ENVISION Phase 3 Results for Givosiran Presented at EASL

12 Apr, 2019 ENVISION Phase 3 Results for Givosiran Presented at EASL

We presented positive complete results from the ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic in development for the treatment of acute hepatic porphyria (AHP), at the European Association for the Study of the Liver (EASL) 54^th Annual International Liver Congress™, held April 10 – 14, 2019 in Vienna, Austria.

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Balwani et al. – “ENVISION, a Phase 3 Study to Evaluate the Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase 1, in Acute Hepatic Porphyria Patients”

Sardh et al. – “Management of Recurrent Acute Hepatic Porphyria (AHP) Attacks in Europe and the United States: EXPLORE International, Prospective, Natural History Study”

Ventura et al. – “Disease Manifestations of Patients with Recurrent Acute Hepatic Porphyria (AHP) and Daily Life Impacts in EXPLORE International, Prospective, Natural History Study”

ENVISION Phase 3 Results
The ENVISION trial enrolled 94 AHP patients at 36 sites in 18 countries. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg quarterly for six months.

• Givosiran met the primary efficacy endpoint with a 74% mean reduction in the annualized composite rate of porphyria attacks in AIP patients relative to placebo.
  • A 90% reduction in median AAR was observed.
  • 50% of patients on givosiran were attack-free during the six-month treatment period (16.3% for placebo).
    • In patients who experienced one or more attacks, patients on givosiran experienced a 50% reduction in AAR relative to placebo.
  • All components of composite attacks were reduced and all subgroup analyses showed givosiran treatment benefit.

• Givosiran also demonstrated statistically significant differences in five of nine hierarchically tested secondary endpoints relative to placebo, including the following:
  • Givosiran demonstrated a 73% reduction in mean AAR in patients with any AHP, relative to placebo.
  • Givosiran resulted in a reduction in days of hemin use of 77% compared to placebo.
  • Givosiran led to sustained ~90% lowering from baseline of ALA and PBG, the neurotoxic liver heme intermediates causal for attacks and other AHP disease manifestations.

• The overall safety and tolerability profile for givosiran was encouraging in AHP, a serious disease.
  • Adverse events were reported in 89.6% of givosiran patients and 80.4% of placebo patients; serious adverse events were reported in 20.8% of givosiran patients and 8.7% of placebo patients.
  • ALT elevations occurred more frequently in givosiran patients than placebo after 3 to 5 doses.
    • 6 of 7 patients with ALT ≥ 3x ULN have continued givosiran dosing.
  • Mild and mostly reversible increases in creatinine and decreases in eGFR were seen more commonly in givosiran than placebo; none led to study drug discontinuation.

• All eligible patients (93/94) continued in the open-label extension period of the study.

• A greater proportion of patients on givosiran reported improvements in their overall health, daily functioning, and treatment satisfaction, compared to placebo.

We believe these results from the ENVISION study are promising and demonstrate a strong treatment effect and encouraging tolerability profile for givosiran in a high unmet need disease.

EXPLORE International, Prospective Natural History Results

Additional results from the EXPLORE international, prospective natural history study in AHP patients were also presented.