Beyonttra

Pharmacotherapeutic group: Cardiac therapy, Other cardiac preparations. ATC code: C01EB25. Mechanism of action Transthyretin amyloid cardiomyopathy is initiated by the dissociation of the transthyretin (TTR) tetramer into its constituent monomers. These misfold and aggregate as oligomeric amyloid precursors that deposit in the heart where they assemble into amyloid fibrils. Acoramidis is a specific stabiliser of TTR. Acoramidis was designed to mimic the disease protective genetic variant (T119M), through the formation of hydrogen bonds with adjacent serine residues within both thyroxine binding sites of the tetramer. This interaction enhances the stability of the tetramer, inhibiting its dissociation into monomers, thus slowing the amyloidogenic process that results in ATTR-CM. Pharmacodynamic effects Near-complete transthyretin stabilisation was observed with acoramidis in wild-type and in all amyloidogenic variant genotypes tested, including the most prevalent genotypes V30M (p.V50M), T60A (p.T80A), and V122I (p.V142I). In the ATTRibute-CM study, in patients (wild-type and variant ATTR) treated with acoramidis (712 mg twice daily), near-complete (≥ 90%) TTR stabilisation was observed at the first post-dose initiation assessment (Day 28) and sustained through Month 30. For all post-baseline measurements (from Day 28 through Month 30), the TTR level was higher in the acoramidis group compared with placebo (at Month 30, mean change from baseline 9.1 mg/dL with acoramidis versus 1.3 mg/dL with placebo). In ATTRibute-CM, the increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) at Month 30 favoured acoramidis and was about half the increase seen with placebo. A lower increase in troponin I was also observed with acoramidis versus placebo. In ATTRibute-CM, the mean serum creatinine (and estimated GFR) at baseline was 110.0 μmol/L (eGFR: 60.9 mL/min/1.73 m 2 ) in the acoramidis group and 109.0 μmol/L (eGFR: 61.0 mL/min/1.73 m 2 ) in the placebo group. At Day 28, there was a change from baseline in the mean serum creatinine (eGFR) that was greater in the acoramidis group (observed values on Day 28 serum creatinine: 129.3 μmol/L, eGFR: 52.4 mL/min/1.73 m 2 ) compared with the placebo group (observed values on Day 28 serum creatinine: 110.6 μmol/L, eGFR: 60.0 mL/min/1.73 m 2 ). After Day 28, serum creatinine (eGFR) remained stable in the acoramidis group for the remainder of the study. There was a progressive rise in serum creatinine, and corresponding progressive decrease in eGFR, in the placebo group from baseline through Month 30. At Month 30, serum creatinine was 123.4 μmol/L (eGFR: 55.1 mL/min/1.73 m 2 ) and 117.2 μmol/L (eGFR: 57.2 mL/min/1.73 m 2 ) for acoramidis and placebo respectively. The observed increase in serum creatinine, and corresponding decrease in eGFR, observed in acoramidis treated patients was reversible in the event of an interruption of therapy. Cardiac electrophysiology The maximum dose of acoramidis, 1 780 mg, studied as a single dose in healthy adult volunteers did not have a clinically relevant effect on cardiac conduction or repolarisation (no concentration-QTc effect was observed). These observations indicate a low risk of pro-arrhythmia. Clinical efficacy ATTRibute-CM was a multicentre, international, randomised, double-blind, placebo-controlled clinical study conducted in 632 participants with wild-type or variant (hereditary or de novo) ATTR-CM and heart failure NYHA Class I-III, with current or prior symptoms of heart failure. Participants were randomised in a 2:1 ratio to receive acoramidis 712 mg (n = 421), or matching placebo (n = 211) twice daily for 30 months. Treatment assignment was stratified by whether participants had variant ATTR‑CM (ATTRv-CM) or wild-type ATTR-CM (ATTRwt-CM) and baseline disease severity, i.e., NT‑proBNP level and renal function as defined by eGFR. Patients with eGFR < 15 mL/min/1.73 m 2 were excluded from participation in the study. Table 2: Demographics and baseline characteristics (mITT population 1 ) Characteristic Acoramidis