OR12 - Stable Factor IX Expression and Sustained Reductions in Factor IX Use 9 Years after Gene Therapy with CSL220 in Adults with Haemophilia B

OR12

Stable Factor IX Expression and Sustained Reductions in Factor IX Use 9 Years after Gene Therapy with CSL220 in Adults with Haemophilia B

W. MIESBACH^1,*, K. Meijer², M. Coppens³, R. Klamroth⁴, P. E. Monahan⁵, N. W. D. Jansen⁵, S. Le Quellec⁵, F. W. G. Leebeek⁶

¹Goethe University Hospital, Coagulation and Haemophilia Centre, Medical Clinic 2, Frankfurt Am Main, Germany, ²Department of Haematology, University Medical Center Groningen University of Groningen, Groningen, ³Amsterdam University Medical Centers, Department of Vascular Medicine, University of Amsterdam and Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, Netherlands, ⁴Vivantes Klinikum im Friedrichshain, Berlin, Germany, ⁵CSL Behring, King of Prussia, PA , United States, ⁶Hematology, Erasmus University Medical Center, Rotterdam, Netherlands

 

Introduction: CSL220 (formerly AMT-060) is an adeno-associated virus serotype 5 (AAV5) vector encoding a codon-optimized wild-type human factor IX (FIX) gene, driven by a liver-specific promoter. The Phase I/II study (NCT02396342) included 10 patients with haemophilia B (FIX ≤2 IU/dL), who received a single infusion of CSL220 (5×10¹² gc/kg [Cohort 1; n=5] or 2×10¹³ gc/kg [Cohort 2; n=5]) and had a follow-up of 5 years post-treatment. Cohorts 1 and 2 differed in mean age [Cohort 1: 60.2 (15.9); Cohort 2: 38.2 (5.9)] and the extent of haemarthropathy prior to treatment. Nine out of 10 patients ceased FIX prophylaxis post-treatment. Median (range) FIX activities were 6.5 (6.3-6.7) IU/dL in Cohort 1 (n=2) and 7.2 (3.8-8.3) IU/dL in Cohort 2 (n=4) at study completion. Durability and safety are key elements for decision-making regarding gene therapy.

Methods: Patients who completed all assessments in the original trial were enrolled in the open-label, Phase I/IIb extension study (NCT05360706). Four of 5 patients from Cohort 1 (including one patient who remained on FIX prophylaxis) and all 5 patients from Cohort 2 enrolled in the extension study. Data currently available is up to 9 years post-treatment. Data presented are without the patient who remained on prophylaxis, therefore Cohort 1: n=3; Cohort 2: n=5.

Results: Median (SD) endogenous FIX activity at Year 9 was 5.0 (3.2-5.5) IU/dL in Cohort 1, and 5.7 (2.9-7.0) IU/dL in Cohort 2. Mean (SD) annualized bleeding rate in Year 9 was 3.6 (4.1) and 1.1 (1.3) for Cohorts 1 and 2, respectively. Mean (SD) annualized spontaneous bleeding rate was 2.3 (3.9) in Cohort 1 and 0.3 (0.7) in Cohort 2. Mean (SD) annualized FIX consumption during Year 9 was 13067 (15416) IU/year in Cohort 1 and 3644 (6090) IU/year in Cohort 2. No new safety events were identified during Year 9, and no patient returned to continuous FIX prophylaxis.

Discussion/Conclusion: This 9-year follow-up after CSL220 administration provides continued evidence for the durability, stability, and safety of FIX expression after AAV5-based gene therapy, particularly at the 2×10¹³ gc/kg chosen for application in Phase 3. CSL220 is the precursor of etranacogene dezaparvovec (CSL222), with only one amino acid difference; hence, these findings might be indicative of the effect of CSL222.

Disclosure of Interest: W. MIESBACH Grant/Research support from: Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Takeda/Shire, and uniQure, K. Meijer Consultant for: Alexion; Consulting fees Therini; Other: participation in data monitoring and endpoint adjudication committee Octapharma; participation in trial steering committee for Bayer; Astra Zeneca, M. Coppens Consultant for: Bayer, CSL Behring, Novo Nordisk, and F. Hoffman-La Roche, and honoraria for lecturing or consultancy from Alexion/AstraZeneca, CSL Behring, Octapharma, Pfizer, Regeneron, Sobi, and Spark Therapeutics. Non-financial conflicts of interest: member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders (EAHAD), Member of the European Reference Network (ERN) EuroBloodNet, R. Klamroth Consultant for: Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma: Other: Grant/research support; Bayer, BioMarin, CSL Behring, Chugai, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, Biotest, Grifols, Roche and Sobi: Consultancy; Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, Biotest, Grifols, Roche/Chugai and Sobi: Other: Speaker fees, P. Monahan Employee of: CSL Behring, N. Jansen Employee of: CSL Behring, S. Le Quellec Employee of: CSL Behring, F. Leebeek Grant/Research support from: CSL Behring, Takeda, and Sobi, Consultant for: CSL, Biomarin and Takeda, of which the fees go to the institution