Patisiran: Autonomic Outcomes

Patisiran: Autonomic Outcomes

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 Summary

Index

Clinical Data – Abbreviations – References

 Clinical Data

Study Design

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.1

An analysis was conducted to assess autonomic outcomes from the APOLLO trial. Autonomic symptoms were measured with the COMPASS-31 questionnaire and Norfolk QOL-DN questionnaire. Nutritional status and wasting due to GI dysfunction was measured with mBMI. Postural BP was measured as a component of the mNIS+7.2

Results

Patient Demographics & Baseline Characteristics

There were 225 patients randomized to receive patisiran [n=148; 138 (93.2%) completed the trial] or placebo [(n=77; 55 (71.4%) completed the trial]. The two groups were generally well balanced with respect to baseline characteristics and disease severity. Baseline assessments of COMPASS-31, the autonomic neuropathy domain of Norfolk QOL-DN, the postural BP component of mNIS+7, and mBMI are presented in Table 1.2

Table 1. Baseline Disease Characteristics of Autonomic Endpoints.2

COMPASS-31

Total COMPASS-31 scores improved in the patisiran group compared with the placebo group and reached statistical significance at 18 months, with an LS mean difference of -7.5 (95% CI: -11.9, -3.2; p=0.0008). Total COMPASS-31 scores improved from baseline in the patisiran group. At 9 months, the LS mean change (SEM) was -3.1 (1.2; 95% CI: -5.5, -0.7) in the patisiran group and 0.4 (1.7) in the placebo group. At 18 months, the LS mean change (SEM) was -5.3 (1.3; 95% CI: -7.9, -2.7) in the patisiran group and 2.2 (1.9; 95% CI: –1.6, 6.1) in the placebo group. Overall, mean values for each COMPASS-31 component were either similar to or improved from baseline in the patisiran group (Figure 1).2

Figure 1. LS Mean Change in COMPASS-31 at 18 Months.2

After 18 months of treatment, a question-level analysis showed that patients in the patisiran group were 3.5 times more likely to report improvement in severity of diarrhea than patients in the placebo group (18% vs. 5%) and 3 times more likely than patients in the placebo group to report improvement in severity of orthostatic intolerance (30% vs. 10%). Patients in the patisiran group were also less likely to report worsening of orthostatic intolerance symptoms than patients in the placebo group after 18 months (14% vs. 23%), as seen in Figure 2 and Figure 3.2

Figure 2. Question-level Analysis of Change From Baseline in Diarrhea Presence and Severity at 18 Months from COMPASS-31.2

Figure 3. Question-level Analysis of Change From Baseline in Orthostatic Intolerance Presence and Severity at 18 Months from COMPASS-31.2

Norfolk QOL-DN: Autonomic Neuropathy Domain

At 18 months, the LS mean change from baseline (SEM) in the Norfolk QOL-DN autonomic neuropathy domain was ‑0.6 (0.2) in the patisiran group and 0.5 (0.3) in the placebo group, with an LS mean difference of ‑1.1 (95% CI: ‑1.8, ‑0.5; p=0.001). A question-level analysis showed that more patients in the placebo group reported moderate or severe diarrhea and/or loss of bowel control in the past 4 weeks at 18 months compared to baseline (43% vs. 33%). In the patisiran group, the analysis showed that fewer patients reported moderate or severe diarrhea and/or loss of bowel control in the past 4 weeks at 18 months compared to baseline (27% vs. 34%).2

Modified Body Mass Index

At 18 months, there was a statistically significant difference in mBMI between the patisiran and placebo groups, favoring patisiran therapy with an LS mean difference of 115.7 (95% CI: -82.4, 149.0; p=8.83×10‑11), as seen in Figure 4. In the patisiran group, 41.2% demonstrated an increase from baseline in mBMI (kg/m2 x g/L) at 18 months, compared with 6.5% in the placebo group.2

Figure 4. Change in LS Mean Total mBMI Score from Baseline.2

mNIS+7: Postural BP Component

At 18 months, the LS mean change from baseline (SEM) in the postural BP component of the mNIS+7 was -0.2 (0.1) in the patisiran group and 0.1 (0.1) in the placebo group, favoring patisiran therapy with an LS mean difference of ‑0.3 points (95% CI: -0.5, –0.1).2

Safety Results

Across both treatment groups, 97% of patients reported AEs, of which the majority were mild or moderate in severity. Orthostatic hypotension was reported as an SAE in 1 out of 77 (1.3%) patients in the placebo group and 3 out of 148 (2.0%) patients in the patisiran group.3 Common 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. 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.1

 Abbreviations

AE = adverse event; BP = blood pressure; CI = confidence interval; COMPASS-31 = Composite Autonomic Symptom Score-31; GI = gastrointestinal; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IRR = infusion-related reaction; IV = intravenous; LS = least squares; mBMI = modified body mass index; mNIS+7 = modified Neuropathy Impairment Score +7; Norfolk QOL-DN  = Norfolk Quality of Life-Diabetic Neuropathy; SAE = serious adverse event; SEM = standard error of the mean.

Updated 22 September 2025

References

1.  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

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.  Supplement to: 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