Givosiran, an ALAS1 targeted siRNA therapy, decreases the frequency of acute attacks in Acute Hepatic Porphyrias by lowering the neurotoxic heme precursors, aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we present real-world data on clinical, biochemical, efficacy and safety for 15 patients with Acute Intermittent Porphyria (ages 18–57 years,12F:3M) followed at our center. All but 1 patient had recurrent attacks (≥4/year) and 1 patient was started on givosiran for significant neuropathy likely secondary to AIP. Five patients were on prophylactic hemin before starting givosiran. Our experience shows that givosiran significantly reduces the frequency of acute attacks, with 12/14 being attack free after approximately 1 year of treatment. Of the 2 patients with recurrent attacks on givosiran, one had concurrent precipitating factors, including treatment interruption. Urine ALA normalized after starting givosiran in all patients with available data and remained normal during breakthrough attacks except for 3 patients. One of these patients had elevated urine ALA during an acute attack associated with treatment interruption. Three patients had normal urine PBG, and the remainder had elevations <4ULN. Pretreatment homocysteine levels were available for 6 patients and 3 were abnormal at baseline. All patients had elevated homocysteine level after commencing treatment. Four patients with normal ALT developed transient ALT elevations (<2.5 ULN) within the first year of treatment. Seven patients had alkaline phosphatase elevation (<2ULN) after starting givosiran, with 4 having concurrent normal AST and ALT. Elevated creatinine was noted in 8/15 patients within 6 months of treatment. Creatinine levels did not uptrend over time, 3 patients had transient elevations and 4 had intermittently abnormal creatinine. Creatinine levels remained abnormal in one patient with a baseline elevation.

Dose reduction was attempted in 8 patients due to adverse events, typically abnormal creatinine, and in 1 patient it was due to severe injection site reaction (ISR). Three patients had breakthrough attacks on a lower dose of 1.25 mg/kg/month which was well tolerated by the rest. One patient’s attack was an isolated event precipitated by taking a porphyrinogenic drug and she remains stable on a lower dose. The most common side effects were nausea, fatigue, and headache. One patient developed ISR but was able to continue treatment on lower dose and premedications. One patient developed acute pancreatitis after 3 doses of givosiran which recurred on redosing. Dosing was resumed and well tolerated at a reduced dose and frequency.

Our experience suggests that treatment can be personalized, and a decrease in dose or frequency can be attempted in patients with adverse events. Homocysteine levels, liver enzymes and renal function should be closely monitored. Long term data are needed to determine the efficacy, safety, and risk benefit profile of modified dosing regimens.