Biomarker and Echo Data Bolster Vutrisiran’s Promise in ATTR-CM

The small interfering RNA (siRNA) agent vutrisiran has beneficial effects on cardiac biomarkers that are seen as early as 6 months in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and is associated with improvement in measures of cardiac structure and function, according to two analyses from the HELIOS-B trial.

Both studies, scheduled as late-breaking trials at the Heart Failure Society of America (HFSA) 2024 meeting, were presented online last weekend after the meeting was canceled due to Hurricane Helene.

Across all prespecified subgroups, including age, ATTR type, NYHA class, and NT-proBNP level, vutrisiran (Amvuttra; Alnylam) demonstrated beneficial effects on cardiac biomarkers in the overall and monotherapy populations, said presenter Mathew S. Maurer, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY).

In an analysis of vutrisiran’s impact on echocardiographic structure and function, Karola Jering, MD (Brigham and Women’s Hospital, Boston, MA), showed that the agent significantly attenuated increases in mean LV wall thickness and LV mass index at 30 months compared with placebo while also improving LV diastolic dysfunction, a hallmark of ATTR-CM.

The main HELIOS-B results, presented in August at the European Society of Cardiology Congress, showed that vutrisiran reduced the risk of CV events and all-cause mortality by 28% compared with placebo in the overall population and by 33% in those not on background tafamidis (Vyndaqel and Vyndamax; Pfizer), which is currently the only drug approved for ATTR-CM by the US Food and Drug Administration.

Tafamidis is considered a stabilizer therapy because it reduces circulating levels of TTR, while vutrisiran is a first-in-class silencer of the transport protein.

Currently, vutrisiran is FDA-approved for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. Alnylam has said it intends to file a supplemental new drug application for vutrisiran for the treatment of ATTR-CM, with additional global regulatory filings expected to follow.

In her discussion of both HELIOS-B analyses during the HFSA meeting, Julie Rosenthal, MD (Mayo Clinic, Phoenix, AZ), noted that not long ago, ATTR-CM was considered a difficult-to-detect and rare disease with few options except supportive care, but this is no longer the case.

“Hopefully, in the near future, we will have three [therapy] choices with many more in the pipeline,” Rosenthal said. “HELIOS-B marks the third landmark treatment trial and the first RNA-interfering technology that demonstrated improvement in all 10 primary and secondary endpoints, including a composite primary endpoint of all-cause mortality and time to recurrent cardiovascular event as well as secondary endpoints, including all-cause mortality, as well as those that looked at quality of life and functional capacity.”

While Rosenthal said vutrisiran appears to be another win for treatment options in ATTR-CM, many questions remain unanswered.

“How do we choose? Who do we treat? How do we assess response? And what are the long-term consequences of these disease-targeted interventions?” she said.

Studies Provide Additional Insights

Most patients enrolled in HELIOS-B had wild-type ATTR-CM, while only about 10% had the heredity type, which results from mutations in the TTR gene. All had a history of symptomatic heart failure and were randomized to receive vutrisiran 25 mg subcutaneously every 12 weeks for up to 36 months (n = 326) or placebo (n = 329). At baseline, 40% of patients were already on tafamidis.

As Maurer showed in the biomarker analysis, baseline levels of NT-proBNP and troponin I were positively associated with subsequent clinical events. At month 30, there was a 32% relative risk reduction from baseline in NT-proBNP in the vutrisiran group compared with placebo, with the difference between groups emerging as early as 6 months. At the same time point, there was also a 32% relative reduction in troponin I in the vutrisiran group compared with placebo (P < 0.000001 for both changes). Again, the difference was seen as early as 6 months and increased over time.

The changes in prognostic biomarkers were seen in all prespecified subgroups in the overall and monotherapy populations.

Maurer and colleagues also looked at these changes in biomarkers in patients who were and who were not on stabilizer therapy with tafamidis at baseline. Among those not on tafamidis, the reduction in NT-proBNP was 43% compared with placebo, while the reduction in troponin I was 45% compared with placebo. Among those already on tafamidis, the reductions were 18% and 10%, respectively.

“The median change from baseline in NT-proBNP in those on vutrisiran was minimal and not really clinically relevant compared with the larger increases in those in the placebo arm,” Maurer added.

The echocardiographic analysis was performed at baseline and at 12 and 30 months.

“Looking at changes in cardiac structure over time in both treatment arms, left ventricular mass index increased during follow-up,” Jering said. “However, this increase was attenuated by vutrisiran, with significant between-group differences evident at 30 months. The effects of vutrisiran on hemodynamics of diastolic dysfunction were much more rapid, and significant between-group differences were observed as early as 12 months.”

Compared with placebo, the vutrisiran patients had improvements in E/e’, E/A ratio, and tissue Doppler imaging lateral e’.

“Whereas in the placebo arm, the E-to-e prime ratio increased during follow-up, it decreased in the vutrisiran therapy arm, suggesting an improvement in diastolic function,” Jering said. “Left ventricular systolic function declined during follow-up, as measured by left ventricular ejection fraction and absolute peak longitudinal strain. Vutrisiran, however, attenuated these declines in left ventricular systolic function, with significant between-group differences evident as early as 18 months.”

According to Rosenthal, taken together with the main study results, these new data provide additional insight into the mechanism of the molecular and structural changes that occur when vutrisiran is added to existing therapies.