Summary Information For: AAV5, FVIII-BDD, Roctavian, NCT03370913 (Phase 3, GENEr8-1 Study)
AAV5, FVIII-BDD, Roctavian, NCT03370913 (Phase 3, GENEr8-1 Study)
Haemophilia A
BioMarin Pharmaceutical
General Study Information
  • ClinicalTrials.gov Identifier: NCT033709131, 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 system3 [supplementary appendix]

Codon-optimized expression cassette for the SQ variant of B-domain–deleted humna hFVIII (AAV-HLP-FVIII-SQ)49

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 signal4 [supplementary material]

    Systemic (peripheral vein infusion)3

Different populations within the same dose cohort were defined here3, 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)
  • As reported here9,  safety and efficacy results included data from the year-3 data cut cutoff36:
    • Mean follow-up was 172.8 (standard deviation [SD], 26.61) weeks
    • Median, 162.4 weeks; range, 66.1–255.0 weeks

    Both OS and CH were carried out23

Efficacy details

The impact of anti-AAV5 TAb and AAV5 TI titers on FVIII activity was reported here9 as follows:

  • 3 pts. 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 pts. 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 pts. 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 correlation between FVIII activity and anti-AAV5 TAb in the ITT Pop. was described here9 as follows:

  • The median  FVIII activity demonstrated no correlation with the peak AAV5 TAb titers at week 104, nor with the AAV5 TAb titers measured at week 8

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:

Mean and median FVIII activity (IU/dL) levels per CH and OS in the mITT Pop. (n =132) at the end of years 1 and 2 post infusion 

 

Year 1 (week 52)

Year 2 (week 104)

FVIII activity (IU/dL) per CH

    Mean ±SD

42.8 ± 45.6

23.0 ± 32.9

    Median (IQR)

23.9 (11.9, 62.3)

11.8 (5.0, 25.7)

FVIII activity (IU/dL) per OS

    Mean ±SD

64.0 ± 64.8

36.1 ± 47.3

    Median (IQR)

40.3 (19.7, 86.9)

21.6 (7.6, 42.2)


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 S56as shown below.

Median FVIII activity (IU/dL) levels per CH and OS in the ITT Pop. at the end of years 1 (week 52) and 2 (week 104) post infusion 

 

Year 1 (N = 134)

Year 2 (N = 132a)

FVIII activity (IU/dL) per CH

n (%)

n (%)

     <3 IU/dL (LLOQb)

13 (9.7)

18 (13.6)

     <5 IU/dL

16 (11.9)

31 (23.5)

     ≥5 and <40 IU/dL

69 (51.5)

81 (61.2)

     ≥40 IU/dL

49 (36.6)

20 (15.2)

FVIII activity (IU/dL) per OS

n (%)

n (%)

     <1 IU/dL (LLOQ)

2 (1.5)

6 (4.5)

     <5 IU/dL

10 (7.5)

18 (13.6)

     ≥5 and <40 IU/dL

56 (41.8)

79 (59.8)

     ≥40 IU/dL

68 (50.7)

35 (26.5)


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:

Mean and median FVIII activity (IU/dL) levels per CH and OS in the mITT Pop. 3-year (n = 17) at the end of Years 1 (week 52), 2 (week 104) and 3 (week 156) post infusion 

FVIII activity (IU/dL) per CH

Year 1 (week 52)

Year 2 (week 104)

Year 3 (week 156)

    Mean ±SD

42.0 ± 51.1

24.5 ± 29.7

16.8 ± 21.1

    Median (IQR)

23.9 (11.2, 55.0)

14.7 (6.4, 25.9)

9.3 (4.6, 13.6)

 

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

Estimated mean and median FVIII activity (IU/dL) per CH using a linear mixes effects (LME) model

Time post infusion

Mean

Median (range)

Week 104

22.3 ± 29.7

11.1 (BLQ-171)

