• ClinicalTrials.gov Identifier: NCT03370913^1, 2 
• Phase III, Open-label, multicenter
• Single-Arm Study, GENEr8-1 Study

Active, not recruiting, Last Update Posted: December 23, 2022¹

• Male ≥18 years of age
• Base FVIII level ≤ 1 IU/dL²
• Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 Eds

 Key exclusion criteria were reported here³ as follows:

• Anti-AAV5 capsid total binding antibodies
• HIV infection (added as a criterion after a protocol amendment)
• Substantial liver dysfunction, substantial liver fibrosis, or liver cirrhosis

AAV5/baculovirus, Spodoptera frugiperda (Sf9) insect-cell production system^{3 [supplementary appendix]}

Codon-optimized expression cassette for the SQ variant of B-domain–deleted hFVIII (AAV-HLP-FVIII-SQ)⁴

HLP is a 251-bp enhancer/promoter fragment containing 

• a 34-bp core enhancer from the human ApoE-HCR gene 
• a modified 217-bp gene promoter comprising the distal X and the proximal A1B regulatory domains from SERPINA1 (α-1-antitrypsin)⁵

The FVIII expression cassette also includes a synthetic polyA signal^{4 [supplementary material]}

    Systemic (peripheral vein infusion)³

Different populations within the same dose cohort were defined here^{3, 6} as follows:

• ITT Pop. (N = 134): an intention-to-treat population of 134 pts. that received one infusion of the AAV5-hFVIII-SQ vector (6e13 vg/kg)
• mITT Pop. (N = 132): a modified intention-to-treat population including the 132 HIV-negative pts.
• mITT Pop. 2-year³ or mITT Pop. 3-year⁶ (N= 17): subgroups of mITT Pop. including 17 pts. with infusion ≥2 or ≥3 years before data cutoff
• RP (N = 112): the rollover population included 112 pts. from mITT Pop. who had ≥ 6 months of prospective data on bleeding and FVIII use from the non-interventional 270-902 study ⁷

    Median follow-up was 60.2 weeks (range, 51.1 to 150.4)³ and 110.9 weeks (range, 66.1 to 197.4)⁶

    Both OS and CH were carried out²⁻³

Efficacy data concerning FVIII activity in the mITT Pop. (n = 132) at the end of year 1 (week 52) and year 2 (week 104) were
presented in Table S3⁶, as follows:

Efficacy data concerning FVIII activity at specific thresholds within the intention-to-treat population (ITT Pop.) at the end of
Year 1 and Year 2 post-infusion were presented in Table S5⁶, as shown below.

^a Data of 2 pts. who discontinued the study before week 104 were excluded
^b LLOQ, lower limit of quantitation

Efficacy data related to FVIII activity in the mITT Pop. 3-year (n = 17) at the end of Year 1 (week 52) and Year 2 (week 104)
were presented in Table S3⁶, as follows:

Extrapolated FVIII activity up to 5 years (Week 260) after the gene transfer was presented in Table 1 here⁶, as shown below:

     BLQ, below the limit of quantitation

The following statements regarding the extrapolated FVIII activity were outlined here⁶, as follows:

• In the present phase 3 study, the mean and median extrapolated FVIII activity levels measured per CH at week 260
  were estimated to be 11.8 and 5.7 IU/dL, respectively
• Among the 7 pts. in the phase 1–2 trial⁸ who received a dose of 6e13 vg/kg, the relative rate of decrease in FVIII activity
  resembled that observed in this phase 3 study

According to Figure 1³, peaks of median FVIII activity levels are achieved

• At 21-32 weeks in the mITT Pop. (n = 132) and  
• At 29-32 weeks in the mITT Pop. 2-year (n= 17) after vector infusion

Efficacy data regarding the ABR in RP (N = 112) were reported here^{3, 6} and were obtained from Figure 1A and Figure 1C⁶ as follows:

Efficacy data for year 1 through year 3 in mITT Pop. 3-year were extracted from Table S2⁶ and summarized as follows:

The data on reported joint and not-joint bleeds by year of post-prophylaxis follow-up in ITT Pop. (N = 134) were extracted from Figure S6A⁶
and summarized as presented below:

^a Treated bleeding events were defined as bleeding events followed by the use of standard half-life, extended half-life, or plasma-derived factor VIII products within 72 hours after the event
^b Year 1 values included the period beginning either at the start of week 5 or 3 days after the end of factor VIII prophylaxis (whichever was later) and ending at week 5
^c Year 2 values included week 53 to week 104
^d Year 3 indicates the period from week 105 to 156
^e One participant was lost to follow-up at week 66. For year 2, his ABR data through week 66 were and for year 3, no ABR data were included

Early data concerning changes from baseline in AIR in RP (N = 112) were extracted from Figure 1B³ and are summarized as follows:

Also, the annualized rates (AR) of FVIII use per year for up to 2 years in RP (N = 112) were obtained from Figure 1B⁶ and summarized as follows:

The One-time prophylaxis use, which was clinically appropriate based on individual risk, as reported here⁶, is summarized as follows:

• Initially reported Infusion-related reactions (IRR) were defined as AEs occurring within 48 hours after infusion³
  • Commonly reported events were nausea (19 pts., 14.2%), fatigue (10 pts., 7.5%) and headache (8 pts, 6.0%), with most events being mild to moderate
  • The following eventswere reported during or shortly after infusion:
    • 7 pts. (5.2%) experienced systemic hypersensitivity
    • 3 pts. (2.2%) reported serious infusion-related reactions:
      • 1 pt. reported maculopapular rash
      • 1 pt. reported an anaphylactic reaction
      • 1 pt. reported a hypersensitivity reaction
• Subsequently, AEs occurring within 48 hours after infusion were defined as infusion-associated reactions (IAR), and those occurring during infusion or 6 hours after infusion as IRRs⁶
• Total IRRs and total IARs in the ITT Pop. (N = 134) for the 2-year follow-up were extracted from Table 2⁶ and are summarized as follows:
  • IARs were reported in 50 pts. (37.3%)
  • IRRs were reported in 19 pts. (9.0%)

