments, increased awareness shine spotlight on cardiac amyloidosis

Amyloidosis, a disease in which misfolded proteins form amyloid fibrils that deposit in tissues and organs including the heart, is a vexing condition with devastating consequences. Encouragingly, new treatment options for cardiac amyloidosis have emerged recently and there is increasing awareness of this disease, once considered very rare. However, the cost of these therapies has raised concerns about the ability of patients to access such therapies.

“In the last 5 to 10 years, we have made dramatic progress in the diagnostic strategies and treatment strategies for the more commonly encountered types of amyloidosis,” Brian M. Drachman, MD, associate chief of cardiovascular medicine at Penn Presbyterian Medical Center and co-director of the Amyloidosis Program at Penn Medicine, told Cardiology Today. “We have taken a set of diseases — which were almost uniformly considered by the provider community to have no options — and given patients not only hope for the future, but hope for the present.”

Most recently, in 2018, results of the ATTR-ACT study, which evaluated the drug tafamidis vs. placebo, were reported at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine. In ATTR-ACT, 441 patients with transthyretin amyloid cardiomyopathy were randomly assigned 80 mg tafamidis, 20 mg tafamidis or placebo for 30 months. Results demonstrated that patients assigned tafamidis had reduced risk for all-cause mortality and CV-related hospitalizations compared with those assigned placebo. Analyses showed a slowing of the decline in a variety of metrics of quality of life with tafamidis in this patient population.

Mathew S. Maurer, MD, from NewYork-Presbyterian Hospital/Columbia University Medical Center, said many doctors often fail to recognize cardiac amyloidosis.

Source: Columbia University Irving Medical Center. Printed with permission.

“The ATTR-ACT results were groundbreaking,” Mazen Hanna, MD, co-director of the amyloidosis center and staff cardiologist in the section of heart failure and cardiac transplantation medicine at Cleveland Clinic, told Cardiology Today. “We never had anything to treat transthyretin amyloid cardiomyopathy.”

Thereafter, the first therapies for patients with cardiomyopathy associated with transthyretin-mediated amyloidosis — tafamidis meglumine (Vyndaqel, FoldRx/Pfizer) and tafamidis (Vyndamax, FoldRx/Pfizer) — were approved by the FDA in May 2019, based on results from the ATTR-ACT trial.

Since then, debate in the community has focused on the list price of the drug, recently addressed in a JAMA Cardiology Viewpoint in January written by Jerry H. Gurwitz, MD, executive director of the Meyers Primary Care Institute and the Dr. John Meyers Professor of Primary Care Medicine at the University of Massachusetts Medical School, and Mathew S. Maurer, MD, medical director of the Cardiac Amyloidosis Program at New York-Presbyterian Hospital/Columbia University Medical Center and co-chair of the ATTR-ACT trial, titled “Tafamidis — A Pricey Therapy for a Not-So-Rare Condition.”

In addition to tafamidis, other drugs have been approved for the treatment of hereditary transthyretin amyloid polyneuropathy including inotersen (Tegsedi, Akcea Therapeutics) and patisiran (Onpattro, Alnylam Pharmaceuticals). Other drugs categorized as RNA inhibitors, stabilizers and monoclonal antibodies are in development to treat these patients and potentially eliminate amyloid in a patient’s heart.

Cardiology Today interviewed leaders in the field about challenges in the diagnosis of cardiac amyloidosis, available treatments and what is in the pipeline and current cost concerns.

Types of cardiac amyloidosis

Ronald M. Witteles

Cardiac amyloidosis is an umbrella term for two main types of the disease: light-chain and transthyretin (TTR) amyloidosis. Then, there are two types of TTR amyloidosis: hereditary or variant amyloidosis (ATTRh) and wild-type amyloidosis (ATTRwt; See Infographic).

The prevalence of cardiac amyloidosis is not definitively known. According to the National Organization for Rare Disorders, there are approximately 4,000 new cases of light-chain amyloidosis per year in the U.S. Cardiomyopathy in patients with familial amyloidosis, more commonly described as hereditary or variant amyloidosis, affects an estimated 40,000 to 50,000 patients globally, although it may be underestimated. There is a higher prevalence in black Americans in part because 3.4% of African Americans harbor a mutation in the TTR gene known as Val122Ile, which is inherited in an autosomal dominant fashion, according to the NIH. Wild-type TTR cardiac amyloidosis, which affects almost exclusively the elderly, is expected to become the most common form of systemic amyloidosis because of the aging population.

