Givosiran: Hemin Use

Givosiran: Hemin Use

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INDEX

Clinical Data –Label Information – Abbreviations – References

Clinical Data

ENVISION Study

Study Design

The ENVISION study was a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of givosiran in patients with a documented diagnosis of AHP. Enrolled patients were randomized on a 1:1 basis to receive subcutaneous injections of givosiran 2.5 mg/kg (n=48) or placebo (n=46) once a month for 6 months, followed by an optional 30 month OLE. The primary endpoint was the annualized rate of composite porphyria attacks among patients with AIP at 6 months.1

Hemin prophylaxis was prohibited in the ENVISION study, and patients were required to discontinue hemin prophylaxis at least 4 days prior to screening. Episodic use of hemin for the treatment of acute or ongoing porphyria attacks was allowed during the study.2

Porphyria attacks were treated according to local standard of care which varied by region but included, carbohydrate loading, oral or IV glucose, oral or IV analgesics, oral cimetidine, and IV hemin. Use of these medications was permitted at any point in the study based on clinical judgment.4

Hemin Use

At 6 months in the double-blind period of the ENVISION study, the mean annualized number of days of hemin use in patients with AIP was 77% lower (p<0.001) in the givosiran group (6.8 days) than in the placebo group (29.7 days).1

Median annualized days of hemin use remained low in the continuous givosiran group during the OLE period and decreased by 97% in the placebo crossover group during the OLE period (Figure 1). The proportion of patients with no days of hemin use increased over time in both the continuous givosiran and placebo crossover groups. Of the patients in the continuous givosiran group, 88% had no days of hemin use at >33–36 months. Of the patients in the placebo crossover group, 90% had no days of hemin use at >33‑36 months (Figure 2).3

Figure 1. Median Annualized Days of Hemin Use: (Left) Continuous Givosiran and (Right) Placebo Crossover.3

Figure 2. Proportion of Patients with 0 Days of Hemin Use by 3-Month Interval.3

Safety Results

The safety profile of givosiran was evaluated in all patients. Median (range) exposure to givosiran was 33.1 (2.7–34.1) months for the continuous givosiran group and 27.7 (1.8–28.3) months for the placebo crossover group. The maximum exposure time to givosiran was 34.1 months.5

The majority of AEs were mild or moderate in severity, and a summary of adverse events is shown in Table 1. The most common AEs included injection-site reactions (39%), nausea (37%), fatigue (27%), and nasopharyngitis (27%). Overall, 4 patients discontinued givosiran treatment due to treatment-related AEs (blood homocysteine increase with concomitant injection-site reaction, blood homocysteine increase with concomitant pancreatitis, abnormal liver function test, and drug hypersensitivity). SAEs considered related to givosiran included increased blood homocysteine, elevated transaminases, retinal vein occlusion, injection-site reaction, pancreatitis, worsening of chronic renal failure, pulmonary embolism, right iliac thrombophlebitis, and worsening of liver tests. There was 1 death due to aortic dissection during the OLE period that was determined to be unrelated to givosiran.3

Table 1. Summary of Patient with ≥1 Adverse Event.3

GIVLAARI PRESCRIBING INFORMATION – Relevant content

For relevant labeling information, please refer to the following section of the GIVLAARI Prescribing Information6:

• CONTRAINDICATIONS Section 4

Abbreviations

AE = adverse event; AHP = acute hepatic porphyria; AIP = acute intermittent porphyria; DB = double-blind; IV = intravenous; OLE = open-label extension; SAE = serious adverse event.

Updated 5 February 2025

References

1.  Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289-2301. doi:10.1056/NEJMoa1913147

2.  Supplement to: Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289-2301. doi:10.1056/NEJMoa1807838

3.  Kuter DJ, Bonkovsky HL, Monroy S, et al. Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial. J Hepatol. 2023;79(5):1150-1158. doi:10.1016/j.jhep.2023.06.013

4.  Protocol for: Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289-2301. doi:10.1056/NEJMoa1913147

5.  Kuter DJ, Bonkovsky HL, Monroy S, et al. Efficacy and safety of givosiran in patients with acute hepatic porphyria: 36-month results of the phase 3 ENVISION randomized clinical trial. Presented at: American Society of Hematology (ASH) Congress; December 11-14, 2021; Atlanta, GA, USA & Virtual.

6.  GIVLAARI (givosiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.