Non-inhibitory antibodies inducing increased emicizumab clearance in a severe haemophilia A inhibitor patient

Harroche, Annie; Sefiane, Thibaud; Desvages, Maximilien; Borgel, Delphine; Lasne, Dominique; Casari, Caterina; Peyron, Ivan; Frenzel, Laurent; Chhun, Stéphanie; Lenting, Peter J.; Bally, Cécile

doi:10.3324/haematol.2021.278579

Cited by 12 publications

(15 citation statements)

References 13 publications

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“…In these studies, the emicizumab safety profile was similar to that seen in clinical trials. A few cases of anti‐emicizumab antibodies have been reported to date 20,21 ; however, the overall outlook is that immunogenicity is very low when using emicizumab compared to that seen with factor replacement therapies 22,23 . Breakthrough bleeds do occur when using emicizumab; however, current data do not show an increased risk of adverse events when these bleeds are treated with diverse replacement haemostatic agents.…”

Section: Emicizumab Rolloutmentioning

confidence: 94%

Emicizumab state‐of‐the‐art update

2022

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Introduction:Emicizumab is a bispecific monoclonal antibody developed to address the unmet needs of clotting factor replacement therapy and has become the benchmark for optimal prophylaxis in managing patients with haemophilia A with inhibitors.We describe the emicizumab rollout and pharmacokinetic strategies and their use in paediatric patients. Methods:The evolving real-world experience in using emicizumab has confirmed its safety, efficacy and pharmacokinetic profile in paediatric, adolescent and adult patients receiving emicizumab at various prophylactic dosing regimens. The emicizumab current global rollout includes over 100 countries with 29 low to middle-income countries accessing emicizumab through the World Federation of Haemophilia (WFH) Humanitarian Aid Program. The diversity of emicizumab dosing and pharmacokinetic tools such as the Calibra® and the WAPPS-Hemo platforms make it possible to achieve prophylaxis goals in line with the WFH Haemophilia treatment guidelines recommendations, with minimal drug wastage. The emerging experience from long term clinical trials and long-term real-world follow-up confirm the safety, efficacy, and pharmacokinetic profile of emicizumab in paediatric haemophilia A patients. A few questions, including inhibitor recurrence, concurrent use of emicizumab with various replacement therapies and inhibitor eradication, are being addressed through multiple ongoing clinical studies. Conclusion:The current global rollout of emicizumab is remarkable, and versatile dosing regimens and evolving pharmacokinetic tools such as the Calibra® and WAPPS-Hemo platforms make it a treatment choice available also for pharmacokinetic guided personalised treatment. Data from paediatric studies are consistent with those seen in adolescent and adult Haemophilia A.

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Section: Emicizumab Rolloutmentioning

confidence: 94%

Emicizumab state‐of‐the‐art update

2022

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“…In addition, the experts indicated that inhibitor formation in previously treated children with hemophilia on any type of PPX is rare. Notably, the experts reported no inhibitor formation for any previously treated patient on EHL products, rFVIIIFc or recombinant pegylated FVIII (rFVIIIpeg), or the non-factor replacement product, emicizumab; note: anti-emicizumab antibodies, including some with emicizumab-neutralizing activity, have been reported in a few people with hemophilia A treated with emicizumab [ 26 – 28 ].…”

Section: Resultsmentioning

confidence: 99%

Expert opinion on current and future prophylaxis therapies aimed at improving protection for people with hemophilia A

et al. 2022

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The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30–50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.

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“…Valsecchi et al investigated the biochemical characterization of a neutralizing ADA that developed in an HA patient who participated in the HAVEN 2 clinical trial and reported that the ADA mainly targeted the Fab region of emicizumab with a small amount of binding to the Fc region 14 . In addition, recently Harroche et al examined anti‐emicizumab antibodies that developed in a HA patient with inhibitors, and showed no inhibition of emicizumab binding to FIX and a modest inhibition of emicizumab binding to FX, but there was no reduction in emicizumab activity using a chromogenic activity assay and a one‐stage clotting assay 16 . Although the measurement principles are different, our results showed that the ADAs in our patient did not bind to the Fc region but Fab region of emicizumab, and ADAs had a neutralizing activity against emicizumab.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that neutralizing activity or rapid clearance from the blood was the causes of decrease in the efficacy which led to discontinuation of emicizumab. [14][15][16] At Sapporo Tokushukai Hospital in Japan, there was an adult FVIII inhibitor-positive HA patient in whom treatment with emicizumab was discontinued 49 weeks from the initiation of emicizumab administration owing to increased bleeding frequency and prolonged activated partial thromboplastin time (APTT). Because of these signs, we suspected a decrease in the efficacy of emicizumab caused by the appearance of ADAs.…”

Section: Introductionmentioning

confidence: 99%

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Detailed analysis of anti‐emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A

Kaneda

Kawasaki²,

Matsumoto³

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Emicizumab is a humanized bispecific monoclonal antibody that bridges activated factor IX (FIXa) and factor X (FX) to mimic the function of factor VIII (FVIII). It suppresses the bleeding tendency in hemophilia A patients with or without FVIII inhibitors. A case of an adult FVIII inhibitor‐positive hemophilia A patient in whom treatment with emicizumab was discontinued owing to the repeated bleeding events and prolonged activated partial thromboplastin time. Objective To analyze the mechanisms of decreased efficacy of emicizumab. Methods Residual plasma samples were used to measure the following: emicizumab concentration in plasma, measured by enzyme‐linked immunosorbent assay; titer of anti‐drug antibody (ADA) against emicizumab, measured by electrochemiluminescence; and neutralizing activity against emicizumab, measured by Bethesda method modified by using emicizumab‐spiked FVIII‐deficient plasma. Results At week 31, emicizumab concentration was 15.0 μg/ml, and ADAs were measured as positive. Emicizumab concentration continued to decrease until emicizumab discontinuation point at week 49, and after week 50, emicizumab concentrations were below the limitation of quantification. The ADA titer increased transiently from week 31, even past the emicizumab discontinuation point at week 49. The ADA titer then gradually decreased until the last sampling point at week 93. Neutralizing activity against emicizumab was detected after emicizumab discontinuation. Epitope analysis showed that the ADAs recognize the anti‐FIXa and anti‐FX Fab arms of emicizumab, but not the Fc region. Conclusion The appearance of ADAs with emicizumab‐neutralizing activity and potential to accelerate emicizumab clearance decreased the efficacy of emicizumab.

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Non-inhibitory antibodies inducing increased emicizumab clearance in a severe haemophilia A inhibitor patient

Abstract: Not available.

Cited by 12 publications

References 13 publications

Emicizumab state‐of‐the‐art update

Emicizumab state‐of‐the‐art update

Expert opinion on current and future prophylaxis therapies aimed at improving protection for people with hemophilia A

Detailed analysis of anti‐emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A

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