CO-57 | NXT007 PROPHYLAXIS IN PEOPLE WITH HEMOPHILIA A WITH OR WITHOUT FACTOR VIII INHIBITORS: COMBINED ANALYSIS OF TWO PHASE I/II MULTIPLE-ASCENDING-DOSE STUDIES

M.E. Mancuso^1|2, M. Shima³, J.M. Staber⁴, Y.C. Chen⁵, F.J. López-Jaime⁶, M.C. Shen⁷, G. Ventriglia⁸, M. Takeyama⁹, C. Schmitt⁸, Y.S. Park¹⁰, A. Kiialainen⁸, N. Mizuno¹¹, M. Niggli⁸, T. Miyake¹¹, D. Matino¹², T. Saito¹¹, V. Jiménez-Yuste¹³, R. Kobayashi¹¹, D. Hart¹⁴, K. Nogami¹⁵ | ¹Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, Italy; ²Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy; ³Thrombosis and Hemostasis Research Center, Nara Medical University, Kashihara, Nara, Japan; ⁴Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, USA; ⁵Hemophilia Care and Research Center, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan; ⁶Servicio de Hematología, Hospital Universitario Regional de Málaga / Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; ⁷Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; ⁸F. Hoffmann-La Roche Ltd, Basel, Switzerland; ⁹Division of Hemophilia, National Hospital Organization, Osaka National Hospital, Osaka, Japan; ¹⁰Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, South Korea; ¹¹Chugai Pharmaceutical Co., Ltd, Tokyo, Japan; ¹²McMaster University, Hamilton, Ontario, Canada; ¹³La Paz University Hospital-IdiPAZ, Autónoma University, Madrid, Spain; ¹⁴Roche Products Ltd, Welwyn Garden City, UK; ¹⁵Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan

Background. NXT007, a next-generation bispecific antibody based on emicizumab that mimics activated factor (F)VIII function in people with hemophilia A (HA), was investigated in two Phase I/II, open-label, non-randomized, multicenter, multiple-ascending-dose (MAD) studies: one in Asia (NXTAGE Part B; jRCT2080224835) and one in the Global (NCT05987449).
Aims. Report outcomes in three pooled NXT007 dose cohorts from two MAD studies (F. Hoffmann-La Roche Ltd/Chugai Pharmaceutical Co., Ltd) with equivalent dosing.
Methods. Eligible participants were emicizumab-naïve and aged 12–64 years (global study: ≤59 years). Subcutaneous NXT007 maintenance doses in NXTAGE cohorts B2, B3, and B4 are identical to Global cohorts 1, 2, and 3 (0.28, 0.70, and 1.08 mg/kg, respectively, every 4 weeks; predicted to achieve non-hemophilic FVIII activity) and are pooled into Groups X, Y, and Z. Loading doses were weekly in NXTAGE Group X and Y (X: six doses; Y: four doses) and as two doses at 2-week intervals in the Global study and NXTAGE Group Z. Informed consent and ethics approval were obtained. Outcomes included safety, pharmacokinetics, pharmacodynamics, immunogenicity, and model-based annualized bleeding rates (ABRs).
Results. Overall, 42 participants received NXT007 (Group X: n=13; Group Y: n=15; Group Z: n=14). Forty (95.2%) had severe HA; one (2.4%; global study) had FVIII inhibitors. Median (range) age was 36 (12–56) years. At cut-off (NXTAGE: 06-Nov-24; Global: 21-Apr-25), median (range) observation periods in Groups X, Y, and Z were 80.0 (61.1–113.3), 44.1 (42.1–72.4), and 21.6 (5.4–34.4) weeks, respectively. NXT007 had favorable safety outcomes across doses. D-dimer remained within normal range, and prothrombin fragment 1+2 elevated slightly; neither increased dose-dependently. ABR (95% confidence interval) for treated bleeds in the maintenance period was 0.3 (0.1–0.8; Figure); 36/42 (85.7%) participants had zero treated bleeds. NXT007 plasma concentrations increased dose-dependently, with no ethnic differences. Thrombin generation peak height increased from baseline with all doses. Overall, 34/42 (81.0%) participants developed anti-drug antibodies (ADAs); one (2.4%; Group Y, NXTAGE) had ADAs impacting pharmacokinetics; none impacted safety or cross-reacted with emicizumab.
Conclusions. NXT007 had favorable safety outcomes, with low treated ABRs. One participant had ADAs impacting pharmacokinetics. These data support progression to Phase III trials.