-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
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868 Inhibit Clinical Trials Platform to Prevent and Eradicate Inhibitors: Feasibility Survey of Current Prophylaxis and Immune Tolerance Practices

Program: Oral and Poster Abstracts
Session: 322. Disorders of Coagulation or Fibrinolysis: Poster I
Hematology Disease Topics & Pathways:
Biological, Adult, Bleeding and Clotting, Diseases, Therapies, Pediatric, Study Population, Clinically relevant, VWD
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Margaret V. Ragni, MD, MPH1, Frederico Xavier, MD, MS2, Craig D. Seaman3, Suchitra Acharya, MD4, Catherine E. McGuinn, MD5, Eric J. Werner, MD6*, Courtney Elizabeth Lawrence, MD, MS7*, Allison P. Wheeler, MD8, Ulrike Reiss, MD9, Irmel Ayala, MD10*, Erin Cockrell, DO11, Cristina Tarango, MD12, Amy Dunn13, Roshni Kulkarni, MD14, Sanjay P Ahuja, MD15, Meera B. Chitlur, MD16, Steven W. Pipe, MD17, Lynn M Malec, MD18, Vilmarie Rodriguez, MD19, Shelley Crary, MD, MS20, Deborah Brown, MD21, Rosa Diaz, MD22*, Maria Velez, MD23*, Cindy A. Leissinger, MD24, Shannon L Carpenter, MD25, Christine M. Knoll, MD26, Michael Wang, MD27, Guy Young, MD28, Courtney D Thornburg, MD29, Joseph L Lasky III, MD30*, Tiffany Lin Lucas, MD31, Nina Hwang, MD32*, Deborah Vehec, MSN, RN33*, Dana Ivanco34*, Tamara L. Haller, BS35*, Marnie Bertolet, PhD36* and Maria M Brooks, PhD37*

1University of Pittsburgh Medicine, Division Hematology/Oncology, Pittsburgh, PA
2Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center and Hemophilia Center of Western PA, Pittsburgh, PA
3University of Pittsburgh, Warrendale, PA
4Pediatric Hematology, Oncology and Cellular Therapy, Cohen Children's Medical Center of New York, New Hyde Park, NY
5Weill Cornell Medical College, New York, NY
6Children's Hospital of The King's Daughters, Norfolk, VA
7Division of Pediatric Hematology / Transfusion Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
8Dept. of Pediatric Hem./Onc., Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN
9Department of Surgery, St. Jude Children's Rsch. Hosp., Memphis, TN
10Pediatric Cancer and Blood Disorders Center, Johns Hopkins All Children's Outpatient Care Center, St. Petersburg, FL
11St. Joseph's Children's Hospital, Tampa, FL
12Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
13Nationwide Children's Hospital, Columbus, OH
14Michigan State University Center for Bleeding and Clotting Disorders, East Lansing, MI
15University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital, Cleveland, OH
16Hemostasis and Thrombosis Center, Children's Hospital of Michigan, Detroit, MI
17Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI
18Blood Research Institute, Versiti, Milwaukee, WI
19Division of Pediatric Hematology, Mayo Clinic, Rochester, MN
20University of Arkansas for Medical Sciences, Little Rock, AR
21Department of Pediatrics- Hematology Division, University of Texas Health Science Center at Houston, Houston, TX
22Texas Children's Hospital, Houston, TX
23Children's Hospital New Orleans, Louisiana State University, New Orleans, LA
24Tulane University, New Orleans, LA
25Children's Mercy Hospital, Kansas City, MO
26Arizona Hemophilia and Thrombosis Center, Phoenix Children's Hospital, Phoenix, AZ
27Anschutz Medical Campus, University of Colorado, School of Medicine, Hemophilia and Thrombosis Center, Aurora, CO
28University of Califormia Los Angeles, Children's Hospital Los Angeles, Los Angeles, CA
29Rady Children's Hospital, San Diego, CA
30University of Nevada, Cure 4 the Kids Foundation, Las Vegas, NV
31University of California, San Francisco, San Francisco, CA
32CHOC Children's Hospital, Orange County, Center for Inherited Blood Disorders (CIBD), Orange, CA
33Hemophilia Center of Western PA, Institute for Transfusion Medicine, Vitalant, Pittsburgh, PA
34Institute for Transfusion Medicine, Hemophilia Center of Western PA, Pittsburgh, PA
35Department of Epidemiology, Epidemiology Data Center, University of Pittsburgh, Pittsburgh, PA
36Epidemiology Data Center, University of Pittsburgh, Pittsburgh, PA
37Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

