Efficacy & Safety
ENVISION: The largest interventional study in acute hepatic porphyria (AHP)1,2
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.3
†All endpoints were considered exploratory in the ENVISION OLE period.4
‡A protocol amendment increased the dose for all patients to 2.5 mg/kg once monthly.2
AHP=acute hepatic porphyria; ALA=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 intravenous (IV) hemin3
ENVISION study patient population3
| 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) |
| Historical annualized attack rate, median (IQR)† | 8 (4-18) | 7 (4-14) | 8 (4-16) |
| 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) |
*The two patients with acute hepatic porphyria without an identified mutation were considered by the trial investigator to have acute intermittent porphyria on the basis of biochemical analysis.3
†IQR=interquartile range.
‡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.
The historical annualized attack rate was calculated as the number of attacks resulting in a composite of hospitalization, a visit to a health care facility, or hemin use at home during the 6 months before randomization.3
All eligible patients (93 of 94) enrolled in the open-label extension (OLE).2
Efficacy in the ENVISION 6-month double-blind period and 24-month interim analysis of the OLE
In patients with AHP in the ENVISION 6-month double-blind period
Treatment with GIVLAARI® (givosiran) led to a significant reduction in porphyria attacks1
Attacks were defined as those requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home.1
In a 24-month interim analysis of patients with AHP in the ENVISION OLE
Patients who continued treatment with GIVLAARI® (givosiran) had sustained attack reduction5
*Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.2
Attacks were defined as those requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home.1
- Attack reduction was sustained in patients continuing treatment with GIVLAARI during the OLE period5
- Patients who crossed over from placebo to GIVLAARI had attack reduction in the OLE period (for a total of 18 months of treatment) similar to that seen in GIVLAARI patients in the double-blind period2
Endpoints in the OLE period are exploratory4
Safety profile of GIVLAARI® (givosiran) in the ENVISION study1
Safety during the 6-month DB period
| 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
- The most frequently occurring (≥20% incidence) adverse reactions reported in patients treated with GIVLAARI were nausea (27%) and injection site reactions (25%)1
Safety during the open-label extension (OLE) period
- The most frequently occurring (≥20%) adverse reactions reported in patients treated with GIVLAARI were injection-site reactions (37%), nausea (34%), fatigue (23%), nasopharyngitis (23%), and headache (20%)2
- Serious adverse events were reported in 28 (30%) of patients during the study. SAEs reported in more than 1 patient included blood homocysteine increased, CKD, device breakage, pyrexia, and urinary tract infections (all reported in 2 patients)2,6
- Three patients discontinued treatment due to adverse events in the OLE period. One patient discontinued treatment due to an AE of hypersensitivity, and two patients discontinued due to SAEs of increased blood homocysteine2,7
- Increased blood homocysteine was reported in 15 of 93 (16%) patients treated with GIVLAARI1
In patients with AHP in the ENVISION 6-month double-blind period
A greater number of patients treated with GIVLAARI had zero attacks vs placebo3
Attacks were defined as those requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home.1
In a 24-month interim analysis of patients with AHP in the ENVISION OLE
The number of patients with zero attacks increased through the study with continued attack-preventive treatment with GIVLAARI2†
Proportion of attack-free* patients by 3-month† intervals during DB and OLE periods2
*Composite porphyria attacks are attacks requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home.2
†1 month = 28 days.2
‡Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.2
§Baseline represents 6 months before randomization.2
Endpoints in the OLE period are exploratory.4
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 24-month interim analysis of patients with AHP in the ENVISION OLE
Days of hemin use decreased for patients who continued GIVLAARI2
68.1%
of patients who continued
treatment with GIVLAARI required
zero days of hemin use2
- 48.9% of patients who crossed over from placebo to GIVLAARI required zero days of hemin use reduction in the ENVISION OLE period (for a total of 18 months of treatment with GIVLAARI) similar to that seen in patients receiving GIVLAARI in the double-blind period (54.2%)1,2
Endpoints in the OLE period are exploratory4
*Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.2
AHP=acute hepatic porphyria; OLE=open-label extension; DB=double blind.
Daily worst pain in AIP patients in ENVISION 6-month period3
Daily worst pain score in AIP patients was a secondary endpoint3
-
Pain was measured using patient-reported daily worst pain scores based on a numeric rating scale (NRS)3
-
A statistical analysis of the change from baseline in daily worst pain score for GIVLAARI vs placebo was conducted3
-
A positive score represents a worsening in daily worst pain from baseline; a negative score represents an improvement from baseline3
-
GIVLAARI did not meet statistical significance for this endpoint based on the prespecified statistical method3
-
The daily worst pain scores were lower with GIVLAARI compared with placebo3
| 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 period3
Analgesic use in AIP patients was a prespecified exploratory endpoint
- Through Month 6, the proportion of days with opioid and nonopioid analgesic use was lower in patients treated with GIVLAARI compared to placebo3
-
An evaluation compared to baseline analgesic use cannot be conducted because the proportion of days with analgesic use was not captured at baseline3
AIP=acute intermittent porphyria.
GIVLAARI targets and causes degradation of ALAS1 mRNA, reducing the production of neurotoxic intermediates associated with AHP attacks and other disease manifestations.1
See How GIVLAARI Works
For more information, please ALAS1=delta-aminolevulinic acid synthase 1; mRNA=messenger RNA.
References: 1. GIVLAARI [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc. 2. Ventura P, Bonkovsky HL, Gouya L, et al. Liver Int. 2021;00:1-12. 3. Balwani M, Sardh E, Ventura P, et al; ENVISION Investigators. N Engl J Med. 2020;382:2289-2301. 4. Balwani M, Sardh E, Ventura P, et al. Protocol. Phase 3 trial of RNAi therapeutic givosiran for acute inter-mittent porphyria. N Engl J Med. 2020;382:2289-301. 5. Data on file. Alnylam Pharmaceuticals, Inc; December 2021. 6. Ventura P, Bonkovsky HL, Gouya L, et al. Liver Int. 2021;00 Suppl 1:S1-16. 7. Kuter DJ, Keel S, Parker C, et al. Presented at: American Society of Hematology (ASH) Congress; December 5-8, 2020; virtual.