Abstract
Introduction
Tafamidis is approved in many countries for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Approval is largely based on findings from an international phase 3 trial. This post-approval commitment study aimed to evaluate the safety and efficacy of tafamidis in patients with ATTR-CM in China.
Methods
A multicenter, single-arm study in Chinese patients with symptomatic ATTR-CM in China. All patients received once-daily, open-label tafamidis free acid 61 mg for 12 months. Safety reporting was ongoing with efficacy assessments at months 6 and 12, including 6-min walk test distance, New York Heart Association (NYHA) functional classification, National Amyloidosis Centre staging, N-terminal pro-B-type natriuretic peptide and troponin I concentrations, Kansas City Cardiomyopathy Questionnaire Overall Summary score, 5-level EQ-5D index score, EQ visual analog scale, and 12-item Short Form Survey.
Results
Patients (n = 53) were aged 60 (standard deviation [SD]: 12) years, 89% were male, and 94% had variant ATTR-CM (21% had A97S [p.A117S]). At baseline, most (81%) patients had NYHA class II symptoms (6% class I; 13% class III) and National Amyloidosis Centre stage I disease (74%; 21% stage II; 6% stage III). Median treatment exposure was 345 (range, 24‒418) days. Overall, 85% of patients reported treatment-emergent adverse events (TEAEs). The nature and incidence of TEAEs were consistent with the known safety profile of tafamidis. There were no serious or severe treatment-related TEAEs. At 6 and 12 months, there were minimal changes from baseline in all efficacy outcomes with tafamidis, and a high proportion of patients (≥ 44%) showed clinically relevant stability or improvement in each measure.
Conclusions
The safety of tafamidis in Chinese patients with ATTR-CM was consistent with that previously determined. Tafamidis treatment was associated with a stable disease profile over 12 months in a population of patients where most had variant ATTR-CM and mild heart failure symptoms.
Trial Registration
Supplementary Information
The online version of this manuscript contains supplementary material available at 10.1007/s40119-025-00408-6.
Keywords: Heart failure, Amyloidosis, Quality of life, Health status, Functional status, Adverse events
Key Summary Points
| Why carry out this study? |
| Tafamidis is approved in many countries for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). |
| This multicenter, single-arm, post-approval commitment study aimed to evaluate the safety and efficacy of tafamidis in patients with ATTR-CM in China. |
| What was learned from the study? |
| The safety of tafamidis in Chinese patients with ATTR-CM was consistent with that previously reported in other international populations with ATTR-CM. |
| Tafamidis treatment was associated with a stable disease profile over 12 months in a population of patients where most had variant ATTR-CM and mild heart failure symptoms. |
Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening condition caused by deposition of transthyretin amyloid in the myocardium [1]. The formation of amyloid can be caused by variations in the transthyretin (TTR) gene (variant ATTR-CM [ATTRv-CM]), or can occur spontaneously with aging (wild-type ATTR-CM [ATTRwt-CM]) [1]. Amyloid deposition leads to cardiomyopathy and heart failure, with median survival reported to be approximately 2–6 years from diagnosis among patients not receiving disease-modifying therapy [2].
Tafamidis is the first disease-modifying therapy approved for the treatment of patients with ATTR-CM. Since its first regulatory approval in 2019, tafamidis has become available in many regions of the world [3]. Although the approved formulation varies across regions, two bioequivalent dosages are used: tafamidis meglumine 80 mg (4 × 20 mg capsules) and tafamidis free acid 61 mg (single capsule) [3]. Regulatory approvals were supported by findings from the pivotal phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT; NCT01994889) [4]. Patients with ATTR-CM treated with tafamidis (meglumine 20 or 80 mg pooled) for 30 months in ATTR-ACT had a 30% lower risk of all-cause mortality and 32% lower risk of cardiovascular hospitalization compared with those treated with placebo [4]. The safety profile of tafamidis was similar to that of placebo, except that permanent discontinuation of treatment and dose reductions due to adverse events (AEs) were more common in the placebo group [4]. Several post hoc analyses of ATTR-ACT data have evaluated the magnitude of benefit afforded by tafamidis treatment in different patient subgroups. One such analysis found significantly higher odds of improvement in measures of heart failure, functional capacity, and health-related quality of life (HRQoL) with tafamidis versus placebo treatment [5].
Patients who completed ATTR-ACT could join an open-label, long-term extension study (NCT02791230) to receive tafamidis treatment for up to 60 months or until available commercially in their region. Interim findings from the long-term extension study after ~ 58 months of total follow-up indicated that patients who received tafamidis in ATTR-ACT had a longer survival and a 41% reduction in the risk of all-cause mortality compared with those who received placebo [6]. These findings highlight the importance of early diagnosis and disease-modifying treatment of patients with ATTR-CM. The long-term safety and efficacy of tafamidis have also been confirmed in several other clinical and real-world studies [2, 7]. To our knowledge, no racial differences in the safety or efficacy of tafamidis treatment have been reported.