AEs occurring in the ITT Pop. (N = 134) during a 2-year follow-up after vector infusion were obtained from Table 2⁶ and
are summarized as follows:

^a These events were assessed only for the total follow-up period
^b Some serious adverse events that were assigned to year 2 were captured in the previous data-cutoff period
^c Infusion-related reactions were defined as adverse events that occurred during infusion or within 6 hours after infusion, irrespective of a causal association with valoctocogene roxaparvovec
^d Infusion-associated reactions were defined as adverse events occurring within 48 hours after infusion, irrespective of causal association with valoctocogene roxaparvovec

Data, including a 2-year follow-up of AEs and SAEs related to glucocorticoid treatment, were extracted from Table 2⁶ and are summarized as follows:

Data regarding specific AEs (occurring in ≥5% of pts.) and SAEs related to glucocorticoids during the early follow-up (all 134 pts. > 51 weeks) were obtained from Table S8³ and are summarized as follows:

^a      Includes pts. who received any glucocorticoids
^b, c  2 and 3 AEs occurred in the same pt.

Safety data regarding ALT elevation levels were reported here^{3, 6} as follows:

• In total, 119/134 (88.8%) pts. had an increase in ALT levels (385 events) within the 2-years period following infusion:
  • Of all 385 events, 202 (52.5%) occurred within 26 weeks of infusion
  • 101 (26.2%) occurred between 26 and 52 weeks post infusion
  • 38 (9.9%) occurred between 52 and 78 weeks post infusion
  • 31 (8.1%) occurred between 78 and 104 weeks post infusion
  • 13 (3.4%) occurred after 104 weeks post-infusion
• The median time to the first elevation in ALT level after infusion was 8.0 weeks and the median duration of elevation was 15 days
• In total, 11/134 (8.2%) pts. had an ALT level increase of grade 3 (13/385 events [3.4%]) during the period of 2 years post infusion
• 2 of these 13 ALT elevation events affecting 2 pts. (1.5%) were SAEs leading to intervention with intravenous methylprednisolone
  • 9 occurred within 26 weeks after infusion³
  • 3 occurred during weeks 26 through 36 weeks after infusion³
  • 1 occurred during weeks 52 trough weeks 78 post infusion³
• No grade 4 or higher elevations in ALT level occurred

• AST elevation occurrences are listed below in the variable AEs possibly/likely related to Study Agent
• Peak level and timing of AST elevation was not reported

    Not reported

The following information regarding the duration of steroid treatment and steroid responsiveness was extracted from here^{3, 6}:

• According to Table S9³, among the ITT Pop. (n = 134) 39/134 pts. (29.1%) used other immunosuppressants than glucocorticoids due to contraindications, side effects, or a poor/no response to glucocorticoid treatment
• According to Table S8⁶, the median (IQR) duration of glucocorticoid treatment per participant was 32.9 weeks (3.1, 86.3) in the ITT Pop. (n = 134)

    Not reported

    Not reported

1. Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301) (BMN 270-301).  Available at: Study Details | Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301) | ClinicalTrials.gov
2. Ozelo, C.M., et al., Efficacy and Safety of Valoctocogene Roxaparvovec Adeno-associated Virus Gene Transfer for Severe Hemophilia A: Results from the Phase 3 GENEr8-1 Trial. ISTH 2021 Congress, 2021. Efficacy and Safety of Valoctocogene Roxaparvovec Adeno-associated Virus Gene Transfer for Severe Hemophilia A: Results from the Phase 3 GENEr8-1 Trial - ISTH Congress Abstracts
3. Ozelo, M.C., et al., Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med, 2022. 386(11): p. 1013-1025. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A | NEJM
4. Rangarajan, S., et al., AAV5-Factor VIII Gene Transfer in Severe Haemophilia A. N Engl J Med, 2017. 377(26): p. 2519-2530. AAV5–Factor VIII Gene Transfer in Severe Hemophilia A | NEJM
5. McIntosh, J., et al., Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood, 2013. 121(17): p. 3335-44. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant | Blood | American Society of Hematology (ashpublications.org)
6. Mahlangu, J., et al., Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med, 2023. 388(8): p. 694-705. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A | NEJM
7. Kenet, G., et al., Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study. J Clin Med, 2021. 10(24). Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study - PMC (nih.gov)
8. Pasi KJ, Laffan M, Rangarajan S, Robinson TM, Mitchell N, Lester W, Symington E, Madan B, Yang X, Kim B, Pierce GF, Wong WY. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia. 2021 Nov;27(6):947-956. doi: 10.1111/hae.14391. Epub 2021 Aug 11. PMID: 34378280; PMCID: PMC9291073. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A - PMC (nih.gov)

AAV, Adeno-associated virus; Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; CH, Chromogenic Assay; Co., cohort; DOACs, Direct oral anticoagulants; D, days; EDs, exposure days; FIX, factor IX; FIX-Padua, gain of function FIX variant; FVIII, factor VIII; gc, genome copies; HEK cells, human embryonic kidney cells; IQR, interquartile range; IRR, Infusion-related reaction; NAbs, neutralizing antibodies; OS, One-stage clotting assay; Pop., population; pt., patient/participant; pts., patients/participants; P1, Participant 1; PI, phase I; PBGD, porphobilinogen deaminase; PBMC, peripheral blood mononuclear cells; SAEs, serious adverse events; SFU, spot-forming units; TAC, tacrolimus; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year