Week 156

16.9 ± 25.0

8.9 (BLQ-156)

Week 208

13.6 ± 22.4

7.2 (BLQ–143)

Week 260

11.8 ± 21.0

5.7 (BLQ–131)

     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 here3, 6 and were obtained from Figure 1A and Figure 1C6 as follows:

Mean and median annualized rates of Treated bleeding episodesa (Figure 1A)6 in RP (n = 112) using the baseline values from a 6-months prospective study (270-902)

Annualized rates

at Baseline

Year 1 b

Year 2 c

All Postprophylaxis

mean ± SD

4.8 ± 6.5

0.9

0.7

0.8

median

2.8

0

0

0

mean (95% CI) change from BL

NA

NA

NA

−4.1 (−5.3 to −2.9) bleeds per year

ABR reduction

NA

NA

NA

84.5%

 

Mean and median annualized rates of All bleeding eventsa (Figure 1C)6 in RP (n = 112)

Annualized rates

at Baseline

Year 1 b

Year 2 c

All Postprophylaxis

mean ± SD

5.4

1.5

1.0

1.2

median

3.3

0

0

0.5

mean (95% CI) change from BL

NA

NA

NA

−4.1 (−5.4 to −2.8) bleeds per year

ABR reduction

NA

NA

NA

77.0%

 

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

Annualized treated bleeding rate a in mITT Pop. 3-year (N = 17)

 

 

Year 1 b

Year 2 c

Year 3 d

Annualized rates

n=17

n=17

n= 16 e

mean ± SD

1.2 ± 3.0

0.5 ± 0.9

0.6 ± 1.7

median (IQR)

0.0 (0.0, 0.0)

0.0 (0.0, 0.0)

0.0 (0.0, 0.5)


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:

Joint and not-joint bleeds in the ITT pop. (n = 134) by year of Postprophylaxis

 

All bleeds

Treated bleeds

Percent of participants (n)

Year 1 b

Year 2 c

Year 1 b

Year 2 c

Problem joints

3.7 (5)

3.0 (4)

3.0 (4)

1.5 (2)

Anywhere except problem joints

42.5 (57)

34.3 (46)

20.1 (27)

17.2 (23)

Not in joints

33.6 (45)

24.6 (33)

15.7 (21)

10.4 (14)


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:

Mean and median changes from baseline in AIR from W4 after infusion in the RP (N = 112)

AIR

Baseline

starting at W4 post infusion

AIR reduction

median (range)

128.6 (39.5 - 363.8)

0

Mean change, -113.9 (95% CI, -143.0 to -124.3), corresponding to 98.6%

mean ±SD

135.9 ±52.0

2.0


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:

Mean and median AR of FVIII use at baseline (BL) period vs the time W4 after infusion in the RP (N = 112)

Annualized rate of FVIII use

Baseline

Year 1

Year 2

All Postprophylaxis

Reduction in AR of FVIII use from BL in comparison to all Postprophylaxis

median

3754.4

0

0

0

Mean change, -3891.3 (95% CI, -4221.0 to -3561.5, P<0.001), corresponding to 98.2%

mean

3961.2

45.4

88.3

69.9


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

Mean (±SD) and median ARs of one-time use of FVIII prophylaxis in 21 pts. in the ITT Pop. (N = 134)

median (range) IU/kg per year

0.0 (0.0 to 639.2) IU/kg

mean ±SD IU/kg per year

15.5±72.1 IU/kg

 

Safety Details
  • 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%)

Statements concerning the observed AEs were reported here9 as follow:

  • 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 a 2-year follow-up after vector infusion were obtained from Table 26 and
are summarized as follows:

Summary of the reported AEs observed in the ITT Pop. (n = 134)

 

Year 1

Year 2

Total

Event 

number (percent)

Any adverse event

134 (100)

112 (83.6)

134 (100)

Adverse event occurring in ≥30% of participantsa

     

     Alanine aminotransferase increase

-

-

119 (88.8)

