Patisiran: Vitamin A Levels

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Summary

 Treatment with patisiran reduces serum TTR levels, resulting in reduced levels of RBP and vitamin A in the serum. In the APOLLO study, serum vitamin A levels were reduced in parallel with reductions in serum TTR levels in patients treated with patisiran.1,2

 In the phase 3 APOLLO and APOLLO-B studies, patients were advised to take vitamin A supplementation at the recommended daily allowance. In the APOLLO study, patients were required to take an oral daily supplemental dose of 2,500 IU of vitamin A.3,4

 In a pooled analysis including data from phase 3 vutrisiran and patisiran clinical studies, no safety findings attributable to vitamin A deficiency were observed or led to study drug discontinuation. Patients were instructed to take daily vitamin A supplementation in these studies.5

 A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any AEs definitively resulting from vitamin A deficiency in patients treated with patisiran.1

 Supplementation at the recommended daily allowance of vitamin A is advised for patients taking patisiran.6 Alnylam is unable to provide patient specific recommendations on the dose or type of vitamin A supplement beyond the recommended daily dose.

Index

Mechanism of Action – Clinical Data – Global Safety Database – Label Information – Abbreviations – References

Mechanism of Action

Serum TTR is a carrier of RBP, facilitating transport of vitamin A in the blood. Treatment with patisiran reduces serum TTR levels, resulting in reduced levels of RBP and vitamin A in the serum. The mechanism of action attributes to the theoretical risk of vitamin A deficiency. However, the transport and tissue uptake of vitamin A can occur through alternative mechanisms in the absence of RBP. Patients receiving TTR-lowering RNAi therapeutics are advised to receive vitamin A supplementation at the recommended daily allowance, as a precautionary measure.5,7–11

Laboratory tests for serum vitamin A do not reflect the total amount of vitamin A in the body and should not be used to guide vitamin A supplementation beyond the recommended daily dose during treatment with patisiran.5

Clinical Data

APOLLO Study

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. Vitamin A levels were measured as a PD assessment, and the percent reduction in vitamin A levels over time was included as an exploratory endpoint.12 All patients in the study were required to take a daily supplement containing the dose of 2,500 IU of vitamin A, the approximate recommended daily allowance.3

At baseline, mean (±SD) serum vitamin A levels were 37.8±13.7 µg/dL (range: 11.0 to 70.0 µg/dL) in the patisiran group and 37.0±12.3 µg/dL (range: 14.0 to 67.0 µg/dL) in the placebo group. In the patisiran arm, serum vitamin A levels decreased in parallel with decreasing serum TTR levels.2 At 18 months, the mean percent change in serum vitamin A was -62.4±14.4% (range: -9 to ‑84%) in the patisiran arm and ‑0.1±15.7% (range: 53 to -29%) in the placebo arm (Figure 1).1

Figure 1. Change in Vitamin A over 18 Months.2,a

A graph of a number of people

Description automatically generated

Abbreviations: SEM = standard error of the mean.

aError bars represent SEM.

From Zhang et al.2

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. After the 12-month double-blind treatment period, all patients received patisiran in an open-label extension period.4

All patients were instructed to take the recommended daily allowance of vitamin A for the duration of their participation in the study. Data regarding change in serum vitamin A levels is not available as it was not evaluated as part of the APOLLO-B study design.13

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.14

Consistent with the expected PD effect from previous studies, serum vitamin A levels decreased in parallel with reductions in the TTR levels in the patisiran reference arm.14

Pooled Safety Analysis

An analysis of pooled data from patients with ATTR-CM or hATTR-PN who received at least 1 dose of vutrisiran, patisiran, or placebo from Phase 3 studies was conducted to evaluate the frequency and event rates of clinical and/or laboratory AEs related to vitamin A deficiency (Table 1).5

There were no reports of visual AEs directly attributed to vitamin A deficiency and therefore were no confirmed cases of clinical vitamin A deficiency. No events attributed to vitamin A deficiency led to study drug discontinuation.5

Table 1. Event Rates for PTs Related to Vitamin A Deficiency.5

PT, n events / EAER (per 100 PY)	Patisiran APOLLO, Patisiran OLEa, APOLLO-B, HELIOS-A N=613; PY=1831.9	Vutrisiran HELIOS-A, HELIOS-B N=709; PY=1915.1	Placebo APOLLO, APOLLO-B, HELIOS-B N=583; PY 1098.5
PTb, Clinical and/or Laboratory
Dry eye	24 / 1.3	17 / 0.9	11 / 1.0
Keratomalacia	0	0	0
Retinopathy	0	0	0
Vitamin A deficiency-related eye disorder	0	0	0
Vitamin A deficiency-related conjunctival disorder	0	0	0
Vitamin A deficiency-related corneal disorder	0	0	0
Xerophthalmia	0	1 / 0.1	1 / 0.1
PTb, Laboratory only
Vitamin A decreased	2 / 0.1	11 / 0.6	NRc
Vitamin A deficiency	2/ 0.1	2 / 0.1	NRc

Abbreviations: AE = adverse event; EAER = exposure-adjusted event rate; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; NR = not reported; OLE = open-label extension; PT = preferred term; PY = patient-years.

aIncludes patients with hATTR-PN from the APOLLO and patisiran Phase 2 OLE study.

bList of PTs has been previously established to monitor for AEs related to vitamin A deficiency in post-marketing aggregate safety reports.

cLaboratory vitamin A decrease or deficiency would not be reported for patients receiving placebo, as they were in the double-blind period of corresponding studies during which vitamin A measurements were prohibited due to risk of unblinding.

Global Safety Database

Patisiran has been associated with decreased vitamin A levels due to reductions in RBP. Clinical consequences of this reduction in vitamin A levels have not been observed despite extensive monitoring in clinical trials. A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any AEs definitively resulting from vitamin A deficiency in patients treated with patisiran.1

ONPATTRO Prescribing Information – Relevant Content

For relevant labeling information, please refer to the following sections of the ONPATTRO Prescribing Information6:

 WARNINGS AND PRECAUTIONS Section 5.2 Reduced Serum Vitamin A Levels and Recommended Supplementation

 ADVERSE REACTIONS Section 6.1 Clinical Trials Experience

 USE IN SPECIFIC POPULATIONS Section 8.1 Pregnancy

 CLINICAL PHARMACOLOGY Section 12.2 Pharmacodynamics

 PATIENT COUNSELING INFORMATION Section 17

Abbreviations

6-MWT = 6-minute walk test; AE = adverse event; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; EAER = exposure‑adjusted event rate; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IU = international unit; IV = intravenous; mNIS+7 = modified Neuropathy Impairment Score +7; NR = not reported; OLE = open-label extension; PD = pharmacodynamic; PT = preferred term; PY = patient-years; RBP = retinol binding protein; RNAi = ribonucleic acid interference; SD = standard deviation; SEM = standard error of the mean; TTR = transthyretin; wtATTR = wild‑type transthyretin amyloidosis.