Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study

Figures & data

Figure 1. Patient disposition. AE: adverse event; OLE: open-label extension.

Table 1. Demographics and disease characteristics at parent study baseline of patients with NfL measurements.

	APOLLO-placebo (n = 47)	APOLLO-patisiran (n = 111)	Phase II OLE-patisiran (n = 26)	All patients (n = 184)
Age in years, median (IQR)	64 (16)	63 (17)	64.5 (29)	64 (18)
Male, n (%)	36 (76.6)	85 (76.6)	17 (65.4)	138 (75.0)
Years from ATTRv amyloidosis diagnosis to first parent study dose, median (IQR)	1.22 (3.70)	1.75 (2.40)	2.45 (1.50)	1.87^a (2.51)
V30M genotype, n (%)	24 (51.1)	47 (42.3)	20 (76.9)	91 (49.5)
mNIS+7^b, median (IQR)	71.50 (52.75)	77.50 (64.50)	47.75 (45.63)	72.50 (57.94)
Norfolk QOL-DN^c, mean (SD)	53.6 (23.13)	59.8 (27.23)	—^d	58.0 (26.18)^e
PND score, n (%)
I: Preserved walking, sensory disturbances	11 (23.4)	24 (21.6)	15 (57.7)	50 (27.2)
II: Impaired walking but walk without stick/crutch	17 (36.2)	32 (28.8)	8 (30.8)	57 (31.0)
IIIA/B: Walk with one or two sticks/crutches	13 (27.7)	33 (29.7)	2 (7.7)	48 (26.1)
IV: Confined to wheelchair/bedridden	6 (12.8)	22 (19.8)	1 (3.8)	29 (15.8)

^an = 184; ^bmNIS+7 range is 0–304, higher score reflects greater impairment; ^cNorfolk QOL-DN range is –4 to 136, higher score reflects worsening QOL; ^dThe phase II OLE study did not assess Norfolk QOL-DN; ^en = 157. ATTRv: hereditary transthyretin (v for variant); IQR: interquartile range; mNIS+7: modified Neuropathy Impairment Score + 7; NfL: neurofilament light chain; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy questionnaire; OLE: open-label extension; PND: polyneuropathy disability; SD: standard deviation.

Figure 2. Integrated changes in mNIS+7 during the parent studies and the Global OLE. (A) APOLLO. (B) Phase II OLE. Data are integrated change from parent study baseline in mNIS+7. (C) Integrated change in Norfolk QOL-DN score during the parent studies and the Global OLE from the APOLLO study. ^aFor APOLLO patients initiating alternative ATTRv amyloidosis treatment, mNIS+7 assessments after alternative treatment are treated as missing. The APOLLO-placebo arm began patisiran treatment at the start of the Global OLE. APOLLO mNIS+7 parent study baseline (mean (SD)): APOLLO-placebo = 74.6 (37.0); APOLLO-patisiran = 80.9 (41.5) [6]. ^bPhase II OLE mNIS+7 parent study baseline (mean (SD)): 53.0 (35.6). ^cData are integrated change from parent study baseline in Norfolk QOL-DN. The APOLLO-placebo arm began patisiran treatment at the start of the Global OLE. APOLLO Norfolk QOL-DN parent study baseline (mean (SD)): APOLLO-placebo = 55.5 (24.3); APOLLO-patisiran = 59.6 (28.2) [6]. ATTRv: hereditary transthyretin (v for variant); BL: baseline; CI: confidence interval; mNIS+7: modified Neuropathy Impairment Score + 7; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy questionnaire; OLE: open-label extension; SD: standard deviation.

Table 2. Change in PND score from parent study baseline and Global OLE enrolment to Global OLE 24 months.

	From parent study baseline			From Global OLE baseline
Assessment, n (%)	APOLLO-placebo (n = 77)	APOLLO-patisiran (n = 148)	Phase II OLE-patisiran (n = 27)	APOLLO-placebo (n = 49)	APOLLO-patisiran (n = 137)	Phase II OLE-patisiran (n = 25)
PND score
Improved	0	12 (8.1)	2 (7.4)	4 (8.2)	12 (8.8)	2 (8.0)
No change	11 (14.3)	67 (45.3)	16 (59.3)	24 (49.0)	67 (48.9)	16 (64.0)
Worsened	23 (29.9)	38 (25.7)	7 (25.9)	6 (12.2)	38 (27.7)	7 (28.0)
Missing	43 (55.8)	31 (20.9)	2 (7.4)	15 (30.6)	20 (14.6)	0

OLE: open-label extension; PND: polyneuropathy disability.

Figure 3. Integrated change in NfL levels during the parent studies and the Global OLE. (A) APOLLO. (B) Phase II OLE. Data are integrated change from parent study baseline in NfL level. The APOLLO-placebo arm began patisiran treatment at the start of the Global OLE. BL: baseline; CI: confidence interval; NfL: neurofilament light chain; OLE: open-label extension.

Table 3. Mean NfL levels (SD) in the APOLLO and Global OLE studies.

