Background
Phase 3, double-blind, placebo-controlled RCT (ENVISION). 94 patients with acute hepatic porphyria (AHP) with ≥2 attacks in the prior year. AHP encompasses four disorders of heme biosynthesis (AIP most common; also HCP, VP, ADP) caused by inborn errors in the heme pathway. Attacks are triggered by cytochrome P450 induction (e.g., drugs, fasting, hormones) leading to accumulation of δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are neurotoxic. Givosiran (Givlaari) is a subcutaneous RNAi therapeutic targeting hepatic δ-aminolevulinic acid synthase 1 (ALAS1) mRNA via N-acetylgalactosamine-conjugated siRNA (GalNAc-siRNA). By silencing ALAS1, givosiran reduces ALA and PBG accumulation, preventing attacks without requiring lifelong hemin infusions.
Interventions and follow up
Arm A: Givosiran 2.5 mg/kg SC once monthly for 6 month
Arm B: Placebo SC once monthly for 6 month
Primary endpoint: Annualized attack rate (AAR) requiring hospitalization, urgent healthcare visit, or IV hemin at home over 6 month
mFollow up: 6 months (primary); extensio
Arm B: Placebo SC once monthly for 6 month
Primary endpoint: Annualized attack rate (AAR) requiring hospitalization, urgent healthcare visit, or IV hemin at home over 6 month
mFollow up: 6 months (primary); extensio
Results
Annualized attack rate: 3.2 (givosiran) vs 12.5 (placebo); rate ratio 0.26, 95% CI 0.16–0.41 — P<.001 (74% reduction)
Median AAR: 1.0 vs 3.0 attacks per year (P<.001)
Urinary ALA reduction: −74.9% (givosiran) vs −16.5% (placebo) — P<.001
Urinary PBG reduction: −76.3% vs −12.4% — P<.001
Hemin use: Significantly reduced in givosiran arm
Median AAR: 1.0 vs 3.0 attacks per year (P<.001)
Urinary ALA reduction: −74.9% (givosiran) vs −16.5% (placebo) — P<.001
Urinary PBG reduction: −76.3% vs −12.4% — P<.001
Hemin use: Significantly reduced in givosiran arm
Adverse events
Main adverse events: Nausea (27% vs 11%), injection-site reactions (25% vs 0%), fatigue (20% vs 15%). Aminotransferase elevations (ALT/AST): grade ≥3 in 15% (givosiran) vs 0% (placebo) — requires liver function monitoring every month. Renal toxicity (CKD progression): observed in long-term extension — ongoing surveillance recommended. Chronic kidney disease is a class effect of GalNAc-siRNA therapeutics at therapeutic doses. No anaphylaxis. Fatal adverse events: 1 in each arm (unrelated to study drug).
Conclusions
Givosiran reduced acute hepatic porphyria attacks by 74% versus placebo, with rapid and sustained reduction in ALA/PBG accumulation, establishing RNAi-targeted ALAS1 silencing as a new therapeutic approach for AHP prevention.
Key Limitations
Key Limitations: 6-month primary analysis is short for a chronic disease. Only recurrent attacker phenotype (≥2 attacks/year) studied — benefit in milder disease or ultra-rare AHP variants not established. Significant ALT/AST elevations (grade ≥3 in 15%) require monthly LFT monitoring and may limit use in patients with pre-existing liver disease. Long-term renal toxicity is a concern in the extension. Givosiran does not cure the underlying gene defect. Liver transplantation remains curative for severely affected AIP patients.
Clinical Context
Givosiran (Givlaari) was FDA approved for AHP in November 2019, becoming the first approved therapy targeting ALAS1. Prior standard was IV hemin (Panhematin) for acute attacks and avoidance of triggers. Givosiran provides preventive treatment for high-frequency attacker patients. The renal toxicity signal in long-term follow-up led to post-marketing surveillance requirements. Lumasiran uses the same GalNAc-siRNA platform for primary hyperoxaluria type 1 (ILLUMINATE trials), and inclisiran (ORION trials) uses a similar approach for LDL-C reduction, demonstrating the platform's versatility.
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