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

Active, not recruiting, Last Update Posted: 2025-03-25¹ 

Information regarding the approval status of Roctavian was collected from references #11 and  #12 and summarized as follows:

• In June 29,  2023, Roctavian was approved in the USA for the treatment of haemophilia A
• In August 24, 2024,  Roctavian was approved by the EMA for the treatment of haemophilia A

Information regarding the marketing status of Roctavian was obtained from a company statement issued by BioMarin Pharmaceutical Inc. (Reference #16) and is summarized below:

• On February 23, 2026, BioMarin announced the voluntary withdrawal of Roctavian (valoctocogene roxaparvovec) from the market following the company’s decision to discontinue commercialization efforts after being unable to identify a buyer for the therapy
• The decision was reported to be unrelated to the therapy’s efficacy or safety profile

• 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 in reference #3 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, as reported in the supplementary appendix of reference #3

Codon-optimized expression cassette for the SQ variant of B-domain–deleted human hFVIII (AAV-HLP-FVIII-SQ)^4, 9

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 in refernces #3, #6 and #14 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, mITT Pop. 3-year⁶  or  mITT Pop. 5-year¹⁴: subgroups of mITT Pop. including 17 pts. with infusion ≥2 to ≥5 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

• Early follow-up times (1- and 2-year follow-ups) were reported in references #3 and #6 as follows:
  • Median follow-up was 60.2 weeks (range: 51.1 to 150.4) and 110.9 weeks (range: 66.1 to 197.4)
• 3-year follow-up, including safety and efficacy results from the year-3 data cutoff,^3,6 was reported in references #9 and #13 as follows:
  • As of the cutoff date, median follow-up was 162.4 weeks (range: 66.1 to 255.0) among all participants, including mITT participants¹³
  • Mean follow-up was 172.8 weeks (standard deviation [SD]: 26.61)9
• 4-year follow-up was reported in reference #14 as follows:
  • Median follow-up duration was 214 weeks (range: 66 to 266 weeks) for all participants, including the 17 mITT participants dosed ≥5 years prior.
  • Five participants discontinued the study overall, including:
    • Two participants who discontinued after the publication of 3-year follow-up data:
      • One participant died (unrelated to treatment) at week 183
      • One participant withdrew consent at week 262
  • Of the 17 mITT participants, two discontinued:
    • One at week 66, and one at week 262
    • Since the 3-year follow-up publication,¹³ an additional seven participants resumed prophylaxis, bringing the total to 24 of 134 participants across all follow-ups

    Both OS and CH were carried out^2, 3

Efficacy data on FVIII activity in the mITT Pop. (N = 132) were extracted from publications reporting sequential follow-up outcomes from the phase 3 GENEr8-1 trial. Year 1 and Year 2 data were obtained from Reference #6, Year 3 data from Reference #13, Year 4 data from Reference #14, and Year 5 data from the final 5-year follow-up publication (Reference #17). The data are summarized in the table below.

    ᵃ Mean ± SE is presented instead of mean ± SD for the Year 4 values

The distributions of median FVIII activity measured by CH and OS in the mITT Pop. (N = 132) at the end of Years 1–5 were extracted from Figure 2B and Figure S3B in Reference #17 and are summarized in the table below.

    CH, chromogenic assay; OS, one-stage assay; Median FVIII activity was calculated over 4- to 6-week windows. Percentages may not total exactly 100% because of rounding

Efficacy data on FVIII activity in the mITT Pop. 5-year (n = 17) at the end of year 1, year 2, and year 3 were retrieved from Table S2 in reference #6. FVIII activity data for the end of year 4 and year 5
were sourced from Figure 2 and Figure S3 in reference #14. The data are summarized in the table below.

    a Mean ± SE is presented instead of Mean ± SD for years 4 and 5

Extrapolated FVIII activity up to 5 years (Week 260) after the gene transfer was presented in Table 1 of reference #6, as shown below:

