Givosiran: ENVISION Study 36-Month Results

Givosiran: ENVISION Study 36-Month Results

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 Summary

 Index

Study Design – Demographics and Baseline Characteristics – Efficacy Results – Safety Results – Abbreviations – References

 Study Design

The phase 3 ENVISION study was a 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 or placebo once a month for 6 months, followed by an optional 30-month OLE.1

The ENVISION study enrolled 94 patients at 36 study sites in 18 countries. All patients completed the 6‑month DB period. Upon completion of dosing in the ENVISION DB period, all eligible patients (93/94) continued in the ENVISION OLE study, receiving monthly givosiran administration.2 In the OLE, patients were initially assigned to givosiran 2.5 mg/kg monthly (N=56) or givosiran 1.25 mg/kg monthly (N=37). The lower dose was introduced in a protocol amendment to assess efficacy and safety. Those enrolled before the amendment received 2.5 mg/kg; therefore, dose allocation in the OLE was not balanced. Patients receiving 1.25 mg/kg who experienced inadequate disease control could revert to 2.5 mg/kg at or after the month 13 visit. A subsequent protocol amendment was enacted to increase the dose for all patients receiving the 1.25 mg/kg monthly dose to the 2.5 mg/kg monthly dose.1

The primary endpoint of the ENVISION 6-month DB period was AAR compared to placebo, defined as those requiring hospitalization, urgent healthcare visit, or IV hemin administration at home, in patients with AIP over the 6-month treatment period. Secondary endpoints evaluated the impact of givosiran treatment on the following outcome measures (all at 6 months unless noted otherwise)2:

         ALA levels at 3 and 6 months in AIP patients

         PBG levels at 6 months in AIP patients

         Annualized days of administered hemin doses in AIP patients

         AAR in patients with AHP (including AIP)

         Daily worst pain in AIP patients

         Daily worst fatigue in AIP patients

         Daily worst nausea in AIP patients

      The PCS of the SF-12 health survey (a 12-question measure capturing global quality of life and overall health status)3 in AIP patients.

All of the above endpoints were considered exploratory endpoints in the OLE, and data from the 1.25 mg/kg monthly and 2.5 mg/kg monthly doses of givosiran have been pooled.4

 Demographics and Baseline Characteristics

Overall patient demographics and baseline characteristics in ENVISION, including baseline disease characteristics and comorbidities, are found in Table 1. The majority of patients were female and had genetically confirmed AIP. Patients had a median, historical AAR of 8 (range, 0 to 46). Across both treatment groups at baseline, 40% of patients had received prior hemin prophylaxis and 52% of patients experienced chronic symptoms between attacks.1 Common comorbidities included increased aminotransferase levels, iron overload, liver disease, hypertension, and renal impairment.2

Table 1. Patient Demographics and Baseline Characteristics in ENVISION.1,2

Efficacy Results

Attack Rate

Continued givosiran treatment during the OLE period led to a sustained reduction in AAR in patients (N=47) who initially received givosiran in the DB period (continuous givosiran group) and in patients (N=46) who received placebo in the DB period and crossed over to receive givosiran in the OLE period (placebo crossover group) (Figure 1). After the initial 6-month DB period, the median number of attacks during the OLE period (>6 months) was 0.36 and 0.87 in the continuous givosiran and placebo crossover groups, respectively.1

Figure 1. Median AAR for DB and OLE Study Periods: (Left) Continuous Givosiran and (Right) Placebo Crossover.1,a,b

The proportion of patients with no attacks by 3-month interval increased with givosiran treatment during the OLE period (Figure 2). Of the patients in the continuous givosiran group, 67% were attack free at >3–6 months, and 86% were attack-free at >33–36 months. Of the patients in the placebo crossover group, 24% were attack free at >3–6 months, and 92% were attack-free at >33–36 months.1

Figure 2. Proportion of Composite Attack-Free Patients by 3-Month Interval During DB and OLE Periods.1,a,b

In a post hoc analysis, the mean time from the start of givosiran treatment to when patients reached and remained below the historical AAR was 2.7 months and 3.7 months in the continuous givosiran and placebo crossover group, respectively. At 36 months, the proportion of patients with an AAR lower than historical AAR was 98% (40/41) and 100% (38/38) for the continuous givosiran and placebo crossover group, respectively.1

Urinary ALA and PBG

In the continuous givosiran and placebo crossover groups, givosiran treatment led to sustained lowering of median ALA levels to near normal and to lowering of PBG levels by >90% at Month 36 (Figure 3).4

Figure 3. Median Levels of (A) Urinary ALA and (B) PBG During DB and OLE Study Periods.5,a

Hemin Use

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 4). 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 5).1

Figure 4. Median Annualized Days of Hemin Use: Continuous Givosiran (Left) and Placebo Crossover (Right).1