     Headache

-

-

55 (41.0)

     Arthralgia

-

-

53 (39.6)

     Nausea

-

-

51 (38.1)

     Aspartate aminotransferase increase

-

-

47 (35.1)

SAE

21 (15.7)

5 (3.7)b

24 (17.9)

Adverse event grade ≥3

31 (23.1)

13 (9.7)

42 (31.3)

Fatal adverse event

0

1 (0.7)

1 (0.7)

Treatment-related adverse event

     

     Any AE

123 (91.8)

28 (20.9)

123 (91.8)

     SAE

5 (3.7)

0

5 (3.7)

Adverse event related to glucocorticoids

     

     Any AE

80 (59.7)

9 (6.7)

81 (60.4)

     SAE

3 (2.7)

0

3 (2.7)

AEs related to nonsteroidal immunosuppressants

    Any AE

12 (9.0)

2 (1.5)

15 (11.2)

     SAE

1 (3.0)

0

1 (0.7)

AEs of special interest

     

     Alanine aminotransferase increase

114 (85.1)

39 (29.1)

119 (88.8)

     Alanine aminotransferase increase of grade ≥3

11 (8.2)

1 (0.7)

11 (8.2)

     Adverse event related to liver function

116 (86.6)

39 (29.1)

119 (88.8)

     Potential Hy’s law case

0

0

0

     Infusion-related reactionc

12 (9.0)

0

12 (9.0)

     Infusion-associated reactiond

50 (37.3)

0

50 (37.3)

     Systemic hypersensitivity

7 (5.2)

0

7 (5.2)

     Anaphylactic or anaphylactoid reaction

3 (2.2)

0

3 (2.2)

     Thromboembolic event

0

0

0

     Anti–factor VIII neutralizing antibodies

0

0

0

     Cancer, except nonmelanoma skin cancer

0

0

0


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:

Adverse events related to glucocorticoid use

 

Year 1

Year 2

total

Any AE related to glucocorticoids

80 (59.7)

9 (6.7)

81 (60.4)

SAE related to glucocorticoids

3 (2.7)

0

3 (2.7)


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:

AEs and SAEs deemed related to glucocorticoid use by the investigator

 

ITT Pop. (n = 110)a

Event 

No. (%)

Any AE related to glucocorticoids

79 (71.8%)

AEs related to glucocorticoids occurring in ≥5% of pts.

     Acne

32 (29.1)

     Insomnia 

23 (20.9%)

     Cushingoid

16 (14.5%) 

     Weight increased

16 (14.5%)

     Folliculitis

10 (9.1%) 

     Rash pustular                 

10 (9.1%) 

     Hypertension 

9 (8.2%)

     Mood swings

8 (7.3%)

     Irritability

6 (5.5%) 

     Fatigue

6 (5.5%)

Any SAE related to glucocorticoids

3 (2.7%)

     Rectal hemorrhage

1 (0.9%) 

     Pneumonia

1 (0.9%)b

     Influenza A virus test positive

1 (0.9%)b

Diabetes mellitus

1 (0.9%)c

Steroid diabetes

1 (0.9%)c

Hypertension

1 (0.9%)c


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

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 here3, 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 concerning the reviewed immune responses were reported here9 as follows:

  • Positive responses were detected during periods of corticosteroid use, suggesting that immune suppression with corticosteroids did not prevent detection of
    AAV5 capsid–specific cellular immune responses as assessed in vitro, although it was associated with reductions in ALT.
  • Following initiation of corticosteroid use, the median time to a ≥10 U/L drop in ALT, or ALT returning to or below the ULN, was 8 days (mean [SD], 12.94 [18.92] days) for the ITT Pop.

The subsequent information regarding the duration of steroid treatment and steroid responsiveness was extracted from previous publicatinos3, 6 and summarized as follows:

  • 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)

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

    Not reported

References:
  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
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  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
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  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)
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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

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