Abstract
Background & AimsUpregulation 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.MethodsInterim 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.ResultsPatients 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.ConclusionsLong‐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.
Highlights
These defects predispose for triggering factors inducing delta-aminolevulinic acid synthase 1 (ALAS1), the initial and normally rate-controlling enzyme of the heme biosynthesis pathway7,8; trigger factors may lead to further induction of ALAS1.9 In Acute hepatic porphyria (AHP), this can lead to accumulation of the potentially toxic porphyrin precursors ALA and porphobilinogen (PBG), thought to be causal for disease manifestations, as well as porphyrins.9-11
Repeated prophylactic use of hemin may be associated with reduced efficacy, and it is associated with adverse event (AE) such as venous damage and thrombophlebitis, coagulation abnormalities, and secondary iron overload
Consistent with the results from the double-blind period, this 24-month interim analysis of the ENVISION study confirms that long-term givosiran dosing leads to continuous and sustained reductions in attack rate (AAR) and hemin use, with 83% and 76% of patients being attack-free, and 68% and 49% of patients, respectively, not requiring supplemental hemin
Summary
Acute hepatic porphyria (AHP) is a family of four rare genetic diseases characterized by potentially life-threatening acute attacks and, for some patients, chronic manifestations impacting daily functioning and quality of life (QOL).1-4 The AHP types are acute intermittent porphyria (AIP; most common), variegate porphyria (VP), hereditary coproporphyria (HCP), and delta-aminolevulinic acid (ALA) dehydratase–deficiency porphyria. Clinical manifestations are due to pathogenic mutations leading to deficiency in an enzyme of hepatic heme biosynthesis. These defects predispose for triggering factors inducing delta-aminolevulinic acid synthase 1 (ALAS1), the initial and normally rate-controlling enzyme of the heme biosynthesis pathway; trigger factors may lead to further induction of ALAS1.9 In AHP, this can lead to accumulation of the potentially toxic porphyrin precursors ALA and porphobilinogen (PBG), thought to be causal for disease manifestations, as well as porphyrins.9-11The most severe symptoms of AHP occur during acute neurovisceral attacks, which manifest most commonly as severe abdominal pain, nausea, vomiting, tachycardia, hypertension, hyponatraemia, mental status changes, muscle weakness, and change in urine colour to red/brown. Attacks often require hospitalization and, without prompt treatment, can result in paralysis, respiratory failure, and, rarely, permanent neurologic deficits or death. Approximately 3% to 8% of symptomatic patients with AIP experience recurrent attacks (≥4 attacks/year). Some patients . 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. 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
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