Although ATTR-ACT enrolled a multinational cohort of patients with ATTR-CM from 13 countries across four continents, none were enrolled in China [4]. Tafamidis free acid 61 mg was approved in China in September 2020 for the treatment of patients with ATTR-CM [8]. This post-approval commitment study aimed to evaluate the safety and efficacy of tafamidis in Chinese patients with ATTR-CM.
Methods
Study Design
This was a multicenter, single-arm, open-label, post-approval commitment study in adult Chinese patients with symptomatic ATTR-CM living in China (NCT04814186). All patients received once-daily, open-label tafamidis free acid 61 mg for up to 12 months, with post-screening assessments at baseline and at 1, 3, 6, 9, and 12 months. An additional post-treatment visit was conducted 28 days after the final dose of study treatment. Patients who discontinued treatment early completed an end-of-treatment follow-up. All assessments were completed in person, except at months 3 and 9, when a reduced range of assessments were made by telephone.
The study was conducted according to ethical principles derived from the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council for Harmonisation Good Clinical Practice guidelines. The study followed all local laws and regulations. Study materials were reviewed and approved by Ethics Committees or Institutional Review Boards at each participating center (Table S1; Approval number at the primary site [Peking Union Medical College Hospital]: KS2021004). All patients (or their legal representatives) provided written informed consent.
Patient Population
Patient eligibility to join the study was assessed during a screening visit conducted up to 45 days prior to baseline. To enroll, patients must have been ≥ 18 years of age with either: (1) ATTRv-CM, determined as having a variant TTR genotype presenting with a cardiomyopathy phenotype, an end-diastolic interventricular septum wall thickness > 12 mm, and amyloidosis confirmed by either biopsy or 99mtechnetium-pyrophosphate (99mTc-PYP) scintigraphy; or (2) ATTRwt-CM, determined as the absence of variant TTR, an end-diastolic interventricular septum wall thickness > 12 mm, and transthyretin amyloidosis confirmed by either biopsy with positive mass spectrometry or immunohistochemistry identification, or 99mTc-PYP scintigraphy. Genotyping, biopsy, and scintigraphy criteria were verified at the screening visit or from findings reported in the 5 years prior to enrollment. Patients were excluded if they had previously taken tafamidis, had light-chain or secondary amyloidosis, a prior liver or heart transplant, or had any other medical condition that made them (per the investigator’s opinion) unsuitable to take part in the study. Patients could continue permitted standard-of-care medications alongside study treatment. The use of diflunisal, tauroursodeoxycholate, doxycycline, digitalis, or calcium channel blockers (e.g., verapamil or diltiazem) was prohibited.
Outcomes
The pre-specified primary outcome of the study was the incidence of treatment-emergent adverse events (TEAEs). Safety reporting occurred throughout the study, with TEAEs defined as AEs reported by the patient or investigator that occurred between the first dose of tafamidis and 28 days after the last dose. All TEAEs were summarized using Medical Dictionary for Regulatory Activities coding. A serious AE (SAE) was a TEAE that resulted in death, was considered life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, a congenital defect, or was considered by the investigator to require medical or surgical intervention to prevent one of these outcomes. A severe AE was a TEAE that prevented normal daily activities. The causality of each AE to treatment was determined per the clinical opinion of the investigator.
Secondary outcomes focused on efficacy and included the change from baseline in 6-min walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, troponin I concentration, 23-item Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, 5-level EQ-5D (EQ-5D-5L) index score, EQ visual analog scale (EQ-VAS) score, 12-item Short Form Health Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and New York Heart Association (NYHA) functional class. The 6MWT distance, NT-proBNP concentration, and troponin I concentration are continuous measures without predefined range. All have prognostic value in patients with heart failure [9–11]. The KCCQ-OS score ranges from 0 to 100, with higher scores indicating better HRQoL. KCCQ-OS score has prognostic value for mortality in patients with heart failure [12]. The EQ-5D-5L index score is a patient-reported measure of HRQoL where 0 represents health as bad as death and 1 represents full health. Mean score among the general urban population in China aged 60 to 69 years is ~ 0.95 [13]. The range of the EQ-VAS is 0 (representing the worst health imaginable) to 100 (the best health imaginable). Mean score among the general urban population in China aged 60 to 69 years is ~ 84 [13]. The SF-12 is another patient-reported measure of HRQoL. The PCS and MCS scores range from 0 to 100, with higher scores indicating better HRQoL. General population mean score for patients aged 55–64 years in the United States is 46.6 (standard deviation [SD] 10.63) for the PCS and 50.6 (SD 9.82) for the MCS [14]; these mean scores have been shown to be valid and equivalent in the Chinese population [15]. The NYHA functional classification system has four stages (I to IV) and has prognostic value in patients with heart failure [9, 12]. Classifications were determined by the investigator at baseline, month 6, and month 12. Blood samples collected at months 1, 6, and 12 were used to measure tafamidis plasma concentration by validated liquid chromatography–tandem mass spectrometry methods.
