Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

Figures & data

Figure 1 The TTR amyloidogenic cascade. When destabilized by TTR pathogenic variants, the tetrameric protein TTR dissociates into monomers that misfold and misassemble into aggregates, including amyloid fibrils associated with transthyretin amyloidosis.

Abbreviation: TTR, transthyretin.

Figure 2 Timeline of the major translational milestones in the development of the TTR kinetic stabilizer tafamidis. Superscript numbers refer to references.

Abbreviations: ATTR-ACT, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; ATTR, amyloidosis, transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTR-PN, transthyretin amyloid polyneuropathy; qd, once daily; THAOS, Transthyretin Amyloidosis Outcomes Survey; TTR, transthyretin.

Table 1 Summary of Methods and Results from Phase 2/3 Clinical Studies of Tafamidis in Patients with ATTR-PN and ATTR-CM

Study/Design/Duration	Major Eligibility Criteria	Population/Baseline Characteristics	Efficacy Outcomes
Merlini et al, 2013^Citation95 Open-label, single-treatment-arm 12 mo	Biopsy-confirmed amyloidosis Non-Val30Met (p.Val50Met), non-Val122Ile (p.Val142Ile) TTR pathogenic variant Neuropathy (autonomic and/or peripheral) and/or cardiomyopathy (KPS ≥50)	Tafamidis, n = 21 Age, y, median (range): 64.3 (56.9–70.8) NIS-LL score, mean (SD): 27.6 (24.7) TQoL, mean (SD): 47.8 (35.1)	TTR tetramer stabilization, % pts (95% CI): Wk 6: 94.7 (74.0–99.9) Mo 12: 100 (80.5–100) NIS-LL score, change, mean (SD), BL to mo 12: 2.7 (6.2) [95% CI: –0.4 to 5.8] TQoL, change, mean (SD), BL to mo 12: 0.1 (18.0) [95% CI: –8.9 to 9.0]
Coelho et al, 2012^Citation60 Randomized, placebo-controlled, double-blind 18 mo	Biopsy-confirmed amyloidosis Val30Met (p.Val50Met) TTR pathogenic variant Neuropathy (autonomic or peripheral) and cardiomyopathy (KPS ≥50)	ITT Tafamidis, n = 64 Placebo, n = 63 EE (n = 87) Tafamidis, n = N/A Placebo, n = N/A Age, y, median (range): Tafamidis: 35.5 (31–44) Placebo: 34.0 (29–47) NIS-LL score, mean (SD): Tafamidis: 8.4 (11.4) Placebo: 11.4 (13.5) TQoL, mean (SD): Tafamidis: 27.3 (24.2) Placebo: 30.8 (26.7)	TTR tetramer stabilization, % pts (95% CI): Wk 8: Tafamidis: 98.4 (95.3–100) Placebo: 6.7 (0.4–13.0); P < 0.0001 Mo 18: Tafamidis: 97.9 (93.9–100) Placebo: 0.0 (0–0); P < 0.0001 NIS-LL score, <2-point increase, BL to mo 18, % pts (95% CI): ITT population: Tafamidis: 45.3 (33.1–57.5) Placebo: 29.5 (18.1–41.0); P = 0.068 EE population: Tafamidis: 60.0 (45.7–74.3) Placebo: 38.1 (23.4–52.8); P = 0.041 TQoL, LS mean change (95% CI), BL to mo 18, points: ITT population: Tafamidis: 2.0 (–2.6 to 6.6) Placebo: 7.2 (2.6–11.9); P = 0.116 EE population: Tafamidis: 0.1 (–5.8 to 6.0) Placebo: 8.9 (2.8–15.0); P = 0.045
Maurer et al, 2015^Citation104 Open-label, single-treatment-arm 12 mo	Val122Ile (p.Val142Ile) or wild-type ATTR-CM confirmed by: Amyloid deposits on cardiac and non-cardiac biopsy Left ventricular wall thickness >12 mm on echocardiography	Tafamidis, n = 35 Age, y, median (range): 76.7 (68.7–86.5) TTR genotype Val122Ile (p.Val142Ile), n = 4 Wild-type, n = 31 NYHA classification, % pts: Class I: 16.1 Class II: 80.6 Class III: 3.2 Duration of symptoms, mo, median (range): 55.6 (6.4–348.9) Age at symptom onset, y, median (range): 74.0 (62.0–85.0)	TTR tetramer stabilization, % pts (95% CI): Wk 6: 96.8 (83.3–99.9) Mo 6: 90.0 (73.5–97.9) Mo 12: 89.3 (71.8–97.7) Preserved NYHA classification status at mo 12, n/N (%): 20/28 (71.4) Clinical progression at mo 12, n/N (%): 15/31 (48.4)
Maurer et al, 2015^Citation19 (ATTR-ACT) Randomized, placebo-controlled, double-blind 30 mo	Variant or wild-type ATTR-CM confirmed by: Amyloid deposits on cardiac and non-cardiac biopsy TTR precursor protein on immunohistochemical analysis, scintigraphy, or mass spectrometry (wild-type ATTR-CM) Cardiac involvement confirmed by: Left ventricular wall thickness >12 mm on echocardiography History of heart failure NT-proBNP level ≥600 pg/mL 6-min walk-test distance >100 m	mITT Tafamidis (pooled), n = 264 Placebo, n = 177 Age, y, median (range): Tafamidis: 75 (46–88) Placebo: 74 (51–89) TTR genotype ATTRv Tafamidis, n = 63 Placebo, n = 43 Wild-type, n = 31 Tafamidis, n = 201 Placebo, n = 134 NYHA classification, % pts Class I Tafamidis: 9.1 Placebo: 7.3 Class II Tafamidis: 61.4 Placebo: 57.1 Class III Tafamidis: 29.5 Placebo: 35.6	Hierarchical combination of all-cause mortality and frequency of CV-related hospitalization (primary analysis) Tafamidis superior to placebo (P < 0.001) Pts alive at mo 30, % Tafamidis: 70.5 Placebo: 57.1 Pts with CV-related hospitalizations, % Tafamidis: 52.3 Placebo: 60.5 CV-related hospitalizations, no. per y Tafamidis: 0.48 Placebo: 0.70