    ^a BLQ, below the limit of quantitation

The following statements regarding the extrapolated FVIII activity were outlined in reference #6, 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
• Among the 7 participants 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 
• The median FVIII levels in that phase 1–2 study, measured per CH, were
  • 60.3, 26.2, 19.9, 14.5, and 8.2 IU per deciliter
  • at weeks 52, 104, 156, 208, and 260, respectively

The impact of anti-AAV5 total binding antibody (TAb) and AAV5 transduction inhibitor (TI) titers on FVIII activity was reported in reference #9 as follows:

• 3 participants who developed detectable anti-AAV5 TAb (titers of < 20, 56, and 91) between screening and day 1 (range, 25–42 days) were treated with valoctocogene roxaparvovec
• Despite this, they demonstrated effective transduction, with FVIII activity levels between 2.0 and 9.2 IU/dL at week 152 or week 156
• There was no associated impact on the safety profile
• At baseline, 11 participants who tested positive for AAV5 TI exhibited a median FVIII activity at week 104, with values ranging between 1.6 and 78.3 IU/dL
• None were AAV5 TAb-positive at baseline or screening, although 1 of 11 was AAV5 TAb-positive at day 1
• At week 156, the mean FVIII activity for these 11 participants was 22.9 IU/dL and the median was 9.0 IU/dL
• Compared to the overall ITT Pop., the mean FVIII activity was 18.2 IU/dL and the median was 8.2 IU/dL
• The median FVIII activity demonstrated no correlation with:
  • peak AAV5 TAb titers at week 104; or
  • AAV5 TAb titers measured at week 8

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 on treated-bleed and all-bleed ABRs in the rollover population (RP; N = 112) were extracted from publications reporting 1- to 5-year follow-up outcomes from the phase 3 GENEr8-1 trial (#3, #6, #13, #14 and #17), and are summarized in the following tables.

   ^a Total Change from Baseline values for Years 2–4 refer to the cumulative all post-prophylaxis follow-up period available at each annual analysis timepoint, rather than to the individual year alone
     ^b The final cumulative 5-year values are presented in the “All post-prophylaxis (N = 112)” column; therefore, the corresponding Year 5 Total Change from Baseline values are shown as NA to avoid duplication

    Notes for both tables above:

• Year 3, Year 4, and Year 5 data were not based on N = 112 because of participant discontinuations
• Data for participants who resumed prophylaxis were not censored

Data on procedure-related bleeding episodes and the corresponding endogenous FVIII activity levels were extracted from the post hoc study of invasive procedures after two years of follow-up (Reference #15) and are summarized in the table below:

• As shown in the table above, endogenous FVIII activity levels were generally higher for untreated procedure-related bleeding episodes than for bleeding episodes managed with FVIII treatment (mean FVIII activity: 60.4 vs 10.4 IU/dL, respectively)

Efficacy data from year 1 through year 4 in the mITT Pop. 4-year group were extracted from Tables S11 (Reference #3),  and S2 (Reference #6) and summarized in the left table.
Data on reported joint and non-joint bleeds by year of post-prophylaxis follow-up in the ITT Pop. (N = 134) were extracted from Figure S6A (Reference #6) and summarized in the right table, as shown 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 data were based on N = 110 due to participants who discontinued the study
   ^e Year 3 indicates the period from week 105 to 156
   ^f 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

Data from another post hoc analysis (Reference #10), which assessed the comparative effectiveness of valoctocogene roxaparvovec versus FVIII prophylaxis using propensity score matching between participants in the rollover population (RP; n = 112) and a contemporaneous external control group (n = 73) from the non-interventional 270-902 study, are summarized as follows:

Efficacy data on the annualized infusion rate (AIR), referred to in Reference #17 as the annualized rate of exogenous FVIII infusions (AFR), in the rollover population (RP; N = 112) were extracted from Figure 1E and are summarized in the table below.

