Emicizumab Prophylaxis Provides Flexible and Effective Bleed Control in Children with Hemophilia Α with Inhibitors: Results from the HAVEN 2 Study

Abstract

Introduction Emicizumab - a bispecific humanized monoclonal antibody given subcutaneously - bridges FIXa and FX to restore the function of missing FVIIIa. It is approved for routine prophylaxis in people with hemophilia A (PwHA) with inhibitors of all ages. Previous data from the HAVEN 2 study of emicizumab in pediatric PwHA with inhibitors <12 years (data cut-off May 8, 2017) showed once-weekly (QW) dosing provided effective bleed control and was well tolerated (Young et al. Blood 2017). We present the primary analysis of the study, including analyses of the bi-weekly (Q2W) and monthly (Q4W) dosing regimens. Methods HAVEN 2 (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12-17 years if <40kg) previously treated with episodic or prophylactic bypassing agents (BPAs) to receive emicizumab prophylaxis for ≥52 weeks. A loading dose of 3mg/kg emicizumab was given QW for 4 weeks followed by a maintenance dose of 1.5mg/kg QW, 3mg/kg Q2W or 6mg/kg Q4W (cumulative dose identical for all regimens). Efficacy analyses included annualized bleed rates (ABRs) for all bleed endpoints and an intra-individual comparison with ABR on prior BPAs from a prospective non-interventional study (NIS; NCT02476942). Safety assessments included records of adverse events (AEs), serious AEs (SAEs), AEs of interest and immunogenicity. Pharmacokinetics (PK) across dosing regimens was also analyzed. Results Eighty-eight patients were enrolled (n=68 QW; n=10 Q2W; n=10 Q4W), 18 of whom were aged ≤2 years old. At clinical cut-off (April 30, 2018), the median (range) emicizumab exposure for each cohort was 57.2 (17.1-92.1), 20.1 (18.1-24.1), and 18.1 (8.1-24.1) weeks, respectively; 59 patients in the QW cohort completed 52 weeks on study; 3 patients discontinued due to switching to commercial emicizumab (n=2 QW) or lack of efficacy (n=1 Q4W). In the QW, Q2W, and Q4W cohorts, the ABR in treated patients aged <12 years was 0.3 (95% confidence interval [CI]: 0.17-0.50), 0.2 (0.03-1.72), and 2.2 (0.69-6.81) for treated bleeds, respectively. Zero treated bleeds were reported in 50/65 (76.9%), 9/10 (90.0%), and 6/10 (60.0%) patients, respectively. Across cohorts, all patients experienced ≤3 treated bleeds (Table 1). Overall, 30 treated bleeds were reported (n=22 QW; n=1 Q2W; n=7 Q4W): 19 occurring in a joint (n=12 QW; n=1 Q2W; n=6 Q4W), 4 in a muscle (n=3 QW; n=1 Q4W), and 7 classified as 'other' (n=7 QW). The majority (25/30; 83.3%) of treated bleeds were traumatic and 5/30 (16.7%) were spontaneous. An intra-individual comparison of 18 patients <12 years old in the QW cohort who had participated in the NIS (15 and 3 on prior prophylactic and episodic BPAs, respectively) showed a 99% (95% CI: 97.7-99.4) reduced risk of treated bleeds with emicizumab compared with prior BPAs (Figure 1). Emicizumab was safe and well tolerated. No thromboembolic or thrombotic microangiopathy events or deaths occurred. The most common AEs are listed in Table 2. Seventeen patients experienced 21 SAEs. Four patients tested positive for anti-drug antibodies (ADA), two of whom had ADA with neutralizing potential based on reduced emicizumab levels; one discontinued emicizumab treatment and the other had no bleeds as of the clinical cut-off date. Mean steady-state trough concentrations of emicizumab were maintained at therapeutic levels across all regimens (Figure 2). Trough plasma concentrations increased with loading doses until Week 5, then were maintained at approximately 50, 45-50 and 38μg/mL with QW, Q2W and Q4W dosing, respectively. As of the data cut-off, 21 minor surgical procedures had been carried out, 14 (66.7%) of which were central venous access device (CVAD) removals. Conclusions To our knowledge, HAVEN 2 is the largest prospective study in pediatric PwHA with inhibitors to date, and demonstrates that emicizumab prophylaxis is well tolerated and can prevent or substantially reduce bleeds in this population. Meaningful efficacy and PK were maintained with less frequent dosing, with no new safety signals, suggesting the potential for reduced treatment burden in the pediatric population. Additionally, the large number of CVAD removals suggests that prophylactic emicizumab may offer a new and effective standard of care for hemophilia that is also more convenient and less invasive, and may offer the potential for flexible treatment regimens based on patient needs. Disclosures Young: Genentech/Roche: Consultancy, Honoraria, Research Funding; Novo Nordisk: Honoraria; Shire: Honoraria. Liesner:Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Roche: Research Funding; Sobi: Speakers Bureau. Sidonio:Uniqure: Honoraria; CSL Behring: Honoraria; Shire: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; Kedrion/Grifols: Research Funding; Bioverativ: Honoraria, Research Funding; Biomarin: Honoraria; Novo Nordisk: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jimenez-Yuste:NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy; Octapharma: Consultancy, Research Funding; Grifols: Consultancy, Research Funding. Mahlangu:Alnylam: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Biomarin: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Kruse-Jarres:Grifols: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; Bayer: Consultancy; CSL Behring: Consultancy. Chang:Genentech: Employment, Equity Ownership. Uguen:F.Hoffmann-LaRoche: Employment. Doral:Genentech: Employment. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership. Levy:Genentech/Roche: Employment, Equity Ownership. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Mancuso:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biotest: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