Abbreviations: ATTR-ACT, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTR-PN, transthyretin amyloid polyneuropathy; ATTRv, variant transthyretin amyloidosis; BL, baseline; CI, confidence interval; CV, cardiovascular; EE, efficacy evaluable; ITT, intent-to-treat; KPS, Karnofsky Performance Status score; LS, least-squares; mITT, modified intent-to-treat; mo, month; N/A, not available; NIS-LL, Neuropathy Impairment Score in the Lower Limbs; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; pts, patients; SD, standard deviation; TQoL, Total Quality of Life score from the Norfolk Quality of Life-Diabetic Neuropathy questionnaire; TTR, transthyretin; wk, week; y, year.

Table 2 Adverse Events Reported by Treatment Group in Pivotal Randomized Controlled Trials of Tafamidis in (A) ATTR-PN⁶⁰ and (B) ATTR-CM (ATTR-ACT)¹⁹

(A) ATTR-PN
Adverse Event	No. of Patients (%)
	Tafamidis (n = 65)		Placebo (n = 63)
≥1 adverse event	60 (92.3)		61 (96.8)
≥1 serious adverse event	6 (9.2)		5 (7.9)
Discontinued treatment due to adverse event	4 (6.2)		3 (4.8)
(B) ATTR-CM (ATTR-ACT)
Adverse Event		Pooled Tafamidis (n = 267)	Placebo (n = 177)
≥1 adverse event		260 (98.5)	175 (98.9)
≥1 serious adverse event		199 (75.4)	140 (79.1)
≥1 severe adverse event		164 (62.1)	114 (64.4)
Discontinued treatment due to adverse event		56 (21.2)	51 (28.8)
Temporarily discontinued due to adverse event		53 (20.1)	46 (26.0)

Note: All adverse events were treatment emergent (all causality).

Abbreviations: ATTR-ACT, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTR-PN, transthyretin amyloid polyneuropathy.

Figure 3 (A) Proportion of NIS-LL responders^a at month 18 in the ITT^b and EE populations. (B) LS mean (±SE) change from baseline to month 18 in the TQoL score from the Norfolk QoL-DN in the ITT^b and EE populations. (C) LS mean (±SE) changes from baseline at months 6, 12, and 18 in the NIS-LL in the ITT population.^90,97 aResponse = increase of <2 in the NIS-LL overall score. ^bProportion of NIS-LL responders and LS mean change from baseline in TQoL score at month 18 in the ITT population were coprimary endpoints of the study.

Abbreviations: EE, efficacy evaluable; ITT, intent-to-treat; LS, least-squares; NIS-LL, Neuropathy Impairment Score in the Lower Limbs; Norfolk QoL-DN, Norfolk Quality of Life-Diabetic Neuropathy questionnaire; SE, standard error; TQoL, Total Quality of Life score from the Norfolk QoL-DN.

Figure 4 All-cause mortality and frequency of cardiovascular-related hospitalizations (primary efficacy analysis) in patients with ATTR-CM treated with tafamidis versus placebo in ATTR-ACT.¹⁹ The combined primary endpoint was hierarchically assessed using the Finkelstein–Schoenfeld method. P < 0.001.

Abbreviations: ATTR-ACT, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; ATTR-CM, transthyretin amyloid cardiomyopathy.

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