“For this condition, in contrast to most other cardiovascular diseases, there is nothing that the patient can do to prevent this disease. This is not lifestyle-related,” Martha Grogan, MD, founder and director of the Cardiac Amyloid Clinic and consultant in the division of structural heart disease at Mayo Clinic, said.

“Because it is a normal protein that is misfolding in wild-type ATTR amyloidosis, this is not something that happens rapidly; it takes years, likely decades, to deposit enough to actually start causing symptoms and problems,” Ronald M. Witteles, MD, professor of medicine and co-director of the Amyloid Center and the Multidisciplinary Sarcoidosis Program at Stanford University Medical Center, told Cardiology Today. “AL amyloidosis, on the other hand, can rapidly progress, making the rapid diagnosis and initiation of therapy an urgent matter in any suspected case.”

Warning signs

There are several warning signs of cardiac amyloidosis that cardiologists should keep in mind, including HFpEF with predominantly right-sided symptoms, severe increased left ventricular wall thickness without significant hypertension and mild to moderate increase in wall thickness but normal or low voltage on an ECG.

Among patients with severe aortic stenosis undergoing valve replacement, 1 in 7 have amyloidosis. The association is simply because both diseases occur in older adults, Maurer said.

Other echocardiographic findings are important in diagnosing cardiac amyloidosis, including the presence of unexplained increased right ventricular wall thickness, biatrial enlargement, thickened mitral and tricuspid valves, small pericardial effusion and reduced global longitudinal strain, in which the basal strain is severely impaired with apical sparing. Associated noncardiac signs include spinal stenosis, biceps tendon rupture and carpal tunnel syndrome, especially when bilateral.

Rodney H. Falk

“By the time heart failure occurs, the left ventricle is usually very thickened,” Rodney H. Falk, MD, director of the Amyloidosis Program and cardiovascular medical specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said in an interview. “Unlike hypertrophic cardiomyopathy, amyloidosis doesn’t tend to predominantly involve one wall over the other, and the degree of left ventricular thickening seen almost always exceeds that present in hypertensive heart disease. There are not a lot of diseases that cause such an increase in left ventricular mass with this appearance.”

Challenging diagnosis

Delays in diagnosing cardiac amyloidosis are common, which can greatly affect how soon a patient can be treated to potentially prolong their life span.

“Despite how common cardiac amyloidosis is, many physicians do not appreciate it, so it often goes unrecognized by doctors for many years,” Maurer told Cardiology Today. “Most patients have seen [multiple] providers ... until the diagnosis is made, and many patients have a delayed diagnosis that can be upwards of months or years before someone confirms it is amyloidosis.”

According to a survey conducted by the Amyloid Research Consortium and presented at the International Symposium on Amyloidosis in 2018, 45% of patients diagnosed with cardiac amyloidosis reported at least one misdiagnosis before receiving a correct diagnosis. Common misdiagnoses or incomplete diagnoses included HF or heart disease (24%), hypertrophic cardiomyopathy (11%), hypertensive heart disease (5%) and arrhythmias (5%)

“In patients with light-chain amyloidosis (AL), the correct diagnosis of cardiac involvement becomes absolutely critical,” Falk said. “Once you diagnose AL cardiac amyloidosis, you should consider treatment of this patient to be an emergency because the median survival from the onset of congestive heart failure to death in AL amyloidosis is less than 5 months untreated. With treatment, survival could be years.”

To provide guidance to cardiologists and other physicians, the Amyloidosis Research Consortium convened a group of experts in this area to determine best practices. Consensus recommendations for the suspicion and diagnosis of TTR cardiac amyloidosis were published in Circulation: Heart Failure in 2019. In that document, recommended testing for cardiac amyloidosis involves assessment for monoclonal protein followed by scinti-graphy or biopsy.

Another helpful aid is a flowchart to diagnose light-chain amyloidosis that was published in JACC: CardioOncology in 2019 by Witteles and colleagues.

Even with available technologies and guidance, accurate interpretation of the precise type of cardiac amyloidosis remains a challenge.

“We are seeing that cardiologists are misinterpreting it on a regular — and very scary — basis,” Grogan said.

Available drugs, novel therapies in the pipeline

Brian M. Drachman

Amyloidosis has been the subject of extensive drug development in hopes of helping a population in need.

Tafamidis and tafamidis meglumine are oral benzoxazole derivatives that bind to transthyretin, and prevent tetramer disassociation and amyloidogenesis.