“…Since that time, however, the treatment of haemophilia A has evolved and a number of molecules that potentially can be used in the setting of patients with inhibitors have been developed, or are in various phases of development. [13][14][15][16] With the arrival of these new molecules, the treatment environment is changing, and there are many unanswered questions about the future of inhibitor management. To provide answers to these and other questions, a group of nine experienced haemophilia treaters came together to discuss the Future of Immunotolerance Treatment (FIT) and to provide some orientation to the haemophilia community in this changing environment.…”

Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors

“…In the last several years, novel therapeutics have been evaluated in clinical trials, among which the bispecific monoclonal antibody, emicizumab, has been licensed for the prevention of bleeding in children and adults with haemophilia with and without inhibitors. [7][8][9][10] While emicizumab mimics factor VIII by bridging factor IXa and factor X, 11,12 it differs from factor VIII biochemically, with no phospholipid binding, only single-site interaction with factor IXa, and limited self-regulation. 13,14 Whether bleed frequency and bleed severity, long-term joint health and quality of life are comparable to that achieved with factor VIII, therefore, remains unknown.…”

An anti‐factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A

“…AHA autoAbs inhibit FVIII:C either completely or incompletely at saturating concentrations, corresponding to type 1 or type 2 inhibitors, respectively. 32 In this context, those cases with type 2 behavior having residual FVIII:C (cases [11][12][13][14][15][16], emicizumab appeared to relatively more effective than in those with type 1 inhibitors (cases 1-10 type 1 patients (40.6 ± 14.5% and 71.0 ± 41.8%, respectively), with significant differences (P = .016 and P = .048, respectively) ( Figure 5).…”

“…Emicizumab concentrations were used according treatment model (Figure 1) and based on clinically therapeutic estimates. [13][14][15][16] High concentrations (30-300 µg/mL) and low concentrations (2.5-20 µg/mL) were added to the plasmas from AHA patients ( Table 1) The presence of lower concentrations of emicizumab also improved peak thrombin levels dose-dependently in all cases ( Figure 4B, left). The median (range) values at 2.5, 5, 10, and 20 µg/mL emicizumab were 13.9% (7.9%-20.7%), 19.5% (3.3%-33%), 27.0% (6.5%-51.4%), and 43.9% (21.0%-77.0%), respectively ( Figure 4B, right).…”

“…9,10 In phase 1/2 and 3 clinical trials, subcutaneous administration of emicizumab substantially diminished bleeding episodes in congenital HA in the presence and absence of inhibitors. [11][12][13][14][15][16] The product has received international regulatory approval for routine prophylaxis in HA.…”