Trial in Progress: An Open-Label, Multi-Center, First in Human, Phase 1/2a Trial to Evaluate the Safety and Preliminary Efficacy of Autologous Tolerogenic Dendritic Cells Ex Vivo Loaded with Recombinant Factor VIII (FVIII) in Adults with Congenital Hemophilia a (HA) with Neutralizing Antibodies to FVIII and Having Failed Immune Tolerance Induction (ITI)

Background Severe hemophilia A is a congenital bleeding disorder caused by a lack of factor VIII (FVIII) in plasma. Without treatment patients experience prolonged bleeding, either spontaneously or following trauma, and even life-threatening bleeds. Replacement therapy with FVIII is the standard of care, but development of neutralizing antibodies to FVIII is common, which reduces or completely prohibits the effect of FVIII treatment.

Idogen AB has developed a cell therapy platform with the main purpose of making patients tolerant to FVIII and thus eliminating the problem of the immune system producing neutralizing antibodies. The cell therapy product, ItolDC-028, is produced from autologous mononuclear cells, collected by leukapheresis. A GMP-facility at Radboud University Hospital in the Netherlands enriches and cultures cells into tolerogenic dendritic cells, finally loaded with FVIII-antigen and cryopreserved. By this unique process the autologous cells has undergone a specific culture process to induce tolerance to FVIII.

Trial Design and Methods This trial is a first-in-human, phase 1/2a, open-label trial, evaluating the safety and preliminary efficacy with ascending single doses of autologous tolerogenic dendritic cells for the management of neutralizing antibodies against FVIII in patients with hemophilia A.

Male subjects aged 18-60 years and diagnosed with severe hemophilia A, with neutralizing antibodies against FVIII, having failed immune tolerance induction (ITI) treatment or for whom it is not possible to treat with ITI, a reported peak titer of ≥ 5 Bethesda Units (BU) and ≥ 1 BU at inclusion are eligible for the trial. Concomitant emicizumab is allowed, but FEIBA and other FVIII-containing treatments are excluded except in the case of an urgent need to treat bleeding.

The primary objective is safety/tolerability of ItolDC-028, evaluated as the number of adverse events (AEs), changes in vital signs, physical examination findings and laboratory assessments including titers of neutralizing antibodies (BU) and ECG recordings from administration of ItolDC-028 up to the week 26 visit.

The secondary objective is to evaluate the preliminary therapeutic efficacy of three dose levels of ItolDC-028 through evaluation of immune response, titer of neutralizing antibodies (BU), FVIII recovery and half-life as response to FVIII challenge at the week 20 visit.

A minimum of nine subjects will be included in a classic 3+3 trial design, with single incremental dose levels of 36x10⁶, 72x10⁶ and 144x10⁶ cells. Three additional subjects can be included in each dose level, upon reported signs of dose-limiting toxicity. An Internal Monitoring Board will evaluate the safety of the first subject at each dose level to decide if the next subject can be treated, and then all subjects at each dose level prior to escalation to the next dose level. There will be at least 2 weeks between treatments within a dose level and at least 6 weeks between the dose levels. Figure 1.

At each clinical site, frozen ItolDC-028 is thawed and given to the subject by an intravenous infusion. Subjects are followed for 26 weeks including physical examinations, vital signs, laboratory assessments, FVIII-antibody titers, immunological changes, bleeding episodes and quality-of-life questionnaires (EQ-5D and Haem-A-QoL). In addition, there will be a long-term follow-up visit after 52 weeks. Figure 2.

Twenty weeks after ItolDC-028 administration, the subject will be challenged by an administration of FVIII (Kovaltry®, 50 IU/kg), to evaluate the preliminary efficacy of ItolDC-028.

The trial will be performed in eight European academic hospitals. The first subject is planned to be enrolled in August 2022. The trial is approved by the Swedish and Norwegian Competent Authorities and by the Swedish Ethical Review Authority (July 2022) and will also be reviewed by EU and UK Authorities.

Karlsson:Idogen AB: Consultancy. Xie:Idogen AB: Consultancy; Oncopeptides AB: Ended employment in the past 24 months.

ItolDC-028 consist of autologous tolerogenic dendritic cells. Cells are collected by leukapheresis from subjects with Hemophilia A with neutralizing antibodies against factor VIII (FVIII). The cells are manufactured to become tolerogenic against FVIII and transferred back to the subject. The main purpose of this trial is to develop a treatment that prevent or reverse neutralizing antibodies against FVIII-therapy in humans.