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

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.

Multiple roles of haem in cystathionine β-synthase activity: implications for hemin and other therapies of acute hepatic porphyria

“…The elevation of plasma [Met] observed in both studies [129,130] suggests impaired conversion of Hcy to Met, possibly mediated by the MTHFR polymorphism and/or decreased availability of hepatic folate and B 12 .…”

“…In addition to the study in 2020 by Ventura et al [2] and that by To-Figueras et al 10 years earlier [1], further reports of the Hcy status in AIP have since appeared. Both the French and Italian Porphyria Centres and others in the Envision givosiran trial have observed strong elevations of [Hcy] in porphyric patients (see [129] and references cited therein). Notable among these reports are those by Petrides et al [129] and To-Figueras et al [130].…”

“…Both the French and Italian Porphyria Centres and others in the Envision givosiran trial have observed strong elevations of [Hcy] in porphyric patients (see [129] and references cited therein). Notable among these reports are those by Petrides et al [129] and To-Figueras et al [130]. In [129], 2 AIP patients receiving 5-ALAS 1 gene silencing therapy with givosiran developed strong elevations of plasma [Hcy] of 100-200 and 100-400 µM.…”

“…Notable among these reports are those by Petrides et al [129] and To-Figueras et al [130]. In [129], 2 AIP patients receiving 5-ALAS 1 gene silencing therapy with givosiran developed strong elevations of plasma [Hcy] of 100-200 and 100-400 µM. Both patients exhibited strong adverse reactions: a severe systemic allergic reaction in one and fulminant pancreatitis in the other, which could be attributed to the severe Hcy elevation.…”

“…Both patients exhibited strong adverse reactions: a severe systemic allergic reaction in one and fulminant pancreatitis in the other, which could be attributed to the severe Hcy elevation. The authors [129] attributed the Hcy elevations in part to a single mutation in the MTHFR gene and to a givosiran-induced decrease in haem availability. This latter explanation is strongly supported by their observation of a prompt decline in plasma [Hcy] upon haem arginate administration that gave way shortly (3 days) after termination of haem therapy to a return of the elevation induced by givosiran.…”