Masri, Ahmad

Background: Atrial fibrillation (AF) significantly impacts quality of life (QoL) and is often observed in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Acoramidis achieves near-complete (≥90%) transthyretin (TTR) stabilization and is approved in the USA, the UK, Europe and Japan for the treatment of ATTR-CM in adults. In the phase 3 ATTRibute-CM study (NCT03860935), acoramidis treatment significantly reduced the time to all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) at Month 30, and resulted in improved 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels relative to placebo. The clinical efficacy of acoramidis has not yet been reported in patients with ATTR-CM and with an AF or atrial flutter (AFL) diagnosis at baseline. Research Question: How does acoramidis treatment affect ACM or first CVH, 6MWD, KCCQ-OS scores, and NT-proBNP levels at Month 30 in participants with ATTR-CM with or without AF/AFL diagnosis at baseline? Methods: The ATTRibute-CM study design has been previously published. This post hoc analysis included participants in the modified intention-to-treat population (N=611) grouped by AF/AFL diagnosis at baseline (defined as recorded AF medical history or the presence of AF or AFL on an ECG at enrollment). The rate of ACM or first CVH at Month 30 was compared between groups using a stratified Cox proportional hazards model. Changes from baseline to Month 30 in 6MWD, KCCQ-OS scores and NT-proBNP levels were summarized descriptively. Results: Overall, 62.8% (384/611) of participants had an AF/AFL diagnosis at baseline (acoramidis: 255/409, placebo: 129/202). These participants had lower mean 6MWD and KCCQ-OS scores and higher median NT-proBNP levels than those without AF/AFL diagnosis at baseline. Treatment with acoramidis reduced ACM or first CVH, slowed the decline in 6MWD and KCCQ-OS scores and blunted the rise in NT-proBNP compared with placebo, regardless of AF/AFL diagnosis at baseline ( Table ). Conclusions: Acoramidis improved clinical outcomes (ACM, CVH), functional status, QoL and NT-proBNP levels relative to placebo in participants with ATTR-CM, regardless of AF/AFL diagnosis at baseline.

BACKGROUND: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46–0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47–0.88) and 0.53 (95% CI, 0.41–0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04988386.