Figure 5. Proportion of Patients with 0 Days of Hemin Use by 3-Month Interval.1

Patient-reported Efficacy Outcomes

Patients in both the continuous givosiran group and the placebo crossover group experienced further increases in QOL scores, as assessed by the SF-12 PCS and MCS scores (including individual domain scores) (Figure 6) and the EQ-VAS scores (Figure 7). Increases in QOL scores were sustained from Month 6 to Month 36 in patients who continued givosiran treatment.1

Figure 6. Mean Changes in SF-12 PCS, MCS, and Individual Domain Scores from Baseline Through OLE Period.1,a

Figure 7. Mean Change in EQ-VAS Scores from Baseline Through OLE Period.1,a

Patients also reported changes in functioning, up to Month 24 per the protocol, using a custom questionnaire, the PPEQ. From the DB period through the Month 24 in the OLE, PPEQ results showed further increases across all domains, including activities of daily living, satisfaction with treatment, and living a more normal life, in the continuous givosiran group (Figure 8). Increases across all domains were also observed from the DB period through the OLE period in the placebo crossover group.4

Figure 8. Percentage of Patients Who Reported Ability Improvements (“Much Better” or “Always”) on PPEQ.4

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.4

The majority of AEs were mild or moderate in severity, and a summary of adverse events is shown in Table 2. 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 2. Summary of Patients with ≥1 Adverse Event.1,a

Hepatic Events

In the 6-month DB period, 1 patient (mentioned above) discontinued treatment with givosiran due to an SAE of abnormal liver-function testing (an ALT level of 9.9 × the upper limit of normal) which met a protocol-defined stopping rule. This event subsequently resolved.2

Hepatic AEs were reported in 9 patients (19%) in the continuous givosiran group and 9 patients (20%) in the placebo crossover group, all of which were mild to moderate in severity. The majority of hepatic AEs reported were elevations of serum aminotransferases. Of all patients who received givosiran, elevated ALT levels were reported in 10 patients (11%) and generally occurred 3–6 months after starting givosiran treatment and resolved over time; elevated AST levels were reported in 6 patients (6%).1,4

Renal Events 

In the 6-month DB period, 2 patients experienced SAEs of CKD that were considered serious due to elective hospitalization for diagnostic evaluation; renal biopsies were performed and were consistent with the underlying disease. There was no indication of immune complex or other primary glomerular renal disorders.2

Renal AEs were reported in 12 patients (25%) in the continuous givosiran group and 9 patients (20%) in the placebo crossover group; the renal AEs were mostly characterized by increased serum creatinine and/or decreased eGFR. No renal AE led to discontinuation of study treatment. Small decreases in eGFR observed early in therapy stabilized over Months 12 to 26. In most patients, mean changes in eGFR remained stable during the OLE.1

 Abbreviations

AAR = annualized attack rate; AE = adverse event; AHP = acute hepatic porphyria; ALA = delta aminolevulinic acid; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CKD = chronic kidney disease; DB = double blind; eGFR = estimated glomerular filtration rate; EQ-VAS = EuroQol visual analog scale; MCS = mental component summary; OLE = open-label extension; PBG = porphobilinogen; PPEQ = Porphyria Patient Experience Questionnaire; PCS = physical component summary; SAE = serious adverse event; QoL = quality of life; SF-12 = 12 item short-form health survey; ULN = upper limit of normal.

Updated 4 November 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.  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.  Clement N, MacDonald D, Simpson A. The minimal clinically important difference in the Oxford knee score and Short Form 12 score after total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2014;22(8):1933-1939. doi:10.1007/s00167-013-2776-5

4.  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.

5.  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

6.  Agarwal S, Habtemarium B, Xu Y, Simon AR, Kim JB, Robbie GJ. Normal reference ranges for urinary δ‐aminolevulinic acid and porphobilinogen levels. JIMD Reports. 2021;57(1):85-93. doi:10.1002/jmd2.12173

7.  Parker SL, Mendenhall SK, Shau DN, et al. Minimum clinically important difference in pain, disability, and quality of life after neural decompression and fusion for same-level recurrent lumbar stenosis: understanding clinical versus statistical significance: Clinical article. J Neurosurg Spine. 2012;16(5):471-478. doi:10.3171/2012.1.SPINE11842

8.  Zanini A, Aiello M, Adamo D, et al. Estimation of minimal clinically important difference in EQ-5D visual analog scale score after pulmonary rehabilitation in subjects with COPD. Respir Care. 2015;60(1):88-95. doi:10.4187/respcare.03272

9.  Nolan CM, Longworth L, Lord J, et al. The EQ-5D-5L health status questionnaire in COPD: validity, responsiveness and minimum important difference. Thorax. 2016;71(6):493-500. doi:10.1136/thoraxjnl-2015-207782