Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

Figures & data

Figure 1. Patient disposition. *Modified intent-to-treat population: all patients who were randomized and received at least one dose of the study drug. ^†Numbers of discontinuations to the end of 18 months. One patient in each treatment group discontinued due to suspected or confirmed diagnosis of COVID-19 or due to the impact of the global COVID-19 pandemic, reported in addition to the primary reason for treatment discontinuation. There were two deaths due to COVID-19, one in each treatment arm.

Table 1. Baseline demographics and clinical characteristics.

Characteristic	APOLLO	HELIOS-A
	Placebo (n = 77)	Vutrisiran (n = 122)	Patisiran (n = 42)	Total (n = 164)
Median age, years (IQR)	63 (15)	60 (20)	60 (12)	60 (18)
Males, n (%)	58 (75.3)	79 (64.8)	27 (64.3)	106 (64.6)
Race, n (%)
White/Caucasian	50 (64.9)	86 (70.5)	29 (69.0)	115 (70.1)
Asian	25 (32.5)	21 (17.2)	8 (19.0)	29 (17.7)
Black or African American	1 (1.3)	4 (3.3)	4 (9.5)	8 (4.9)
Other*	1 (1.3)	11 (9.0)	1 (2.4)	12 (7.3)
Median time since ATTRv amyloidosis diagnosis, years (IQR)	1.41 (3.04)	1.94 (4.34)	2.39 (3.01)	2.22 (4.15)
TTR genotype, n (%)
V30M	40 (51.9)	54 (44.3)	20 (47.6)	74 (45.1)
Early-onset V30M (<50 years)	10 (13.0)	25 (20.5)	8 (19.0)	33 (20.1)
Non-V30M^†	37 (48.1)	68 (55.7)	22 (52.4)	90 (54.9)
Previous tetramer stabilizer use, n (%)	41 (53.2)	75 (61.5)	33 (78.6)	108 (65.9)
Tafamidis	27 (35.1)	53 (43.4)	25 (59.5)	78 (47.6)
Diflunisal	14 (18.2)	22 (18.0)	8 (19.0)	30 (18.3)
Neuropathy Impairment Score, n (%)
<50	35 (45.5)	78 (63.9)	27 (64.3)	105 (64.0)
≥50–<100	33 (42.9)	39 (32.0)	13 (31.0)	52 (31.7)
≥100	9 (11.7)	5 (4.1)	2 (4.8)	7 (4.3)
PND score,^‡ n (%)
I	20 (26.0)	44 (36.1)	15 (35.7)	59 (36.0)
II	23 (29.9)	50 (41.0)	17 (40.5)	67 (40.9)
IIIA	22 (28.6)	16 (13.1)	7 (16.7)	23 (14.0)
IIIB	11 (14.3)	12 (9.8)	3 (7.1)	15 (9.1)
NT-proBNP,^§ n (%)
≤3000 ng/L	66 (85.7)	112 (91.8)	37 (88.1)	149 (90.9)
>3000 ng/L	9 (11.7)	10 (8.2)	5 (11.9)	15 (9.1)
Cardiac subpopulation,^ǁ n (%)	36 (46.8)	40 (32.8)	14 (33.3)	54 (32.9)

*Includes more than one race, vutrisiran n = 1 (0.8%); other, vutrisiran n = 10 (8.2%), patisiran n = 1 (2.4%); missing, placebo n = 1 (1.3%).

^†The non-V30M TTR genotype represents 25 different TTR mutations in HELIOS-A.

^‡PND score I: preserved walking, sensory disturbances; II: impaired walking but can walk without stick or crutch; IIIA: walk with one stick or crutch; IIIB: walk with two sticks or crutches; 1 patient (1.3%) in APOLLO placebo group had a PND score IV defined as confined to wheelchair or bedridden.

^§NT-proBNP missing for 2 patients in APOLLO placebo group.

^ǁCardiac subpopulation was defined as mITT population patients who had preexisting evidence of cardiac amyloid involvement (baseline left ventricular wall thickness ≥1.3 cm and no aortic valve disease or hypertension in medical history).

ATTRv: hereditary transthyretin; IQR: interquartile range; mITT: modified intent-to-treat; NT-proBNP: N-terminal pro-brain natriuretic peptide; PND: polyneuropathy disability; TTR: transthyretin.

Figure 2. Key efficacy and pharmacodynamic endpoints assessing the effect of vutrisiran. LS mean change from baseline in (A) mNIS+7, (B) Norfolk QOL-DN, and (C) percent change from baseline in serum TTR levels with vutrisiran and patisiran through 18 months of the HELIOS-A study. The mNIS+7 and Norfolk QOL-DN data were calculated using the modified intent-to-treat population; the reduction in serum TTR was calculated using the TTR per-protocol population. *Higher scores of mNIS+7 indicate more neuropathy impairment (range, 0–304). At baseline, the mean (±SD) mNIS+7 was 60.6 (36.0) in the vutrisiran group and 74.6 (37.0) in the external placebo group. Data at 9 months are from the ANCOVA/multiple imputation model and data at 18 months are from the MMRM model. ^†Higher scores of Norfolk QOL-DN indicate worse quality of life (range, –4 to 136). At baseline, the mean (±SD) Norfolk QOL-DN score was 47.1 (26.3) in the vutrisiran group and 55.5 (24.3) in the external placebo group. Data at 9 months are from the ANCOVA/multiple imputation model and data at 18 months are from the MMRM model. ANCOVA: analysis of covariance; CI: confidence interval; LS: least squares; LSMD: least squares mean difference; MMRM: mixed-effects model for repeated measures; mNIS+7: modified Neuropathy Impairment Score +7; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy; SD: standard deviation; SE: standard error; TTR: transthyretin.

