Leaflet BEYONTTRA 356mg film-coated tablets

Pharmacotherapeutic group: Cardiac therapy, Other cardiac preparations. ATC code: C01EB25.

Transthyretin amyloid cardiomyopathy is initiated by the dissociation of the transthyretin (TTR)tetramer into its constituent monomers. These misfold and aggregate as oligomeric amyloid precursorsthat deposit in the heart where they assemble into amyloid fibrils.

Acoramidis is a specific stabiliser of TTR. Acoramidis was designed to mimic the disease protectivegenetic variant (T119M), through the formation of hydrogen bonds with adjacent serine residueswithin both thyroxine binding sites of the tetramer. This interaction enhances the stability of thetetramer, inhibiting its dissociation into monomers, thus slowing the amyloidogenic process thatresults in ATTR-CM.

Near-complete transthyretin stabilisation was observed with acoramidis in wild-type and in allamyloidogenic 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 wasobserved at the first post-dose initiation assessment (Day 28) and sustained through Month 30. For allpost-baseline measurements (from Day 28 through Month 30), the TTR level was higher in theacoramidis group compared with placebo (at Month 30, mean change from baseline 9.1 mg/dL withacoramidis 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 introponin 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 m2) in the acoramidis group and 109.0 μmol/L(eGFR: 61.0 mL/min/1.73 m2) in the placebo group. At Day 28, there was a change from baseline inthe 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 m2) compared with the placebogroup (observed values on Day 28 serum creatinine: 110.6 μmol/L, eGFR: 60.0 mL/min/1.73 m2).

After Day 28, serum creatinine (eGFR) remained stable in the acoramidis group for the remainder ofthe study. There was a progressive rise in serum creatinine, and corresponding progressive decrease ineGFR, in the placebo group from baseline through Month 30. At Month 30, serum creatinine was123.4 μmol/L (eGFR: 55.1 mL/min/1.73 m2) and 117.2 μmol/L (eGFR: 57.2 mL/min/1.73 m2) foracoramidis and placebo respectively. The observed increase in serum creatinine, and correspondingdecrease in eGFR, observed in acoramidis treated patients was reversible in the event of aninterruption of therapy.

The maximum dose of acoramidis, 1 780 mg, studied as a single dose in healthy adult volunteers didnot have a clinically relevant effect on cardiac conduction or repolarisation (no concentration-QTceffect was observed). These observations indicate a low risk of pro-arrhythmia.

ATTRibute-CM was a multicentre, international, randomised, double-blind, placebo-controlled clinicalstudy conducted in 632 participants with wild-type or variant (hereditary or de novo) ATTR-CM andheart failure NYHA Class I-III, with current or prior symptoms of heart failure. Participants wererandomised in a 2:1 ratio to receive acoramidis 712 mg (n = 421), or matching placebo (n = 211) twicedaily 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 m2were excluded from participation in the study.

Table 2: Demographics and baseline characteristics (mITT population1)

Acoramidis Placebo

Characteristic N = 409 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 genotype2 — 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)eGFR2 (mL/min/1.73 m2) - number (%)eGFR ≥ 45 344 (84.1) 173 (85.6)eGFR < 45 65 (15.9) 29 (14.4)

NT-proBNP2 (pg/mL) - number (%)≤ 3 000 268 (65.5) 133 (65.8)> 3 000 141 (34.5) 69 (34.2)

ATTR NAC stage3 — 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 = estimatedglomerular filtration rate, NT-proBNP = N-terminal prohormone of brain natriuretic peptide, TTR = transthyretin1 mITT = modified intent to treat (baseline eGFR ≥ 30 mL/min/1.73 m2).2 Stratification factors.3 NAC Stage I (NT-proBNP ≤ 3 000 pg/mL and eGFR ≥ 45 mL/min/1.73 m2), Stage II (NT-proBNP≤ 3 000 pg/mL and eGFR < 45 mL/min/1.73 m2 or NT-proBNP > 3 000 pg/mL and eGFR≥ 45 mL/min/1.73 m2), Stage III (NT-proBNP > 3 000 pg/mL and eGFR < 45 mL/min/1.73 m2).

Participants were permitted to initiate open label tafamidis if prescribed as a concomitant medicinalproduct after 12 months in the study. A total of 107 participants received tafamidis, 61 (14.9%) in theacoramidis arm and 46 (22.8%) in the placebo arm.

