• ClinicalTrials.gov Identifier: NCT03001830¹
• Phase I/II, open-label, non-randomized dose-escalation trial (GO-8)

• Ongoing development, Recruiting¹
• Last Update Posted: October 25, 2023¹

Baseline plasma hFVIII levels of <1% of normal males with mutationst hat have a low risk for inhibitor development, such as¹:

• Intron 22 inversions, intron 1 inversions
• Splice-site mutations, small deletions/insertions, 
• Duplications and missense mutations

• Detectable neutralising anti-AAV8 antibodies
• Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations of the F8 gene
• Received an AAV vector, or any other gene transfer agent in the previous 6 months 
• Patients at high risk of thromboembolic events and those with acquired thrombophilia

AAV8, Mammalian HEK293T² / Plasmid DNA³

Codon optimized FVIII variant, FVIII-V3 containing  a 17 amino-acid peptide with 6 N-linked glycosylation motifs from the human FVIII B-domain²

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)⁴
    

Systemic²

Co. 1: 6e11 (1) and Co. 2: 2e12 (2)²

13-47 weeks²

OS²

FVIII expression was detectable within 2 weeks and was > 5 IU/dl by 6 weeks of gene transfer in all 3 pts.²

Not reported

Not reported

AAV8-HLP-hFVIII-V3 was well tolerated in all pts. with no infusion-related reactions²

No Grade III (CTCAE v4.03) or greater AE have been observed over a period of 47 weeks after administration of AAV8-HLP-hFVIII-V3²
    

Not reported

• Co. 1: 1/1 pts. (peak 1.5 x ULN/4-6 weeks)
• Co. 2: 1/2 pts. (peak 1.5 x ULN/4-6 weeks)

Not reported

Not reported

Yes (duration not reported)

In 3/3 pts. no loss of FVIII expression observed due to transaminitis ²¹
    

Not reported

1. Gene Therapy for Haemophilia A. (GO-8). Available at: Study Details | Gene Therapy for Haemophilia A. | ClinicalTrials.gov
2. Nathwani, A.C., et al., GO-8: Preliminary Results of a Phase I/II Dose Escalation Trial of Gene Therapy for Haemophilia a Using a Novel Human Factor VIII Variant. Blood 2018. 132(Suppl. 1): p. 489.  GO-8: Preliminary Results of a Phase I/II Dose Escalation Trial of Gene Therapy for Haemophilia a Using a Novel Human Factor VIII Variant | Blood | American Society of Hematology (ashpublications.org)
3. Peyvandi, F. and I. Garagiola, Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia, 2019. 25(5): p. 738-746. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia - PubMed (nih.gov)
4. 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 - PubMed (nih.gov)

AAV, Adeno-associated virus; 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