Exploratory efficacy outcomes evaluated the proportion of patients who showed stability or improvement from baseline in a range of disease measures. Patients with stability or improvement were determined as all those who did not meet the thresholds for deterioration. Thresholds for deterioration were conservative and clinically relevant, based on previously published consensus statements [16]. They were: (1) ≥ 30 m decrease in 6MWT distance; (2) increase in NYHA functional class; (3) increase in National Amyloidosis Centre (NAC) stage; (4) ≥ 30% or 300 ng/l increase in NT-proBNP concentration; (5) ≥ 30% increase in troponin I concentration; (6) ≥ 5-point decrease in KCCQ-OS score; (7) ≥ 10% decrease in EQ-5D-5L score; or (8) ≥ 10% decrease in EQ-VAS score. NAC was categorized as stage I in patients with NT-proBNP ≤ 3000 ng/l and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m2; stage III in patients with NT-proBNP > 3000 ng/l and eGFR < 45 ml/min/1.73 m2; and stage II in the remainder of patients [17]. eGFR was calculated as 186 × creatinine concentration−1.154 in mg/dl; × age−0.203; × 0.742 if female; and × 1.233 for Chinese race.
Statistical Analysis
Power calculations completed before the study began suggested ≥ 53 patients were required to have an 80% probability of observing ≥ 1 TEAE, with an incidence rate of 3%. It was planned for all outcomes to be reported descriptively. Safety findings are reported for the full study period. Efficacy assessments are reported as mean (SD) change from baseline or proportion (%) of patients with stable or improved disease measures at the 6- and 12-month in-person assessments.
Results
Patients
Between July 2021 and September 2022, 53 patients with ATTR-CM were enrolled in China and treated with open-label tafamidis free acid 61 mg (Fig. 1). The baseline demographics and clinical characteristics of the 53 treated patients are shown in Table 1. Mean age among all patients was 60 years, 89% were male, and 94% had ATTRv-CM. The most common TTR variant was A97S (p.A117S; in 21% of all patients). All but one patient were of Han Chinese ethnicity; all were Asian. The majority of patients (64%) had a left ventricular ejection fraction of ≥ 50%, and mild heart failure symptoms, as denoted by an NYHA functional classification of II in 81% and a NAC stage of I in 74%. Despite this, patients reported significant physical and functional limitations (mean SF-12 PCS score 28, mean 6MWT distance 290 m) and an elevated NT-proBNP concentration (mean 2950 ng/l). Patients reported fair-to-good HRQoL (mean KCCQ-OS score 58) and lower EQ-5D-5L index (mean 0.5) and EQ-VAS scores (mean 63) than might be expected for their age [13].
Fig. 1.
Patient disposition
Table 1.