The primary objective of the study was to establish superiority of acoramidis versus placebo on ahierarchical endpoint that included all-cause mortality (ACM) and cumulative frequency ofcardiovascular-related hospitalisation (CVH). Secondary objectives included assessment of ACM,

CVH, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summaryscore (a measure of quality of life), serum TTR level and NT-proBNP. The main efficacy analyseswere conducted in the 611 participants in the modified intent to treat (mITT) population without anyadjustment for the introduction of open label tafamidis.

Efficacy analysis

The efficacy analysis applied the stratified Finkelstein-Schoenfeld (F-S) test hierarchically to ACMand CVH over the 30-month study. The method compared each participant to every other participantwithin each stratum in a pair-wise manner. In this hierarchical approach, participants in each pair arefirst compared on ACM, and then on CVH only if the comparison on ACM resulted in a tie. The resultof this analysis was statistically significant (Table 3).

All-cause mortality was reported in 19.3% and 25.7% of participants in the acoramidis and placebogroups, respectively. The majority (79%) of deaths were cardiovascular (CV)-related with acoramidisdemonstrating 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 placebogroups, respectively; hazard ratio: 0.709 (95% CI: 0.476, 1.054, p = 0.0889, Cox proportional hazardsmodel).

A Cox regression analysis indicated a 35.5% decrease in the risk of the composite of ACM or first CVhospitalisation (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 inthe ITT population (all randomised subjects irrespective of baseline eGFR).

Table 3: Efficacy results on Finkelstein-Schoenfeld analysis, all-cause mortality andcardiovascular-related hospitalisation at Month 30 in ATTRibute-CM (mITTpopulation)

Acoramidis Placebo

Parameter N = 409 N = 202

Combination of ACM and cumulative frequency of CVH

Win ratio (95% CI) 1.464 (1.067, 2.009)

F-S1 p-value p = 0.0182

Number (%) of participants alive at Month 302 330 (80.7%) 150 (74.3%)

Number (%) of participants with CVH 109 (26.7%) 86 (42.6%)

Number of total CVH events 182 170

Frequency of CVH per year per participant (mean)3 0.29 0.55

Relative risk ratio4 0.496p-value p < 0.0001

Abbreviations: F-S = Finkelstein-Schoenfeld; ACM = all-cause mortality; CVH = cardiovascular hospitalisation;mITT = modified intent-to-treat; CI = confidence interval1 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 ofapproaching 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 suchparticipants are alive based on 30-month vital status follow-up assessment. Vital status at Month 30 wasknown for all participants.

3 CVH per year for each participant is calculated as (participant’s total number of observed CVH)/(durationof 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 diuretictherapy for management of decompensated heart failure.

4 From negative binomial regression model.

Figure 1: Time to all-cause mortality or first cardiovascular-related hospitalisation6-Minute Walk Distance (6MWD) and KCCQ

The treatment effect of acoramidis on functional capacity and health status was assessed by the6MWD 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 effectfavouring 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

Baseline Mean Change from Baseline to Treatment(SD) Month 30, LS Mean (SE) Difference from

Acoramidis Placebo Acoramidis Placebo Placebo LS

Endpoints* N = 409 N = 202 N = 409 N = 202 Mean (96% CI) p-value6MWD 362.78 351.51 -64.65 -104.29 39.64(metres) (103.50) (93.83) (5.51) (7.77) (20.18, 59.10) < 0.0001

KCCQ-OS 71.73 70.48 -11.48 -21.42 9.94(19.37) (20.65) (1.18) (1.65) (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.

Results from the F-S test applied to ACM and CVH (complemented by the win ratio) consistentlyfavoured acoramidis versus placebo across the stratification parameter (wild type or variant), NYHAclass 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 m2), Stage II (NT-proBNP ≤ 3 000 pg/mL and eGFR< 45 mL/min/1.73 m2 or NT-proBNP > 3 000 pg/mL and eGFR ≥ 45 mL/min/1.73 m2), Stage III (NT-proBNP> 3 000 pg/mL and eGFR < 45 mL/min/1.73 m2)1 The win ratio is the number of pairs with acoramidis treated-participant “wins” divided by number of pairswith placebo-treated participant “wins.”

The European Medicines Agency 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 informationon paediatric use).