Patisiran: Vitamin A Levels

Patisiran: Vitamin A Levels

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The full Prescribing Information for ONPATTRO® (patisiran) is provided here. Alnylam Pharmaceuticals does not recommend the use of its products in any manner that is inconsistent with the approved Prescribing Information. This resource may contain information that is not in the approved Prescribing Information.

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INDEX

Mechanism of Action – Clinical Data – Global Safety Database – Labeling 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. Consequentially, 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 during treatment with patisiran.1

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.8 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.2

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.4 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.l±15.7% (range: 53 to -29%) in the placebo arm (Figure 1).1

Figure 1. Change in Vitamin A over 18 Months.4

APOLLO-B

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.3

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.5

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.6

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.6 At 18 months, the AE of vitamin A decreased was reported in 2 patients (4.8%) in the patisiran arm. This AE was considered by the Investigator to be related to patisiran treatment.7

Global Safety Database

Vitamin A deficiency is a clinical syndrome resulting from low vitamin A levels. Typical signs and symptoms include night blindness, xeropthalmia, and keratomalacia.9 In patisiran clinical studies, vitamin A deficiency events were identified by using the following Preferred Terms: “Keratomalacia,” “Night blindness,” “Vitamin A decreased,” “Vitamin A deficiency,” “Vitamin A deficiency eye disorder,” “Vitamin A deficiency related conjunctival disorder,” “Vitamin A deficiency related corneal disorder,” and “Xerophthalmia.”1

Patisiran has been associated with decreased vitamin A levels due to reductions in RBP. However, physiologic consequences of this reduction in vitamin A levels have not been observed despite extensive monitoring in clinical trials, including electroretinography. 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. No new and important safety information relevant to this risk was identified in any of the available sources.1

onpattro us prescribing information – Relevant content

The WARNINGS AND PRECAUTIONS section of the ONPATTRO US Prescribing Information provides the following information10:

Reduced Serum Vitamin A Levels and Recommended Supplementation

ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking ONPATTRO. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum vitamin A levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

The ADVERSE REACTIONS section of the ONPATTRO US Prescribing Information provides the following information10:

Clinical Trials Experience

Patients were instructed to take the recommended daily allowance of vitamin A. Sixty-four percent of patients treated with ONPATTRO had normal vitamin A levels at baseline, and 99% of those with a normal baseline developed low vitamin A levels. In one case, the decreased vitamin A level was reported as an adverse reaction.

The USE IN SPECIFIC POPULATIONS section of the ONPATTRO US Prescribing Information provides the following information10:

Pregnancy

There are no available data on ONPATTRO use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. ONPATTRO treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking ONPATTRO. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by ONPATTRO and of vitamin A supplementation are unknown.

The CLINICAL PHARMACOLOGY section of the ONPATTRO US Prescribing Information provides the following information10:

Pharmacodynamics

Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months.

Abbreviations

6-MWT = 6-minute walk test; AE = adverse event; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IU = international unit; IV = intravenous; mNIS+7 = modified Neuropathy Impairment Score +7; PD = pharmacodynamic; PT = Preferred Term; RBP = retinol binding protein; SD = standard deviation; SEM = standard error of the mean; TTR = transthyretin; wtATTR = wild-type transthyretin amyloidosis.

Updated 2 October 2024

References

1.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTR02-2300176.

2.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTR02-1800579.

3.  Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553-1565. doi: 10.1056/NEJMoa2300757.

4.  Zhang X, Goel V, Attarwala H, Sweetser MT, Clausen VA, Robbie GJ. Patisiran pharmacokinetics, pharmacodynamics, and exposure‐response analyses in the phase 3 APOLLO trial in patients with hereditary transthyretin‐mediated (hATTR) amyloidosis. J Clin Pharmacol. 2019;60(1):37-49. doi:10.1002/jcph.1480

5.  Alnylam Pharmaceuticals, Inc. APOLLO-B: a study to evaluate patisiran in participants with transthyretin amyloidosis with cardiomyopathy (ATTR amyloidosis with cardiomyopathy). ClinicalTrials.gov website. Updated September 19, 2024. Accessed October 2, 2024. ClinicalTrials.gov Identifier: NCT03997383.

6.  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

7.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2200007.

8.  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

9.  Johnson LE. Vitamin A deficiency - nutritional disorders. Merck Manuals Professional Edition. November 2022. Accessed September 21, 2023. https://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency,-dependency,-and-toxicity/vitamin-a-deficiency.

10.  ONPATTRO (patisiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.