# Real-World Experience With Givosiran in Acute Porphyrias: A Narrative Review and a Novel Hypothesis

## TL;DR

This paper reviews real-world use of givosiran for acute porphyria and proposes a new hypothesis about gallbladder involvement in treatment resistance.

## Contribution

The paper introduces a novel hypothesis linking gallbladder function and bile acid metabolism to givosiran-resistant porphyria attacks.

## Key findings

- Real-world data confirms givosiran's high efficacy but also reports adverse effects like homocysteinemia and kidney issues.
- Breakthrough attacks remain a challenge, suggesting incomplete therapeutic control in some patients.
- A new hypothesis proposes gallbladder dysfunction and bile acid metabolism as potential contributors to treatment resistance.

## Abstract

Real-world experience with givosiran has been accumulating after its approval for the treatment of patients with acute porphyria and chronic attacks in the United States and in Europe, respectively. Up to now, nearly as many patients from various countries have been treated after the registration of the drug and reported in real-world studies as treated in the randomized phase 3 ENVISION trial. Most reports confirm high drug efficiency, but some also report adverse effects (homocysteinemia, lipase elevation, and kidney function impairment). Moreover, many patients suffer from breakthrough attacks, which remain a conundrum. Since gallbladder epithelial cells also contain the asialoglycoprotein receptor, which is a prerequisite for the uptake of givosiran, it could be that the siRNA-induced depletion of haem leads to a disturbance of the function of the gallbladder. Therefore, we hypothesize a potential role of the gallbladder and the metabolism of bile acids in the development of porphyria and givosiran-resistant attacks, which has to be supported by clinical or experimental validation.