Patisiran: Orthostatic Hypotension

Patisiran: Orthostatic Hypotension

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 Summary

Index

Cross Study Analysis of PBP – APOLLO: Orthostatic Intolerance Component of COMPASS-31 – Safety Results – Abbreviations – References

 Cross Study Analysis of PBP

A cross study analysis was conducted to evaluate the quantitative effect of patisiran and vutrisiran on orthostatic hypotension in patients with hATTR-PN across the APOLLO, Global OLE, and HELIOS‑A studies.1

Study Overviews

APOLLO was a multicenter, international, randomized (2:1), double-blind, placebo-controlled, phase 3 study designed to assess 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.3

The Global OLE study (N=211) was a multicenter, international study designed to evaluate the long-term safety and efficacy of IV patisiran in patients with hATTR-PN. Patients with hATTR-PN who completed the patisiran Phase 2 OLE study or phase 3 APOLLO study and met eligibility criteria were able to start or continue IV patisiran 0.3 mg/kg every 3 weeks for up to 5 years. The study enrolled 25 patients from the patisiran Phase 2 OLE study (Phase 2 OLE-patisiran group), 137 patients from the APOLLO-patisiran arm (APOLLO-patisiran group), and 49 patients from the APOLLO-placebo arm (APOLLO-placebo group).4

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.5

Efficacy Results: mNIS+7-PBP Component

PBP was evaluated to assess the quantitative effect of patisiran on orthostatic hypotension. Orthostatic hypotension was calculated as the mean of 2 supine readings of SBP taken 15 minutes apart minus the lowest SBP upon standing at 1, 3, and 5 minutes. A smaller reduction in SBP between supine and upright positions indicated better PBP. The severity of orthostatic hypotension was categorized as follows: normal (<20 mmHg reduction), moderate (≥20–<30 mmHg reduction), and severe (≥30 mmHg reduction).1

The baseline assessments of PBP in the APOLLO, Global OLE, and HELIOS-A studies are presented in Figure 1.

Figure 1. Percentage of Patients in Each PBP Category at Baseline of the APOLLO, Global OLE, and HELIOS-A Studies.1,a

In the APOLLO-placebo arm, the proportion of patients with normal PBP decreased from APOLLO baseline to Global OLE baseline. However, in the APOLLO-patisiran arm, there was an increase in the proportion of patients with normal PBP from APOLLO baseline to Global OLE baseline. Figure 2 shows the change in observed PBP across all 3 studies.1

Figure 2. Change in Observed PBP across the APOLLO, Global OLE, and HELIOS-A Studies.1,a

At Month 18 in the APOLLO study, 91.2% of patients in the patisiran group with a PBP assessment had improvement or stabilization in PBP compared to baseline. The majority of patients in the APOLLO-patisiran group also showed improvement or stabilization during patisiran treatment after 36 months of patisiran treatment in the Global OLE (76.5%).1

At Month 18 in the Global OLE, 68.6% of patients in the APOLLO-placebo group, who received placebo during APOLLO and began patisiran during the Global OLE period, had improvement or stabilization in PBP compared to baseline. Rates of stabilization or improvement increased to 77.8% after 36 months of patisiran treatment in the Global OLE.1

At Month 18 in the HELIOS-A study, stabilization or improvement in PBP was seen in 81.6% of patients in the patisiran arm compared to baseline.1

 APOLLO: Orthostatic Intolerance Component of COMPASS-31

During the APOLLO study, the impact of patisiran on orthostatic hypotension was assessed using the orthostatic intolerance domain of COMPASS-31. COMPASS-31 is a 31-question patient-reported outcome assessment that measures autonomic symptoms across six weighted domains: orthostatic intolerance (40 points); vasomotor (5 points); secretomotor (15 points); gastrointestinal (25 points); bladder (10 points); and pupillomotor (5 points), on a 100-point scale; a higher score indicates worse autonomic dysfunction.2

Baseline Disease Characteristics

Baseline values of the COMPASS-31 total score and the orthostatic intolerance domain are summarized in Table 1.2

Table 1. Baseline Disease Characteristics of Autonomic Endpoints.2

Efficacy Results

At Month 18, total COMPASS-31 scores improved in the patisiran group vs. the placebo group with an LSMD of ‑7.5 (95% CI: -11.9, -3.2; p=0.0008). An improvement was also observed across each of the six autonomic domains of COMPASS-31. As seen in Figure 3, at Month 18, 30% of patients in the patisiran group experienced improvement in their orthostatic intolerance vs. 10% in the placebo group.2

Figure 3. Question-Level Analysis of Orthostatic Intolerance Domain at Month 18 of the APOLLO Study.2

 Safety Results

Safety outcomes were not evaluated as part of the cross study PBP analysis.1

Safety Results: APOLLO

Across both treatment groups, 97% of patients reported AEs, of which the majority were mild or moderate in severity. AEs which occurred more frequently in the patisiran group were peripheral edema (30% vs. 22%) and IRRs (19% vs. 9%), which were mild or moderate in severity. One patient withdrew from the study due to a moderate IRR of flushing. IRR symptoms reported in ≥3% of patients in either group included back pain, flushing, abdominal pain, and nausea. There were no serious or severe IRRs, and the frequency of IRRs decreased over time.3

Death occurred in 7 patients (5%) in the patisiran group and in 6 patients (8%) in the placebo group. The causes of death were determined to be primarily cardiovascular in nature and were consistent with expected events in the hATTR population. The incidence of cardiac AEs (patisiran = 28%; placebo = 36%), cardiac serious AEs (patisiran = 14%, placebo = 13%), and cardiac failure (patisiran = 9%, placebo = 10%) was similar between the two groups. The incidence of cardiac arrhythmias was lower with patisiran (19%) than with placebo (29%).3

The safety profile of patisiran in the Global OLE and HELIOS-A studies was consistent with that in the APOLLO study.4,5

 Abbreviations

AE = adverse event; COMPASS-31 = Composite Autonomic Symptom Score-31 questionnaire; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IRR = infusion-related reaction; IV = intravenous; LS = least squares; LSMD = least squares mean difference; mNIS+7 = modified Neurologic Impairment Score +7; OLE = open-label extension; PBP = postural blood pressure; SBP = systolic blood pressure; SD = standard deviation; SE = standard error.

Updated 19 March 2026

 References

1.  Slama MS, Obici L, Okumura T, et al. Effect of RNAi therapeutics patisiran and vutrisiran on orthostatic hypotension due to dysautonomia in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at: European Society of Cardiology (ESC) Annual Scientific Meeting; August 26-29, 2022; Barcelona, Spain.

2.  González-Duarte A, Berk JL, Quan D, et al. Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis. J Neurol. 2020;267(3):703-712. doi:10.1007/s00415-019-09602-8

3.  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

4.  Adams, Polydefkis, González-Duarte, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. 2021;20(1):49-59. doi:10.1016/S1474-4422(20)30368-9

5.  Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023;30(1):18-26. doi:10.1080/13506129.2022.2091985