Other agents approved by the FDA for the treatment of hereditary transthyretin amyloid polyneuropathy include RNA inhibitors and stabilizers. Inotersen and patisiran are currently indicated for patients with polyneuropathy associated with hereditary ATTR amyloidosis. The APOLLO-B study is underway to assess the efficacy and safety of patisiran in patients with TTR cardiac amyloidosis.

AG-10 (Eidos) is a stabilizer currently undergoing a phase 3 clinical trial that works similar to tafamidis. The ATTRIBUTE-CM trial is assessing the safety and efficacy of 800 mg twice per day of AG-10 in patients with symptomatic TTR amyloid cardiomyopathy.

Other drugs currently in development for the TTR form of cardiac amyloidosis include another TTR stabilizer and next-generation RNA inhibitors from the same companies that manufacture inotersen and patisiran.

Light-chain amyloidosis is treated with several chemotherapeutic agents, immunomodulators and autologous stem cell transplantation. Daratumumab (Darzalex, Janssen Biotech), an antibody directed against plasma cells, has been used off-label for this form of the disease, although it is not currently indicated for cardiac amyloidosis by the FDA.

Diflunisal is another drug that is not approved by the FDA but that has been used for TTR cardiac amyloidosis. It is a nonsteroidal anti-inflammatory agent that was repurposed after researchers found that it can stabilize transthyretin. In a trial published in JAMA in 2013, diflunisal significantly slowed disease progression in patients with familial amyloid polyneuropathy.

“Diflunisal does seem to work in cardiac patients, but it hasn’t been studied in a big trial because more advanced cardiac patients have trouble with fluid retention, many need to be on anticoagulants, and diflunisal increases the risk of bleeding,” Grogan said.

Development for the monoclonal antibody birtamimab (NEOD001, Prothena) for light-chain amyloidosis ceased after the VITAL phase 3 trial failed. CAEL-101 (Caelum Biosciences) is another antibody directed to the light-chain amyloid in the affected organ, experts told Cardiology Today.

Akcea Therapeutics announced it initiated a phase 3 clinical trial — CARDIO-TTransform — for AKCEA-TTR-LRx, an antisense drug to inhibit transthyretin production, according to a company press release.

Martha Grogan

Prothena is developing PRX004, a monoclonal antibody, which is currently in a phase 1 study of patients with TTR amyloidosis, Drachman said.

“We are on the precipice of all these other drug combinations with tafamidis working and taking it to the next level and even showing reversal of disease, it’s going to change the disease,” Hanna said.

Cost controversy

Many of the drugs to treat amyloidosis were approved as orphan drugs and recently the spotlight has been on cost. Affordability of the agents for cardiac amyloidosis is “a big issue,” Hanna said.

The list price of tafamidis is $225,000 per year. The annual list price for each of patisiran and inotersen, which are approved for different forms of TTR amyloidosis, is $450,000.

“Many of us who see cardiac amyloid patients are very upset about the cost — the financial toxicity — for patients,” Grogan said.

“Both [tafamidis and tafamidis meglumine] carry a high price tag. ... While this is lower than the price of other ATTR drugs (inotersen and patisiran) approved for treating polyneuropathy in hereditary transthyretin-mediated amyloidosis (but not ATTR-CM), tafamidis meglumine and tafamidis are still the world’s most expensive medications for cardiovascular disease. Annual sales are projected to exceed $1 billion by 2024, but this estimate could prove conservative as the prevalence of ATTR-CM increases because of greater awareness and higher rates of diagnosis,” Gurwitz and Maurer wrote in the JAMA Cardiology Viewpointpublished in January.

Speaking with Cardiology Today, Maurer said the price of tafamidis has had a negative impact on his patients.

“Every single day, I see 10 of these people, and they are ... worried, upset, anxious,” Maurer said. “They have a terrible disease, they are afraid they are going to die, and now they are afraid they are not going to afford the medicine that could make them live longer.”

Patients with Medicare also face issues accessing these drugs due to regulations that prevent pharmaceutical companies from subsidizing the cost of a drug once Medicare has paid its share, experts told Cardiology Today.

“It falls on the patient, and since the vast majority of patients with cardiac amyloidosis are of Medicare age, it turns out that over 50% of patients with TTR amyloidosis who have Medicare despite having additional insurance are on the hook for over $1,000 a month copay for a drug that costs over $200,000 a year,” Falk said. “Patients themselves are now spending for a pill a day $12,000 or $15,000 a year for a drug that doesn’t actually make them feel better but just slows the disease.”

Cardiology Today spoke with Mark Soued, U.S. head of marketing for tafamidis, who provided insight on how the company set the price of tafamidis.