Table 2. Select secondary and exploratory endpoints in the mITT population.

	APOLLO	HELIOS-A
	Placebo (n = 77)	Vutrisiran (n = 122)
Endpoints at Month 9*
Norfolk QOL-DN
Baseline	n = 76	n = 121
Mean (SD) score	55.5 (24.3)	47.1 (26.3)
Change from baseline to Month 9	n = 65	n = 114
LS mean change (SE)	12.9 (2.2)	−3.3 (1.7)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	−16.2 (−21.7, −10.8)
p value	5.43 × 10^–9
10-MWT (gait speed ms^−1)
Baseline	n = 77	n = 122
Mean (SD)	0.790 (0.319)	1.006 (0.393)
Change from baseline to Month 9	n = 68	n = 113
LS mean change (SE)	−0.133 (0.025)	−0.001 (0.019)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	0.131 (0.070, 0.193)
p value	3.10 × 10.0^–5
mBMI^†‡
Baseline	n = 77	n = 122
Mean (SD)	989.9 (214.2)	1057.5 (234.0)
Change from baseline to Month 9	n = 68	n = 112
LS mean change (SE)	−60.2 (10.1)	7.6 (7.9)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	67.8 (43.0, 92.6)
p value	8.46 × 10^–8
R-ODS^†
Baseline	n = 76	n = 122
Mean (SD)	29.8 (10.8)	34.1 (11.0)
Change from baseline to Month 9	n = 66	n = 113
LS mean change (SE)	−4.9 (0.7)	−0.6 (0.5)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	4.3 (2.7, 6.0)
p value	3.26 × 10^–7
Endpoints at Month 18^§
mNIS+7
Baseline	n = 77	n = 122
Mean (SD)	74.6 (37.0)	60.6 (36.0)
Change from baseline to Month 18	n = 51	n = 112
LS mean change (SE)	28.1 (2.3)	−0.46 (1.6)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	−28.6 (−34.0, −23.1)
p value	6.50 × 10^–20
Norfolk QOL-DN
Change from baseline to Month 18	n = 48	n = 111
LS mean change (SE)	19.8 (2.6)	−1.2 (1.8)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	−21.0 (−27.1, −14.9)
p value	1.84 × 10^–10
10-MWT (gait speed ms^−1)
Change from baseline to Month 18	n = 55	n = 112
LS mean change (SE)	−0.264 (0.036)	−0.024 (0.025)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	0.239 (0.154, 0.325)
p value	1.21 × 10^–7
mBMI
Change from baseline to Month 18	n = 52	n = 113
LS mean change (SE)	−115.7 (13.4)	25.0 (9.5)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	140.7 (108.4, 172.9)
p value	4.16 × 10^–15
R-ODS
Change from baseline to Month 18	n = 54	n = 113
LS mean change (SE)	−9.9 (0.8)	−1.5 (0.6)
Vutrisiran vs APOLLO placebo
LS mean difference (95% CI)	8.4 (6.5, 10.4)
p value	3.54 × 10^–15

*Data from the analysis of covariance/multiple imputation model.

^†Exploratory efficacy endpoints.

^‡mBMI is defined as [weight in kilograms divided by square of height in meters] × albumin level in grams per liter.

^§Data from the mixed-effects model for repeated measures.

Table 3. Summary of adverse events.

At least one event, n (%)	APOLLO	HELIOS-A
	Placebo (n = 77)	Vutrisiran (n = 122)	Patisiran (n = 42)
Summary of AEs*
Any AE	75 (97.4)	119 (97.5)	41 (97.6)
Serious AEs	31 (40.3)	32 (26.2)	18 (42.9)
Severe AEs	28 (36.4)	19 (15.6)	16 (38.1)
AEs leading to treatment discontinuation	11 (14.3)	3 (2.5)	3 (7.1)
AEs leading to stopping study participation	9 (11.7)	3 (2.5)	2 (4.8)
Deaths	6 (7.8)	2 (1.6)	3 (7.1)
AEs occurring in ≥10% in vutrisiran-treated patients*
Fall	22 (28.6)	22 (18.0)	6 (14.3)
Pain in extremity	8 (10.4)	18 (14.8)	3 (7.1)
Diarrhea	29 (37.7)	17 (13.9)	7 (16.7)
Edema peripheral	17 (22.1)	16 (13.1)	4 (9.5)
Urinary tract infection	14 (18.2)	16 (13.1)	8 (19.0)
Arthralgia	0	13 (10.7)	4 (9.5)
Dizziness	11 (14.3)	13 (10.7)	0

*Safety reported in the safety population during the 18-month treatment period.

AE: adverse event.

Data availability statement

De-identified individual participant data that support these results will 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 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.