Tafamidis
(Synonyms: 氯苯唑酸) 目录号 : GC37719
A TTR kinetic stabilizer
Cas No.:594839-88-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Tafamidis is a kinetic stabilizer of transthyretin (TTR) that prevents amyloidogenesis by wild-type and mutant TTRs.1 It binds to TTR with negative cooperativity (Kd1 = 3 nM; Kd2 = 278 nM) to stabilize the TTR dimer-dimer interface and inhibit tetrameric dissociation. Tafamidis stabilizes wild-type and clinically significant V30M and V122I mutant TTR amyloidogenic homotetramers (EC50s = 2.7-3.2 μM) under fibril-promoting, denaturing, and physiological conditions in vitro. It stabilizes TTR heterotetramers containing wild-type and mutant subunits ex vivo in human plasma derived from patients carrying V30M or V1221 mutations when used at a concentration of 7.2 μM. Formulations containing tafamidis have been used for the treatment of familial amyloid polyneuropathy.2
1.Bulawa, C.E., Connelly, S., Devit, M., et al.Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascadeProc. Natl. Acad. Sci. USA109(24)9629-9634(2012) 2.Scott, L.J.Tafamidis: A review of its use in familial amyloid polyneuropathyDrugs74(12)1371-1378(2014)
| Cas No. | 594839-88-0 | SDF | |
| 别名 | 氯苯唑酸 | ||
| Canonical SMILES | O=C(C1=CC=C2N=C(C3=CC(Cl)=CC(Cl)=C3)OC2=C1)O | ||
| 分子式 | C14H7Cl2NO3 | 分子量 | 308.12 |
| 溶解度 | DMSO: 37.5 mg/mL (121.71 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2455 mL | 16.2274 mL | 32.4549 mL |
| 5 mM | 0.6491 mL | 3.2455 mL | 6.491 mL |
| 10 mM | 0.3245 mL | 1.6227 mL | 3.2455 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy
N Engl J Med 2018 Sep 13;379(11):1007-1016.PMID:30145929DOI:10.1056/NEJMoa1805689.
Background: Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. Methods: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of Tafamidis, 20 mg of Tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Results: In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received Tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, Tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. Conclusions: In patients with transthyretin amyloid cardiomyopathy, Tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).
Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy
Circ Heart Fail 2022 Jan;15(1):e008193.PMID:34923848DOI:10.1161/CIRCHEARTFAILURE.120.008193.
Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of Tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same Tafamidis dose or, if previously treated with placebo, randomized (2:1) to Tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to Tafamidis free acid 61 mg (bioequivalent to Tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with Tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to Tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous Tafamidis group (n=176) and 57.1 months in the placebo to Tafamidis group (n=177). There were 79 (44.9%) deaths with continuous Tafamidis and 111 (62.7%) with placebo to Tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous Tafamidis (versus placebo to Tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06). Conclusions: In the LTE, patients initially treated with Tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.
Efficacy and safety of Tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study
Eur J Heart Fail 2021 Feb;23(2):277-285.PMID:33070419DOI:10.1002/ejhf.2027.
Aims: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose. Methods and results: In ATTR-ACT, patients were randomized (2:1:2) to Tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to Tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose Tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with Tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with Tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with Tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with Tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both Tafamidis doses were comparable to placebo. Conclusion: Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support Tafamidis 80 mg as the optimal dose. Clinical trial registration: ClinicalTrials.gov NCT01994889; NCT02791230.
Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial
Neurology 2012 Aug 21;79(8):785-92.PMID:22843282DOI:10.1212/WNL.0b013e3182661eb1.
Objectives: To evaluate the efficacy and safety of 18 months of Tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received Tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the Tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more Tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and Tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored Tafamidis. TTR was stabilized in 98% of Tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, Tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg Tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with Tafamidis, which was well tolerated over 18 months.
Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy
Ann Pharmacother 2020 May;54(5):470-477.PMID:31735059DOI:10.1177/1060028019888489.
Objective: To review the pharmacology, efficacy, and safety of the selective transthyretin inhibitor Tafamidis for transthyretin amyloid cardiomyopathy (ATTR-CM). Data Sources: A PubMed (1966 to October 2019) and ClinicalTrials. gov search was conducted using the keywords Tafamidis, Fx-1006A, Vyndaqel, and Vyndamax. Additional articles were identified from references. Study Selection and Data Extraction: We included English-language clinical studies evaluating the pharmacology, efficacy, or safety of Tafamidis in humans for ATTR-CM. Data Synthesis: Tafamidis binds to the thyroxine-binding sites of the transthyretin tetramer and inhibits its dissociation into monomers, which is the rate-limiting step in the amyloidogenic process. Treatment with Tafamidis was significantly associated with a significant reduction in mortality, lowered cardiovascular-related hospitalizations, less functional decline, and improved transthyretin stabilization compared with placebo. Additionally, Tafamidis was found to have fewer adverse events, with no difference found compared with placebo. Relevance to Patient Care and Clinical Practice: Historically, symptomatic management for ATTR-CM was the only option, and the treatment of the underlying disease was limited to liver or heart transplantation. Tafamidis is the first medication approved for the treatment of ATTR-CM and the only medication that showed a reduction in all-cause mortality and cardiovascular-related hospitalizations in patients with amyloidosis. However, the role of Tafamidis in patients with the New York Heart Association class III/IV heart failure or mutated transthyretin remains unclear. Conclusion: Tafamidis is an effective and safe oral medication for the treatment of the cardiomyopathy of transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.