Summary Information For: AAV5, FVIII-BDD, Roctavian, NCT02576795 (Phase 1/2 Study) ¹⁸ˑ ¹⁹ˑ ³⁸ˑ ⁵⁹
AAV5, FVIII-BDD, Roctavian, NCT02576795 (Phase 1/2 Study) ¹⁸ˑ ¹⁹ˑ ³⁸ˑ ⁵⁹
Haemophilia A
BioMarin Pharmaceutical
General Study Information
  • ClinicalTrials.gov Identifier:  NCT02576795
  • A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, 
    an Adenovirus-Associated Virus Vector-Mediated gene transfer of human FVIII in Patients with severe Haemophilia A
  • Ongoing development, Active, not recruiting
  • Last Update Posted: October 14, 2022 *
  • Male ≥18 years of age with base FVIII level ≤ 1 IU/dL
  • Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 Eds
  • Detectable pre-existing immunity to the AAV5 capsid a
  • Prior treatment with any vector or gene transfer agent
  • Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral infusion

a   Cell-based in vitro transduction-inhibition assay and total antiAAV5 antibody assay
        

AAV5/baculovirus, Spodoptera frugiperda (Sf9) insect-cell production system 18

    Codon-optimized expression cassette for the SQ variant of B-domain–deleted human FVIII 18

    HLP is a 251-bp enhancer/promoter fragment containing 

  • A 34-bp core enhancer from the human ApoE-HCR gene and
  • A modified 217-bp gene promoter comprising the distal X and
  • The proximal A1B regulatory domains from SERPINA1 (α-1-antitrypsin) 46 

    The FVIII expression cassette also includes a synthetic polyA signal 18 [supplementary material]

    Systemic (peripheral vein infusion) 18

  • Co. 1: 6e12 (1) 18
  • Co. 2: 2e13 (1) 18
  • Co. 3: 6e13 (7) 1819 , 59
  • Co. 4: 4e13 (6) 19, 59

    52 weeks 18, 3 years 19, 4 years 59 and 5 years 38

  • FVIII activity levels were assessed by both OS and CH clotting assays  1819 
  • OS FVIII activity levels were approximately 1.6 19 to 1.65 18 times as high as the FVIII levels from CH 
Efficacy details

 

FVIII activity levels in the low and intermediate cohorts through week 54 18 

Cohort

FVIII activity levels through week 54

Co. 1 (6e12 vg/kg, n=1)

    < 1IU/dl

Co. 2 (2e13 vg/kg, n=1)

stable but low level of 1 to 3 IU/dL

 

FVIII activity levels in the high dose cohort, Co. 3 (6e13 vg/kg, n=7) through week 52 18 

at week 2

by week 16

> week 20

at week 52

> 5 IU/dL
in 4/7 pts.

> 5 IU/dL
in 7/7 pts.

> 50 IU/dL in 6/7 pts., 
12 - 32 IU/dL in 1/7 pt.

median (IQR)
77IU/dl (19-64)

mean ±SD
(93 IU/dl ±48)

 

Multiyear mean FVIII activity levels per OS in the high dose cohorts 19, 38, Co. 3 and Co. 4 

Dose cohort

Year 1

Year 2

Year 3

Year 4

Year 5

Co. 3 (6e13 vg/kg, n=7)        

104

59

52

-

18.7

Co. 4 (4e13 vg/kg, n=6

31

23

-

9.5

-

 

Activity decrease vs. the previous year in the high dose cohorts, Co. 3 and Co. 4 19, 38

Dose cohort

Year 2

Year 3

Year 4

Year 5

Co. 3 (6e13 vg/kg, n=7)        

43%

10%

 -

14%

Co. 4 (4e13 vg/kg, n=6)

30%

-

6%

 -

 

Median (IQR) FVIII activity levels (IU/dL) per CH at year 3 and year 4 59 for the high dose cohorts

 

Co. 3 (6e13 vg/kg, n=7)

Co. 4 (4e13 vg/kg, n=6)

FVIII activity levels      

at Year 4

at Year 3

CH-Median (IQR)

16.4 (9.2–29.5) IU/dL

7.9 (3.4–18.0) IU/dL

 

According to Figure 1 published here 59

  • 20 to 24 weeks in Co. 3 (6e13 vg/kg, n=7) and
  • 44 weeks in Co. 4 (4e13 vg/kg, n=6)

Early follow-up efficacy data related to ABR in Co. 1 – Co. 3 were reported here 18 and summarized as follows:

  • Co. 1: not applicable, as the only pt. in this cohort resumed FVIII prophylaxis after W16
  • Co. 2: the ABR increased from 3 to 11 events in 1/1 pts. with stable but low FVIII activity level (1 to 3 IU/dL) through W54
  • Co. 3: the median ABR dropped from 16 events per year before the study to 1event per year after gene transfer (mean reduction in rate, from 16 to 2 events)

Multiyear follow-up of ABRs after treatment were reported here 19, 38, 59 and summarized as follows:

