An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

Figures & data

Figure 1. Standard pairwise Bucher method used to estimate the relative efficacy of patisiran vs. tafamidis from baseline to 18 months.

Table 1. Overview of trials included in the analysis.

	APOLLO	Fx-005
Primary publication	Adams et al. [16]	Coelho et al. [9]^a
Intervention	Patisiran	Tafamidis
Comparator	Placebo	Placebo
Phase	III	II/III
Key inclusion criteria	Age 18–85 years TTR mutation hATTR amyloidosis with sensorimotor peripheral neuropathy diagnosis NIS 5–130 PND score ≤IIIb Adequate liver and renal function	Age 18–75 years V30M TTR mutation hATTR amyloidosis with peripheral or autonomic neuropathy Biopsy-confirmed amyloid deposits Karnofsky performance status ≥50 Adequate liver and renal function
Duration	18 months	18 months
Primary outcomes	Change in mNIS+7	NIS-LL response Change in Norfolk QoL-DN
Select other outcomes	Change in Norfolk QoL-DN (secondary) Change in mBMI (secondary)	Change in NIS-LL (secondary) Change in mBMI (secondary)
Key findings, LS mean difference (study drug vs. placebo)^b	mNIS+7: −34.0 points^c Norfolk QoL-DN: −21.1 points^c NIS-LL: −11.2 points^c,d mBMI: +115.7 kg/m^2 × g/dL^c	NIS-LL response: 45.3% (tafamidis) vs. 29.5% (placebo) Norfolk QoL-DN: −5.2 points NIS-LL: −2.7 points^c mBMI: +73.1 kg/m^2 × g/dL^c

^aFor this analysis, NIS-LL data for the Fx-005 trial were extracted from Keohane et al. [28]; all other data were extracted from the primary publication.

^bAPOLLO results taken from the modified intent-to-treat population; Fx-005 results taken from the intent-to-treat population.

^cp < 0.05.

^dChange in NIS-LL was derived from the components of NIS+7; NIS-LL response was calculated post hoc.

hATTR: hereditary ATTR amyloidosis; LS: least-squares; mBMI: modified body mass index; mNIS+7: modified Neuropathy Impairment Score +7;

NIS: Neuropathy Impairment Score; NIS-LL: Neuropathy Impairment Score-Lower Limbs; Norfolk QoL-DN: Norfolk Quality of Life-Diabetic Polyneuropathy;

PND: polyneuropathy disability; TTR, transthyretin; V30M, valine to methionine mutation at amino acid 30.

Table 2. Baseline demographics and disease characteristics of patients in the APOLLO and Fx-005 trials.

	Patisiran APOLLO (n = 225)	Tafamidis Fx-005 (n = 125)
Age, mean (years)
Treatment arm	59.6	39.8
Placebo arm	62.2	38.4
Sex, male (%)
Treatment arm	73.6	50.0
Placebo arm	75.3	42.6
V30M (%)
Treatment arm	37.8	100.0
Placebo arm	51.9	100.0
Disease duration, mean (SD) (months)
Treatment arm	28.7 (39.1)	47.0 (48.4)
Placebo arm	31.2 (38.9)	34.7 (32.9)
FAP Stage 1 patients (%)
Treatment arm	45.3	100.0^a
Placebo arm	48.1	100.0^a
FAP Stage 2 patients (%)
Treatment arm	54.7	0
Placebo arm	50.6	0
FAP Stage 3 patients (%)
Treatment arm	0.0	0.0
Placebo arm	1.3	0.0
Prior hATTR amyloidosis pharmacotherapy (%)
Treatment arm	52.7	0.0
Placebo arm	53.2	0.0

^aPresumed figure based on: Tafamidis for Transthyretin Familial Polyneuropathy (TTR-FAP): Evidence Review Group assessment of manufacturer submission for the Advisory Group for National Specialised Services. 2013.

FAP: familial amyloidotic polyneuropathy; hATTR amyloidosis: hereditary transthyretin-mediated amyloidosis; SD: standard deviation; V30M: valine to methionine mutation at amino acid 30.

Table includes data from Adams et al. [16] and Coelho. et al. [9].

Figure 2. PRISMA diagram of literature search and inclusion of randomized controlled trials (RCTs) of tafamidis.

SLR: systematic literature review.

Table 3. Baseline measures of neuropathy, QoL, and nutritional status for the Fx-005 ITT population and APOLLO base-case and sensitivity analyses populations.

Trial	Population	Treatment	No. of patients	NIS-LL, mean (SD)	Norfolk QoL-DN, mean (SD)	mBMI, mean (SD)
Fx-005	ITT	Tafamidis	64	8.4 (11.4)	27.3 (24.2)	1004.6 (165.2)
		Placebo	61	11.4 (13.5)	30.8 (26.7)	1011.5 (212.9)
APOLLO (base-case analysis)	FAP Stage 1	Patisiran	67	23.0 (13.5)	45.5 (27.0)	1021.4 (179.8)
		Placebo	37	20.9 (11.7)	43.7 (21.2)	1027.4 (219.0)
APOLLO (sensitivity analyses)	mITT	Patisiran	148	36.8 (18.2)	59.6 (28.2)	969.7 (210.5)
		Placebo	77	34.8 (17.8)	55.5 (24.3)	989.9 (214.2)
	FAP Stage 1 and V30M	Patisiran	24	29.0 (13.6)	51.4 (29.4)	1066.2 (164.1)
		Placebo	20	23.2 (13.5)	38.8 (18.7)	1046.6 (237.3)
	FAP Stage 1 and treatment naïve	Patisiran	31	23.1 (13.5)	49.4 (29.4)	1049.4 (214.3)
		Placebo	17	15.7 (9.0)	43.4 (21.5)	1039.0 (249.8)

FAP: familial amyloidotic polyneuropathy; ITT: intent-to-treat; mBMI: modified body mass index; mITT: modified intent-to-treat; NIS-LL: Neuropathy Impairment Score-Lower Limbs; Norfolk QoL-DN: Norfolk Quality of Life-Diabetic Neuropathy questionnaire; SD: standard deviation; V30M: valine to methionine mutation at amino acid 30.

Table includes data from Adams et al. [16] and Coelho. et al. [9].

Figure 3. Results of the indirect treatment comparison of Fx-005 ITT population and APOLLO base-case and sensitivity analyses populations for (a) change in mean NIS-LL score; (b) change in mean NIS-LL response; (c) change in mean Norfolk QoL-DN; and (d) change in mean mBMI score. CI: confidence interval; FAP: familial amyloidotic polyneuropathy; mBMI: modified body mass index; mITT: modified intent-to-treat; NIS-LL: Neuropathy Impairment Score-Lower Limb; Norfolk QoL-DN: Norfolk Quality of Life-Diabetic Neuropathy questionnaire.

Table 4. Key safety outcomes in the APOLLO and Fx-005 trials.

	APOLLO		Fx-005
Patients, %	Patisiran arm	Placebo arm	Tafamidis arm	Placebo arm
Any AE	96.6	97.4	92.3	96.8
Any SAE	36.5	40.3	9.2	7.9
AE leading to discontinuation	4.7	14.3	6.2	4.8
Deaths	4.7	7.8	3.1	4.8

AE: adverse event; SAE: serious adverse event.

Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21.

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Coelho T, Maia LF, Da Silva AM, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785–792.

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Keohane D, Schwartz J, Gundapaneni B, et al. Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial. Amyloid. 2017;24(1):30–36.

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