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Clinical Trial
. 2024 Apr;22(4):990-1000.
doi: 10.1016/j.jtha.2023.12.016. Epub 2023 Dec 22.

FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic

Steven R Lentz  1 , Pratima Chowdary  2 , Lidia Gil  3 , Francisco J Lopez-Jaime  4 , Johnny Mahlangu  5 , Irina Matytsina  6 , Anne Louise Nielsen  6 , Jerzy Windyga  7
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Free article
Clinical Trial

FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic

Steven R Lentz et al. J Thromb Haemost. 2024 Apr.
Free article

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Abstract

Background: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality.

Objectives: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors.

Methods: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab.

Results: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5).

Conclusion: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase.

Keywords: clinical trial; factor VIII; hemophilia A; pharmacokinetics; safety.

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Conflict of interest statement

Declaration of competing interests S.R.L. has consulted for Argenx, Novo Nordisk, and Takeda. P.C. has served on advisory boards for ApcinteX, Bayer, Boehringer Ingelheim, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, Sobi, and Takeda, and has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, Sobi, and Takeda. F.L.J. has served as a speaker or on advisory boards for Amgen, Bayer, CSL Behring, Novartis, Novo Nordisk, Pfizer, Roche, Rovi, Sobi, and Takeda, and has received research funding from Sobi. J.M. has received research grants from BioMarin, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, and UniQure; served as a consultant for BioMarin, Novo Nordisk, Roche, Sanofi, Spark, and Takeda; and served on a speaker’s bureau for the International Society on Thrombosis and Haemostasis, Novo Nordisk, Pfizer, Roche, Sanofi, Takeda, and World Federation of Hemophilia. I.M. and A.L.N. are employed at Novo Nordisk and own stocks in the company. J.W. has received research funding and honorarium from AlfaSigma, Alnylam, Amgen, AstraZeneca, Bayer AG, CSL Behring, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Siemens, Sobi, Swixx BioPharma, and Takeda. L.G. has no competing interests to disclose.

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