Note: Year 3, Year 4, and Year 5 data were not based on N = 112 because of participant discontinuations. Data for participants who resumed prophylaxis were not censored
Abbreviations: AFR, annualized rate of exogenous FVIII infusion; BL, baseline

Data on annualized FVIII utilization (AFU) in the rollover population (RP; N = 112) during the 5-year follow-up period were extracted from Table S2 of Reference #17 and are summarized in the table below.

Endogenous FVIII activity levels prior to medical procedures, as reported in a post hoc analysis (Reference #15) of invasive procedures after 2 years of follow-up, are summarized in the table below:

• As shown in the table above, the authors of Reference #15  noted that participants who received FVIII treatment for procedure-related bleeding episodes had numerically lower mean endogenous FVIII activity than those who did not receive FVIII treatment

Early data concerning changes from baseline in AIR in the rollover population (RP; N = 112) were extracted from Figure 1B of Refrence #3 and are summarized as follows:

Data on one-time prophylactic FVIII use, considered clinically appropriate based on individual bleeding risk, were reported in the 2-year follow-up publication (Reference #6) and are summarized as follows:

Initially reported infusion-related reactions (IRRs) were defined as AEs occurring within 48 hours after infusion (Reference #3).

• Commonly reported events included:
  • nausea: 19 participants (14.2%)
  • fatigue: 10 participants (7.5%)
  • headache: 8 participants (6.0%)
• Most events were mild to moderate.
• The following events were reported during or shortly after infusion:
  • systemic hypersensitivity in 7 participants (5.2%)
  • serious infusion-related reactions in 3 participants (2.2%), including:
    • maculopapular rash in 1 participant
    • an anaphylactic reaction in 1 participant
    • a hypersensitivity reaction in 1 participant

Subsequently, AEs occurring within 48 hours after infusion were defined as infusion-associated reactions (IARs), whereas AEs occurring during infusion or within 6 hours after infusion were defined as IRRs. Total IARs and IRRs in the ITT population (ITT Pop.; N = 134) during the 2-year follow-up were reported in Reference #6 and are summarized below:

• IARs were reported in 50 participants (37.3%)
• IRRs were reported in 12 participants (9.0%)

Data on infusion-related and infusion-associated reactions in the intention-to-treat population (ITT Pop.; N = 134) were extracted from Table 1 of the final 5-year follow-up publication (Reference #17) and are summarized in the table below.

Statements concerning the observed AEs were reported in reference #9  as follows:

• Through 3 years of follow-up post-administration, no participants developed a clinically meaningful FVIII inhibitor response
• The most common adverse event, elevated alanine aminotransferase (ALT) levels (≥1.5x baseline or above the upper limit of
  normal [ULN]), was observed in 90.3% of participants through year 3
• The median time to ALT rise above the ULN was 8.1 weeks. No ALT elevations that emerged after year 2 were managed with immunosuppressants
• In year 1, 114 (85.1%) study participants experienced an ALT elevation, with incidence declining in years 2 and 3 (40 [29.9%] and 31 [23.7%] participants, respectively).
• ALT elevations that started after week 52 were not associated with unanticipated drops in FVIII activity; thus, treatment with corticosteroids was not deemed to be beneficial.
• Cases of infusion-related reactions and systemic hypersensitivity and other safety results for up to 2 years were previously published.

AEs occurring in the ITT Pop. (N = 134) during the 5-year follow-up after vector infusion were obtained from Table 1 in reference #17  and are summarized in the table below.

Abbreviations: AE, adverse event; SAE, serious adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FVIII, factor VIII; MedDRA, Medical Dictionary for Regulatory Activities; NMSC, non-melanoma skin cancer.

Table annotations:

• Values are presented as n (%).
• AEs were coded using MedDRA version 24.0 and graded for severity using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
• Relationship to study drug was determined by the investigator.
• Percentages were calculated using the total number of participants (N) in each analysis population as the denominator.
• Participants with >1 AE within the same category were counted only once for that category.