N = 409 Placebo N = 202 Age - years Mean (standard deviation) 77.3 (6.5) 77.0 (6.7) Sex - number (%) Male 374 (91.4) 181 (89.6) Female 35 (8.6) 21 (10.4) TTR genotype 2 - number (%) ATTRv 39 (9.5) 20 (9.9) ATTRwt 370 (90.5) 182 (90.1) NYHA class - number (%) NYHA class I 51 (12.5) 17 (8.4) NYHA class II 288 (70.4) 156 (77.2) NYHA class III 70 (17.1) 29 (14.4) eGFR 2 (mL/min/1.73 m 2 ) – number (%) eGFR ≥ 45 344 (84.1) 173 (85.6) eGFR < 45 65 (15.9) 29 (14.4) NT‑proBNP 2 (pg/mL) – number (%) ≤ 3 000 268 (65.5) 133 (65.8) > 3 000 141 (34.5) 69 (34.2) ATTR NAC stage 3 - number (%) I 241 (58.9) 120 (59.4) II 130 (31.8) 66 (32.7) III 38 (9.3) 16 (7.9) History of permanent pacemaker – number (%) 77 (18.8) 38 (18.8) History of atrial fibrillation – number (%) 236 (57.7) 117 (57.9) Abbreviations: ATTRv = variant transthyretin amyloid, ATTRwt = wild-type transthyretin amyloid, NAC = National Amyloidosis Centre (London UK), NYHA = New York Heart Association, eGFR = estimated glomerular filtration rate, NT‑proBNP = N-terminal prohormone of brain natriuretic peptide, TTR = transthyretin 1 mITT = modified intent to treat (baseline eGFR ≥ 30 mL/min/1.73 m 2 ). 2 Stratification factors. 3 NAC Stage I (NT‑proBNP ≤ 3 000 pg/mL and eGFR ≥ 45 mL/min/1.73 m 2 ), Stage II (NT‑proBNP ≤ 3 000 pg/mL and eGFR < 45 mL/min/1.73 m 2 or NT-proBNP > 3 000 pg/mL and eGFR ≥ 45 mL/min/1.73 m 2 ), Stage III (NT‑proBNP > 3 000 pg/mL and eGFR < 45 mL/min/1.73 m 2 ). Participants were permitted to initiate open label tafamidis if prescribed as a concomitant medicinal product after 12 months in the study. A total of 107 participants received tafamidis, 61 (14.9%) in the acoramidis arm and 46 (22.8%) in the placebo arm. The primary objective of the study was to establish superiority of acoramidis versus placebo on a hierarchical endpoint that included all-cause mortality (ACM) and cumulative frequency of cardiovascular-related hospitalisation (CVH). Secondary objectives included assessment of ACM, CVH, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score (a measure of quality of life), serum TTR level and NT-proBNP. The main efficacy analyses were conducted in the 611 participants in the modified intent to treat (mITT) population without any adjustment for the introduction of open label tafamidis. Efficacy analysis The efficacy analysis applied the stratified Finkelstein-Schoenfeld (F-S) test hierarchically to ACM and CVH over the 30-month study. The method compared each participant to every other participant within each stratum in a pair-wise manner. In this hierarchical approach, participants in each pair are first compared on ACM, and then on CVH only if the comparison on ACM resulted in a tie. The result of this analysis was statistically significant (Table 3). All-cause mortality was reported in 19.3% and 25.7% of participants in the acoramidis and placebo groups, respectively. The majority (79%) of deaths were cardiovascular (CV)-related with acoramidis demonstrating a 30% relative risk reduction in CV-related mortality compared with placebo. CV‑related mortality was reported in 14.9% and 21.3% of participants in the acoramidis and placebo groups, respectively; hazard ratio: 0.709 (95% CI: 0.476, 1.054, p = 0.0889, Cox proportional hazards model). A Cox regression analysis indicated a 35.5% decrease in the risk of the composite of ACM or first CV hospitalisation (hazard ratio: 0.645 [95% CI: 0.500, 0.832; p = 0.0008]). Separation in the Kaplan-Meier curves was observed at Month 3 and steadily diverged through Month 30 (Figure 1). The efficacy results on ACM and CVH demonstrated in the mITT population were also observed in the ITT population (all randomised subjects irrespective of baseline eGFR). Table 3: Efficacy results on Finkelstein-Schoenfeld analysis, all-cause mortality and cardiovascular-related hospitalisation at Month 30 in ATTRibute-CM (mITT population) Parameter Acoramidis N = 409 Placebo N = 202 Combination of ACM and cumulative frequency of CVH Win ratio (95% CI) F-S 1 p-value 1.464 (1.067, 2.009) p = 0.0182 Number (%) of participants alive at Month 30 2 330 (80.7%) 150 (74.3%) Number (%) of participants with CVH Number of total CVH events Frequency of CVH per year per participant (mean) 3 109 (26.7%) 182 0.29 86 (42.6%) 170 0.55 Relative risk ratio 4 p-value 0.496 p < 0.0001 Abbreviations: F-S = Finkelstein-Schoenfeld; ACM = all-cause mortality; CVH = cardiovascular hospitalisation; mITT = modified intent-to-treat; CI = confidence interval 1 The F-S method compares every participant pair within each stratum in a hierarchical fashion, starting with ACM. If pairs are tied on ACM, they are then assessed on CVH. 2 Heart transplantation and cardiac mechanical assist device implantation are considered indicators of approaching end stage. As such, these events are treated in the analysis as equivalent to death. Therefore, such participants are not included in the count of “Number of participants alive at Month 30” even if such participants are alive based on 30-month vital status follow-up assessment. Vital status at Month 30 was known for all participants. 3 CVH per year for each participant is calculated as (participant's total number of observed CVH) / (duration of follow-up in years) and include events of clinical interest (EOCI). EOCI is defined as medical visits (e.g., emergency department/ward, urgent care clinic, day clinic) of < 24 hours for intravenous diuretic therapy for management of decompensated heart failure. 4 From negative binomial regression model. Figure 1: Time to all-cause mortality or first cardiovascular-related hospitalisation 6‑Minute Walk Distance (6MWD) and KCCQ The treatment effect of acoramidis on functional capacity and health status was assessed by the 6MWD and the KCCQ Overall Summary score (KCCQ-OS); composed of the physical limitation, symptom, social limitation and quality of life domains), respectively (Table 4). A treatment effect favouring acoramidis was first observed for 6MWD and KCCQ-OS at Month 18 and Month 3, respectively, and was sustained through Month 30. Table 4: 6MWD and KCCQ-OS scores Endpoints* Baseline Mean (SD) Change from Baseline to Month 30, LS Mean (SE) Treatment Difference from Placebo LS Mean (96% CI) p-value Acoramidis N = 409 Placebo N = 202 Acoramidis N = 409 Placebo N = 202 6MWD (metres) 362.78 (103.50) 351.51 (93.83) -64.65 (5.51) -104.29 (7.77) 39.64 (20.18, 59.10) < 0.0001 KCCQ-OS 71.73 (19.37) 70.48 (20.65) -11.48 (1.18) -21.42 (1.65) 9.94 (5.79, 14.10) < 0.0001 Abbreviations: 6MWD = 6‑minute walk distance; CI = confidence interval; KCCQ‑OS = Kansas City Cardiomyopathy Questionnaire Overall Summary score, LS = least squares, SD = standard deviation, SE = standard error * Higher values indicate better health status. Subgroup analysis Results from the F-S test applied to ACM and CVH (complemented by the win ratio) consistently favoured acoramidis versus placebo across the stratification parameter (wild type or variant), NYHA class and ATTR National Amyloidosis Centre (NAC) stage subgroups (Figure 2). Figure 2: Hierarchical combination of all-cause mortality and CV-related hospitalisation, Finkelstein-Schoenfeld and win ratio results overall and by subgroup (mITT population) 1 Abbreviations: ACM = all-cause mortality; ATTRwt-CM = wild-type ATTR-CM; ATTRv-CM = variant ATTR‑CM; CVH = cardiovascular-related hospitalisation; F-S = Finkelstein-Schoenfeld; NAC = National Amyloidosis Centre (London, UK); NYHA = New York Heart Association; NAC Stage I (NT‑proBNP ≤ 3 000 pg/mL and eGFR ≥ 45 mL/min/1.73 m 2 ), Stage II (NT‑proBNP ≤ 3 000 pg/mL and eGFR < 45 mL/min/1.73 m 2 or NT-proBNP > 3 000 pg/mL and eGFR ≥ 45 mL/min/1.73 m 2 ), Stage III (NT‑proBNP > 3 000 pg/mL and eGFR < 45 mL/min/1.73 m 2 ) 1 The win ratio is the number of pairs with acoramidis treated-participant “wins” divided by number of pairs with placebo-treated participant “wins.” Paediatric population The Licensing Authority has waived the obligation to submit the results of studies with BEYONTTRA in all subsets of the paediatric population in ATTR-CM (see section 4.2 for information on paediatric use).