New cardiac amyloidosis therapies offer hope for the future
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While currently there is no cure for systemic amyloidosis, treatment options have recently expanded and have led to improved survival for both wild-type transthyretin and light-chain type amyloidosis that most commonly affect the heart.
Healio spoke with Martha Grogan, MD, founder and director of the Cardiac Amyloid Clinic and assistant professor of medicine and consultant in the division of cardiovascular diseases at Mayo Clinic, Rochester, Minn., about current therapies and applications for symptom management, new FDA-approved drugs for amyloid deposit reduction and greatest unmet needs in diagnoses of amyloidosis.
Current treatment options
Amyloidosis is caused by misfolded proteins that can lead to deposition of an abnormal insoluble substance (amyloid) in the organs and tissues in the body. The most serious forms of amyloidosis are those that affect the heart. The main types of these are AL (light chain) and two forms of transthyrein amyloidosis (ATTR); hereditary (hATTR), which is due to an inherited protein mutation, and the non-hereditary, wild-type (wtATTR).
AL amyloidosis is treated with chemotherapy and sometimes with a procedure call autologous stem cell transplant. These treatments are directed at abnormal cells in the bone marrow that produce the protein that causes AL amyloidosis. In recent years, results for treatment of AL amyloidosis have improved. Treatment options for ATTR cardiac amyloidosis have been limited until recently to organ transplantation or supportive care. Within the past few years, medications have been approved for treatment of ATTR amyloidosis, offering hope to patients with this disease.
Grogan said the recommended treatment for patients with ATTR depends on the stage of disease and whether the patient has hATTR or the more common wtATTR. Patients with hATTR who have neuropathy are candidates for two approved medications in the United States; patisiran (Onpattro, Alnylam Pharmaceuticals) and inotersen (Tegsedi, Akcea Therapeutics). These medications dramatically reduce the amount of TTR produced by the liver.
The presence or absence of neuropathy, a common condition associated with hATTR, should be taken into consideration when recommending medication, she said.
“Right now, the main thing that decides which treatment we’re going to offer patients will depend on whether or not they have cardiac amyloidosis with or without neuropathy, or if they have neuropathy alone,” she told Healio. “If they have neuropathy alone and they are hereditary, then they can be treated with one of the two commercially available silencer drugs, or they can be considered for clinical trials. It depends on the organ system that’s involved.”
Grogan told Healio that further studies on patisiran and inotersen in cardiac amyloidosis are under way.
Patients with wtATTR, she explained, have the option of taking the recently FDA-approved drug tafamidis (Vyndamax and Vyndaqel; FoldRx/Pfizer), the first approved medication in the U.S. for transthyretin cardiac amyloidosis.
The drug has been shown to reduce the risk for death or hospitalization for heart failure and stabilize transthyretin proteins, which slows the progression of amyloidosis.
“After years of not having any medications, the results of these three trials came out in the summer of 2018,” Grogan said. “There is quite a revolution in the world of TTR amyloidosis.”
She also noted that there are other drugs in the pipeline, include another stabilizer drug, AG10 (Eidos Therapuetics), which is being tested in an phase 3 study of cardiac patients and PRX-004 (Prothena) a monoclonal antibody, currently in phase 1 study of patients with neuropathy due to hATTR.
Managing symptoms
Patients with cardiac amyloidosis often require diuretic therapy to prevent fluid build-up due to heart failure. Standard medications for heart failure (eg, beta-blockers, ACE-inhibitors, angiotensin receptor blockers) are usually not indicated for cardiac amyloidosis. Medications for neuropathy may help lessen pain and physical and occupational therapy are helpful. Patients with amyloidosis should participate in light to moderate exercise whenever possible to maintain mobility and combat pain and fatigue, as well as supplement clinical treatments through a healthy diet to try to improve overall wellness.
Challenges, future needs
Barriers to treatment include preexisting clinical needs, the organ system affected by the disease and type of amyloidosis, Grogan told Healio.
“You have to know is the type because that determines the treatment. The types of amyloid are not completely different diseases, but almost, because they come from different sources.”