    ᵃ Severity and relationship to study drug were assessed by the investigator.
    ᵇ Valoctocogene roxaparvovec-related AEs reported during Year 5 were:

• ALT elevation (2 participants)
• AST elevation (1 participant)
• Increased FVIII level (1 participant)
• Hepatic steatosis (1 participant)

    ᶜ The threshold for an AE of special interest involving ALT elevation evolved during the trial as follows:

1. ALT ≥1.5 × ULN (ULN = 43 U/L);
2. ALT >ULN when ALT was >2 × baseline; and
3. ALT >ULN or ≥1.5 × baseline

    ᵈ A potential Hy’s law case requires all of the following:

1. ALT or AST >3 × ULN, often substantially greater (>5 × or >10 × ULN);
2. Total bilirubin >2 × ULN without evidence of obstruction (e.g., elevated alkaline phosphatase), malignancy, or impaired glucuronidation capacity; and
3. No alternative explanation for the concurrent ALT/AST and bilirubin elevations (e.g., viral hepatitis or pre-existing liver disease)

    ᵉ Infusion-related reactions were defined as AEs occurring during infusion or within 6 hours after infusion, irrespective of causal association with valoctocogene roxaparvovec
    ᶠ Infusion-associated reactions were defined as AEs occurring within 48 hours after infusion, irrespective of causal association with valoctocogene roxaparvovec

The most recent data on glucocorticoid-related adverse events in the intention-to-treat population (ITT Pop.; N = 134) were extracted from Table 1 of the final 5-year follow-up publication (Reference #17) and are summarized in the table below.

Data, including a 2-year follow-up of AEs and SAEs related to glucocorticoid treatment, were extracted from Table 2 (Reference #6) and are summarized as follows:

Data regarding specific AEs (occurring in ≥5% of participants) and SAEs related to glucocorticoids during the early follow-up (all 134 participants > 51 weeks) were obtained from Table S8 of Reference #3 and are summarized as follows:

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

The correlation between ALT levels and anti-AAV5 TAb in the ITT Pop. was described here⁹ as follows:

• There was no correlation between the AAV5 TAb titers at week 8 or maximum AAV5 TAb titers at week 104 and peak ALT levels in the ITT Pop.

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

Data regarding the peaks of AAV5 TAb and AAV5 TI titers were described here⁹ as follows.:

• All 127/134 ITT Pop. participants with AAV5 TAb assessments available on week 8, the first time point assessed after dosing, were AAV5 TAb positive
• Mean AAV5 TAb titers first peaked at week 36 and were generally sustained thereafter
• Similar to results for AAV5 TAb, all participants were AAV5 TI positive by week 8
• Mean AAV5 TI titers began to plateau at week 36 and were generally sustained

Data regarding the FVIII TAb and neutralizing antibodies were described here⁹ as follows:

• To date, 12/134 (9.0%) ITT Pop. participants have tested positive at least once for FVIII TAb
• 11/32 (34.4%) of these positive tests occurred prior to dosing (Table 2⁹)
• FVIII TAb positivity was not associated with ALT elevations above the ULN based on proximal ALT levels
• At week 104 only 2/12 participants who were FVIII TAb–positive had FVIII activity below the mild hemophilia range (5–40 IU/dL)
• These sporadic FVIII TAb–positive results were not considered clinically relevant because they are consistent with transient, low-titer FVIII TAb
  that do not typically progress to FVIII neutralizing antibodies (FVIII inhibitors), and none of these participants were positive for FVIII neutralizing inhibitors at any time point
• A total of 4 participants in the ITT Pop. had single-positive results in a Nijmegen modified Bethesda assay for FVIII neutralizing antibodies before or after day 1 (titer range, 0.7 -4.0 BU; Table S2⁹),
  all of which were negative for FVIII TAb at all available/assessed time points.
• These results did not meet the specified criteria for clinically meaningful inhibitor responses, which is defined as a positive Bethesda titer ≥0.6 BU in the Nijmegen-modified Bethesda assay confirmed
  with 2 independent samples taken within a 1- to 4-week period
• Additionally, none of the 4 participants were positive for FVIII TAb at any time point

