In patients with acute hepatic porphyria, by what percentage did the main annual attack rate fall in the givosiran (RNAi therapeutic) group compared to the placebo group in the ENVISION trial?

ENVISION Trial: Givosiran Attack Rate Reduction in Acute Hepatic Porphyria

In the ENVISION trial, givosiran reduced the annualized attack rate by 74% compared to placebo in patients with acute intermittent porphyria. 1

Primary Efficacy Results

The phase 3 ENVISION trial demonstrated that among 89 patients with acute intermittent porphyria (the most common subtype of AHP):

• Mean annualized attack rate was 3.2 in the givosiran group versus 12.5 in the placebo group 1
• This represented a 74% reduction in attack rate (P<0.001) 1
• Results were consistent across the broader population of 94 patients with all AHP subtypes 1

Long-Term Sustained Efficacy

The durability of this effect was maintained throughout extended follow-up:

• At 24 months, patients on continuous givosiran maintained a median annualized attack rate of 0.0 in the open-label extension period 2
• At 36 months (final analysis), the median annualized attack rate remained 0.4 with sustained treatment 3
• By end of the open-label extension, 86% of continuous givosiran patients and 92% of placebo crossover patients had zero attacks 3

Additional Clinical Benefits Beyond Attack Reduction

Givosiran demonstrated multiple secondary benefits that directly impact morbidity and quality of life:

• Hemin use decreased dramatically: median annualized days of hemin use fell from 14.98 to 0.71 in placebo crossover patients, with 88-90% of patients requiring zero days of hemin by study end 3, 2
• Pain scores improved: daily worst pain scores were significantly better than placebo during the double-blind period 1
• Quality of life increased substantially: SF-12 physical component scores increased by 8.6 points and mental component scores by 8.1 points in the continuous givosiran group 3
• Biochemical markers normalized: sustained lowering of urinary delta-aminolevulinic acid and porphobilinogen levels was maintained throughout treatment 3, 2

Important Safety Considerations

While the efficacy is compelling, clinicians must monitor for specific adverse events that occurred more frequently with givosiran:

• Hepatic monitoring is essential: serum aminotransferase elevations >3× upper limit of normal occurred during the first 3-6 months of treatment, requiring monthly liver enzyme monitoring during this period 4
• Renal function surveillance: changes in serum creatinine and estimated glomerular filtration rate were observed, necessitating at least annual monitoring (more frequently in patients on givosiran) 4, 1
• Additional laboratory monitoring: homocysteine, amylase, and lipase elevations require screening 4

Clinical Context and Guideline Recommendations

The American Gastroenterological Association (2023) recommends:

• Givosiran should be prescribed only for patients with recurrent acute attacks that are both biochemically and genetically confirmed 4
• Contraindicated in pregnancy: due to limited safety data, givosiran should not be used in women who are pregnant or planning pregnancy 4
• The 74% reduction in attack rate represents a clinically meaningful improvement in a disease where patients experience substantial chronic burden, with 65% reporting chronic symptoms and 46% experiencing daily symptoms 4

The magnitude of benefit (74% reduction) combined with the sustained long-term efficacy and improvements in quality of life establishes givosiran as a transformative therapy for patients with recurrent AHP attacks, though careful patient selection and monitoring protocols are mandatory given the hepatic and renal safety signals.