Efficacy and safety of givosiran for acute hepatic porphyria: 24‐month interim analysis of the randomized phase 3 ENVISION study

Abstract

Background & Aims Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria. Methods Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. Results Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period. Conclusions Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.

Spotlight on Givosiran as a Treatment Option for Adults with Acute Hepatic Porphyria: Design, Development, and Place in Therapy

“…With the statistically significant results in the phase III ENVISION study an OLE study was performed for a 24-month interval on all eligible patients from the ENVISION study for a total of 30 months. 66 The givosiran group from the ENVISION study continue to receive givosiran 2.5 mg/kg while the placebo group from ENVISION study crossed over and received givosiran 1.25 mg/kg. Givosiran treatment led to sustained lowering of median ALA levels to near normal and PBG levels by >75% through month 24 as seen in Figure 6 .…”

“…Renal adverse events were reported in 21 patients; however, none required treatment discontinuation. 66 …”

“…There are concerns that the decrease in ALAS1 could eventually cause hepatic heme deficiency and would also impact heme-dependent processes in hepatocytes. There have been reports of elevated homocysteine levels in AHP patients that are being treated with givosiran, 66 , 68 especially in patients with variants that reduce activity of the methylene-tetrahydrofolate reductase [MTHFR] gene. 69 , 70 Several mechanisms have been proposed for this finding, including cystathionine beta-synthase (CBS) impairment caused by low heme availability in the liver.…”

Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

“…A novel siRNA-based agent, givosiran, exploits the native RNA-induced silencing complex (RISC) to specifically modulate liver ALAS1 mRNA translation [ 10 , 11 , 12 ]. Givosiran has shown excellent results in terms of reduction in acute attacks per year and an overall improvement of quality of life in symptomatic patients with AHP [ 10 , 11 ].…”

“…In recent years, a novel siRNA-based drug, givosiran, has been approved for the treatment of acute hepatic porphyrias [ 10 , 11 ]: by specifically inhibiting the liver isoform of ALA synthase (ALAS1), the first and rate-limiting enzyme of the heme biosynthetic pathway, givosiran has shown to be highly efficacious in reducing the frequency of porphyric attacks and improving the quality of life of patients with AHPs [ 12 ].…”