Transition between Patisiran and Vutrisiran

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Summary

 Patients who received patisiran during the 18-month treatment period of the HELIOS-A study were transitioned to vutrisiran during the RTE period (patisiran/vutrisiran group).1

o At Month 18 of the RTE period, a consistent clinical effect was observed across efficacy endpoints, including mNIS+7, Norfolk QOL-DN, 10-MWT, R-ODS, PND score, and mBMI in the patisiran/vutrisiran group.1

o A sustained serum TTR reduction was observed during the RTE period in the patisiran/vutrisiran group and was comparable with the serum TTR reduction observed in patients who received vutrisiran during both the 18-month treatment period and the RTE (vutrisiran/vutrisiran group).1

o Through Month 42 of the RTE period, the majority of AEs with vutrisiran were mild or moderate in severity. No deaths were considered related to study drug by the investigators.1

 Studies evaluating the transition of patients from vutrisiran to patisiran have not been conducted to date.2,3

Index

Transition from Patisiran to Vutrisiran – Transition from Vutrisiran to Patisiran – Abbreviations – References

Transition from Patisiran to Vutrisiran

HELIOS-A Study

HELIOS-A was a phase 3, global, randomized, open-label study designed to evaluate the efficacy and safety of vutrisiran in patients with hATTR-PN. Patients were randomized (3:1) to receive either vutrisiran 25 mg every 3 months by subcutaneous injection (n=122) or patisiran 0.3 mg/kg every 3 weeks by IV infusion (as a reference group, n=42) for 18 months. This study used the placebo arm of the APOLLO study as an external control arm (n=77) for the primary endpoint and most other efficacy endpoints. The primary endpoint was the change from baseline in mNIS+7 at 9 months.4

Exclusion Criteria

Patients were excluded from the study if they had received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR.5

HELIOS-A RTE Study

After the 18-month treatment period of HELIOS-A was completed, eligible patients (N=149), including those on patisiran as a reference group, entered the RTE and were randomized 1:1 to receive either vutrisiran 25 mg every 3 months (n=76) or vutrisiran 50 mg every 6 months (n=73) by subcutaneous injection for up to 42 months (Figure 1).1,6 For patients transitioning from patisiran to vutrisiran, the first dose of vutrisiran was administered 3 weeks after the last dose of patisiran.1

During the RTE period, a protocol amendment was enacted to transition patients on vutrisiran 50 mg every 6 months to vutrisiran 25 mg every 3 months due to serum TTR recovery observed at the end of the 50 mg every 6 months dosing interval compared with the 25 mg every 3 months dosing interval. The first patient transitioned on Day 505 of the RTE.1

Figure 1. HELIOS-A RTE Study Design.6

Abbreviations: 10-MWT = 10-meter walk test; FAP = familial amyloid polyneuropathy; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IV = intravenous; KPS = Karnofsky Performance Status; mBMI = modified body mass index; mNIS+7 = modified Neuropathy Impairment Score +7; NIS = Neuropathy Impairment Score; Norfolk QOL-DN = Norfolk Quality of Life-Diabetic Neuropathy; PND = polyneuropathy disability; Q3M = every 3 months; Q6M, every 6 months; Q3W = every 3 weeks; R-ODS = Rasch-built Overall Disability Scale; RTE = randomized treatment extension; SC = subcutaneous; TTR = transthyretin.

From Cauquil et al.6

Pharmacodynamic Results

A sustained TTR reduction was observed in patients who received patisiran during the 18-month treatment period and maintained in the patients who were transitioned to vutrisiran during the RTE (patisiran/vutrisiran). The TTR reduction observed in patients in the patisiran/vutrisiran group was comparable to the TTR reduction observed in patients who received vutrisiran during both the 18‑month treatment period and the RTE (vutrisiran/vutrisiran) (Figure 2).1,4

Figure 2. Mean (±SE) Percent Change from Baseline in Serum TTR During the RTE.1

Abbreviations: BL = baseline; D = day; M = month; RTE = randomized treatment extension; Q3M = every 3 months; Q6M = every 6 months; SE = standard error; TTR = transthyretin.

