Impact of baseline polyneuropathy severity on patisiran treatment outcomes in the APOLLO trial

Figures & data

Table 1. Baseline demographics and disease characteristics of patients across the NIS quartiles and the mITT population.

Characteristic	Q1: NIS 6–<31		Q2: NIS 31–<57		Q3: NIS 57–<85.5		Q4: NIS 85.5–141.6
	Placebo (n = 19)	Patisiran (n = 37)	Placebo (n = 22)	Patisiran (n = 34)	Placebo (n = 20)	Patisiran (n = 36)	Placebo (n = 16)	Patisiran (n = 41)
Median age, years (range)	57 (36–80)	57 (24–69)	63 (34–75)	61 (31–79)	70 (47–77)	66 (36–83)	63 (43–77)	65 (42–79)
Male sex, n (%)	12 (63.2)	26 (70.3)	18 (81.8)	28 (82.4)	15 (75.0)	24 (66.7)	13 (81.3)	31 (75.6)
Median time since ATTRv amyloidosis diagnosis, years (range)	1.5 (0.2–13.0)	1.8 (0.0–21.0)	1.3 (0.0–9.1)	1.1 (0.1–17.5)	1.4 (0.1–16.5)	1.3 (0.1–8.1)	1.6 (0.1–8.8)	1.7 (0.0–14.3)
TTR genotype, n (%)
V30M	11 (57.9)	11 (29.7)	10 (45.5)	14 (41.2)	13 (65.0)	13 (36.1)	6 (37.5)	18 (43.9)
Non-V30M*	8 (42.1)	26 (70.3)	12 (54.5)	20 (58.8)	7 (35.0)	23 (63.9)	10 (62.5)	23 (56.1)
Early-onset V30M	4 (21.1)	5 (13.5)	3 (13.6)	2 (5.9)	1 (5.0)	3 (8.3)	2 (12.5)	3 (7.3)
Previous TTR stabilizer use, n (%)	10 (52.6)	22 (59.5)	13 (59.1)	15 (44.1)	12 (60.0)	20 (55.6)	6 (37.5)	21 (51.2)
Median NIS (range)	15.0 (7.0–30.0)	20.0 (6.0–30.0)	44.3 (31.0–56.6)	44.0 (31.5–55.6)	73.8 (57.0–80.0)	68.7 (57.0–84.5)	102.4 (85.5–125.5)	105.5 (86.0–141.6)
PND score, n (%)
I: preserved walking, sensory disturbances	13 (68.4)	29 (78.4)	7 (31.8)	5 (14.7)	0	1 (2.8)	0	1 (2.4)
II: impaired walking without need for a stick or crutches	6 (31.6)	5 (13.5)	10 (45.5)	17 (50.0)	6 (30.0)	12 (33.3)	1 (6.3)	9 (22.0)
IIIA: walking with one stick or crutch	0	3 (8.1)	4 (18.2)	10 (29.4)	9 (45.0)	17 (47.2)	9 (56.3)	11 (26.8)
IIIB: walking with two sticks or crutches	0	0	1 (4.5)	2 (5.9)	4 (20.0)	6 (16.7)	6 (37.5)	20 (48.8)
IV: confined to wheelchair or bedridden	0	0	0	0	1 (5.0)	0	0	0
Karnofsky Performance Status, n (%)
60	2 (10.5)	1 (2.7)	3 (13.6)	3 (8.8)	10 (50.0)	10 (27.8)	7 (43.8)	35 (85.4)
70–80	15 (78.9)	24 (64.9)	13 (59.1)	28 (82.4)	9 (45.0)	23 (63.9)	8 (50.0)	5 (12.2)
90–100	2 (10.5)	12 (32.4)	6 (27.3)	3 (8.8)	1 (5.0)	3 (8.3)	1 (6.3)	1 (2.4)

ATTRv: hereditary transthyretin-mediated (v for variant); mITT: modified intent-to-treat; NIS: Neuropathy Impairment Score; PND: polyneuropathy disability; Q: quartile; TTR: transthyretin.