In cardiac amyloidosis, costs of treatments pose another serious challenge to treating the disease, especially for the older patient population.
“Many of our patients do face a challenge. If they have very limited income, then there are programs to help with personal costs. But anyone who makes over a certain amount — and that might not be that hard to achieve if you’re a retirement couple — often have a very high personal copay, which could be $12,000 or $15,000 a year and a major burden.”
She added that tafamidis has a cost of $225,000 per year and is a financial challenge for patients, especially those who are on a fixed income. The other newly approved medications are nearly double that.
“The silencer drugs [patisiran and inotersen] each have a starting cost of $450,000. Many of our patients have gotten those medications covered through their insurance, but obviously it’s still a huge cost to the health care system.”
Diflunisal is a non-steroidal anti-inflammatory medication that is also a transthyretin stabilizer and has been shown to slow the progression of neuropathy in patients with hATTR. Diflunisal is used for patients with neuropathy due to hATTR but has not been specifically tested in heart patients. Due to cost concerns with the newly approved treatments, diflunisal is an alternative that is used in some patients with cardiac ATTR, although it is considered off-label for that purpose. Unfortunately, patients with advanced heart failure are not candidates for diflunisal because it may cause fluid retention. bleeding, and deterioration in kidney function.
“Some of our heart patients early in the disease can tolerate diflunisal, and it’s affordable at less than $400 a year. Some of our patients will opt to take the less expensive medication, even if it has some risks associated with it and has not been tested in specific cardiac trials,” Grogan told Healio.”
Grogan also emphasized the need for an accurate and timely diagnoses to alter outcomes and obtain early treatment. Tackling this comes through raising awareness with health care providers, especially on the commonality of wild-type amyloidosis, she said.
“It’s not unusual for it to take more than a year, and people often have to travel by airplane to get the diagnosis,” Grogan said. “We need a more rapid diagnosis, especially for AL amyloid because it’s rapidly and progressively fatal when it involves the heart. Earlier diagnosis is key, and the only way we can really do that is raise awareness with providers.”
However, Grogan is optimistic about the future of amyloidosis.
“Historically, patients with AL amyloidosis often had a very poor prognosis, but that has really improved. TTR amyloid is more slowly progressive, and we have medications that can help that. It really used to be this fatal disease. Now, I think providers need to know that there is hope for patients with amyloidosis and that's why we focus so much on diagnosing patients early.” – by Tiffany Magennis
References:
Amyloidosis Foundation. Wild-type ATTR. https://amyloidosis.org/facts/wild-type/. Accessed February 13, 2020.
Cancer.net. Amyloidosis: Treatment Options. https://www.cancer.net/cancer-types/amyloidosis/treatment-options. Accessed February 13, 2020.
Cedars Sinai. Conditions and Treatments: Amyloidosis. https://www.cedars-sinai.edu/Patients/Health-Conditions/Amyloidosis.aspx. Accessed February 18, 2020.
Diet and nutrition in AL amyloidosis. https://academy.myeloma.org.uk/wp-content/uploads/sites/2/2014/09/AL-amyloidosis-Diet-and-nutrition-Infosheet-Aug-2014. Accessed February 19, 2020.
FDA. FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease. https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease. Accessed February 20, 2020.
FDA. FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatments-heart-disease-caused-serious-rare-disease-transthyretin-mediated. Accessed February 11, 2020.
Healio. New treatments, increased awareness shine spotlight on cardiac amyloidosis. https://www.healio.com/cardiology/hf-transplantation/news/print/cardiology-today/%7B5e835fbb-2d17-4969-8040-631717aeb05c%7D/new-treatments-increased-awareness-shine-spotlight-on-cardiac-amyloidosis?page=4. Accessed April 22, 2020.
Healthline. 8 Natural and Complementary Therapies for Amyloidosis. https://www.healthline.com/health/amyloidosis/natural-therapies-for-amyloidosis#1. Accessed February 14, 2020.
Shin SC, Robinson-Papp J. Amyloid neuropathies. 2012;doi:10.1002/msj.21352.
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