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

Chart depicting the ENVISION study design
Chart depicting the ENVISION study design

*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

Baseline Demographic and Clinical Characteristics of Patients With AHP1,3
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)
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

Double-blind Period

In patients with AHP in the ENVISION 6-month double-blind period

Treatment with GIVLAARI® (givosiran) led to a significant reduction in porphyria attacks1

Average rate of study-defined porphyria attacks compared to those on placebo
Average rate of study-defined porphyria attacks compared to those on placebo
70% fewer attacks on average with GIVLAARI vs placebo 70% fewer study-defined attacks* on average with GIVLAARI vs placebo
  • Attack rate ratio: GIVLAARI vs placebo
    0.3 (95% CI: 0.2, 0.4; P<0.0001)1

Attacks were defined as those requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home.1

OLE Period

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

Chart showing the average number of attacks compared to those on placebo and crossover through OLE period

*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 reactions that occurred at least 5% more frequently in patients treated with GIVLAARI compared with patients receiving placebo in the 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
  • 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
Double-blind Period

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

Zero attack rate chart through the 6-month double-blind period
Zero attack rate chart through the 6-month double-blind period
50% of patients receiving attack prevention treatment with GIVLAARI had zero attacks* in the 6-month DB period vs 17% of placebo patients 50% of patients receiving attack prevention treatment with GIVLAARI had zero attacks* in the 6-month DB period vs 17% of placebo patients

Attacks were defined as those requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home.1

OLE Period

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

Zero attack rate chart through the OLE period

*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.

Double-blind Period

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

Chart showing hemin use through the double-blind period
Chart showing hemin use through the double-blind period

In the ENVISION 6-month DB period, 54% of AIP patients (N=25/46) treated with GIVLAARI had zero days of hemin compared with 23% of patients (N=10/43) receiving placebo3

  • 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.

OLE Period

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.

Double-blind Period

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

Daily worst pain scores in AIP patients (AUC of mean change from baseline)3
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.

Double-blind Period

Analgesic use in AIP patients in the ENVISION 6-month double-blind period3

Analgesic use in AIP patients was a prespecified exploratory endpoint

Chart showing analgesic use during the double-blind period

  • 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

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.

 

IMPORTANT SAFETY INFORMATION

Contraindications

GIVLAARI® (givosiran) is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.

Anaphylactic Reaction

Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.

Hepatic Toxicity

Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.

Renal Toxicity

Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.

Injection Site Reactions

Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.

Blood Homocysteine Increased

Increases in blood homocysteine levels have occurred in patients receiving GIVLAARI. In the ENVISION study, during the open label extension, adverse reactions of blood homocysteine increased were reported in 15 of 93 (16%) patients treated with GIVLAARI. Measure blood homocysteine levels prior to initiating treatment and monitor for changes during treatment with GIVLAARI. In patients with elevated blood homocysteine levels, assess folate, vitamins B12 and B6. Consider treatment with a supplement containing vitamin B6 (as monotherapy or a multivitamin preparation).

Drug Interactions

Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

Adverse Reactions

The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).

INDICATION

GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP).

For additional information about GIVLAARI, please see full Prescribing Information.