Effect of emicizumab prophylaxis on bone and joint health markers in people with haemophilia A without factor VIII inhibitors in the HAVEN 3 study

Anna Kiialainen, Markus Niggli, Christine L Kempton, Giancarlo Castaman, Tiffany Chang, Ido Paz-Priel, Joanne I Adamkewicz, Gallia G Levy, Anna Kiialainen, Markus Niggli, Christine L Kempton, Giancarlo Castaman, Tiffany Chang, Ido Paz-Priel, Joanne I Adamkewicz, Gallia G Levy

Abstract

Introduction: Emicizumab prophylaxis significantly reduces bleeding events; however, the associated impact on bone/joint health is unknown.

Aim: To explore the effect of emicizumab prophylaxis on bone/joint health in people with haemophilia A (PwHA) without FVIII inhibitors enrolled in HAVEN 3 (NCT02847637).

Methods: Haemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Weeks 49 and 97 in PwHA receiving emicizumab (n = 134), and at baseline and Weeks 49, 73 and 97 in PwHA who switched to emicizumab after 24 weeks of no prophylaxis (n = 17). Bone and joint biomarkers were measured in 117 PwHA at baseline and at Weeks 13, 25, 49 and 73.

Results: HJHS was lower for PwHA who were previously on FVIII prophylaxis, aged <40 years or had no target joints at baseline compared with PwHA who were receiving no prophylaxis, aged ≥40 years or with target joints. Clinically significant mean (95% confidence interval) improvements from baseline of -2.13 (-3.96, -.29) in HJHS joint-specific domains were observed at Week 49 in PwHA with at least one target joint at study entry (n = 71); these changes were maintained through Week 97. Improvements in HJHS from baseline were also observed for PwHA aged 12-39 years. Biomarkers of bone resorption/formation, cartilage degradation/synthesis, and inflammation did not change significantly during emicizumab prophylaxis.

Conclusions: Clinically relevant improvements in HJHS were observed in younger PwHA and those with target joints after 48 weeks of emicizumab in HAVEN 3. Biomarkers of bone/joint health did not show significant changes during 72 weeks of emicizumab prophylaxis.

Keywords: biomarkers; bone; emicizumab; factor VIII; haemophilia A; joints; prophylaxis.

Conflict of interest statement

A.K. is an employee of F. Hoffmann‐La Roche Ltd and holds stock in the company. M.N. is an employee of F. Hoffmann‐La Roche Ltd. C.K. has received honoraria for participation in advisory boards for Sanofi US, Takeda, Genentech, Inc. and Spark Therapeutics. G.C. has received honoraria from uniQure, Bayer, Sobi, CSL Behring, Novo Nordisk, Kedrion, LFB, Grifols, Werfen, BioMarin, Sanofi, Takeda, and F. Hoffmann‐LaRoche Ltd. T.C. is an employee of Spark Therapeutics, a member of the Roche Group, and a former employee of Genentech, Inc., and holds stock in F. Hoffmann‐La Roche Ltd. I.P‐P. is a former employee of Genentech, Inc. J.A. is an employee of Genentech, Inc., a member of the Roche Group and holds stock in F. Hoffmann‐ La Roche Ltd. G.L. is a former employee of Genentech, Inc., holds stock in F. Hoffmann‐LaRoche Ltd and is a current employee of Spark Therapeutics.

© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Proportion of HAVEN 3 participants with HJHS scores * at baseline and individual baseline HJHS scores by, target joint status (A), participant age (B) and previous treatment (C). The HJHS 2.1 consists of eight item scores on joint level and a global gait score. Scores range from 0 to 20 per joint and the global gait score ranges from 0 to 4, resulting in a HJHS total score (0–124); a higher score indicates worse joint health. *A cut‐off score of 11 was used (median in the FVIII prophylaxis population based on the data collected). FVIII, factor VIII; HJHS, haemophilia joint health score; PwHA, people with haemophilia A
FIGURE 2
FIGURE 2
Mean improvement from baseline in total HJHS (including gait score) after 48, 96 and 97/LOCF weeks of emicizumab prophylaxis in evaluable HAVEN 3 participants with versus without target joints (A) and participants aged n = 90 participants with ≥1 target joint), 15.9 (16.8; for n = 43 participants with no target joints), 14.8 (13.5; for n = 78 participants aged <40 years) and 33.4 (22.9; for n = 55 participants aged ≥40 years). (A) and (B) exclude Arm C and include only those with an evaluable HJHS score at both baseline and Weeks 49 and 97. CI, confidence interval; HJHS, haemophilia joint health score; LOCF, last observation carried forward; MMRM, mixed‐effect model repeated measure; PwHA, people with haemophilia A; SD, standard deviation
FIGURE 3
FIGURE 3
Change in biomarker concentration from baseline until after 72 weeks of emicizumab prophylaxis. Trend lines correspond to total population; all participants included in Arms A and B were aged ≥18 years. OPG and sRANKL are essential for regulation of bone remodelling and exert their effect by controlling the activation state of RANK on osteoclasts; as such, the ratio of these biomarkers (OPG/sRANKL ratio) enables consideration of possible synergistic effects. COMP, cartilage oligomeric matrix protein; CS846, aggrecan chondroitin sulphate epitope 846; CTX‐I, C‐terminal telopeptide of type I collagen; CTX‐II, C‐terminal telopeptide of type II collagen; IL, interleukin; OC, osteocalcin; OPG, osteoprotegerin; P1NP, N‐terminal pro‐peptide of type I procollagen; sRANKL, soluble receptor activator of nuclear factor‐κβ; TNFα, tumour necrosis factor alpha

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