Mazen Hanna

“We arrived at the price of tafamidis, which we believe is appropriate, based on the transformational value that tafamidis delivers to patients and the size of the population it treats. If the prevalence turns out to be very different than we believe it is, we would revisit the price,” Soued said.

Alnylam used similar factors for the price of patisiran, Barry Greene, president of the company, told Cardiology Today.

“First, [we considered] the urgent unmet need in this disease setting,” he said. “Secondly, the outcomes seen in our clinical trials that showed Onpattro has the ability to potentially reverse neuropathy impairment in a majority of patients with an encouraging safety profile. Next, due to the rare nature of the disease, Onpattro is priced relative to the population it will treat. In addition, Onpattro represents a whole new class of medicines that has the potential to transform the treatment of diseases.”

Pfizer, Alnylam and Akcea have support programs to help patients access therapy, including a copay assistance program and a pre-medicines program for patients who are uninsured, underinsured or unable to afford their copay. Alnylam has the Alnylam Assist Commercial Copay Program that offers eligible patients $0 for out-of-pocket costs for patisiran and a Patient Assistance Program that also offers the treatment at no cost. Pfizer also has a copay assistance program that covers 100% of the copay from commercial insurance and a pre-medicines program that aids patients who are under- or uninsured. Akcea also offers patients a program to help pay for inotersen.

“Akcea believes that we have a responsibility to help sustain access to therapies for patients living with rare diseases,” according to an emailed statement from the company. “As part of this commitment, the Akcea patient services hub, known as Akcea Connect, helps patients thoroughly explore financial services options. Akcea Connect is an entirely free service to patients and health plans staffed by a team of dedicated nurse case managers who understand the challenges of living with a rare disease and who work directly with patients to help them navigate their health insurance in order to help make Tegsedi affordable for them.”In the JAMA Cardiology Viewpoint, Gurwitz and Maurer offered several policy recommendations including ones aimed toward the FDA.

“As competitors may lower prices, the FDA should accelerate the review of competitors of approved products that exceed the responsible price or acceptable budget impact thresholds,” they wrote. “If new data emerge indicating that the prevalence of a disease or condition actually exceeds 200,000, the awarding of an orphan drug designation by the FDA and its associated market exclusivity provisions should be revisited.”

Debate surrounding cost will continue, and Cardiology Today will follow the story closely.

Multidisciplinary approach to care

Regardless of the type of cardiac amyloidosis a patient has, a multidisciplinary team of health care professionals is the best way to approach treatment in these patients, experts said. This includes cardiologists, hematologists, nephrologists and neurologists. Depending on the type of amyloidosis and the symptoms a patient presents with, this team can also include gastroenterologists, genetic counselors and palliative care.

A multidisciplinary approach in addition to the progress made in diagnosing and treating patients with cardiac amyloidosis has given some hope to patients, experts said, especially if it is diagnosed in a timely manner.

“The interest and awareness of the cardiology community in this disease has really ramped up,” Hanna said. “If you go to any major cardiology meeting now, there are at least two sessions. If you look at JACC, one of the top cardiology journals, it seems like at least once every other week there’s an article on it. This is something that seems to be coming on everybody’s radar, which is good to see.” – by Darlene Dobkowski

Disclosures: The ATTR-ACT trial was funded by Pfizer. Drachman reports no relevant financial disclosures. Falk reports he consulted for Alnylam, Ionis and Pfizer, received research funding from Ionis and serves on a board for Caelum Biosciences. Greene is an employee of Alnylam. Grogan reports she received clinical trial funding from Alnylam, Eidos, Pfizer and Prothena and received consultant fees to her institution. Hanna reports he served on advisory boards for Akcea, Alnylam and Pfizer. Maurer reports he was co-chair of the steering committee for the ATTR-ACT trial; served as a site principal investigator for trials conducted by Akcea, Alnylam, Eidos, Ionis, Pfizer and Prothena; served as a key opinion leader for several companies and has received funding from the NIH. Soued is an employee of Pfizer. Witteles reports he was a site principal investigator for Alnylam, Eidos and Pfizer and has served on the scientific advisory board for Alnylam, Eidos, Ionis and Pfizer.

Amyloidosis, a disease in which misfolded proteins form amyloid fibrils that deposit in tissues and organs including the heart, is a vexing condition with devastating consequences. Encouragingly, new treatment options for cardiac amyloidosis have emerged recently and there is increasing awareness of this disease, once considered very rare. However, the cost of these therapies has raised concerns about the ability of patients to access such therapies.

