Efficacy & Safety
ENVISION: The largest interventional study in acute hepatic porphyria (AHP)1
ENVISION is a randomized, double-blind, placebo-controlled, multinational Phase 3 study in patients with AHP (N=94), with a 30-month open-label extension (OLE) (N=93)1-3


*These measures were in AIP patients only.2
†All endpoints were considered exploratory in the ENVISION OLE period.3
‡A protocol amendment increased the dose for all patients to 2.5 mg/kg once monthly.3
ALA=delta-aminolevulinic acid; PBG=porphobilinogen; qM=once monthly; SC=subcutaneous.
- Patients who experienced an AHP attack during the study were treated according to the local standard of care, which could include IV hemin1,2
ENVISION study patient population1-3
GIVLAARI (N=48) | Placebo (N=46) | Overall (N=94) | |
Mean age, years (range) | 42 (19, 65) | 36 (20, 60) | 37.5 (19, 65) |
Female, n (%) | 43 (90) | 41 (89) | 84 (89) |
Caucasian, n (%) | 39 (81) | 34 (74) | 73 (78) |
AHP type, n (%) | |||
– AIP | 46 (96) | 43 (93) | 89 (95) |
– HCP | 1 (2) | 0 (0) | 1 (1) |
– VP | 1 (2) | 1 (2) | 2 (2) |
– No identified mutation | 0 (0) | 2 (4) | 2 (2) |
Attacks* in past 6 months, median (range) | 4 (2, 24) | 3 (0, 25) | 3 (0, 25) |
Prior hemin prophylaxis, n (%) | 20 (42) | 18 (39) | 38 (40) |
Prior chronic opioid use, n (%)† | 14 (29) | 13 (28) | 27 (29) |
Prior chronic symptoms, n (%)‡ | 23 (48) | 26 (57) | 49 (52) |
*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1
†Use of opioids was defined as chronic if patients reported taking them for porphyria daily, or on most days, when not having an attack.
‡Symptoms were chronic if patients experienced symptoms of porphyria daily, or on most days, when not having an attack.
All eligible patients (93 of 94) enrolled in the open-label extension (OLE).3
Efficacy in the ENVISION 6-month double-blind period and 12-month OLE
In patients with AHP in the ENVISION 6-month double-blind period
Treatment with GIVLAARI led to a significant reduction in porphyria attacks1*
*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1
In a 12-month interim analysis of patients with AHP in the ENVISION OLE
Patients who continued treatment with GIVLAARI® (givosiran) had sustained attack* reduction3
- Attack* reduction was sustained in patients continuing treatment with GIVLAARI during the OLE period3
- Patients who crossed over from placebo to GIVLAARI had attack* reduction in the OLE period (for a total of 6 months of treatment) similar to that seen in GIVLAARI patients in the double-blind period3†
- Endpoints in the OLE period are exploratory3
*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1
†Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.3
Safety profile of GIVLAARI in the ENVISION 6-month double-blind period1
Adverse Reaction | GIVLAARI (N=48) n (%) |
Placebo (N=46) n (%) |
Nausea | 13 (27) | 5 (11) |
Injection site reactions | 12 (25) | 0 |
Rash* | 8 (17) | 2 (4) |
Serum creatinine increase† | 7 (15) | 2 (4) |
Transaminase elevations | 6 (13) | 1 (2) |
Fatigue | 5 (10) | 2 (4) |
*Grouped term includes pruritus, eczema, erythema, rash, rash pruritic, urticaria.
†Grouped term includes blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease (decreased estimated glomerular filtration rate).
- Permanent discontinuation of GIVLAARI occurred in 1 patient (2.1%) due to elevated transaminases, in adherence with prespecified protocol-defined stopping rules1,3
- No additional discontinuations due to adverse events in the ENVISION OLE period3
- The most frequently occurring (≥20%) adverse reactions reported in patients treated with GIVLAARI were nausea (27%) and injection site reactions (25%)1
- The safety profile of GIVLAARI in the OLE period through Month 12 was similar to that observed in the 6-month double-blind period3
eGFR=estimated glomerular filtration rate; OLE=open-label extension.
In patients with AHP in the ENVISION 6-month double-blind period
A greater number of patients treated with GIVLAARI had zero attacks* vs placebo1,2*
*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1
AHP=acute hepatic porphyria; DB=double blind.
In a 12-month interim analysis of patients with AHP in the ENVISION OLE
The number of patients with zero attacks* increased with continued treatment with GIVLAARI3†
In the patients who crossed over from placebo to GIVLAARI, more had zero attacks* after starting GIVLAARI3
*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1
†Data or GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.3
DB=double-blind; OLE=open-label extension.
In patients with AHP in the ENVISION 6-month double-blind period
Significantly less hemin was used by patients treated with GIVLAARI1
70% reduction in average days of hemin use with GIVLAARI vs placebo
- Ratio of average days of hemin use (GIVLAARI:placebo): 0.3 (95% CI: 0.1, 0.5; P=0.0002)1
AHP=acute hepatic porphyria; AIP=acute intermittent porphyria; DB=double-blind.
In the 12-month interim analysis of patients with AHP in the Envision OLE
Days of hemin use decreased with continued treatment with GIVLAARI2,3
- Patients who crossed over from placebo to GIVLAARI had hemin use reduction in the ENVISION OLE period (for a total of 6 months of treatment with GIVLAARI) similar to that seen in patients receiving GIVLAARI in the double-blind period3*
*Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.3
AHP=acute hepatic porphyria; DB=double-blind; OLE=open-label extension.
Daily worst pain in AIP patients in ENVISION 6-month period2,4
Daily worst pain score in AIP patients was a secondary endpoint2
-
Pain was measured using patient-reported daily worst pain scores based on a numeric rating scale (NRS)2
-
A statistical analysis of the change from baseline in daily worst pain score for GIVLAARI vs placebo was conducted2
-
A positive score represents a worsening in daily worst pain from baseline; a negative score represents an improvement from baseline2
-
GIVLAARI did not meet statistical significance for this endpoint based on the prespecified statistical method4
-
The daily worst pain scores were lower with GIVLAARI compared with placebo2
GIVLAARI (N=46) (95% CI) |
Placebo (N=43) (95% CI) |
Treatment difference (95% CI) |
-12.876 (-21.776, -3.976) | -0.196 (-9.468, 9.077) | -12.680 (-25.526, 0.166) |
AIP=acute intermittent porphyria; AUC=area under the curve.
Analgesic use in AIP patients in the ENVISION 6-month double-blind period2,3
Analgesic use in AIP patients was a prespecified exploratory endpoint
- Through Month 6, the proportion of days with opioid and non-opioid analgesic use was lower in patients treated with GIVLAARI compared to placebo
-
An evaluation compared to baseline analgesic use cannot be conducted because the proportion of days with analgesic use was not captured at baseline
AIP=acute intermittent porphyria.
GIVLAARI targets and causes degradation of ALAS1 mRNA, reducing the production of neurotoxic intermediates associated with AHP attacks.1,5
See How GIVLAARI WorksReferences: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 2. Balwani M, Sardh E, Ventura P, et al; ENVISION Investigators. N Engl J Med. 2020;382(24):2289-2301. 3. Data on file. Alnylam Pharmaceuticals, Inc. 4. Gouya L, Sardh E, Balwani M, et al; ENVISION investigators. Poster presented at: International Congress on Porphyrins and Porphyrias; September 10, 2019; Milan, Italy. 5. Sardh E, Harper P, Balwani M, et al. N Engl J Med. 2019;380(6):549-558.