Introduction: Among the most challenging complications of hemophilia A is inhibitor formation. A T-cell dependent B-cell response to exogenous factor VIII (FVIII), inhibitors result in a high burden of disease, with poorly controlled bleeding, twice the hospitalizations, 10-fold the cost, and 3.5-fold the mortality of non-inhibitor patients. Thus, a major goal of hemophilia management is to prevent and eradicate inhibitors. With the availability of novel therapies, including eloctate, a recombinant Fc-fusion protein (rFVIII-Fc) which induces regulatory T cells to promote FVIII tolerance, and emicizumab, a bispecific monoclonal FVIII mimetic, we designed the INHIBIT Clinical Trials Platform (X01HL143024), Fig.1. The platform is composed of two linked randomized phase III trials, the Inhibitor Prevention Trial (NCT04303559), comparing rFVIII-Fc vs emicizumab prophylaxis to prevent inhibitors, and the Inhibitor Eradication Trial (NCT04303572), comparing rFVIII-Fc immune tolerance induction (ITI) plus emicizumab vs rFVIII-Fc ITI alone to eradicate inhibitors. The platform uses adaptive design to incorporate historical data (Bayesian priors) on inhibitor formation to increase power and promote efficient use of rare data. Yet, there is equipoise regarding the optimal approach to inhibitor prevention and eradication, and, as clinical practice is changing, we aimed to test the feasibility of the INHIBIT trial design.

Methods: To establish design feasibility, we conducted interviews with 30 hemophilia treatment center (HTC) physicians participating in the INHIBIT trials, to determine prophylaxis and tolerance regimens they prescribe and perceived barriers to the INHIBIT trials design. A 4-question survey was subsequently emailed to these physicians to ascertain the initial prophylaxis regimens they prescribe in previously untreated patients (PUPs) with severe hemophilia A, and the initial immune tolerance induction (ITI) they prescribe in high-responding inhibitor patients with severe hemophilia A; if new inhibitors had been observed during emicizumab prophylaxis, and willingness to participate in post-trial surveillance.

Results: In interviews, HTC physicians indicated the issues that influenced choice of prophylaxis/ ITI regimen were patient preference, family history of inhibitors, infusion frequency, IV access, port requirement, and family fatigue. In the absence of clinical trials data in PUPs, there was general agreement that emicizumab prophylaxis, with it simpler subcutaneous (SQ) administration, might delay or potentially prevent inhibitors. Survey findings in Table 1 indicated 75% of physicians prescribe extended half-life (EHL) FVIII in a once-weekly prophylaxis regimen, as planned in the Prevention Trial, despite the persistent 27% inhibitor rate (ALong PUPs Trial, Königs et al, ISTH 2020) and potential risks with port use. There was support for the 1:3 preferential randomization to emicizumab in the Prevention Trial due to the simpler SQ route, despite concern it might delay rather than prevent inhibitor formation, although no inhibitors were reported by physician survey with emicizumab use alone. There was also concern that breakthrough bleeds requiring FVIII during emicizumab prophylaxis, might lead to immune activation and inhibitor formation. There was strong agreement, however, in 29 (97%) of physicians to participate in post-trial surveillance for long-term inhibitor outcomes. FVIII ITI was considered essential to eradicate inhibitors, despite the intensity of the infusion regimen. Notably, 60% prescribe emicizumab with FVIII ITI, as planned in the Eradicate Trial, although the every-other-day infusion was considered a potential barrier to participation. Omitting FVIII ITI was not favored due to the risk of inhibitor anamnesis if FVIII treatment was subsequently required for surgery or acute hemorrhages. Despite these concerns, there was agreement to participate in the trials.

Discussion: Physician interviews and surveys confirm there is heterogeneity in current hemophilia clinical practice, specifically in initial prophylaxis regimens and in initial immune tolerance regimens, including agent choice and duration. However, there is physician consensus with the INHIBIT trial aims and with the proposed INHIBIT trial regimens to prevent and eradicate inhibitors.

Disclosures: Ragni: Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam/Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; ATHN: Research Funding; Sangamo: Research Funding. Seaman: Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Takeda: Consultancy. Acharya: Novonordisk: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding. Wheeler: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees. Tarango: Sanofi: Honoraria, Other; Bayer: Consultancy, Other. Dunn: ATHN: Research Funding; Spire: Honoraria; Medscape: Honoraria; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy; Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment. Kulkarni: Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Ahuja: Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding. Chitlur: Takeda: Honoraria; Biovertiv: Honoraria; Agios Pharmaceuticals: Research Funding; Pfizer: Honoraria; Novo Nordisk: Consultancy, Honoraria. Pipe: Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Malec: Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy; Takeda: Consultancy; Bayer: Consultancy; SOBI: Consultancy. Leissinger: Bayer: Consultancy; Kedrion: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; HEMA Biologics: Consultancy; Takeda: Consultancy; Uniqure: Consultancy; Spark: Consultancy. Carpenter: Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding. Knoll: NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Wang: Bayer: Honoraria; Bioverativ Inc: Honoraria; Catalyst Biologics: Consultancy; NovoNordisk: Consultancy; Hema biologics / LFB: Consultancy; Takeda: Honoraria; Genentech: Honoraria; Biomarin: Honoraria; CSL Behring: Honoraria. Young: Genentech/Roche, Grifols, and Takeda: Research Funding; Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Thornburg: Genentech: Speakers Bureau; Spark Therapeutics: Consultancy; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; American Thrombosis and Hemostasis Network: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lucas: CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hwang: Shire: Honoraria; Takeda: Honoraria.

*signifies non-member of ASH