Patisiran beneficial in ATTR amyloidosis with cardiomyopathy
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In patients with transthyretin-mediated amyloidosis with cardiomyopathy, patisiran improved functional capacity and quality of life at 12 months compared with placebo, according to the results of the APOLLO-B trial.
For the phase 3 trial, presented at the International Symposium on Amyloidosis by Mathew S. Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, the researchers randomly assigned 360 patients (mean age, 76 years; 89% men) with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy to patisiran (Onpattro, Alnylam), a small interfering RNA agent, or placebo.
Patisiran is approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis, but is not yet approved to treat ATTR amyloidosis with cardiomyopathy (ATTR-CM).
Approximately 25% of the cohort was already taking tafamidis (Vyndamax, Pfizer), which is FDA approved to treat ATTR-CM.
‘Worse than some cancers’
ATTR-CM “is worse than some cancers,” John L. Berk, MD, associate professor of medicine, director of clinical trials for familial amyloidosis and director of the Localized Amyloid Clinic at Boston University School of Medicine, and an author of the study, told Healio. “There is already a drug approved by the FDA, tafamidis, which is designed to ... minimize amyloid formation. We know from the clinical trial that led to the registration of that drug that the rate of survival, cardiovascular hospitalizations, 6-minute walk distance and quality of life demonstrated drug effect. People did better when they were on the drug. However, all of those metrics went downhill, even when on the drug. Tafamidis is a significant step forward in therapeutics because there was none to begin with, but it does not stop disease progression, so there is a huge unmet need. Now, there is a second class of drug for TTR disease. The gene silencers appear to have a significantly greater effect and more capacity to actually stop disease than has been seen with the oral TTR protein stabilizers.”
The primary endpoint was change in functional capacity as measured by 6-minute walk test at 12 months. The key secondary endpoint was cardiomyopathy symptoms and health status as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 months.
At 12 months, serum transthyretin was reduced by 86.8% (standard deviation, 13.6) in the patisiran group, but did not change in the placebo group, Maurer said during the presentation.
The change from baseline to 12 months in 6-minute walk test was –21.35 m in the placebo group and –8.15 m in the patisiran group (Hodges-Lehmann estimate of median difference, 14.693; 95% CI, 0.693-28.692; P = .0162), according to the researchers.
The key secondary endpoint also favored the patisiran group, as the least squared mean change in KCCQ overall summary score was 0.3 in the patisiran group and –3.408 in the placebo group (least squared mean difference, 3.709; standard error of mean, 1.796; P = .0397), Maurer said during the presentation.
The secondary composite endpoints of all-cause mortality/frequency of CV events/change from baseline in 6-minute walk test, all-cause mortality/frequency of all-cause hospitalizations/urgent HF visits in patients not taking tafamidis at baseline and all-cause mortality/frequency of all-cause hospitalizations/urgent HF visits in the overall cohort, all at 12 months, were not significant, the researchers found.
During the 12-month duration of the study, 5.6% of the placebo group died compared with 2.2% of the patisiran group (HR = 0.355; 95% CI, 0.11-1.138), according to the presentation.
‘A big win’
Whether those results are clinically meaningful “is the wrong question,” Berk told Healio. “The tafamidis study [ATTR-ACT] was extended from 24 to 30 months [because the researchers] were concerned there would not be enough endpoint events to demonstrate drug effect. The longer you observe, the greater the chance you will see drug effect. In [ATTR-ACT], the survival curves did not diverge until 18 months, and hospitalization rates at 9 months. In APOLLO-B, 12 months is incredibly early in the course of the disease, and we are recruiting people who are not as sick [as those from ATTR-ACT], and 25% of them are on tafamidis, a drug that alters the course of disease already. I was not anticipating dramatic differences between the curves, and the mere fact that there is a clear signal of drug effect is a big win. That in my estimation predicts that the hard endpoints of survival benefit and reduction of hospitalization rates are going to play out similarly at a later time with a much more dramatic effect.”
In an exploratory endpoint, the patisiran group had less rise in N-terminal pro-B-type natriuretic peptide during the study period than the placebo group (ratio of adjusted geometric mean fold-change, 0.8; 95% CI, 0.73-0.89; P = 1.825 x 10-5).
Most adverse events during the study period were mild or moderate, and the events that occurred more commonly in the patisiran group than the placebo group were infusion-related reaction, arthralgia and muscle spasms, Maurer said during the presentation.
He said the patisiran group had fewer cardiac disorders, cardiac arrhythmias and cardiac failures during the study period compared with the placebo group.
“How does this impact my considerations for treatment of patients? Considerably,” Berk told Healio. “The signal is a surrogate endpoint that predicts the harder endpoints are also going to be achieved. The results confirm my optimistic view that [gene silencers] are going to considerably outperform tafamidis.”
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Maurer MS, et al. APOLLO-B. Presented at: International Symposium on Amyloidosis; Sept. 4-8, 2022; Heidelberg, Germany.
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