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LBA-5 Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
Clinical Trials, Bleeding and Clotting, Hemophilia, Clinical Research, Diseases
Tuesday, December 14, 2021, 9:00 AM-10:30 AM

Lynn Malec1, An Van Damme2, Anthony Chan3, Mariya Spasova4*, Nisha Jain5, Charlotte Sensinger5*, Jennifer Dumont5*, Stefan Lethagen6*, Manuel Carcao7 and Flora Peyvandi8,9

1Versiti Blood Research Institute, Milwaukee, WI
2Paediatric Hémato-oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
3Pediatrics, McMaster Children's University, Hamilton, ON, Canada
4UMHAT Sv Georgi, EAD, Bulgaria
5Sanofi, Cambridge, MA
6Sobi, Stockholm, Sweden
7The Hospital for Sick Children, Toronto, ON, Canada
8Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
9Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8–13.8) (n=31); negative titer to normal recovery was 6.9 (3.5–12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3–20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021).

Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors.

Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs).

Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8–16.0) years, and historical peak inhibitor titer was 22.4 (6.2–256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2–17.8), 6.8 (5.4–22.4), and 11.7 (9.8–26.2) (ie, 2.7 [2.3–6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0–10.1) overall, 0 (0–2.6) for spontaneous, 1 (0–4) for traumatic, and 0 (0–3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0–2.4); spontaneous, 0 (0–0); traumatic, 0 (0–1.3); and joint, 0 (0–0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported.

Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority.

Disclosures: Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees.

OffLabel Disclosure: adheres to routine clinical practice