Givosiran: Use in Patients with Prior History of Hemin Prophylaxis

Givosiran: Use in Patients with Prior History of Hemin Prophylaxis

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 Summary

Index

Study Design – Patient Demographics & Baseline Characteristics – Efficacy Results – Safety Results – Abbreviations – References

 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

Per the study protocol, the use of hemin prophylaxis was prohibited, 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 A post-hoc analysis of the ENVISION study was conducted to evaluate the treatment outcomes of givosiran in patients with or without prior hemin prophylaxis.1,3

 Patient Demographics and Baseline Characteristics

Ninety-four patients were enrolled in the 6-month double-blind period, and 93 patients entered the OLE period. The median (range) duration of historical hemin use was 5 (1-33) years. The baseline demographic and clinical characteristics by prior hemin prophylaxis use are presented in Table 1.3,4

Table 1. Patient Demographics and Baseline Characteristics by Prior Hemin Prophylaxis Status in ENVISION.4

 Efficacy Results

Attack Rate

During the 6-month double-blind period, the median AAR for patients treated with givosiran was 2.1 in those with prior hemin prophylaxis (n=20) and 0 in those without hemin prophylaxis (n=27). The median AAR for patients treated with placebo was 23.8 in those with prior hemin prophylaxis (n=18) and 6.7 in those without (n=28) prior hemin prophylaxis.3

During the OLE period, a sustained reduction in median AAR was observed in continuous-givosiran group, regardless of prior hemin prophylaxis status. Furthermore, a reduction in median AAR was observed in the placebo-crossover group, regardless of prior hemin prophylaxis status (Figure 1).3

Figure 1. Median AAR for DB and OLE periods, by Treatment and Prior Hemin Prophylaxis Status.3

Regardless of prior hemin prophylaxis, the proportion of attack-free patients (Figure 2) and the proportion of patients whose AAR was lower and remained lower than the historical AAR (Figure 3) increased from the double-blind period through the OLE period in both treatment groups.3

Figure 2. Proportion of Attack-Free Patients, by 3-Month Interval, Treatment, and Prior Hemin Prophylaxis Status.3

Figure 3. Proportion of Patients with an AAR That Was Lower Than the Historical AAR and Remained Lower, by 3-Month Interval, Treatment, and Prior Hemin Prophylaxis Status.3

In the continuous-givosiran group, the estimated median (95% CI) time to first attack was 95.5 (8, not estimated) and 264 (37, not estimated) days in those with and without prior hemin prophylaxis, respectively. In the placebo-crossover group, the estimated median (95% CI) time to first attack was 7.5 (5, 10) and 41.5 (18, 104) days in those with and without prior hemin prophylaxis, respectively.3

Patient-Reported Quality of Life

Increases in mean SF-12 PCS and MCS scores were observed from baseline to the end of the double-blind and OLE periods in both treatment groups, regardless of prior hemin prophylaxis status (Table 2).3

Table 2. Mean Change from Baseline in SF-12 Summaries by Treatment and Prior Hemin Prophylaxis Status.3

 Safety

The safety results of givosiran for the subgroup of patients with prior hemin prophylaxis status are not available. The majority of AEs were mild or moderate in severity, and a summary of AEs is shown in Table 3. The most common AEs included injection-site reactions (39%), nausea (37%), and fatigue (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.1

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

Abbreviations

AAR = annualized attack rate; AE = adverse event; AHP = acute hepatic porphyria; AIP = acute intermittent porphyria;
ALA = delta-aminolevulinic acid BL = baseline; CI = confidence interval; Cr = creatinine; DB = double-blind; IV = intravenous; MCS = mental component summary; OLE = open-label extension; PBG = porphobilinogen; PCS = physical component summary; SAE = serious adverse event; SF-12 = 12-item Short Form Health Survey; ULN = upper limit of normal.

Updated 20 March 2025

 References

1.  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

2.  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

3.  Deering RW, Silver S, Keel S, Jia G. Clinical outcomes in patients with acute hepatic porphyria treated with givosiran who stopped hemin prophylaxis at study entry: Post hoc analyses from the phase 3 ENVISION study through month 36. Presented at: Hemostasis and Thrombosis Research Society (HTRS) Scientific Symposium; March 10–12, 2023; Orlando, FL, USA.

4.  Supplement to: 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