ISTH 2021 - Clinical Outcomes in Adults with Hemophilia B With Pre-existing Neutralizing Antibodies to AAV5: 6 Month Data from the HOPE-B Trial

Clinical Outcomes in Adults with

Hemophilia B With and Without Pre-existing Neutralizing Antibodies to AAV5: 6 Month Data from the Phase 3 Etranacogene Dezaparvovec HOPE-B Gene Therapy Trial

Frank W.G. Leebeek1, Wolfgang Miesbach2, Michael Recht3, Nigel S. Key4, Susan Lattimore3, Giancarlo Castaman5,

Eileen K. Sawyer6, David Cooper6, Valerie Ferreira6, Steven W, Pipe7, on behalf of the HOPE-B investigators

1Erasmus MC, University Medical Center Rotterdam, Netherlands; 2University Hospital Frankfurt, Frankfurt, Germany; 3Oregon Health & Science University, Portland, OR, USA 4University of North Carolina, Chapel Hill, NC, USA; 5Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy; 6uniQure BV, Amsterdam, the Netherlands/ uniQure Inc. Lexington, MA, USA; 7University of Michigan, Ann Arbor, MI, USA

1

Disclosures for Frank W.G. Leebeek

In compliance with COI policy, ISTH requires the following disclosures to the session audience:

Research Support/P.I.	Unrestricted research grants from CSL
	Behring, Takeda, Sobi, UniQure
Employee	No relevant conflicts of interest to declare
Consultant	CSL Behring, UniQure, Biomarin of which fees
	paid to the university
Major Stockholder	No relevant conflicts of interest to declare
Speakers Bureau	No relevant conflicts of interest to declare
Honoraria	DSMB Roche
Scientific Advisory Board	Takeda, fees paid to the university

HOPE-B: Etranacogene dezaparvovec (AAV5-PaduahFIX)

• Ongoing Phase 3 study in hemophilia B
• • N=54
  • Mean FIX activity increased to near-normal levels at 6 months post-etranacogene dezaparvovec, meeting the first co-primary endpoint1
  • Anti-AAV5neutralizing antibodies (NAbs) are assessed via luciferase assay2 but are not exclusionary
• Here we report safety and efficacy outcomes

at 6 months post treatment by presence of pre-existinganti-AAV5 NAbs at baseline

Etranacogene dezaparvovec:

Hyperactive FIX Padua variant

AAV5

LP-1	Hyperactive FIX Padua variant
(Liver-specific
promoter)
	AAV; adeno-associated virus; FIX, Factor IX

1. Pipe S, et al. Oral presentation at the 62nd Virtual American Society of Hematology Annual Meeting & Exposition. Dec 5-8, 2020; 2 Majowicz A, Nijmeijer B, Lampen MH, et al. Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existingAnti-AAV5 NABs. Molecular Therapy - Methods & Clinical Development 2019;14:27-36.3

Rationale for not excluding pre-existinganti-AAV5 NAbs

• Pre-existingNAbs resulting from previous exposure to AAV may prevent efficient transduction of the therapeutic transgene due to the host's immune response against the vector1
• However, prior clinical data have not shown pre-existinganti-AAV5 NAbs to have predictive value:
• Phase I/II (AMT-060):AAV5-WThFIX (N=10)2
• • Initial NAb analysis (GFP-based) did not detect NAbs
  • • Retrospective NAb analysis (luciferase-based) found 3/10 NAb positive3
    • Subject with highest titer of 340 showed highest circulating FIX activity levels of this cohort3
  • Stable FIX activity over 4.5-5 years post dosing4
  • No new treatment -related AEs* observed during the last 12 months of observation post-treatment4
• Ongoing Phase 2b (AMT-061-01): AAV5 with Padua FIX variant (N=3)5
• • • All patients NAb positive prior to treatment5
    • • 2 patients in this trial had been denied another gene therapy trial entry based on pre-existinganti-AAV NAbs
    • Mean FIX activity at 2 years was 44.2% with no new treatment-related AEs.6
  • Treatment related adverse events; GFP, Green fluorescent protein; NAbs, neutralizing antibodies.

1. Boutin S. et al. Hum Gene Ther. 2010;21:704-122; 2. Miesbach W, et al. Blood. 2018;131:1022-1031; 3. 2 Majowicz A, Nijmeijer B, Lampen MH, et al. Therapeutic hFIX Activity Achieved after

Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existingAnti-AAV5 NABs. Molecular Therapy - Methods & Clinical Development 2019;14:27-36 4. Leebeek FWG, et al,
ASH 2020; Poster #33724; 5. Von Drygalski A, et al. Blood Adv. 2019;3:3241-3247; 6. Von Drygalski A, et al, ASH 2020; Oral presentation #672;	4

HOPE-B(AMT-061): study design1

Key inclusion criteria

• Male adults ≥18 years
• FIX activity ≤2% of normal
• Continuous prophylaxis for ≥2 months

Key exclusion criteria

▪ Factors that might affect the evaluation

of AMT-061 efficacy or safety, e.g.

▪ FIX inhibitors

Lead-in phase (26 weeks)

Dosing visit

Post-treatment

Screening visit

~ 4 wks

Visits every 2 months,

phone calls on alternating

months

~ 4 wks

Single dose of AMT-061
2×1013 gc/kg	Week 1
Weekly visits
Week 12

▪ Active hepatitis B/C infection

▪ Uncontrolled HIV infection

follow up

Monthly visits

Month 12

Pre-existinganti-NAbs were assessed, but not used as an exclusion criteria

No prophylactic immunosuppression

Long-term follow up

Every 6 months

Month 60

1. Pipe S, et al. Oral presentation at the 62nd Virtual American Society of Hematology Annual Meeting & Exposition. Dec 5-8, 2020;
HIV, human immunodeficiency virus; NAbs, neutralizing antibodies; wks, weeks.	5