Baseline demographics and clinical characteristics
| Enrolled patients, n = 53 | |
|---|---|
| Age, mean (SD), years | 60 (12.0) |
| Sex, n (%) | |
| Male | 47 (88.7) |
| Female | 6 (11.3) |
| Asian race, n (%) | 53 (100) |
| Ethnicity, n (%) | |
| Han Chinese | 52 (98.1) |
| Other | 1 (1.9) |
| TTR genotype, n (%) | |
| Variant | 50 (94.3) |
| A97S (p.A117S) | 11 (20.8) |
| V30M (p.V50M) | 6 (11.3) |
| D18N (p.D38N) | 6 (11.3) |
| S23N (p.S43N) | 3 (5.7) |
| V30L (p.V50L) | 3 (5.7) |
| E61K (p.E81K) | 3 (5.7) |
| Other* | 18 (34.0) |
| Wild-type | 3 (5.7) |
| NAC stage, n (%) | |
| I | 39 (73.6) |
| II | 11 (20.8) |
| III | 3 (5.7) |
| NYHA functional classification, n (%) | |
| I | 3 (5.7) |
| II | 43 (81.1) |
| III | 7 (13.2) |
| IV | 0 |
| 6MWT distance, mean (SD), m [n = 40] | 290 (111.1) |
| NT-proBNP concentration, mean (SD), ng/l | 2950 (4312.5) |
| KCCQ-OS score, mean (SD) | 58 (25.8) |
| SF-12 PCS score, mean (SD) | 28 (9.6) |
| SF-12 MCS score, mean (SD) | 43 (11.9) |
| EQ-5D-5L index score, mean (SD) | 0.5 (0.4) |
| EQ-VAS score, mean (SD) | 63 (18.5) |
| Troponin I concentration, mean (SD), µg/l | 0.2 (0.3) |
| LVEF | |
| Mean (SD), % | 53 (10.9) |
| ≤ 40%, n (%) | 10 (18.9) |
| 41–49%, n (%) | 9 (17.0) |
| ≥ 50%, n (%) | 34 (64.2) |
| eGFR, mean (SD), ml/min/1.73 m2 | 117 (37.9) |
6MWT 6-min walk test, eGFR estimated glomerular filtration rate, EQ-5D-5L 5-level EQ-5D, EQ-VAS EQ visual analog scale, KCCQ-OS Kansas City Cardiomyopathy Questionnaire Overall Summary, LVEF left ventricular ejection fraction, MCS Mental Component Summary, NAC National Amyloidosis Centre, NT-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association, PCS Physical Component Summary, SD standard deviation, SF-12 12-item Short Form Survey, TTR transthyretin
*Other variants each identified in ≤ 2 patients: E89K, G53E, A81V, (each in two patients), A19D, A36P, D39Y, E92K, E42G, G47V, H88R, I84N, L55P, S77F, V122I, and c.*3 *11 del (each in one patient)
At baseline, 66% of patients took ≥ 1 cardiac medication of interest, including 38% who took a potassium-sparing diuretic, 42% another diuretic, 23% a beta-blocker, 8% an angiotensin receptor/neprilysin inhibitor, 6% an angiotensin II receptor antagonist, 4% a calcium channel blocker, 2% an angiotensin-converting enzyme inhibitor, 2% a sodium-glucose cotransporter 2 inhibitor, and 36% another cardiac therapy.
Overall, 92% of patients had an ongoing concomitant medical condition. The most frequent were hereditary neuropathic amyloidosis (17%), cardiac failure, chronic gastritis, and hypertension (each in 15%). The majority (96%) of patients took ≥ 1 concomitant medication during the study. No patient had a pacemaker fitted during the study.
Median treatment exposure among all patients was 345 (range 24–418) days, and 87% of patients received ≥ 253 days of treatment. Ten patients discontinued tafamidis treatment during the study, including six due to death and one due to a TEAE. Overall, 43 patients completed the 12 months of planned treatment.
The plasma concentration of tafamidis was evaluated in the 53 enrolled patients. Findings were consistent with those previously reported (Table S2) [18, 19].
Safety
During study treatment and the 28 days following the final dose, 45 (85%) patients reported ≥ 1 TEAE (129 TEAEs in total; Table 2). The nature of the TEAEs was consistent with the known safety profile of tafamidis (Table S3) [4, 6].
Table 2.
Treatment-emergent adverse events
| Patients, n (%) | Treated patients, n = 53 |
|---|---|
| ≥ 1 reported TEAE | 45 (84.9) |
| Considered treatment-related | 3 (5.7) |
| ≥ 1 SAE | 21 (39.6) |
| Considered treatment-related | 0 |
| ≥ 1 severe TEAE | 17 (32.1) |
| Considered treatment-related | 0 |
| Discontinued study due to TEAE* | 1 (1.9) |
| Considered treatment-related | 0 |
| With ≥ 1 dosing interruption due to TEAEs | 3 (5.7) |
| Considered treatment-related | 1 (1.9) |
| With study drug withdrawal due to a TEAE | 1 (1.9) |
| Considered treatment-related | 0 |
| With a TEAE leading to death | 6 (11.3) |
| Considered treatment-related | 0 |
SAE serious treatment-emergent adverse event, TEAE treatment-emergent adverse event
*Except death
Among patients with TEAEs, most reported only mild- or moderate-intensity events (62% of patients with TEAEs; 105 events). There were 24 severe TEAEs reported in 17 patients; those reported in > 1 patient were cardiac failure (n = 6); COVID-19 infection (n = 3); and acute cardiac failure, disease progression, and pneumonia (n = 2 each). A total of 31 SAEs were reported in 47% of patients with TEAEs (Table S4); the most common were cardiac failure (n = 6); acute cardiac failure and COVID-19 infection (n = 3 each); disease progression and pneumonia (n = 2 each). One patient discontinued the study due to a TEAE of hemorrhagic cerebral infarction that was not considered to be treatment-related. Three patients each reported one TEAE that was considered to be treatment-related: abnormal hepatic function (mild severity), gouty arthritis (moderate severity), and hematuria (mild severity). Of these, one patient (with the TEAE of gouty arthritis) had a temporary dosing amendment.
