Efficacy & Safety

ENVISION: The largest interventional study in acute hepatic porphyria (AHP)1

The efficacy and safety of GIVLAARI® (givosiran) were evaluated in ENVISION, a pivotal, randomized,
double-blind, placebo-controlled, multinational Phase 3 study in adult patients with AHP (N=94)1,2

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

*All patients in the open-label extension received GIVLAARI 2.5 mg/kg or 1.25 mg/kg once monthly.

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 hemin1,3
  • Prophylactic hemin use during the study was not permitted2

ENVISION study patient population2,3

Baseline Demographic and Clinical Characteristics of Patients With AHP
GIVLAARI (N=48) Placebo (N=46) Overall (N=94)
Mean age, years (range) 40 (19, 65) 37 (20, 60) 39 (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

Symptoms were chronic if patients experienced symptoms of porphyria daily, or on most days, when not having an attack. 

Use of opioids was defined as chronic if patients reported taking them for porphyria daily, or on most days, when not having an attack.

All eligible patients (93 of 94) enrolled in the open-label extension (OLE) study.4

Treatment with GIVLAARI 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
During the 6-month treatment period, patients with AHP experienced 70% fewer study-defined 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

*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1

50% of patients with AHP treated with GIVLAARI had no attacks*
during the 6-month treatment period vs 17% of patients treated with placebo3

Chart showing percentage of patients who experienced no study-defined attacks
Chart showing percentage of patients who experienced no study-defined attacks

*Attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.1

Significantly less hemin was used by AHP patients treated with GIVLAARI1

Chart showing the average number of days of hemin use compared to those on placebo
Chart showing the average number of days of hemin use compared to those on placebo
70% reduction 70% reduction

in the average days of hemin use
with GIVLAARI vs placebo

during the 6-month treatment period1 

GIVLAARI targets and causes degradation of ALAS1 mRNA, reducing the production of neurotoxic intermediates associated with AHP attacks.1,5

See How GIVLAARI Works

ALAS1, delta-aminolevulinic acid synthase 1; mRNA, messenger RNA.

Safety profile of GIVLAARI in ENVISION1

Adverse Reactions That Occurred at Least 5% More Frequently in Patients
Treated With GIVLAARI Compared to Patients Treated With Placebo
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 liver transaminases
  • The most frequently occurring (>20%) adverse reactions reported in patients treated with GIVLAARI
    were nausea (27%) and injection site reactions (25%)

References: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 2. Gouya L et al; ENVISION investigators. 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. Oral presentation at: International Congress on Porphyrins and Porphyrias; September 10, 2019; Milan, Italy. 3. Data on file. Alnylam Pharmaceuticals, Inc. 4. Balwani et al; ENVISION investigators. 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. Poster presented at: European Association for the Study of the Liver International Liver Congress; April 13, 2019; Vienna, Austria. 5. Sardh E et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380(6):549-558. 

 

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.

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.