ABSTRACTIntroduction/AimsThe degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo.MethodsData from the NEURO‐TTRansform trial on patients with ATTRv‐PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor‐based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL‐Diabetic Neuropathy (Norfolk QoL‐DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed.ResultsMeaningful improvement in mNIS+7 was estimated as −4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL‐DN were −12.8 to −4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were −2.4 to −1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m2 × g/L and deterioration was −40.9 kg/m2 × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences.DiscussionEplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal condition characterized by worsening heart failure (HF), exercise intolerance, cardiac arrhythmias, aortic stenosis, and orthopedic manifestations. Recent analyses have shown ATTR-CM presents a significant burden to the healthcare system, but data on healthcare resource utilization (HCRU) comparing ATTR-CM to non-ATTR HF in the US are lacking. Aim: To compare HCRU and costs in patients (pts) with ATTR-CM to that of pts with non-ATTR HF using medical and pharmacy claims. Methods: Using the Optum Clinformatics Data Mart (Jan 2016-Sep 2023), pts with ATTR-CM were identified based on presence of HF and/or cardiomyopathy (CM) occurring within 2 years of first amyloidosis diagnosis (excluding light-chain amyloidosis) and followed for at least 12 months after first HF/CM diagnosis. ATTR-CM pts were matched 1:1 to non-ATTR HF pts using propensity score matching. After index diagnosis, both groups were assessed for HCRU, including inpatient acute cardiovascular (CV) hospitalizations (CVH), length of stay, and cost. Hospitalizations were considered CV if a pt received a CV diagnosis during the hospitalization period. Results: There were 4581 pts with ATTR-CM (mean [±SD] age: 76 [9.13] years; 56.2% male) who met inclusion criteria and were matched to 4581 non-ATTR HF pts (mean [±SD] age: 76 [8.86] years; 56.0% male) for comparison (Table). ATTR-CM pts had a higher trend of CVH and a higher number of total CVHs and mean hospitalizations per pt compared to non-ATTR HF pts (p<0.001). The mean cost per hospitalization (p=0.00463) and mean cost per annual hospitalizations per pt (p<0.001) were higher for ATTR-CM compared to non-ATTR HF. ATTR-CM pts were also hospitalized for more mean days annually for CV-related reasons compared to non-ATTR HF pts (p<0.001). On average, pts with ATTR-CM spent 2.3 days more than matched non-ATTR HF pts in the hospital each year. Conclusion: Compared to non-ATTR HF, ATTR-CM is associated with a greater burden on the healthcare system as evaluated by hospitalization rate, costs per hospitalization, annual hospitalization costs, and days hospitalized annually.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is estimated to occur in 120,000 US adults and remains underdiagnosed. However, awareness of ATTR-CM has improved following the introduction of new diagnostic tools and disease-modifying treatments. Hence, patients (pts) enrolled in contemporary clinical trials could be at an earlier stage of the disease than pts in past clinical studies. Aim: To assess temporal trends in the baseline risk of pts with ATTR-CM enrolled in clinical trials. Methods: Embase, MEDLINE, CENTRAL, and conference websites were searched on November 23, 2023, for peer-reviewed articles and abstracts. Randomized and single-arm clinical trials examining treatments for ATTR-CM were included, and baseline characteristics and outcomes in pts treated with placebo (PBO) were compared across studies. Results: We reviewed 39 publications derived from 4 randomized and 4 single-arm trials. Studies enrolled pts between 2008 and 2021, although 1 study (INOCARD, 2022) did not report years of enrollment. Several baseline characteristics were comparable across studies, including sex, age, race/ethnicity, genotype, and troponin I level. NYHA class at baseline varied with year of enrollment, with fewer NYHA class III pts in recent trials (Figure). Recent trials also showed a trend toward lower NT-proBNP levels (medians ranging from 1911-3178 pg/mL) and higher eGFR levels (means ranging from 54.7-69.0 mL/min/1.73 m 2 ). In PBO groups, all-cause mortality (ACM) rates at 12 months dropped from 9% in ATTR-ACT (enrolled 2013-2015) to 6.9% in ATTRibute-CM (enrolled 2019-2020) and 5.6% in APOLLO-B (enrolled 2019-2021); ACM rates at 30 months dropped from 42.9% in ATTR-ACT to 25.7% in ATTRibute-CM. Conclusions: This systematic review found that disease-modifying treatments and diagnostic advances have led to earlier diagnosis of pts with ATTR-CM. Recent clinical trials appear to have enrolled pts with a better prognosis. Comparisons of results across these trials are limited and should acknowledge the potential impact of variability in baseline risks among trial populations.

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. METHODS: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. RESULTS: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were −14.7%, −22.2%, and −16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 ( P =0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (−11.4%), with no significant worsening from baseline through week 56 ( P =0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 ( P =0.62 and P =0.56, respectively). CONCLUSIONS: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

Background The phase 2 PIONEER‐HCM (Phase 2 Open‐label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer‐term treatment are less well described. We report interim results from the PIONEER‐OLE (PIONEER Open‐Label Extension) study, the longest‐term study of mavacamten in patients with symptomatic obstructive HCM. Methods and Results Patients who previously completed PIONEER‐HCM (n=20) were eligible to enroll in PIONEER‐OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire–Overall Summary Score, and serum NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received β‐blockers concomitantly. Treatment‐emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, −50 [55] mm Hg; Valsalva, −70 [41] mm Hg), and serum NT‐proBNP levels (median [interquartile range] change from baseline: −498 [−2184 to −76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire–Overall Summary Score (mean [SD] change from baseline: +17 [16]). Conclusions This long‐term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03496168.

Importance Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR ( NCT01737398 ; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group. Interventions Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P &amp;lt; .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P &amp;lt; .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P &amp;lt; .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration ClinicalTrials.gov Identifier: NCT04136184 ; EU Clinical Trials Register: EudraCT 2019-001698-10