Multiyear follow-up of ABRs after treatment in comparison to the ABRs before treatment 19, 38

 

Co. 3 (6e13 vg/kg, n = 6)

Co. 4 (4e13 vg/kg, n = 6)

 

pretreatment

Year 1

Year 2

Year 3

Year 4

Year 5

pretreatment

Year 1

Year 2

Year 3

Year 4

median ABR

16.5

0

0

0

0

0

8

0

0

0

1.0

mean ABR

16.3

0.9

0.2

0.7

1.3

0.7

12.2

0.9

1.2

0.5

1.7

                         

 

Mean ABR reduction at the indicated years from the pretreatment mean

 

Cohorts

Co. 3 (6e13 vg/kg)

Co. 4 (4e13 vg/kg)

Years after treatment

Year 3

Year 4

Year 5

Year 2

Year 3

Year 4

Mean ABR reduction

96%

95%

95%

92 %

93 %

92%

Reference

19

59

38

19

59

38

 

Early follow-up efficacy data related to AIR in Co. 1Co. 2 were reported here 18 and summarized as follows:

Infusions per year before the study in comparison to the infusions per year after gene transfer for the low- and intermediate-dose cohorts

Infusions / Year

Co. 1 (6e12 vg/kg, n = 1)

Co.2 (2e13 vg/kg, n = 1)

Before the study

95

104

After gene transfer

123

14

 

Multiyear follow-up efficacy data of AIRs in Co. 3Co. 4 after treatment were reported here 19, 38 and summarized as follows:

Mean and median AIRs after treatment in comparison to the AIRs before treatment

 

Co. 3 (6e13 vg/kg, n = 6)

Co. 4 (4e13 vg/kg, n = 6)

Years

pretreatment

Year 1

Year 2

Year 3

Year 4

Year 5

pretreatment

Year 1

Year 2

Year 3

Year 4

median AIR

138.5

0

0

0

0.5

0

155.5

0

0.5

1.5

3.0

mean AIR

136.7

2.1

8.8

5.5

4.6

5.5

146.5

2

6.8

8.6

7.8

 

Safety Details

3/7 (42.9%) pts. in Co. 3 (6e13 vg/kg) and 4/6 pts. (66.7%) in Co. 4 affected by IRRs 38

Total AEs and SAEs for all cohorts were extracted from Table S2 38 and summarized as follows:
 

 

total (n=15)

 

reported AEs 

no. (%) 

Events

Any AE

15 (100)

307

Any SAE 

3 (20.0)

3

AE assessed by Investigator as Related

13 (86.7)

38

SAE assessed by Investigator as Related

1 (6.7) 

1

Grade 1* AE

15 (100)

263

Grade 2* AE

13 (86.7)

39

Grade 3* AE

2 (13.3)

2

Treated ALT elevations

10 (66.7)

12

 

 

AEs and SAEs for Co. 3 and Co. 4 were extracted from Table 1 38

reported AEs a

no. (%) within Co. 3 (6e13 vg/kg)

no. (%) within Co. 4 (4e13 vg/kg, n = 6)

Years post-infusion

Y1

Y2

Y3

Y4

Y5

Y1

Y2

Y3

Y4

Any AE

7 (100)

6 (85.7)

7 (100.0)

7 (100.0)

6 (85.7)

6 (100.0)

5 (83.3)

5 (83.3)

4 (66.7)

Any SAE

0

1 (14.3)

1 (14.3)

1 (14.3)

0

1 (16.7)

0

1 (16.7)

1 (16.7)

Any treatment related-related SAE

6 (85.7)

1 (14.3)

1 (14.3)

2 (28.6)

0

6 (100.0)

0

0

0

     Grade 1 treatment-related AE

4 (57.1)

1 (14.3)

1 (14.3)

2 (28.6)

0

4 (66.7)

0

0

0

     Grade 2 treatment-related AE

2 (28.6)

0

0

0

0

2 (33.3)

0

0

0

     Grade 3 treatment-related AE

0

0

0

0

0

0

0

0

0

Any AE of Grade ≥3a

0

0

0

0

0

1 (16.7)

0

0

0

Fatal AEs

0

0

0

0

0

0

0

0

0

AEs of special interest

 

 

 

 

 

 

 

 

 

     ALT elevation

6 (85.7)

0

0

1 (14.3)b

1 (14.3)c

4 (66.7)

0

1 (16.7)d

0

     AEs of liver dysfunction

6 (85.7)

1 (14.3)

0

1 (14.3)b

1 (14.3)c

5 (83.3)

0

1 (16.7)d,e

0

     Potential Hy’s law case

0

0

0

0

0

0

0

0

0

     Infusion-related reactions

3 (42.9)

0

0

0

0

4 (66.7)