*Non-V30M TTR genotype represents 38 different TTR variants.

Table 2. NIS, R-ODS, 10-MWT, grip strength, and Norfolk QOL-DN at baseline and 18 months by baseline NIS quartiles.

Assessment	Q1: NIS 6–<31		Q2: NIS 31–<57		Q3: NIS 57–<85.5		Q4: NIS 85.5–141.6
	Placebo	Patisiran	Placebo	Patisiran	Placebo	Patisiran	Placebo	Patisiran
NIS
n at baseline	19	37	22	34	20	36	16	41
Mean (SEM) score at baseline	17.9 (1.8)	18.3 (1.1)	43.7 (1.7)	43.2 (1.3)	71.6 (1.6)	69.4 (1.5)	103.7 (3.2)	105.1 (2.2)
n at 18 months	13	36	14	32	15	33	9	36
Mean (SEM) score at 18 months	27.1 (3.6)	21.3 (1.9)	68.0 (5.0)	43.0 (2.9)	107.9 (7.4)	76.9 (4.0)	130.1 (4.0)	108.7 (3.6)
Mean (SEM) change from baseline to 18 months	10.8 (2.7)	2.8 (1.5)	24.9 (4.6)	–0.1 (2.9)	37.3 (7.1)	6.7 (3.4)	27.4 (4.1)	3.8 (2.7)
Mean (SEM) percent change from baseline to 18 months	75.5 (21.5)	16.7 (10.0)	59.7 (12.4)	1.3 (7.5)	53.6 (10.5)	9.3 (5.3)	27.5 (4.2)	3.7 (2.6)
R-ODS
n at baseline	19	37	22	34	19	36	16	41
Mean (SEM) score at baseline	40.1 (1.6)	40.4 (1.4)	34.4 (1.2)	33.5 (1.5)	25.2 (1.4)	28.3 (1.3)	16.6 (1.8)	18.0 (1.1)
n at 18 months	14	36	15	32	15	34	10	36
Mean (SEM) score at 18 months	37.1 (2.3)	41.6 (1.2)	22.7 (2.1)	34.7 (1.4)	14.5 (2.0)	27.1 (1.3)	5.8 (1.1)	15.0 (1.4)
Mean (SEM) change from baseline to 18 months	–3.8 (1.2)	1.0 (1.0)	–12.9 (1.8)	0.3 (1.2)	–11.7 (1.8)	–1.4 (1.4)	–10.8 (2.5)	–2.9 (0.9)
Mean (SEM) percent change from baseline to 18 months	–9.7 (3.0)	6.1 (5.3)	–36.4 (5.2)	2.8 (4.0)	–45.7 (7.3)	–0.1 (5.7)	–57.9 (8.3)	–13.0 (6.8)
10-MWT
n at baseline	19	37	22	34	20	36	16	40
Mean (SEM) gait speed at baseline (m/s)	1.05 (0.06)	1.14 (0.06)	0.89 (0.06)	0.90 (0.05)	0.68 (0.06)	0.71 (0.05)	0.49 (0.05)	0.46 (0.05)
n at 18 months	14	36	15	32	15	34	11	36
Mean (SEM) gait speed at 18 months (m/s)	1.00 (0.08)	1.32 (0.07)	0.59 (0.05)	0.93 (0.06)	0.33 (0.07)	0.71 (0.06)	0.25 (0.10)	0.42 (0.06)
Mean (SEM) change from baseline to 18 months (m/s)	–0.06 (0.07)	0.17 (0.05)	–0.33 (0.05)	0.01 (0.05)	–0.36 (0.08)	0.01 (0.03)	–0.28 (0.09)	–0.04 (0.04)
Mean (SEM) percent change from baseline to 18 months	–4.31 (6.07)	17.53 (7.26)	–34.67 (6.48)	5.96 (5.66)	–49.90 (10.62)	0.07 (5.76)	–61.97 (15.97)	–5.08 (8.48)
Grip strength
n at baseline	19	37	22	34	20	36	16	41
Mean (SEM) grip strength at baseline (kg)	25.2 (1.8)	28.4 (2.3)	22.4 (2.5)	22.8 (2.3)	14.0 (1.3)	16.4 (1.3)	7.3 (1.4)	7.7 (1.4)
n at 18 months	14	35	15	32	16	33	11	35
Mean (SEM) grip strength at 18 months (kg)	19.1 (2.1)	29.5 (2.1)	12.9 (2.0)	21.8 (1.6)	5.6 (1.1)	14.4 (1.3)	1.3 (0.8)	6.8 (1.3)
Mean (SEM) change from baseline to 18 months (kg)	–6.6 (2.3)	0.7 (1.9)	–10.8 (2.1)	–1.6 (1.9)	–7.4 (1.1)	–2.0 (0.9)	–6.4 (1.7)	–1.3 (0.9)
Mean (SEM) percent change from baseline to 18 months	–23.1 (6.2)	8.7 (5.2)	–44.4 (5.1)	1.8 (5.3)	–58.1 (6.2)	–7.7 (5.7)	–85.8 (7.0)	12.6 (16.0)
Norfolk QOL-DN
n at baseline	19	37	22	34	19	36	16	41
Mean (SEM) Norfolk QOL-DN score at baseline	36.4 (3.9)	39.7 (4.7)	50.9 (4.9)	54.8 (4.3)	65.4 (4.7)	59.4 (3.7)	72.9 (5.2)	81.8 (3.0)
n at 18 months	13	35	14	32	14	33	8	36
Mean (SEM) Norfolk QOL-DN score at 18 months	49.6 (9.1)	32.1 (4.9)	69.2 (7.4)	47.1 (4.6)	84.1 (5.6)	57.6 (3.6)	90.1 (4.8)	83.3 (3.2)
Mean (SEM) change from baseline to 18 months	15.6 (5.8)	–8.1 (4.0)	23.1 (4.1)	–6.1 (3.8)	22.9 (6.2)	0.5 (3.4)	18.0 (10.4)	2.8 (3.2)
Mean percent change from baseline to 18 months	49.4 (22.9)	–17.9 (9.3)	56.6 (11.8)	–4.6 (9.1)	46.7 (14.4)	12.3 (11.0)	42.4 (28.6)	6.1 (4.5)