There were six deaths reported; none were considered related to treatment: two were due to disease progression; two due to aggravated heart failure; one due to syncope; and one due to COVID-19 infection, severe pneumonia, and respiratory failure.
Efficacy
After 6 and 12 months of treatment with tafamidis, there were minimal changes from baseline in all efficacy measures, suggesting stabilization of ATTR-CM progression (Fig. 2). At month 12, mean change from baseline in 6MWT distance was 2 m, NT-proBNP concentration − 422 ng/l, troponin I concentration 0 µg/l, KCCQ-OS score − 0.3, SF-12 PCS score 0, SF-12 MCS score 1.5, EQ-5D-5L index score 0, and EQ-VAS score 3. Additionally, mean (SD) change from baseline in eGFR was − 1 ml/min/1.73 m2 (20.4; n = 48) at month 6 and − 4 ml/min/1.73 m2 (22.8; n = 41) at month 12.
Fig. 2.
Change in efficacy measures at 6 and 12 months. 6MWT 6-min walk test, EQ-5D-5L 5-level EQ-5D, EQ-VAS EQ visual analog scale, KCCQ-OS Kansas City Cardiomyopathy Questionnaire Overall Summary, MCS Mental Component Summary, NT-proBNP N-terminal pro-B-type natriuretic peptide, PCS Physical Component Summary, SD standard deviation, SF-12 12-item Short Form Survey
Using clinically relevant thresholds to define deterioration, exploratory analyses showed substantial proportions of patients experienced stability or improvement in each disease measure at months 6 and 12 (Fig. 3). At month 12, 65% of patients showed stability or improvement in 6MWT distance, 95% in NYHA class, 93% in NAC stage, 70% in NT-proBNP concentration, 45% in troponin I concentration, 65% in KCCQ-OS score, 53% in EQ-5D-5L index score, and 77% in EQ-VAS score.
Fig. 3.
Proportion of patients with stability or improvement in efficacy measures. 6MWT 6-min walk test, EQ-5D-5L 5-level EQ-5D, EQ-VAS EQ visual analog scale, KCCQ-OS Kansas City Cardiomyopathy Questionnaire Overall Summary, NAC National Amyloidosis Centre, NT-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association
Discussion
Findings from this post-approval commitment study confirm the safety profile of tafamidis in Chinese patients with ATTR-CM was similar to that previously observed in other international populations [4, 6]. No new safety findings were observed. Further, tafamidis was associated with disease stabilization over the 12-month treatment period in a patient population in which most had ATTRv-CM and mild heart failure.
ATTR-ACT was the largest prospective clinical study of the safety and efficacy of tafamidis completed to date and has informed regulatory approval for the treatment in many countries worldwide, including China [4, 8]. ATTR-ACT included 441 patients treated with either tafamidis (n = 264) or placebo (n = 177) for 30 months [4]. The patient population in this current study versus ATTR-ACT was slightly younger (mean 60 vs. 74 years), all were Asian (vs. 81% White in ATTR-ACT), and the majority had ATTRv-CM (94% vs. 24%) [4]. Although patients in this study had a similar baseline NT-proBNP concentration (~ 3000 ng/l) as those in ATTR-ACT, overall, patients had milder heart failure, as indicated by their NYHA functional classification (class I: 6% vs. 8%; class II: 81% vs. 60%; class III: 13% vs. 32%) and NAC stage (I: 74% vs. 43%; II: 21% vs. 38%; III: 6% vs. 19%) [4, 20]. Despite these findings, patients in this study versus ATTR-ACT had numerically shorter mean 6MWT distance (290 m vs. ~ 350 m) and lower KCCQ-OS score (58 vs. ~ 66) [4]. EQ findings also suggested poorer health status among patients in this study compared with ATTR-ACT [21]. Differences in the populations may be related to the proportion of patients with ATTRv-CM, possibly suggesting polyneuropathy was more prevalent among those enrolled in this study (17% of patients in this study reported hereditary neuropathic amyloidosis at baseline). The most common TTR variant in this study was A97S (p.A117S). TTR variants are heterogeneous in China but the A97S variant is common among Asian patients with ATTR-CM and associated with an early-onset, often mixed phenotype [22–24].
