Final Results of the Prospective ADVATE® Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII

Amy D Shapiro; Alejandro Fernandez; Jerome Teitel; Jaco Botha; Kate Khair

doi:10.2147/JBM.S329883

Final Results of the Prospective ADVATE^® Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII

J Blood Med. 2021 Nov 20:12:991-1001. doi: 10.2147/JBM.S329883. eCollection 2021.

Authors

Amy D Shapiro¹, Alejandro Fernandez², Jerome Teitel³, Jaco Botha², Kate Khair⁴

Affiliations

¹ Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA.
² Takeda Pharmaceutical International AG, Zürich, Switzerland.
³ St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
⁴ Centre for Outcomes and Experience Research in Children's Health Illness and Disability (ORCHID), Great Ormond Street Hospital, London, UK.

Abstract

Introduction: Neutralizing antibodies to coagulation factor VIII (FVIII) remain a major complication associated with FVIII replacement therapy.

Aim: To assess safety and efficacy of immune tolerance induction (ITI) therapy with ADVATE^® (antihemophilic factor [recombinant] [rAHF]) in patients who participated in the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study.

Methods: The PAIR study was an international, multicenter, open-label, prospective, observational study in patients with hemophilia A and inhibitors, prescribed rAHF ITI therapy in clinical practice. The primary endpoint was adverse event (AE) reporting; the secondary endpoints included incidence of central venous access device-related complications and success rates of ITI therapy. Maintenance of immune tolerance was monitored for 12 months post-ITI therapy.

Results: Of 44 patients, 36 completed ITI therapy, including 31 completing the 12-month follow-up. Most patients received rAHF 90-130 IU/kg/day (59.1%) and a mean of 6.0 doses/week; the median duration of rAHF ITI therapy during the PAIR study was 600 days. Overall, 284 AEs were reported; 56 AEs were serious, of which none were considered rAHF-related. Of 228 nonserious AEs, 14 (in six patients) were deemed rAHF-related: increase of FVIII inhibitors titer due to anamnestic response, nausea, catheter site pain, pyrexia, urticaria, upper respiratory tract infection, arthralgia, and hemarthrosis. None were severe or led to ITI discontinuation. Eighteen patients experienced ≥1 central venous access device-related complication, and 21 of 36 completers achieved a negative inhibitor titer. The Kaplan-Meier estimate of success for achievement of first negative titer at 18 months of ITI therapy was 68.3% (95% confidence interval 51.8-83.6%) among completers. Of patients with partial or complete success post-ITI, 87% (20/23) maintained immune tolerance at 12-month follow-up.

Conclusion: Data suggest that rAHF ITI therapy in the PAIR study was effective, with no unexpected safety signals reported.

Keywords: adverse effects; hemophilia A; immune tolerance; post-marketing product surveillance; therapeutics.

Grants and funding

The PAIR study was funded by Baxalta US Inc., a Takeda company, Lexington, MA, USA. Medical writing support was provided by Nasser Malik, PhD, CMPP, of Excel Medical Affairs (Southport, CT, USA), and was funded by Takeda Development Center Americas Inc., a Takeda Company, Lexington, MA, USA.