From Cauquil et al.1

Efficacy Results

The change from baseline in efficacy endpoints among patients who previously received patisiran during the 18-month treatment period and switched to vutrisiran during the RTE are presented in Table 1.1

Table 1. Change from Baseline for Select Clinical Efficacy Endpoints for Patients Who Switched From Patisiran to Vutrisiran During the RTE.1

Endpoint	Patients Previously on Patisiran During the Treatment Period (n=42)
mNIS+7a
Study baseline, mean (SD)	57.7 (33.7), n=42
Change from study baseline to end of 18‑month treatment period, mean (SD)	1.6 (21.5), n=36
Change from study baseline to RTE at Month 18, mean (SD)	3.7 (20.8), n=32
Norfolk QOL-DNb
Study baseline, mean (SD)	47.3 (29.9), n=42
Change from study baseline to end of 18‑month treatment period, mean (SD)	-0.6 (19.3), n=38
Change from study baseline to RTE at Month 18, mean (SD)	1.8 (19.3), n=32
10-MWTc, m/s
Study baseline, mean (SD)	1.011 (0.400) n=42
Change from study baseline to end of 18‑month treatment period, mean (SD)	-0.043 (0.276), n=38
Change from study baseline to RTE at Month 18, mean (SD)	-0.092 (0.250), n=32
mBMI, kg/m2 x g/L
Study baseline, mean (SD)	1058.1 (228.8), n=42
Change from study baseline to end of 18‑month treatment period, mean (SD)	6.9 (91.8), n=38
Change from study baseline to RTE at Month 18, mean (SD)	26.8 (113.2), n=29
R-ODSd
Study baseline, mean (SD)	34.0 (10.4), n=42
Change from study baseline to end of 18‑month treatment period, mean (SD)	-1.2 (5.9), n=38
Change from study baseline to RTE at Month 18, mean (SD)	-3.0 (6.2), n=32
PND scoree, %
Study baseline, 0/1/11/IIIA/IIIB/IV, %	0/35.7/40.5/16.7/7.1/0, n=42
Change from study baseline to end of 18‑month treatment period, disease stabilization/improvement/worsening, %f	71.4/2.4/16.7, n=38
Change from study baseline to RTE at Month 18, disease stabilization/improvement/worsening, %f	61.9/0/16.7, n=33

Abbreviations: 10-MWT = 10-meter walk test; mBMI = modified body mass index; mNIS+7 = modified Neuropathy Impairment Score +7; Norfolk QOL-DN = Norfolk Quality of Life-Diabetic Neuropathy; PND = polyneuropathy disability; R-ODS = Rasch-built Overall Disability Scale; RTE = randomized treatment extension; SD = standard deviation.

aMean of two non-missing assessments at the last scheduled efficacy assessment visit before the first dose of the RTE period or a single assessment score performed at the RTE visits after component imputation. Lower scores indicate less neurologic impairment (range: 0–304).

bComposite of 35 quality-of-life questions; lower scores indicate higher quality of life (range: –4 to 136).

c10 meters/mean time (seconds) taken to complete two assessments from the last scheduled efficacy assessment visit before the first dose of the RTE period; and single assessment performed at RTE months 9 and 18 visits. Imputed as 0 for patients unable to perform the walk; higher speeds indicate greater ambulatory function.

dComposite of 24 disability questions; higher scores indicate lower disability (range: 0–48).

ePND score I: preserved walking, sensory disturbances; II: impaired walking but can walk without stick or crutch; III A: walk with one stick or crutch; III B: walk with two sticks or crutches; IV: confined to wheelchair or bedridden.

fPercentages are based on total number of patients (n=42); number of patients with assessments at each visit are indicated.

