Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Petro E Petrides,Christian Loehr,Michael Klein,Maria K Beykirch,Elfriede Schuhmann,Heike Torkler,Zahra Obermeier,Brigitte Molitor

doi:10.1007/s00277-021-04547-3

Petro E Petrides, Christian Loehr + Show 6 more

Open Access

https://doi.org/10.1007/s00277-021-04547-3

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Abstract

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC–MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.

Highlights

PatientsAcute porphyrias are inborn errors of heme metabolism which are characterized by abdominal attacks and neurological disturbances in symptomatic patients [1]
The latter has been most successful with the recent completion of the phase 3 study and subsequent approval of givosiran which suppresses ∂-aminolevulinic (ALA)-synthase 1, the first enzyme of heme biosynthesis [7]
For the first couple of months she was given 1.25 mg givosiran monthly, at injection 13, the dose was adjusted to 2.5 mg

Summary

Introduction

Acute porphyrias are inborn errors of heme metabolism which are characterized by abdominal attacks and neurological disturbances in symptomatic patients [1]. Since there is a medical need, new therapies are being developed which range from enzyme substitution therapy over mRNA application to silencer RNA (siRNA) approaches [4,5,6]. The latter has been most successful with the recent completion of the phase 3 study and subsequent approval of givosiran which suppresses ∂-aminolevulinic (ALA)-synthase 1, the first enzyme of heme biosynthesis [7]. Heme is important for electron transfer systems in mitochondria (such as cytochrome b5) and—just to name a few—for various enzymes such as the family of cytochrome P450 enzymes, catalase, tryptophan pyrrolase, or cystathionine-ß-synthase, an important enzyme for homo-cysteine degradation

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