“In the last 5 to 10 years, we have made dramatic progress in the diagnostic strategies and treatment strategies for the more commonly encountered types of amyloidosis,” Brian M. Drachman, MD, associate chief of cardiovascular medicine at Penn Presbyterian Medical Center and co-director of the Amyloidosis Program at Penn Medicine, told Cardiology Today. “We have taken a set of diseases — which were almost uniformly considered by the provider community to have no options — and given patients not only hope for the future, but hope for the present.”

Most recently, in 2018, results of the ATTR-ACT study, which evaluated the drug tafamidis vs. placebo, were reported at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine. In ATTR-ACT, 441 patients with transthyretin amyloid cardiomyopathy were randomly assigned 80 mg tafamidis, 20 mg tafamidis or placebo for 30 months. Results demonstrated that patients assigned tafamidis had reduced risk for all-cause mortality and CV-related hospitalizations compared with those assigned placebo. Analyses showed a slowing of the decline in a variety of metrics of quality of life with tafamidis in this patient population.

Mathew S. Maurer, MD, from NewYork-Presbyterian Hospital/Columbia University Medical Center, said many doctors often fail to recognize cardiac amyloidosis.

Source: Columbia University Irving Medical Center. Printed with permission.

“The ATTR-ACT results were groundbreaking,” Mazen Hanna, MD, co-director of the amyloidosis center and staff cardiologist in the section of heart failure and cardiac transplantation medicine at Cleveland Clinic, told Cardiology Today. “We never had anything to treat transthyretin amyloid cardiomyopathy.”

Thereafter, the first therapies for patients with cardiomyopathy associated with transthyretin-mediated amyloidosis — tafamidis meglumine (Vyndaqel, FoldRx/Pfizer) and tafamidis (Vyndamax, FoldRx/Pfizer) — were approved by the FDA in May 2019, based on results from the ATTR-ACT trial.

Since then, debate in the community has focused on the list price of the drug, recently addressed in a JAMA Cardiology Viewpoint in January written by Jerry H. Gurwitz, MD, executive director of the Meyers Primary Care Institute and the Dr. John Meyers Professor of Primary Care Medicine at the University of Massachusetts Medical School, and Mathew S. Maurer, MD, medical director of the Cardiac Amyloidosis Program at New York-Presbyterian Hospital/Columbia University Medical Center and co-chair of the ATTR-ACT trial, titled “Tafamidis — A Pricey Therapy for a Not-So-Rare Condition.”

PAGE BREAK

In addition to tafamidis, other drugs have been approved for the treatment of hereditary transthyretin amyloid polyneuropathy including inotersen (Tegsedi, Akcea Therapeutics) and patisiran (Onpattro, Alnylam Pharmaceuticals). Other drugs categorized as RNA inhibitors, stabilizers and monoclonal antibodies are in development to treat these patients and potentially eliminate amyloid in a patient’s heart.

Cardiology Today interviewed leaders in the field about challenges in the diagnosis of cardiac amyloidosis, available treatments and what is in the pipeline and current cost concerns.

Types of cardiac amyloidosis

Ronald M. Witteles

Cardiac amyloidosis is an umbrella term for two main types of the disease: light-chain and transthyretin (TTR) amyloidosis. Then, there are two types of TTR amyloidosis: hereditary or variant amyloidosis (ATTRh) and wild-type amyloidosis (ATTRwt; See Infographic).

The prevalence of cardiac amyloidosis is not definitively known. According to the National Organization for Rare Disorders, there are approximately 4,000 new cases of light-chain amyloidosis per year in the U.S. Cardiomyopathy in patients with familial amyloidosis, more commonly described as hereditary or variant amyloidosis, affects an estimated 40,000 to 50,000 patients globally, although it may be underestimated. There is a higher prevalence in black Americans in part because 3.4% of African Americans harbor a mutation in the TTR gene known as Val122Ile, which is inherited in an autosomal dominant fashion, according to the NIH. Wild-type TTR cardiac amyloidosis, which affects almost exclusively the elderly, is expected to become the most common form of systemic amyloidosis because of the aging population.

“For this condition, in contrast to most other cardiovascular diseases, there is nothing that the patient can do to prevent this disease. This is not lifestyle-related,” Martha Grogan, MD, founder and director of the Cardiac Amyloid Clinic and consultant in the division of structural heart disease at Mayo Clinic, said.