0

0

0

     Systemic hypersensitivity

0

0

0

0

0

0

0

0

0

     Anaphylactic or anaphylactoid

     reactions

0

0

0

0

0

0

0

0

0

     Thromboembolic events

0

0

0

0

0

0

0

0

0

                     

a Percentages were calculated using the total number of pts. (N) in each analysis population as the denominator. Pts. with more than one AE of the same category were counted only once for that category
b A Grade 1 AE of ALT increase (1.4 × ULN) occurred on study day 1389. The AE was deemed not related to the study drug by the investigator and resolved by the next study visit on day 1431 without treatment.
c A Grade 1 AE of ALT increase (1.3 × ULN) occurred on study day 1626. The AE was deemed not related to the study drug by the investigator and resolved by study day 1631. d A Grade 1 AE of ALT increase (2.1 × ULN)
  occurred on study day 1100. The AE was deemed not related to the study drug by the investigator and resolved by the next study visit on day 1135 without treatment.
e A Grade 1 AE of AST increase (1.7 × ULN) occurred on study day 1100. The AE was deemed not related to the study drug by the investigator and resolved by the next study visit on day 1135 without treatment

Further statements related to AEs and SAEs were reported here 19, 38 and summarized as follows:

  • Most common AEs associated with valoctocogene roxaparvovec were transient, asymptomatic, and mild-to-moderate ALT elevations
  • Treatment related SAE of grade 2 pyrexia developed along with myalgia and headache in 1/1 pt. (P13, Co. 4) within 24 hours after the administration of AAV5-hFVIII-SQ
    - Symptoms resolved within 48 hours after the participant received Acetaminophen

 

Not reported 

8/9 pts. (59-128 U/L, 4-52 weeks) 18 and 11/15 pts. (peak and timing not reported) 59

3/9 pts. (peak levels and timing not reported) 18 and 10/15 pts. (peak levels and timing not reported) 19 

Data regarding capsid directed T cell activation were reported by different publications as follows:

  • 0/9 pts. (peak and timing not reported) 18 and Sporadic, transient positives in some pts. 19 
  • All 15 pts. were tested negative for the AAV5-specific IFN-g responses at baseline 54
  • 4 /15 pts. were tested positive (R50 SFU/106 PBMCs) for AAV5-specific IFN-g responses at a single time point a post-administration and negative at all subsequent time points tested (Figure 4A) 54

PBMC samples were collected at baseline and at several time points after administration that varied by cohort but were generally every 2–4 weeks during the first 6 months, 4–8 weeks through the rest of year 1, and every 3 months thereafter

  •  Yes, all pts. with elevated ALT levels were steroid responsive  (mean duration of steroid treatment was 21 weeks in 7/9 pts.) 18
  •  Co. 3: Steroid treatment in 2/3 participants did not inhibit ALT elevations (duration not reported) 19
  • The increase in ALT levels led to decline in the FVIII activity in 1/9 (11 %) pts. in Co. 3 18. The level in this pt. declined from 227 IU/dL to 52 IU/dL in conjunction with an increase in the ALT level from W28 to W35. The FVIII activity level subsequently increased, and no bleeding was reported 18
  • The elevations in the ALT level appeared to have been temporally associated with decreases in FVIII expression in 4/9 pts. (P4, 5, 7, and 8) in the high dose cohort, Co. 3 19 

 Follow-up data regarding a diagnosed cancer in a pt. were taken from here 63 and summarized as follows: 

  • One SAE in a pt. was diagnosed as salivary gland cancer
  • The cancerous mass was removed, and the pt. was monitored
  • The study investigator considered the SAE as being unrelated to the treatment
     
  • BioMarin announced the findings from genomic analysis from a tissue sample containing the mass, stating that: “The results  showed a comparable pattern of integration between healthy and tumor containing tissues, with no evidence emerging that vector integration contributed to the salivary gland mass.”
References:

   *  ClinicalTrials.gov
18. 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
19. Pasi, K.J., et al., Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Haemophilia A. New England Journal of Medicine, 2020. 382(1): p. 29-40. 
      Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A | NEJM       
38. Pasi, K.J., et al., Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia, 2021. 27(6): p. 947-956.
      Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A - PMC (nih.gov)
46. 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)
54. Long, B.R., et al., Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A. Mol Ther, 2021. 29(2): p. 597-610.
       Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A - PMC (nih.gov)
59. Pasi, K., et al., Hemostatic Response is Maintained for up to 5 Years Following Treatment with Valoctocogene Roxaparvovec, an AAV5-hFVIII-SQ Gene Therapy for Severe Hemophilia A [abstract].
       ISTH 2021 Congress, 2021. Hemostatic Response is Maintained for up to 5 Years Following Treatment with Valoctocogene Roxaparvovec, an AAV5-hFVIII-SQ Gene Therapy for Severe Hemophilia A - ISTH Congress Abstracts
63. BioMarin follows up on previously-reported serious adverse event in its phase I/II gene therapy clinical trial for haemophilia A. 2022, WFH World Federation of Hemophilia.
       BioMarin follows up on previously-reported serious adverse event in its phase I/II gene therapy clinical trial for haemophilia A – WFH - World Federation of Hemophilia

AAV, Adeno-associated virus; AEs, Adverse events; ABR, Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 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

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