Data regarding the peaks of AAV5 capsid–specific cellular immune response was described here⁹ as follows:

• AAV5 capsid–specific enzyme-linked immunosorbent spot (ELISpot) data were available for 124 of 134 (92.5%) ITT Pop. participants, 117 (94.4%) of whom tested positive at 1 or more time points
  through a maximum of 208 weeks of follow-up
• Following stimulation with AAV5 capsid peptides, positive responses were detected in 5 of 95 (5.3%) baseline samples, and the incidence of positive responses peaked at week 2 (Figure 2 and Table S3)
• The proportion of positive responses declined over time, with 17 of 74 (23.0%) participants testing positive at week 26 and 10 of 60 (16.7%) at week 52
• A higher rate of response was observed following stimulation with AAV5 peptide pool 2 (which spans amino acids 1–370) compared with peptide pool 1 (which spans amino acids 371 - 724);
  113 of 125 (90.4%) participants tested had a positive response to AAV5 peptide pool 2 at any time point to date compared with 101 of 125 (80.8%) for peptide pool 1

Statements regarding immune responses were reported in Reference #9 as follows:

• Positive AAV5 capsid–specific cellular immune responses were detected during periods of corticosteroid use, suggesting that corticosteroid-mediated immune suppression did not prevent detection of these responses in vitro, although corticosteroid use was associated with reductions in ALT
• Following initiation of corticosteroid treatment, the median time to a ≥10 U/L decrease in ALT, or return of ALT to or below the ULN, was 8 days (mean [SD], 12.94 [18.92] days) in the ITT population

Additional data on the duration of steroid treatment and steroid responsiveness were extracted from previous publications (#3 and #6) and are summarized as follows:

• According to Table S9 in Reference #3, 39 of 134 participants (29.1%) in the ITT population used non-glucocorticoid immunosuppressants because of contraindications, side effects, or poor/no response to glucocorticoid treatment
• According to Table S8 in Reference #6, the median duration of glucocorticoid treatment per participant in the ITT population (N = 134) was 32.9 weeks (IQR, 3.1–86.3)

Statements concerning the observed FVIII activity in relation to ALT elevations were reported here⁹ as follow:

• ALT elevations that started after week 52 were not associated with unanticipated drops in FVIII activity;
  Thus, treatment with corticosteroids was not deemed to be beneficial

A case of B-cell acute lymphoblastic leukemia (B-ALL) was reported Reference #13 as follows:

• Almost 3 years after infusion of 6e13 vg/kg valoctocogene roxaparvovec, 1 participant was diagnosed with B-ALL via bone marrow biopsy
• This serious AE was considered unrelated to the treatment
• Genetic testing and whole-genome sequencing were performed on enriched populations of leukemic and healthy blood cells
• A Philadelphia-like chromosomal translocation was detected in 85% of bone marrow cells
• Extremely low levels of valoctocogene roxaparvovec vector DNA were detected in 5 cell populations:
  • < 1 copy per 100 cells in 5 populations: 2 leukemic cell-enriched and 3 healthy
  • All cell populations underwent genomic analysis by multisite droplet digital PCR, with leukemic cells containing the lowest levels of vector copies
  • No vector-host integration sites were identified by whole-genome sequencing in any samples
• Based on these analyses, this instance of B-ALL was very likely not related to valoctocogene roxaparvovec

In the final 5-year follow-up publication (Reference #17), no new malignancies, excluding non-melanoma skin cancer, were reported during Years 4 or 5. The all-follow-up value was 1 of 134 participants (0.7%), corresponding to the previously reported B-ALL case

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AAV, Adeno-associated virus; Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BU, Bethesda units; 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; TAb, total binding antibody; TAC, tacrolimus; TI, orthogonal cell-based transduction inhibitor; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year