“Because it is a normal protein that is misfolding in wild-type ATTR amyloidosis, this is not something that happens rapidly; it takes years, likely decades, to deposit enough to actually start causing symptoms and problems,” Ronald M. Witteles, MD, professor of medicine and co-director of the Amyloid Center and the Multidisciplinary Sarcoidosis Program at Stanford University Medical Center, told Cardiology Today. “AL amyloidosis, on the other hand, can rapidly progress, making the rapid diagnosis and initiation of therapy an urgent matter in any suspected case.”

Warning signs

There are several warning signs of cardiac amyloidosis that cardiologists should keep in mind, including HFpEF with predominantly right-sided symptoms, severe increased left ventricular wall thickness without significant hypertension and mild to moderate increase in wall thickness but normal or low voltage on an ECG.

PAGE BREAK

Among patients with severe aortic stenosis undergoing valve replacement, 1 in 7 have amyloidosis. The association is simply because both diseases occur in older adults, Maurer said.

Other echocardiographic findings are important in diagnosing cardiac amyloidosis, including the presence of unexplained increased right ventricular wall thickness, biatrial enlargement, thickened mitral and tricuspid valves, small pericardial effusion and reduced global longitudinal strain, in which the basal strain is severely impaired with apical sparing. Associated noncardiac signs include spinal stenosis, biceps tendon rupture and carpal tunnel syndrome, especially when bilateral.

Rodney H. Falk

“By the time heart failure occurs, the left ventricle is usually very thickened,” Rodney H. Falk, MD, director of the Amyloidosis Program and cardiovascular medical specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said in an interview. “Unlike hypertrophic cardiomyopathy, amyloidosis doesn’t tend to predominantly involve one wall over the other, and the degree of left ventricular thickening seen almost always exceeds that present in hypertensive heart disease. There are not a lot of diseases that cause such an increase in left ventricular mass with this appearance.”

Challenging diagnosis

Delays in diagnosing cardiac amyloidosis are common, which can greatly affect how soon a patient can be treated to potentially prolong their life span.

“Despite how common cardiac amyloidosis is, many physicians do not appreciate it, so it often goes unrecognized by doctors for many years,” Maurer told Cardiology Today. “Most patients have seen [multiple] providers ... until the diagnosis is made, and many patients have a delayed diagnosis that can be upwards of months or years before someone confirms it is amyloidosis.”

According to a survey conducted by the Amyloid Research Consortium and presented at the International Symposium on Amyloidosis in 2018, 45% of patients diagnosed with cardiac amyloidosis reported at least one misdiagnosis before receiving a correct diagnosis. Common misdiagnoses or incomplete diagnoses included HF or heart disease (24%), hypertrophic cardiomyopathy (11%), hypertensive heart disease (5%) and arrhythmias (5%)

“In patients with light-chain amyloidosis (AL), the correct diagnosis of cardiac involvement becomes absolutely critical,” Falk said. “Once you diagnose AL cardiac amyloidosis, you should consider treatment of this patient to be an emergency because the median survival from the onset of congestive heart failure to death in AL amyloidosis is less than 5 months untreated. With treatment, survival could be years.”

To provide guidance to cardiologists and other physicians, the Amyloidosis Research Consortium convened a group of experts in this area to determine best practices. Consensus recommendations for the suspicion and diagnosis of TTR cardiac amyloidosis were published in Circulation: Heart Failure in 2019. In that document, recommended testing for cardiac amyloidosis involves assessment for monoclonal protein followed by scinti-graphy or biopsy.

PAGE BREAK

Another helpful aid is a flowchart to diagnose light-chain amyloidosis that was published in JACC: CardioOncology in 2019 by Witteles and colleagues.

Even with available technologies and guidance, accurate interpretation of the precise type of cardiac amyloidosis remains a challenge.

“We are seeing that cardiologists are misinterpreting it on a regular — and very scary — basis,” Grogan said.

Available drugs, novel therapies in the pipeline

Brian M. Drachman

Amyloidosis has been the subject of extensive drug development in hopes of helping a population in need.

Tafamidis and tafamidis meglumine are oral benzoxazole derivatives that bind to transthyretin, and prevent tetramer disassociation and amyloidogenesis.

Other agents approved by the FDA for the treatment of hereditary transthyretin amyloid polyneuropathy include RNA inhibitors and stabilizers. Inotersen and patisiran are currently indicated for patients with polyneuropathy associated with hereditary ATTR amyloidosis. The APOLLO-B study is underway to assess the efficacy and safety of patisiran in patients with TTR cardiac amyloidosis.

AG-10 (Eidos) is a stabilizer currently undergoing a phase 3 clinical trial that works similar to tafamidis. The ATTRIBUTE-CM trial is assessing the safety and efficacy of 800 mg twice per day of AG-10 in patients with symptomatic TTR amyloid cardiomyopathy.