	APOLLO-placebo					APOLLO-patisiran
Timepoint	n	Mean (SD) (pg/mL)	Mean change from APOLLO baseline (%)	Mean change from Global OLE baseline (%)^a	Time on patisiran	n	Mean (SD) (pg/mL)	Mean change from APOLLO baseline (%)	Time on patisiran
APOLLO baseline	47	63.2 (32.2)	0	—	—	111	72.0 (45.7)	0	—
APOLLO day 21	46	66.9 (33.0)	9.3	—	—	104	73.8 (47.9)	6.2	21 Days
APOLLO day 126	47	82.2 (34.0)^b	41.6	—	—	106	51.6 (29.4)^c	–21.4	126 Days
APOLLO month 18/Global OLE baseline	47	99.5 (60.0)^b	67.8	—	—	111	48.8 (29.9)^c	–24.4	18 Months
Global OLE month 12	28	64.0 (51.2)^d	–12.0	–34.9	12 Months	76	50.1 (31.9)^c	–20.0	30 Months
Global OLE month 24	24	42.8 (24.6)^b,d	–23.6	–41.8	24 Months	87	44.1 (27.6)^c	–27.5	42 Months

^aThe APOLLO-placebo arm began patisiran treatment at the start of the Global OLE.

^bStatistically significant difference compared with APOLLO-placebo parent study baseline.

^cStatistically significant difference compared with APOLLO-patisiran parent study baseline.

^dStatistically significant difference compared with APOLLO-placebo Global OLE baseline.

NfL: neurofilament light chain; OLE: open-label extension; SD: standard deviation.

Table 4. Mean NfL levels (SD) in the phase II OLE and Global OLE studies.

Timepoint	n	Mean (SD) (pg/mL)	Mean change from phase II OLE baseline (%)	Months on patisiran
Phase II OLE baseline	26	32.9 (14.4)	0	—
Phase II OLE month 9	25	24.5 (16.7)^a	–22.6	9
Phase II OLE month 18	25	26.1 (16.2)^a	–21.1	18
Phase II OLE month 24/Global OLE baseline^b	25	29.6 (19.9)	–11.7	24
Global OLE month 12	23	26.0 (16.3)	–14.3	36
Global OLE month 24	23	23.0 (12.9)^a	–21.9	48

^aStatistically significant difference compared with phase II parent study baseline.

^bPatients in the phase II OLE study continued with patisiran treatment at the start of the Global OLE study.

NfL: neurofilament light chain; OLE: open-label extension; SD: standard deviation.

Table 5. Exposure and overall safety in the Global OLE.

Patients with ≥1 event	APOLLO-placebo (n = 49)	APOLLO-patisiran (n = 137)	Phase II OLE-patisiran (n = 25)	Global OLE all patients (n = 211)
Exposure in Global OLE
Mean exposure, months (range)	24.5 (1.2–45.6)	29.9 (1.3–50.8)	42.3 (34.8–46.2)	30.1 (1.2–50.8)
Cumulative no. of doses	1694	5838	1487	9019
Safety
AE	48 (98.0)	136 (99.3)	25 (100.0)	209 (99.1)
Severe AE	27 (55.1)	42 (30.7)	7 (28.0)	76 (36.0)
SAE	34 (69.4)	59 (43.1)	11 (44.0)	104 (49.3)
IRR	13 (26.5)	15 (10.9)	3 (12.0)	31 (14.7)
AE leading to study withdrawal	18 (36.7)	12 (8.8)	0	30 (14.2)
Death^a	16 (32.7)	13 (9.5)	0	29 (13.7)

Data are n (%) unless otherwise stated.

^aAll deaths summarized, including deaths due to AEs that are not treatment emergent. Data as of interim cut-off 7 October 2019. Exposure extends 21 days past the final dose of patisiran. AE: adverse event; IRR: infusion-related reaction; OLE: open-label extension; SAE: serious adverse event.

Table 6. Integrated exposure-adjusted mortality rates in the parent and Global OLE studies.

	APOLLO-placebo (n = 49)	APOLLO-patisiran (n = 148)	Phase II OLE-patisiran (n = 27)	All patients^a (n = 224)
Mean exposure since first dose of patisiran in any study, months (range)	24.6 (1.2–45.6)	45.7 (0.03–69.5)	64.2 (21.6–71.1)	43.3 (0.03–71.1)
Cumulative number of doses	1694	9578	2422	13,694
Total patient-years of exposure^b	100.3	563.7	144.5	808.5
Deaths^c, n (%)	16 (32.7)	17 (11.5)	2 (7.4)	35 (15.6)
Exposure-adjusted mortality rate (95% CI), deaths per 100 patient-years^d	16.0 (9.4, 25.1)	3.0 (1.8, 4.7)	1.4 (0.2, 4.3)	4.3 (3.1, 5.9)

^aThe integrated safety population encompasses all patients exposed to patisiran. Data are recorded from first patisiran dose in either the APOLLO, phase II OLE, or Global OLE studies until data cut-off (7 October 2019).

^bFor each patient, exposure in years is defined as: (last dose date of study drug – first dose date of study drug + 91)/365.25. Total patient-year exposure time is calculated as the sum of each patient’s time using minimum of exposure in years or follow-up in years.

^cOnly deaths from the period of first dose of patisiran to 90 days after last dose are included.

^dExposure-adjusted mortality rate is calculated as: (total number of deaths/total patient-years of exposure) × 100. CI: confidence interval; OLE: open-label extension.

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. doi: 10.1056/NEJMoa1716153.

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Data availability statement

Anonymized individual participant data that support these results would be made available in a secure-access environment 12 months after study completion and when the product and indication have been approved for no less than 12 months in the US and/or the EU.

Access will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.