Background Acute hepatic porphyria (AHP) is a group of rare, chronic, multisystem disorders characterized by acute attacks, chronic symptoms, progressive elements, and long-term complications requiring proactive management. Givosiran is an RNAi therapeutic approved for AHP treatment. In ENVISION (NCT03338816), givosiran treatment led to sustained reductions in annualized attack rate (AAR). Among patients who completed the study through month (M) 36, 58% were attack-free after their first 6M of givosiran treatment for the duration of the trial. In this analysis, we examined treatment outcomes in patients who were not attack-free after their first 6M of givosiran treatment.

Methods Eligible patients had AHP, were aged ≥12 years, and had experienced ≥2 attacks requiring hospitalization, urgent care, or intravenous (IV) hemin at home within 6M before study enrollment. A 6M placebo-controlled double-blind (DB) period was followed by a 30M open-label extension (OLE) period in which all patients received givosiran. This post hoc, descriptive analysis included patients who were randomized in the DB period and completed the OLE period. Subgroups were defined based on patient attack frequency after the first 6M of givosiran treatment (0 attacks, attack-free; ≥1 attack, not attack-free).

Results 94 patients were randomized, and 79 completed ENVISION; 46 (58%) were attack-free and 33 (42%) were not attack-free. Among patients who were not attack-free, the mean percentage reduction in composite AAR (attacks requiring hospitalization, urgent care, or IV hemin at home) per 6M interval were 57% after >6–12M of givosiran treatment and 85% after >30–36M, relative to historical composite AAR (mean [SD], 12.8 [9.6]). Of those patients who were not attack-free in the first 6M of treatment, the percentage of patients who were attack-free during 6M treatment intervals increased from 9% after >6–12M to 79% after >30–36M of further treatment. Quality of life improved in both groups: after 6M and 36M of treatment, mean SF-12 version 2 Physical Component Summary scores increased from baseline by 7.3 and 8.3 points (attack-free group) and 4.1 and 9.1 (not attack-free group); EQ-VAS scores increased by 6.9 and 19.9 points (attack-free group) and 2.2 and 17.5 points (not attack-free group). After 6M and 36M of givosiran treatment, median percentage reductions from baseline in aminolevulinic acid levels were 88% and 93% (attack-free group) and 85% and 92% (not attack-free group), and median percentage reductions from baseline in porphobilinogen levels were 88% and 97% (attack-free group) and 86% and 93% (not attack-free group).

Conclusions Both patient groups had reduced attacks and other treatment-related improvements within the first 6M of givosiran treatment. Those who were not attack-free after the first 6M of treatment experienced further attack reductions and quality of life improvements with longer-term givosiran treatment, similar to those observed in the attack-free group.