Other drugs currently in development for the TTR form of cardiac amyloidosis include another TTR stabilizer and next-generation RNA inhibitors from the same companies that manufacture inotersen and patisiran.

Light-chain amyloidosis is treated with several chemotherapeutic agents, immunomodulators and autologous stem cell transplantation. Daratumumab (Darzalex, Janssen Biotech), an antibody directed against plasma cells, has been used off-label for this form of the disease, although it is not currently indicated for cardiac amyloidosis by the FDA.

Diflunisal is another drug that is not approved by the FDA but that has been used for TTR cardiac amyloidosis. It is a nonsteroidal anti-inflammatory agent that was repurposed after researchers found that it can stabilize transthyretin. In a trial published in JAMA in 2013, diflunisal significantly slowed disease progression in patients with familial amyloid polyneuropathy.

“Diflunisal does seem to work in cardiac patients, but it hasn’t been studied in a big trial because more advanced cardiac patients have trouble with fluid retention, many need to be on anticoagulants, and diflunisal increases the risk of bleeding,” Grogan said.

Development for the monoclonal antibody birtamimab (NEOD001, Prothena) for light-chain amyloidosis ceased after the VITAL phase 3 trial failed. CAEL-101 (Caelum Biosciences) is another antibody directed to the light-chain amyloid in the affected organ, experts told Cardiology Today.

PAGE BREAK

Akcea Therapeutics announced it initiated a phase 3 clinical trial — CARDIO-TTransform — for AKCEA-TTR-LRx, an antisense drug to inhibit transthyretin production, according to a company press release.

Martha Grogan

Prothena is developing PRX004, a monoclonal antibody, which is currently in a phase 1 study of patients with TTR amyloidosis, Drachman said.

“We are on the precipice of all these other drug combinations with tafamidis working and taking it to the next level and even showing reversal of disease, it’s going to change the disease,” Hanna said.

Cost controversy

Many of the drugs to treat amyloidosis were approved as orphan drugs and recently the spotlight has been on cost. Affordability of the agents for cardiac amyloidosis is “a big issue,” Hanna said.

The list price of tafamidis is $225,000 per year. The annual list price for each of patisiran and inotersen, which are approved for different forms of TTR amyloidosis, is $450,000.

“Many of us who see cardiac amyloid patients are very upset about the cost — the financial toxicity — for patients,” Grogan said.

“Both [tafamidis and tafamidis meglumine] carry a high price tag. ... While this is lower than the price of other ATTR drugs (inotersen and patisiran) approved for treating polyneuropathy in hereditary transthyretin-mediated amyloidosis (but not ATTR-CM), tafamidis meglumine and tafamidis are still the world’s most expensive medications for cardiovascular disease. Annual sales are projected to exceed $1 billion by 2024, but this estimate could prove conservative as the prevalence of ATTR-CM increases because of greater awareness and higher rates of diagnosis,” Gurwitz and Maurer wrote in the JAMA Cardiology Viewpointpublished in January.

Speaking with Cardiology Today, Maurer said the price of tafamidis has had a negative impact on his patients.

“Every single day, I see 10 of these people, and they are ... worried, upset, anxious,” Maurer said. “They have a terrible disease, they are afraid they are going to die, and now they are afraid they are not going to afford the medicine that could make them live longer.”

Patients with Medicare also face issues accessing these drugs due to regulations that prevent pharmaceutical companies from subsidizing the cost of a drug once Medicare has paid its share, experts told Cardiology Today.

“It falls on the patient, and since the vast majority of patients with cardiac amyloidosis are of Medicare age, it turns out that over 50% of patients with TTR amyloidosis who have Medicare despite having additional insurance are on the hook for over $1,000 a month copay for a drug that costs over $200,000 a year,” Falk said. “Patients themselves are now spending for a pill a day $12,000 or $15,000 a year for a drug that doesn’t actually make them feel better but just slows the disease.”

PAGE BREAK

Cardiology Today spoke with Mark Soued, U.S. head of marketing for tafamidis, who provided insight on how the company set the price of tafamidis.

Mazen Hanna

“We arrived at the price of tafamidis, which we believe is appropriate, based on the transformational value that tafamidis delivers to patients and the size of the population it treats. If the prevalence turns out to be very different than we believe it is, we would revisit the price,” Soued said.

Alnylam used similar factors for the price of patisiran, Barry Greene, president of the company, told Cardiology Today.

