Background Givosiran is an interfering RNA therapeutic targeting hepatic ALAS1 mRNA, and the first-in-its-class drug approved for treatment of acute hepatic porphyrias (AHP). It reduces ALAS1 expression, thus reducing delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) over-production and accumulation. Here, we present a case of a patient with acute intermittent porphyria (AIP) who is on prophylaxis with givosiran and continues to have sporadic acute attacks in spite of normalization of ALA and PBG.

Case This 21-year-old Black female initially presented with multiple episodes of abdominal pain, nausea, and emesis associated with the luteal phase of the menstrual cycle. After several months she was diagnosed with AIP and responded to treatment with hemin for amelioration of attacks. She was admitted for an acute attack shortly after relocating to Texas. Labs at that time showed a PBG of 67.3 mg/g creatinine (ref 0–7) and ALA of 45 mg/g creatinine (ref 0–4). The attack resolved with treatment that included hemin and opioids. Givosiran 2.5mg/kg subcutaneously was started after discharge. She has received 21 doses of givosiran over 612 days, with dosing intervals ranging from 26–38 days. Initially her PBG was 43.2 mg/g Cr, but normalized on givosiran and has remained normal during treatment (range 0.7–2.7). Attacks have been less frequent, but she was hospitalized with acute attacks between doses 4–5, 7–8 and 15–16. PBG levels on these admissions were normal, at 1.1, 2.7, and 1.0 mg/g Cr respectively, and the attacks resolved after treatment with hemin (1–4 doses). ALA levels were also normal at the time of the attacks. She remains well between less frequent attacks on prophylactic givosiran with normal PBG and ALA levels.

Discussion An elevation in urine PBG is the hallmark of a porphyria attack and is considered a criterion for diagnosis of AHP attacks. Additionally, PBG levels are expected to decrease as symptoms resolve. The goal of givosiran prophylaxis is normalization of urine PBG and prevention of attacks. In clinical trials of givosiran, attack rates were substantially reduced in AHP patients, but levels of ALA and PBG that occurred during infrequent attacks were not described. In this case, occasional acute AIP attacks were observed during givosiran treatment in spite of sustained normalization of PBG and ALA levels. This suggests that mechanisms additional to elevation in levels of ALA and PBG, which are potentially neurotoxic, may contribute to symptoms during attacks of AHP.