Although there are limited reports of the epidemiology of ATTR-CM in China, current evidence suggests this study population was typical of that diagnosed nationally [24, 25]. As in many regions worldwide, the awareness of ATTR-CM in China is low among non-specialist clinicians. This may contribute to the observed diagnostic delays and the relatively low proportion of patients with ATTRwt-CM in this study [23, 25]. Furthermore, both ATTRwt-CM and ATTRv-CM are thought to be underdiagnosed in China and worldwide [24, 26, 27]. As ATTRwt-CM is more common than ATTRv-CM in most other regions, it is likely that ATTRwt-CM is quite significantly underdiagnosed in China [25–27]. Tafamidis treatment has been shown to be efficacious in patients with ATTRwt-CM or ATTRv-CM [2]. As the value of tafamidis treatment is greatest when started early in the disease course, enhanced screening of at-risk patients could help improve clinical outcomes [6]. Screening relies on the identification of risk factors or ‘red flags.’ Although a number of red flags have been extensively studied in Western populations, these factors may benefit from further evaluation in Asian populations [23, 27].
The overall safety profile of tafamidis in Chinese patients with ATTR-CM was consistent with that seen in those residing in other countries [4, 6]. Tafamidis treatment was well tolerated with few treatment-related TEAEs reported; all were mild or moderate in intensity. Some reported TEAEs reflect that the study occurred during a respiratory disease pandemic. Although real-world evidence on the effectiveness of tafamidis remains limited, findings consistently support the benefit of treatment among regional, national, and international cohorts of patients with ATTR-CM, and with no safety concerns raised [2, 7, 28].
This study found tafamidis to be associated with stability in several measures of disease progression after 6 and 12 months of treatment in Chinese patients, most of whom had ATTRv-CM and mild heart failure symptoms. These findings were consistent with other studies of similar duration [7, 29, 30]. In the multinational ATTR-ACT, efficacy was first evident in patients’ KCCQ-OS score and 6MWT distance at 6 months, and in mortality at 18 months [4]. In a previous post hoc analysis of ATTR-ACT data, patients administered tafamidis meglumine 80 mg or 20 mg had significantly higher odds of numerical improvement (not including stability [no numerical change]) in 6MWT distance, KCCQ-OS score, and NT-proBNP concentration at 12 months compared with those who received placebo. Missing data were imputed as deterioration [5]. In that analysis, the proportion of patients who showed improvement at month 12 was numerically higher in those treated with tafamidis versus placebo for all outcomes assessed: 6MWT distance (31% vs. 19%), KCCQ-OS score (40% vs. 24%), NT-proBNP concentration (37% vs. 19%), Patients’ Global Assessment of overall health (34% vs. 32%), and NYHA classification (12% vs. 10%) [5]. At 30 months, the odds of improvement were significantly higher for patients treated with tafamidis versus placebo in all measures except NYHA classification (odds ratio range 2.9–5.3; P < 0.05; NYHA odds ratio was 2.0; P > 0.05) [5].
The demonstration of efficacy is limited in this study due to the lack of a control arm, small cohort size, and limited duration of follow-up. Findings should be interpreted with caution. Despite this, a strength of the current study is the inclusion of a broader range of disease progression measures than the post hoc analysis of ATTR-ACT, additionally utilizing clinically relevant thresholds to determine stability and improvement [16]. Findings showed high proportions of patients achieved stability and improvement in each measure after 12 months of treatment, including in 65% as assessed by 6MWT distance, 95% by NYHA classification, 93% by NAC stage, 70% by NT-proBNP concentration, 45% by troponin I concentration, 65% by KCCQ-OS score, 53% by EQ-5D-5L index score, and 77% by EQ-VAS score. These findings add to evidence demonstrating the benefit of tafamidis treatment in patients with ATTR-CM, including those of Chinese ethnicity.
Conclusions
In this small multicenter, single-arm, open-label, post-approval commitment study, the safety of tafamidis in Chinese patients with ATTR-CM was consistent with that previously observed in international populations. High proportions of patients showed clinically relevant stability or improvement in efficacy measures at 6 and 12 months of tafamidis treatment. Though it is challenging to evaluate efficacy in this single-arm study, findings support the use of tafamidis for the treatment of Chinese patients with ATTR-CM.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors wish to thank all of the participants in the study. They also acknowledge Franca S. Angeli for contributions to data analysis, interpretation, and development of initial manuscript drafts.
Medical Writing/Editorial Assistance
Medical writing support was provided by Jennifer Bodkin of Engage Scientific Solutions and was funded by Pfizer.
Author Contributions
Zhuang Tian, Daoquan Peng, Wei Ma, Jiangtao Yan, Jian'an Wang, Yida Tang, Wei Jin, Ying Liu, and Shuyang Zhang participated in the collection, analysis and interpretation of the data, reviewed the manuscript drafts for intellectual content, and approved the final version of the manuscript to be published. Caiping Jia, Yingxu Gao, Yankun Gong, Xiaohong Sun, Naihan Chen, and Shuiqing Zhu participated in the design of the study, the analysis and interpretation of the data, reviewed the manuscript drafts for intellectual content, and approved the final version of the manuscript to be published.
