Extending givosiran use may help non–attack-free AHP patients achieve attack-free status

Patients with acute hepatic porphyria (AHP) who do not achieve an attack-free status after the first 6 months of givosiran treatment can still benefit from further attack reductions and quality of life improvements with treatment extension up to 36 months, according to the results from the phase III ENVISION trial presented at EASL 2024.

“Considering the longitudinal trajectory, in these patients … the mean composite annualized attack rate (AAR) decreased continuously over time,” said lead author Dr Paolo Ventura from the Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy.

From a historical AAR with a mean of 12.8 attacks per year, the mean composite AAR reduced to 7 after >0 to 6 months of givosiran treatment, reflecting a mean reduction of −39.7 percent. The magnitude of reduction increased further as the duration of treatment extended, reaching −84.5 percent after >24 to 30 months and −85.4 percent after >30 to 36 months of treatment. [EASL 2024, poster WED-165]

Longer-term givosiran treatment

ENVISION was a registrational randomized trial to assess the efficacy and safety of givosiran, a conjugated small interfering RNA-based therapy directed towards δ-aminolevulinic acid synthase 1, vs placebo in patients with symptomatic AHP (n=94). [N Engl J Med 2020;382:2289-2301]

After a 6-month double-blind, placebo-controlled period, patients in both arms entered a 30-month open-label extension, during which all patients received givosiran. [J Hepatol 2023;79:1150-1158]

Composite attacks defined in the trial were attacks that required hospitalization, an urgent healthcare visit, or intravenous haemin administration at home.

Based on the attack frequency after the first 6 months of givosiran treatment, 79 patients who completed the 36-month trial were categorized into two groups: attack-free (0 attacks; 58.2 percent) and not attack-free (≥1 attack; 41.8 percent). Those who were not attack-free tended to be younger in age (median at screening, 36 vs 41.5 years).

Historical AAR, serving as the baseline, represents the annualized number of composite attacks during the 6 months prior to randomization.

Quality of life, biochemical markers

Among patients experiencing ≥1 attack, health-related quality of life (HRQoL) improved after 6 months of givosiran treatment, as reflected by the mean changes in EuroQol Visual Analogue Scale (EQ-VAS; 2.2) and 12-item Short Form Health Survey (SF-12) version 2 Physical Component Summary (PCS; 4.1) scores. These scores became noticeably greater after 30 months of treatment (10.9 and 8, respectively), and even more so after 36 months (17.5 and 9.1).

While the HRQoL improvements after 6 months of givosiran treatment were generally smaller in patients who were not attack-free vs those who were attack-free (mean changes, 2.2 vs 6.9 [EQ-VAS] and 4.1 vs 7.3 [SF-12 PCS]), the improvements towards the end of the study exceeded the clinically meaningful differences for both QoL measures.

With regard to the exploratory endpoints of urinary levels of δ-aminolevulinic acid and porphobilinogen, the levels of both biochemical disease markers reduced by a median of >80 percent from baseline after 6 months and by >90 percent after 36 months of treatment.

“The long-term treatment with givosiran provides sustained benefits for patients with AHP, including those who are not attack-free after 6 months of treatment," concluded Ventura.