Safety Results

A summary of AEs observed during the RTE period compared with the 18-month treatment period are presented in Table 2. In the total vutrisiran group, the median treatment duration was 27.3 months (range: 0.7-44.6 months). The majority of AEs reported were mild or moderate in severity.1

The most common AEs reported in ≥10% of patients in the total vutrisiran group were COVID-19 (31.5%), urinary tract infection (17.4%), and fall (14.8%). No SAEs or deaths were considered related to vutrisiran in the RTE. There were no new safety concerns identified during the RTE period. The safety profile of vutrisiran was consistent with that observed previously in the treatment period of the HELIOS-A study.1

Table 2. AEs with Vutrisiran During the RTE (RTE Population) and 18-Month Treatment Period (Safety Population) of HELIOS-A, and with External Placebo from APOLLO.1

n (%)/ER (number of events per 100 PY)	HELIOS-A RTE	HELIOS-A 18-month treatment period	APOLLO
n (%)/ER (number of events per 100 PY)	Total Vutrisiran (N=149; PY=376.2)	Vutrisiran, 25 mg Q3M (n = 122; PY=191.3)	Placebo (n=77; PY=96.1)
Treatment duration, months, mean (range)	30.3 (0.7-44.6)	18.8 (1.7-19.4)	15.0 (1.3-18.8)
Any AE	139 (93.3)/291.6	119 (97.5)/552.6	75 (97.4)/1280.5
Treatment-related	10 (6.7)/6.9	29 (23.8)/33.5	30 (39.0)/197.6
Severe AEs	51 (34.2)/30.3	19 (15.6)/20.9	28 (36.4)/91.5
SAE	59 (39.6)/40.4	32 (26.2)/32.9	31 (40.3)/103.0
AE leading to treatment discontinuation	11 (7.4)/2.9	3 (2.5)/1.6	11 (14.3)/15.6
AE leading to stopping study participation	11 (7.4)/2.9	3 (2.5)/1.6	9 (11.7)/11.4
Deatha	13 (8.7)	2 (1.6)	6 (7.8)

Abbreviations: AE = adverse event; ER = event rate; PY = patient-years; RTE = randomized treatment extension; SAE = serious adverse event.

aIncludes death reported in 1 patient in the vutrisiran 25 mg group that occurred after the patient stopped study participation.

Transition from Vutrisiran to Patisiran

Studies evaluating the transition of patients from vutrisiran to patisiran have not been conducted to date.

APOLLO Study

APOLLO was a multicenter, international, randomized (2:1), double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of IV patisiran 0.3 mg/kg every 3 weeks (n=148) versus placebo (n=77) in patients with hATTR-PN. The primary endpoint was the change from baseline in the mNIS+7 at 18 months.2

Exclusion Criteria

Patients were excluded from the study if they had received an investigational agent or device within 30 days of anticipated study drug administration or within 5 half-lives of the investigational drug(s), whichever was longer.7

APOLLO-B Study

APOLLO-B was a multicenter, randomized (1:1), double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of IV patisiran 0.3 mg/kg every 3 weeks (n=181) versus placebo (n=179) in patients with ATTR-CM, including both hATTR and wtATTR. The primary endpoint was the change from baseline in the 6-MWT at 12 months.3

Exclusion Criteria

Patients were excluded from the study if they had received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR.8

Abbreviations

6-MWT = 6-minute walk test; 10-MWT = 10-meter walk test; AE = adverse event; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; BL = baseline; D = day; FAP = familial amyloid polyneuropathy; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IV = intravenous; KPS = Karnofsky Performance Status; M = month; mBMI = modified body mass index; mNIS+7 = modified Neuropathy Impairment Score +7; NIS = Neuropathy Impairment Score; Norfolk QOL‑DN = Norfolk Quality of Life-Diabetic Neuropathy; OLE = open-label extension; PND = polyneuropathy disability; PY = patient-years; Q3M = every 3 months; Q6M = every 6 months; Q3W = every 3 weeks; R‑ODS = Rasch-built Overall Disability Scale; RTE = randomized treatment extension; SAE = serious adverse event; SC = subcutaneous; SD = standard deviation; SE = standard error; TTR = transthyretin; wtATTR = wild-type transthyretin amyloidosis.