Funding
This study was sponsored by Pfizer. The journal’s Rapid Service Fee was funded by Pfizer.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
Declarations
Conflict of Interest
Zhuang Tian, Daoquan Peng, Wei Ma, Jiangtao Yan, Jian'an Wang, Wei Jin, Yida Tang, Ying Liu, and Shuyang Zhang have nothing to disclose. Caiping Jia, Yingxu Gao, Yankun Gong, Xiaohong Sun, Naihan Chen, and Shuiqing Zhu: employees of Pfizer and hold share/share options.
Ethical Approval
The study was conducted according to ethical principles derived from the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council for Harmonisation Good Clinical Practice guidelines. The study followed all local laws and regulations. Study materials were reviewed and approved by Ethics Committees or Institutional Review Boards at each participating center (Table S1; Approval number at the primary site [Peking Union Medical College Hospital]: KS2021004). All patients (or their legal representatives) provided written informed consent.
Footnotes
Prior Presentation: Parts of this work were previously presented at the XIX International Symposium on Amyloidosis (ISA), May 26–30, 2024, Rochester, MN, USA. The abstract has been published (number 13): https://doi.org/10.1080/13506129.2024.2347124.
Zhuang Tian, Daoquan Peng, and Wei Ma contributed equally to this work and are joint first authors.
References
- 1.Ruberg FL, Maurer MS. Cardiac amyloidosis due to transthyretin protein: a review. JAMA. 2024;331:778–91. 10.1001/jama.2024.0442. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Wang J, Chen H, Tang Z, Zhang J, Xu Y, Wan K, et al. Tafamidis treatment in patients with transthyretin amyloid cardiomyopathy: a systematic review and meta-analysis. EClinicalMedicine. 2023;63: 102172. 10.1016/j.eclinm.2023.102172. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Burton A, Castaño A, Bruno M, Riley S, Schumacher J, Sultan MB, et al. Drug discovery and development in rare diseases: taking a closer look at the tafamidis story. Drug Des Dev Ther. 2021;15:1225–43. 10.2147/dddt.S289772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379:1007–16. 10.1056/NEJMoa1805689. [DOI] [PubMed] [Google Scholar]
- 5.Mazen H, Fine NM, Gundapaneni B, Sultan MB, Witteles RM. Improvements in efficacy measures with tafamidis in the tafamidis in transthyretin cardiomyopathy clinical trial. JACC Adv. 2022;1: 100148. 10.1016/j.jacadv.2022.100148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Elliott P, Drachman BM, Gottlieb SS, Hoffman JE, Hummel SL, Lenihan DJ, et al. Long-term survival with tafamidis in patients with transthyretin amyloid cardiomyopathy. Circ Heart Fail. 2022;15: e008193. 10.1161/circheartfailure.120.008193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Ghoneem A, Bhatti AW, Khadke S, Mitchell J, Liu J, Zhang K, et al. Real-world efficacy of tafamidis in patients with transthyretin amyloidosis and heart failure. Curr Probl Cardiol. 2023;48: 101667. 10.1016/j.cpcardiol.2023.101667. [DOI] [PubMed] [Google Scholar]
- 8.Zhi W, Liu M, Yang D, Zhang S, Lu Y, Han J. Analysis of marketed orphan drugs in China. Intractable Rare Dis Res. 2023;12:132–40. 10.5582/irdr.2023.01030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Passantino A, Lagioia R, Mastropasqua F, Scrutinio D. Short-term change in distance walked in 6 min is an indicator of outcome in patients with chronic heart failure in clinical practice. J Am Coll Cardiol. 2006;48:99–105. 10.1016/j.jacc.2006.02.061. [DOI] [PubMed] [Google Scholar]
- 10.Hartmann F, Packer M, Coats AJS, Fowler MB, Krum H, Mohacsi P, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation. 2004;110:1780–6. 10.1161/01.CIR.0000143059.68996.A7. [DOI] [PubMed] [Google Scholar]
- 11.Tsutamoto T, Kawahara C, Nishiyama K, Yamaji M, Fujii M, Yamamoto T, et al. Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure. Am Heart J. 2010;159:63–7. 10.1016/j.ahj.2009.10.022. [DOI] [PubMed] [Google Scholar]
