Gene-silencing therapies improved several important outcomes for people with transthyretin amyloid cardiomyopathy (ATTR-CM), but the benefits might depend on if patients also take a transthyretin (TTR) stabilizer therapy, found a meta-analysis of two large clinical trials published recently in JAMA Network.
Transthyretin-stabilizing treatments, such as tafamidis, prevent TTR proteins from misfolding and forming amyloid clumps, the driver of disease in ATTR-CM. Gene-silencing therapies, on the other hand, reduce how much TTR the body creates.
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The analysis included 2,086 patients from the HELIOS-B and CARDIO-TTRansform trials. These studies evaluated the TTR gene-silencing therapies vutrisiran in 654 patients and eplontersen in 1,432 patients. Most patients had the wild-type form of ATTR-CM, and 70% to 78% had New York Heart Association class II disease. Follow-up lasted a median of 2.7 years in CARDIO-TTRansform and 3.0 years in HELIOS-B.
Compared with placebo, gene-silencing treatment lowered the risk of either dying from any cause or experiencing repeated cardiovascular events by 20%. The treatment also lowered the risk of death from any cause by about 26% and reduced the likelihood of reaching a first death or cardiovascular event during the study period. These findings indicate that the benefits were not limited to a single type of heart-related complication.
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The therapies also helped patients maintain their ability to be physically active and their quality of life. On average, patients receiving gene-silencing treatment were able to walk 22.2 meters farther during a 6-minute walking test than those receiving placebo, after accounting for the difference between the groups at the end of the study.
Treatment was also associated with a 4.5-point higher score on a questionnaire measuring symptoms, physical limitations and quality of life related to heart disease. The authors noted that gene silencing “favorably modified a range of clinically meaningful outcomes,” including survival, cardiovascular events, physical function and health-related quality of life.
The study found that the amount of benefit varied depending on whether patients were already taking a transthyretin stabilizer. Among patients who were not taking a stabilizer, gene-silencing treatment lowered the risk of death or repeated cardiovascular events by 31%. In contrast, among patients who were already taking a stabilizer, the study did not find evidence that adding gene-silencing treatment provided a significant additional reduction in this risk. Similar patterns were seen for walking ability and quality of life.
These results do not necessarily mean that gene silencing does not work when combined with a stabilizer. Differences between the patients in the two groups or other factors may have contributed to the findings, and the researchers said more study is needed to understand why the additional benefit appeared smaller among patients already receiving a stabilizer.
For patients, the findings support gene-silencing therapy as an effective treatment option for ATTR-CM, particularly for those not already receiving a transthyretin stabilizer. The authors cautioned that more research is needed to better understand the effects of using both a gene-silencing therapy and a TTR stabilizer.
“These results should not be interpreted as definitive evidence that gene-silencing therapies could not provide incremental clinical benefit on top of background stabilizers or that all gene-silencing therapies will have equivalent efficacy when administered on a background of stabilizers,” they noted.
