November 9, 2026
Effects of Eplontersen on Cardiac Structure and Function in Patients With Transthyretin Amyloidosis With Cardiomyopathy: Insights from the CARDIO-TTRansform Trial.
Key result
Eplontersen attenuates mean LV wall thickness increase by ~0.24 mm vs placebo at 140 weeks.
Why the study?
In CARDIO-TTRansform, the TTR silencer eplontersen did not significantly reduce the primary endpoint of cardiovascular death and recurrent cardiovascular events in patients with TTR amyloidosis with cardiomyopathy, although treatment effects varied by baseline TTR stabilizer use. Whether eplontersen favorably affects cardiac structure and function remained unknown.
Does eplontersen favorably affect echocardiographic measures of cardiac structure and function compared to placebo in patients with transthyretin amyloidosis with cardiomyopathy?
Key Points
- To assess whether the transthyretin silencer eplontersen favorably alters cardiac structure and function in patients with transthyretin amyloidosis with cardiomyopathy.
- In a multicenter randomized clinical trial (NCT04136171, 2019-002835-27), 1432 patients with transthyretin amyloidosis with cardiomyopathy were assigned to subcutaneous eplontersen (45 mg every 4 weeks) or placebo.
- Serial echocardiograms were performed at baseline and weeks 61, 97, and 140, with between-group differences at week 140 analyzed using mixed models for repeated measures.
- At week 140 (n=554 eplontersen, n=506 placebo), eplontersen attenuated increases in mean left ventricular wall thickness (LSM difference, -0.24 mm [95% CI, -0.48 to -0.01]) and preserved left ventricular stroke volume (LSM difference, 1.88 mL [95% CI, 0.07-3.69]).
- Eplontersen also lessened declines in myocardial contraction fraction (LSM difference, 0.88% [95% CI, 0.25-1.57]), average E/e' (LSM difference, -0.71 [95% CI, -1.36 to -0.07]), and right ventricular outflow tract velocity-time integral (LSM difference, 0.42 [95% CI, 0.00-0.85]).
- Structural and functional benefits were driven almost exclusively by participants not receiving baseline transthyretin stabilizers, with no significant treatment effects observed among those taking stabilizers.
Study Design
Type
RCT (n=1,432)
Blinding
Placebo-controlled
Randomization
Randomized
Structured PICO
Does eplontersen favorably affect echocardiographic measures of cardiac structure and function compared to placebo in patients with transthyretin amyloidosis with cardiomyopathy?
P
Population
1,432 patients with transthyretin amyloidosis with cardiomyopathy (1,426 with baseline echocardiograms; mean age 76±7 years, 91% men, 85% wild type, 57% receiving stabilizers) followed for 140 weeks.
I
Intervention
Eplontersen 45 mg subcutaneously every 4 weeks up to week 140
C
Comparator
Placebo (with 57% of overall cohort receiving background TTR stabilizers at baseline)
O
Outcome
Between-group differences at week 140 in echocardiographic measures of cardiac structure and function (including mean LV wall thickness, LV stroke volume, myocardial contraction fraction, average E/e', and right ventricular outflow tract velocity-time integral)surrogate
Main Result
Mean Difference: -0.24 (95% CI -0.48–-0.01)
Eplontersen modestly attenuated echocardiographic deterioration in LV systolic, diastolic, and RV function over 140 weeks in TTR amyloidosis with cardiomyopathy, driven primarily by patients not on baseline TTR stabilizers.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“In CARDIO-TTRansform, the largest ATTR-CM trial to date, eplontersen achieved reductions in circulating serum TTR, although the trial did not demonstrate a significant reduction in the primary end point in the overall population. Baseline stabilizer use appeared to influence the primary results. No additional benefit was observed in patients receiving background stabilizer therapy, while fewer primary end point events were observed with eplontersen in patients not receiving a stabilizer.”
“Although we are disappointed that the study did not meet the primary endpoint, these results have the potential to guide the treatment landscape for ATTR-CM and contribute to advancing future care for patients.”
Implication
Supports eplontersen in stabilizer-naive TTR-CM; extends neutral primary CV outcomes with echocardiographic benefits.
Abstract
BACKGROUND: In CARDIO-TTRansform, the TTR (transthyretin) silencer eplontersen did not significantly reduce the primary end point of cardiovascular death and recurrent cardiovascular events in patients with TTR amyloidosis with cardiomyopathy, although treatment effects varied by baseline TTR stabilizer use. Whether eplontersen favorably affects cardiac structure and function is unknown. METHODS: CARDIO-TTRansform randomized 1432 patients with TTR amyloidosis with cardiomyopathy to eplontersen (45 mg) subcutaneously every 4 weeks or placebo. Echocardiograms were performed at baseline and weeks 61, 97, and 140. Associations of baseline echocardiographic measures with all-cause mortality and the primary end point were evaluated using Cox and semiparametric proportional rates models. Between-group differences at week 140 were analyzed with mixed models for repeated measures. RESULTS: Among 1426 participants with baseline echocardiograms (mean age, 76±7 years, 91% men, 85% wild type, 57% receiving stabilizers), baseline measures of left ventricular systolic function (LV ejection fraction, global longitudinal strain, stroke volume, myocardial contraction fraction), diastolic function (E wave deceleration time, septal e', average E/e'), and right ventricular function and hemodynamics were independently associated with all-cause mortality or the primary end point. At week 140 (echocardiograms available in 554 patients in the eplontersen group and 506 in the placebo group), eplontersen attenuated increases in mean LV wall thickness (least-squares mean [LSM] difference, -0.24 mm [95% CI, -0.48 to -0.01]) and declines in LV stroke volume (LSM difference, 1.88 mL [95% CI, 0.07-3.69]), myocardial contraction fraction (LSM difference, 0.88% [95% CI, 0.25-1.57]), average E/e' (LSM difference, -0.71 [95% CI, -1.36 to -0.07]), and right ventricular outflow tract velocity-time integral (LSM difference, 0.42 [95% CI, 0.00-0.85]) versus placebo in the overall cohort. Beneficial effects were driven almost exclusively by patients not receiving stabilizers at baseline. No significant treatment effects were observed in patients receiving stabilizers. CONCLUSIONS: Among patients with TTR amyloidosis with cardiomyopathy, eplontersen modestly attenuated deterioration in prognostically important measures of LV systolic, diastolic and right ventricular function, primarily among patients not receiving stabilizers at baseline. These findings complement the clinical findings of CARDIO-TTRansform and suggest that TTR silencing may attenuate progression of cardiac dysfunction in TTR amyloidosis with cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04136171; URL: xxx; Unique identifier: 2019-002835-27.
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Cite This Study
Jering et al. (2026) conducted an RCT in Transthyretin amyloidosis with cardiomyopathy (n=1,432). Eplontersen vs. Placebo was evaluated on Between-group differences in echocardiographic measures of cardiac structure and function at week 140 (specifically mean LV wall thickness) (MD -0.24, 95% CI -0.48 to -0.01). Eplontersen attenuated increases in mean LV wall thickness and functional decline at week 140 vs placebo.