- 12.Greene SJ, Butler J, Spertus JA, Hellkamp AS, Vaduganathan M, DeVore AD, et al. Comparison of New York Heart Association class and patient-reported outcomes for heart failure with reduced ejection fraction. JAMA Cardiol. 2021;6:522–31. 10.1001/jamacardio.2021.0372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Yang Z, Busschbach J, Liu G, Luo N. EQ-5D-5L norms for the urban Chinese population in China. Health Qual Life Outcomes. 2018;16:210. 10.1186/s12955-018-1036-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ware J, Kosinski M, Keller S. SF-12: how to score the SF-12 Physical and Mental Health Summary Scales. Boston: The Health Institute, New England Medical Center; 1995. [Google Scholar]
- 15.Lam CL, Tse EY, Gandek B. Is the standard SF-12 health survey valid and equivalent for a Chinese population? Qual Life Res. 2005;14:539–47. 10.1007/s11136-004-0704-3. [DOI] [PubMed] [Google Scholar]
- 16.Garcia-Pavia P, Bengel F, Brito D, Damy T, Duca F, Dorbala S, et al. Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J Heart Fail. 2021;23:895–905. 10.1002/ejhf.2198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39:2799–806. 10.1093/eurheartj/ehx589. [DOI] [PubMed] [Google Scholar]
- 18.Huh Y, Riley S, Harnisch L, Nicholas T. Population pharmacokinetic modelling and simulation of tafamidis in healthy subjects and patients with transthyretin amyloidosis. Br J Clin Pharmacol. 2021;87:3574–87. 10.1111/bcp.14773. [DOI] [PubMed] [Google Scholar]
- 19.Lockwood PA, Le VH, O’Gorman MT, Patterson TA, Sultan MB, Tankisheva E, et al. The bioequivalence of tafamidis 61-mg free acid capsules and tafamidis meglumine 4 × 20-mg capsules in healthy volunteers. Clin Pharmacol Drug Dev. 2020;9:849–54. 10.1002/cpdd.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Sperry BW, Sultan MB, Gundapaneni B, Tai SS, Witteles RM. Effect of tafamidis on renal function in patients with transthyretin amyloid cardiomyopathy in ATTR-ACT. JACC CardioOncol. 2024;6:300–6. 10.1016/j.jaccao.2024.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hanna M, Damy T, Grogan M, Stewart M, Gundapaneni B, Patterson TA, et al. Impact of tafamidis on health-related quality of life in patients with transthyretin amyloid cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Am J Cardiol. 2021;141:98–105. 10.1016/j.amjcard.2020.10.066. [DOI] [PubMed] [Google Scholar]
- 22.Hsueh HW, Chao CC, Chang K, Jeng YM, Katsuno M, Koike H, et al. Unique phenotypes with corresponding pathology in late-onset hereditary transthyretin amyloidosis of A97S vs. V30M. Front Aging Neurosci. 2021;13:786322. 10.3389/fnagi.2021.786322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lin W, Chattranukulchai P, Lee AP, Lin YH, Yu WC, Liew HB, et al. Clinical recommendations to diagnose and monitor patients with transthyretin amyloid cardiomyopathy in Asia. Clin Cardiol. 2022;45:898–907. 10.1002/clc.23882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yongsheng Z, Chong S, Bingyou L, Jianian H, Haofeng C, Chongbo Z, et al. Prevalence estimation of ATTRv in China based on genetic databases. Front Genet. 2023;14:1126836. 10.3389/fgene.2023.1126836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.He S, Tian Z, Guan H, Li J, Fang Q, Zhang S. Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy. Orphanet J Rare Dis. 2019;14:251. 10.1186/s13023-019-1235-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR epidemiology, genetics, and prognostic factors. Methodist Debakey Cardiovasc J. 2022;18:17–26. 10.14797/mdcvj.1066. [DOI] [PMC free article] [PubMed]
- 27.Wang CC, Chang WT, Lin YH, Tzeng BH, Chao TH, Hung CL, et al. 2023 expert consensus of the Taiwan Society of Cardiology on the diagnosis and treatment of cardiac amyloidosis. Acta Cardiol Sin. 2023;39:511–43. 10.6515/acs.202307_39(4).20230610a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7:709–16. 10.1016/j.jchf.2019.04.010. [DOI] [PubMed] [Google Scholar]
- 29.Ochi Y, Kubo T, Baba Y, Sugiura K, Miyagawa K, Noguchi T, et al. Early experience of tafamidis treatment in Japanese patients with wild-type transthyretin cardiac amyloidosis from the Kochi amyloidosis cohort. Circ J. 2022;86:1121–8. 10.1253/circj.CJ-21-0965. [DOI] [PubMed] [Google Scholar]
- 30.Rettl R, Duca F, Binder C, Dachs TM, Cherouny B, Camuz Ligios L, et al. Impact of tafamidis on myocardial strain in transthyretin amyloid cardiomyopathy. Amyloid. 2023;30:127–37. 10.1080/13506129.2022.2131385. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.