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Novel therapy offers benefit for rare transthyretin amyloid cardiomyopathy
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MUNICH — Treatment with tafamidis reduced risk for all-cause mortality and CV-related hospitalizations in patients with hereditary and wild-type transthyretin amyloid cardiomyopathy, according to new data from the ATTR-ACT study presented at the European Society of Cardiology Congress.
Tafamidis (Pfizer) is a novel therapy that binds to transthyretin, thus preventing tetramer dissociation and amyloidogenesis. In late May, Pfizer announced that tafamidis received a Breakthrough Therapy designation from the FDA for the treatment of patients with transthyretin cardiomyopathy. It is currently an investigational therapy and is not yet approved for this indication.
ATTR-ACT “is the first phase 3 trial that offers a chance to patients with a terrible disease,” Claudio Rapezzi, MD, director of cardiology at University of Bologna, Italy, said during a press conference. “In the last [few] years, one trial was conducted. We became aware that this disease is much more underdiagnosed than rare.”
New data
The multicenter, double-blind, placebo-controlled, phase 3 ATTR-ACT study enrolled 441 patients (median age, 75 years) with transthyretin amyloid cardiomyopathy. The researchers randomly assigned patients, in a 2:1:2 ratio to 80 mg tafamidis, 20 mg tafamidis or placebo once daily for 30 months. If adverse events occurred and had the potential to affect adherence, patients were given the option to receive a reduced dose.
Patients assigned tafamidis (n = 264) had lower rates of the primary outcome of interest — all-cause mortality and CV-related hospitalizations — compared with those assigned placebo (n = 177; P < .001 for comparison). All-cause mortality occurred in 29.5% of the tafamidis group vs. 42.9% of the placebo group (HR = 0.7; 95% CI, 0.51-0.96). The annual rate of CV-related hospitalization was 0.48 per year with tafamidis treatment vs. 0.7 per year with placebo treatment (relative risk ratio = 0.69; 95% CI, 0.56-0.81), according to results presented here.
“The effect on overall survival emerged after approximately 18 months,” Mathew S. Maurer, MD, medical director of The HCM Center at New York-Presbyterian Hospital/Columbia University Medical Center, and colleagues wrote in The New England Journal of Medicine. “This dissociation between the effect on symptoms and survival has also been observed with other therapies for systolic heart failure in which ventricular remodeling takes months to achieve.”
The researchers also evaluated key secondary endpoints including change in 6-minute walk distance, functional capacity and quality of life. Patients assigned tafamidis had a slower decline in 6-minute walk test vs. placebo (P < .001). Tafamidis treatment was also associated with a reduced decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary score vs. placebo (P < .001). Differences between the groups in both secondary endpoints were first observed at 6 months’ follow-up, according to the researchers.
Adverse events were similar in both treatment groups. Dose reduction related to adverse events occurred in two patients in the tafamidis group and four patients in the placebo group.
Focus on diagnosis
Transthyretin cardiomyopathy is a rare, fatal and underdiagnosed condition associated with progressive HF. While the prevalence of transthyretin cardiomyopathy is presently unknown, it is estimated that less than 1% of people with this cardiomyopathy are diagnosed. The average life expectancy is 3 to 5 years from diagnosis of transthyretin cardiomyopathy.
“It can be easily diagnosed when suspected, so the first point is the fastening of the suspicion,” Rapezzi said during the press conference. “If you’re able to falter the suspicion, now we have noninvasive possibility of diagnosis of the disease.”
C. Cristina Quarta, MD, principal clinical and research fellow at the National Amyloidosis Centre at University College London, and Scott D. Solomon, MD, director of noninvasive cardiology at Brigham and Women’s Hospital and professor of cardiovascular medicine at Harvard Medical School, discussed the ATTR-ACT study findings in an editorial published in NEJM.
“It is possible that by slowing or halting amyloid deposition, tafamidis may allow the activation of local recovery processes that progressively result in a remodeling of the amyloid deposits, a reduction in the strain on the cardiac walls and ultimately in a clinical benefit,” Quarta and Solomon wrote. “Once amyloid has caused irreversible organ damage, disease-modifying treatments may be less likely to be effective.”
Pfizer announced that it has established an expanded-access treatment protocol to make tafamidis available to patients with this rare cardiomyopathy who may benefit from treatment prior to regulatory approval.
“We believe the ATTR-ACT study findings bring us a significant step closer to our goal of providing an urgently needed therapy for a serious and often fatal disease,” Brenda Cooperstone, MD, senior vice president and chief development officer of rate disease for Pfizer Global Product Development, stated in a company press release. “We look forward to continuing discussions with global regulatory authorities about the potential of tafamidis as a treatment option for people living with ATTR-CM.” – by Darlene Dobkowski
References:
Maurer MS, et al. Hot Line 3 Press Conference. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.
Maurer MS, et al. N Engl J Med. 2018;doi:10.1056/NEJM0a1805689.
Quarta CC, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1810074.
Disclosures: The trial was funded by Pfizer. Maurer reports he received grants from Alnylam, Eidos, Ionis, Pfizer and Prothena and personal fees from Akcea, Eidos, GlaxoSmithKline, Ionis, Pfizer and Prothena. Quarta reports no relevant financial disclosures. Solomon reports he received grants from Alnylam, Eidos and Ionis and personal fees from Alnylam. Cooperstone is an employee of Pfizer.
Perspective
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Michael Böhm, MD
This is a very interesting approach to a disease which is untreatable so far. It is pathophysiologically very challenging and interesting. It is the first approach to treat this deadly disease. The number of patients is very low, but still there is a clear result that shows how malignant of a disease it is. It is one of the breakthroughs in this disease.
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