10-MWT: 10-meter walk test; m/s: meter per second; NIS: Neuropathy Impairment Score; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy; R-ODS: Rasch-built Overall Disability Scale; SEM: standard error of the mean.

Figure 1. Mean mNIS+7 (A) and NIS (B) scores at baseline, 9 months, and 18 months according to baseline polyneuropathy group. BL: baseline; mNIS+7: modified Neuropathy Impairment Score+7; m: months; NIS: Neuropathy Impairment Score; Q: quartile; SEM: standard error of the mean.

Figure 2. Mean R-ODS score at baseline and 18 months according to baseline polyneuropathy group. BL: baseline; m: months; NIS: Neuropathy Impairment Score; Q: quartile; R-ODS: Rasch-built Overall Disability Scale; SEM: standard error of the mean.

Figure 3. Mean 10-MWT, in m/s, at baseline and 18 months according to baseline polyneuropathy group. *n = 14. 10-MWT: 10-meter walk test; BL: baseline; m: months; m/s: meters per second; NIS: Neuropathy Impairment Score; Q: quartile; SEM: standard error of the mean.

Figure 4. Mean grip strength, in kg, at baseline and 18 months according to baseline polyneuropathy group. *n = 32; ^†n = 10. BL: baseline; m: months; NIS: Neuropathy Impairment Score; Q: quartile; SEM: standard error of the mean.

Figure 5. Mean Norfolk QOL-DN scores at baseline, 9 months, and 18 months according to baseline polyneuropathy group. BL: baseline; m: months; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy; NIS: Neuropathy Impairment Score; Q: quartile; QOL: quality of life; SEM: standard error of the mean.