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Emicizumab: Two Minds, One Dream

December 12, 2023
Nadine Abdallah, MD, (@nadineabdal), Joselle Cook, MBBS, (@JoselleCookMD)
Division of Hematology, Mayo Clinic, Rochester, MN

The 2023 Ernest Beutler Awardees

"I have not failed. I've just found 10,000 ways that won't work." The words of Thomas Edison resonate with Takehisa Kitazawa, DVM, PhD, as he reflects on his journey in uncovering the drug that changed the lives of patients with hemophilia A. In transitioning this discovery from the bench to the clinical setting, Johnny Mahlangu, MBBCh, MMed , witnesses the impact of his success through his patient’s own words: “I now have a hemophilia-free mind, which I never thought was possible.” 

This year, the Ernest Beutler Prize was awarded to Dr. Kitazawa from Chugai Pharmaceutical and Dr. Mahlangu from the University of the Witwatersrand, Johannesburg in recognition of their outstanding contributions in reshaping the landscape of hemophilia management.  

Factor VIII replacement therapy has long been the mainstay of hemophilia A management. However, the burden of intravenous infusion, breakthrough bleeding, and the challenges associated with development of factor-neutralizing antibodies, prompted the search for alternative strategies. The approval of emicizumab in 2017 introduced a paradigm shift in the management of hemophilia A, ushering in an era in which non-replacement therapy took the forefront. By bridging activated factors IX and X, this novel bispecific monoclonal antibody mimics the function of factor VIII and restores the hemostatic function of the coagulation cascade. In under 60 minutes, Drs. Kitazawa and Mahlangu summarized a journey spanning more than a decade, from drug discovery and preclinical development to clinical trial and real-world outcomes. 

With a long-term dream of “creating an epoch-making drug,” Dr. Kitazawa chose veterinary medicine as a pathway to drug discovery before joining Chugai pharmaceutical industry. When he was assigned to the thrombosis and hemostasis drug discovery program, he was “instantly captivated by this field of research” he shared. In his lecture, he paid tribute to his mentor Dr. Kunihiro Hattori, “an excellent biologist and a distinguished idea man,” who inspired the concept of a factor VIII mimetic back in 2000. Reflecting on the impact of Dr. Hattori in his career, he added: “His blunt and straightforward advice always hit the heart of the matters, and the heated debates with him have fostered my growth as a biologist.” As with most ground-breaking discoveries, numerous unsuccessful attempts were prerequisites for reaching this breakthrough. Dr. Kitazawa shared what he referred to as the “APTT-trick”; he had mistakenly assumed that a hemostatic effect would be achieved by shortening the coagulation time. However, he understood that “factor VIII needed time to be activated by thrombin to exert its cofactor function, and a bispecific antibody would not require this.” With this recognition, he reached the correct path for creating an effective bispecific antibody. His dream was first realized with the phase I study results. Dr. Kitazawa vividly recalled his tears of joy while reading the questionnaire responses provided by patients and caregivers. One of the most heartwarming testimonies, he recalled, was that of one patient’s mother: “Since my son was born a little more than 20 years ago, I had never experienced such calm and peaceful days (since he was treated with emicizumab) … I have been emotionally rescued.” 

Dr. Mahlangu continued this remarkable journey with the advancement of emicizumab to phase III clinical trials. After starting his career in stem cell transplantation, Dr. Mahlangu recognized an unmet need in hemophilia and redirected his career to clinical research in this area. In his lecture, Dr. Mahlangu elegantly summarized the phase III efficacy and safety data that eventually carried emicizumab to the finish line, leading to its approval for treatment of congenital hemophilia A with and without inhibitors. The real-world data served as confirmation of its efficacy, demonstrating a decrease in treatment burden with subcutaneous administration, a reduction in annual bleeding rates, and a significantly lower rate of immunogenicity compared to traditional therapies. 

Dr. Mahlangu witnessed firsthand the impact of emicizumab on the lives of patients with hemophilia A and their caregivers, which is best conveyed in the caregiver’s own words: “My child has not missed school, and I have not missed work since we started emicizumab” shared one parent. “I can keep up with business partners on the golf course without the worry that every round of golf is followed by treatment of a bleed,” expressed another older patient. The last 20 years of Dr. Mahlangu’s career have been devoted to clinical research, including international clinical trials, serving to accelerate the development of novel therapies for bleeding disorders. Most recently, he worked on the development of valoctocogene roxaparvovec, the first gene therapy for hemophilia A, offering patients the prospect of a hemophilia-free life.  

From bench to patient, the journey of emicizumab conveys a remarkable tale of inspiration, mentorship, partnership, and dedication. Dr. Mahlangu assured us that this is just the beginning, as unwavering efforts persist to paint a brighter and more vibrant picture of tomorrow. 

 

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