“First, [we considered] the urgent unmet need in this disease setting,” he said. “Secondly, the outcomes seen in our clinical trials that showed Onpattro has the ability to potentially reverse neuropathy impairment in a majority of patients with an encouraging safety profile. Next, due to the rare nature of the disease, Onpattro is priced relative to the population it will treat. In addition, Onpattro represents a whole new class of medicines that has the potential to transform the treatment of diseases.”

Pfizer, Alnylam and Akcea have support programs to help patients access therapy, including a copay assistance program and a pre-medicines program for patients who are uninsured, underinsured or unable to afford their copay. Alnylam has the Alnylam Assist Commercial Copay Program that offers eligible patients $0 for out-of-pocket costs for patisiran and a Patient Assistance Program that also offers the treatment at no cost. Pfizer also has a copay assistance program that covers 100% of the copay from commercial insurance and a pre-medicines program that aids patients who are under- or uninsured. Akcea also offers patients a program to help pay for inotersen.

“Akcea believes that we have a responsibility to help sustain access to therapies for patients living with rare diseases,” according to an emailed statement from the company. “As part of this commitment, the Akcea patient services hub, known as Akcea Connect, helps patients thoroughly explore financial services options. Akcea Connect is an entirely free service to patients and health plans staffed by a team of dedicated nurse case managers who understand the challenges of living with a rare disease and who work directly with patients to help them navigate their health insurance in order to help make Tegsedi affordable for them.”In the JAMA Cardiology Viewpoint, Gurwitz and Maurer offered several policy recommendations including ones aimed toward the FDA.

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“As competitors may lower prices, the FDA should accelerate the review of competitors of approved products that exceed the responsible price or acceptable budget impact thresholds,” they wrote. “If new data emerge indicating that the prevalence of a disease or condition actually exceeds 200,000, the awarding of an orphan drug designation by the FDA and its associated market exclusivity provisions should be revisited.”

Debate surrounding cost will continue, and Cardiology Today will follow the story closely.

Multidisciplinary approach to care

Regardless of the type of cardiac amyloidosis a patient has, a multidisciplinary team of health care professionals is the best way to approach treatment in these patients, experts said. This includes cardiologists, hematologists, nephrologists and neurologists. Depending on the type of amyloidosis and the symptoms a patient presents with, this team can also include gastroenterologists, genetic counselors and palliative care.

A multidisciplinary approach in addition to the progress made in diagnosing and treating patients with cardiac amyloidosis has given some hope to patients, experts said, especially if it is diagnosed in a timely manner.

“The interest and awareness of the cardiology community in this disease has really ramped up,” Hanna said. “If you go to any major cardiology meeting now, there are at least two sessions. If you look at JACC, one of the top cardiology journals, it seems like at least once every other week there’s an article on it. This is something that seems to be coming on everybody’s radar, which is good to see.” – by Darlene Dobkowski

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Disclosures: The ATTR-ACT trial was funded by Pfizer. Drachman reports no relevant financial disclosures. Falk reports he consulted for Alnylam, Ionis and Pfizer, received research funding from Ionis and serves on a board for Caelum Biosciences. Greene is an employee of Alnylam. Grogan reports she received clinical trial funding from Alnylam, Eidos, Pfizer and Prothena and received consultant fees to her institution. Hanna reports he served on advisory boards for Akcea, Alnylam and Pfizer. Maurer reports he was co-chair of the steering committee for the ATTR-ACT trial; served as a site principal investigator for trials conducted by Akcea, Alnylam, Eidos, Ionis, Pfizer and Prothena; served as a key opinion leader for several companies and has received funding from the NIH. Soued is an employee of Pfizer. Witteles reports he was a site principal investigator for Alnylam, Eidos and Pfizer and has served on the scientific advisory board for Alnylam, Eidos, Ionis and Pfizer.

    Perspective
    Carl J. Pepine

    Carl J. Pepine

    These developments are very exciting since we have had few options for this progressive disease in the past. In Florida, we see a lot of elderly patients with HF with preserved ejection fraction, and screening with technician pyrophosphate scans is increasing. Additionally, our elderly transcatheter aortic valve replacement population is exploding, but many continue to have a very limited quality of life despite a technically successful TAVR. Survey data from the Amyloidosis Research Consortium suggest that about 4 out of 10 patients with wild-type TTR amyloidosis received an initial misdiagnosis. This undiagnosed condition is an important public health concern for our rapidly growing senior population.

    • Carl J. Pepine, MD, MACC
    • Cardiology Today Chief Medical Editor University of Florida, Gainesville

    Disclosures: Pepine reports no relevant financial disclosures.