EVALUATION OF THE OVERALL HAEMOSTATIC CAPACITY OF MIM8 WITH GLOBAL HAEMOSTASIS ASSAYS AND FIBRIN CLOT ULTRASTRUCTURE (Mim8-TGT)

Hemophilia A is an X linked disorder characterized by a deficiency in Factor VIII. The clinical hallmark of this disease is increased tendency to spontaneous bleeding with hemarthrosis accounting for 90% of the hemorrhages. In addition to development of hemophilic arthropathy, the emergence of alloantibodies that inhibit the coagulant activity of FVIII remains the most feared complication related to the treatment of hemophilia A. 30% of patients with hemophilia A develop these inhibitors, making treatment with standard replacement therapy ineffective. Up until the approval of emicizumab, bypassing agents like activated prothrombin complex concentrate (aPCC) and activated recombinant activated factor VII (rFVIIa) were the only approved therapies for the treatment hemophilia A with inhibitors. The response to bypassing therapy is often unpredictable, variable and difficult to monitor.

Emicizumab is a first generation bispecific antibody mimicking the activity of FVIIIa in tenase complex. Early in the HAVEN 1 clinical trial with emicizumab (1), cases of thrombotic microangiopathy (TMA) and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of aPCC was administered for 24 hours or more to patients receiving emicizumab, resulting in a protocol adjustment for the HAVEN 1 trial and subsequent trials to recommend using the lowest doses of bypassing agents expected to achieve hemostasis, and avoiding the combination of emicizumab and aPCC if possible. So far the only proposed strategies for treating events of breakthrough bleeds in patients on emicizumab prophylaxis include rFVIIa, FVIII in patients with a low titer of inhibitors, and lower doses of aPCC, knowing that emicizumab provides an existing level of thrombin generation. (2) While the exact mechanism leading to the development of thrombotic complications (TMA and VTE) remains poorly understood, many speculated on the accumulation of FIX and FX, the substrates of emicizumab, with multiple doses of aPCC (3)

Mim8 is a novel, next-generation FVIIIa mimetic designed for the subcutaneous prophylactic treatment of patients with HA with and without inhibitors. Mim8 is a fully human, bispecific antibody that mimics FVIIIa function by bridging FIXa and FX on the phospholipid surface of activated platelets, enhancing the proteolytic activity of FIXa, and thus facilitating effective FX activation. Data from studies using in vitro HA-like human blood, as well as in vivo HA mouse models, indicate that Mim8 is ~15-fold more potent than a sequence identical analogue (SIA) of the FVIII mimetic emicizumab (4). Mim8 nonclinical safety program in cynomolgus monkeys showed that subcutaneous administration of up to 3 mg/kg/week (several fold greater than expected clinical exposure) for 26 weeks resulted in relevant pharmacodynamic effects, observed in thrombin generation and APTT, with no signs of thrombi or excessive coagulation activation. So far, Mim8 procoagulant activity was evaluated in platelet poor plasma samples only (5,6)

This in vitro study aims to evaluate TGA to monitor Mim8. We hypothesized that TG profiles (ETP and peak thrombin) may be different with different triggers used. We recently modified TGA to better detect haemostatic activity of emicizumab, by using a combined trigger (low TF+low FIXa). Differently from emicizumab, Mim8 stimulates the proteolytic activity of FIXa in the range of 15,000-fold. TGA test conditions may be therefore different for Mim8 and emicizumab.

Study Overview

• Status: Recruiting
• Conditions: Hemophilia A
• Intervention / Treatment: Other: blood test

• Study Type: Observational
• Enrollment (Estimated): 6

Contacts and Locations

• Study Contact: Name: Gamze DARGAUD, Pr; Phone Number: +33 04 72 11 88 10; Email: Gamze.dargaud@chu-lyon.fr
• Study Contact Backup: Name: Emilie PROME COMBEL; Phone Number: +33 04 72 11 66 99; Email: emilie.prome@chu-lyon.fr

Study Locations

• France
  • Rhone
    • Bron, Rhone, France, 69500
      • Recruiting
      • Centre de Référence Hémophilie, Hôpital Louis Pradel- Hospices Civils de Lyon
      • Contact: Gamze DARGAUD, Pr; Phone Number: +33 04 72 11 88 10; Email: Gamze.dargaud@chu-lyon.fr
      • Contact: Emilie PROME COMBEL; Phone Number: +33 04 72 11 66 99; Email: emilie.prome@chu-lyon.fr
      • Principal Investigator: Gamze DARGAUD, Pr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

6 Adults patients with severe hemophilia A (FVIII<2%) who are:

• on prophylaxis with FVIII concentrates after a washout period of 48h for SHL FVIII molecules and at least 4 days for EHL FVIII
• or receive on demand FVIII treatment without any FVIII treatment since 48h for SHL FVIII molecules and since 4 days for EHL FVIII

Description

Inclusion Criteria:

• Male patients,
• Age > 18 years at time of inclusion
• Diagnosis of severe hemophilia A (FVIII <2%)
• Severe hemophilia A (FVIII <2%) and not receiving emicizumab prophylaxis
• Obtaining the patient's non-opposition
• Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria:

• Not willing to provide extra blood for the experiments
• Patients carrying the diagnoses of other coagulopathies in addition to hemophilia A
• Patients that have received any hemostatic agent within 5 half-lives of the blood draw.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adults patients with severe hemophilia A (FVIII<2%); Adults patients with severe hemophilia A (FVIII<2%) who are: on prophylaxis with FVIII concentrates after a washout period of 48h for SHL FVIII molecules and at least 4 days for EHL FVIII; or receive on demand FVIII treatment without any FVIII treatment since 48h for SHL FVIII molecules and since 4 days for EHL FVIII	Other: blood test; blood test at the inclusion 10 tubes of 2.7mL blood

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of thrombin generation (TG) (ETP and peak thrombin) will be obtained in platelet-poor plasma from patients with severe HA	27 ml blood samples will be taken from each patient, and FVIII activity will be measured in the samples. Mim8 and emicizumab will be added to the blood samples, and thrombin generation will be performed using different triggers. All statistical analyses were performed using GraphPad Prism and GraphPad Instat softwares (GraphPad Software, La Jolla, CA, USA). The probability of statistical difference between experimental groups will be determined by unpaired Mann-Whitney and ANOVA tests. Results will be expressed as mean ± standard deviation (SD). A p-value < 0.05 will be considered statistically significant	One point at the inclusion

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2024
• Primary Completion (Estimated): May 28, 2025
• Study Completion (Estimated): May 28, 2025

Study Registration Dates

• First Submitted: January 8, 2024
• First Submitted That Met QC Criteria: January 8, 2024
• First Posted (Actual): January 19, 2024

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Haemophilia A; Mim8; TGT
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: 69HCL23_1202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No