Long-term givosiran use shows sustained clinical benefit in patients with AHP

Elaine Soliven
15 Jan 2022
Long-term givosiran use shows sustained clinical benefit in patients with AHP

Long-term treatment with givosiran showed continued reduction in the composite annualized attack rate (AAR) of porphyria among patients with acute hepatic porphyria (AHP), according to the ENVISION* open-label extension (OLE) study presented at ASH 2021.

“The [previous] 6-month double-blind (DB) period of ENVISION showed [that] givosiran treatment was associated with reductions in AAR and ALA** and PBG** levels, hemin use, and daily pain scores vs placebo,” said lead author Dr David Kuter from Massachusetts General Hospital in Boston, Massachusetts, US. [N Engl J Med 2020;382:2289-2301]

“[Givosiran] is now approved for [the treatment of] AHP in the US and European Union,” he noted.

This study involved 94 patients with AHP who were previously randomized to either monthly subcutaneous givosiran 2.5 mg/kg or placebo for a 6-month DB period. At 6 months, all patients who were randomized to givosiran previously continued to receive the drug at a dose of 2.5 or 1.25 mg/kg (continuous givosiran group; n=48, median age 42 years), and placebo recipients were crossed over to receive givosiran (placebo-givosiran crossover group; n=46, median age 36 years) for a 30-month OLE period. [ASH 2021, abstract 3069]

From the DB to OLE period, the median number of AAR was reduced in both the continuous givosiran group (from 1.04 to 0.36) and the placebo-givosiran crossover group (from 10.65 to 0.87), which showed a 92.0 percent drop when they were switched to givosiran.

Of note, patients on placebo showed no change in ALA and PBG levels during the DB period, but when they were switched to givosiran, a rapid drop in ALA levels to near normal and in PBG levels by >90.0 percent were observed at month 36.

The placebo-givosiran crossover group also achieved a 97.0 percent decrease in the median number of annualized days of hemin use from the DB to OLE period (from 16.2 to 0.4 days), while the continuous givosiran group reported no use of hemin during the DB period and the OLE period, Kuter noted.

Both continuous givosiran and placebo-givosiran crossover groups achieved sustained improvements in quality of life (QoL), as shown by an increase in SF-12 PCS+ scores, at 36 months (mean change from baseline, from 5.1 to 8.6 and from 1.7 to 9.4, respectively). “[Of note,] those on placebo initially had a dramatic rise in the QoL when they were switched over to givosiran,” said Kuter.

Overall, injection-site reactions (32.0 percent), nausea (21.0 percent), and fatigue (14.0 percent) were the most common treatment-related adverse events (AEs) reported. Most AEs were considered mild or moderate in severity. However, one death occurred in the continuous givosiran group, and was “not felt to be related to the study drug,” Kuter said.

“In summary, the ENVISION 36-month analysis further confirms that long-term dosing with givosiran provides sustained and continuous benefits to patients with AHP … The analysis showed a sustained reduction in AAR, ALA and PBG levels, as well as hemin use, with additional improvements in QoL and physical functioning,” said Kuter.

“Long-term use [of givosiran] demonstrated a durable response, … 86.0 percent and 92.0 percent of the patients in the continuous givosiran and the placebo crossover groups, respectively, were attack-free during months 33–36,” Kuter added.


*ENVISION: A study to evaluate the efficacy and safety of givosiran (ALN-AS1) in patients with acute hepatic porphyrias (AHP)

**ALA: Delta-aminolevulinic acid

***PBG: Porphobilinogen
+PCS: Physical Component Summary

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