Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A
Study Details
- Hemophilia A
- Drug: Gene therapy
- Inclusion Criteria:
- Able to provide informed consent for the protocol approved by the Institutional Review Board.
- Male subjects who are \>= 18 years of age.
- Diagnosis of severe hemophilia A (\<1 IU/dL factor VIII activity) based on one-stage coagulation assay.
- Documented history of more than 150 days of factor VIII treatment.
- Average of at least 4 bleeds requiring treatment per year over the prior three years, or at least 4 bleeds per year during the 3 years preceding the initiation of prophylaxis, or evidence of joint damage (knee, elbow or ankle) on physical or radiographic examination thought to be related to hemophilia.
- Performance status (Karnofsky score) of at least 70.
- Willingness to use effective barrier contraception or limit sexual intercourse to postmenopausal, surgically sterilized, or contraception-practicing partners, for 12 weeks (3 months) after transplantation.
- Willing and able to comply with the requirements of the protocol.
- Exclusion Criteria:
- History of spontaneous central nervous system bleeding within the last 5 years.
- Significant functional deficits in major organs which would interfere with successful outcome following autologous stem cell transplant, the following guidelines will be utilized:
- Cardiac: There should be no evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of \< 50%) and no marked cardiomegaly. There should not be uncontrollable hypertension.
- Renal: GFR \< 60 mL/min/1.73m2 per local institutional standard such as CKD-EPI creatinine equation or equivalent.
- Hepatic: There should be no evidence of hepatic dysfunction which is defined as a serum total bilirubin of \> 1.5 mg/dL and AST/ALT \> 3X the upper limit of normal.
- Hematologic: Absolute neutrophil counts (ANC) \<1000/ µL or platelets counts \< 150,000/µL.
- Pulmonary function with a corrected carbon monoxide diffusing capacity (cDLCO) \< 50% predicted.
- History of a fVIII inhibitor (\> 0.4 Bethesda Units/mL) including at least 2 measurements done at least a week apart or any single titer \> 5 BU/mL.
- Subjects who have had prior cellular based therapy or gene editing/ gene therapy including a previous stem cell transplant.
- Subjects with any evidence of active infection or any immunosuppressive disorder, including currently detectable HIV viral load
- Subjects who are RPR, anti-HTLV-1 and II antibody, CMV PCR, VZV antibody and HSV PCR positive at screening.
- Subjects who have allergic reactions or hypersensitivity to any of the drugs used in the study (i.e., anti-thymocyte globulin, plerixafor, G-CSF, busulfan, levetiracetam) or to the constituents of the investigational product formulation.
- Evidence of hepatitis B active infection or chronic carrier based on a positive Hepatitis B DNA testing at screening.
- Positive (detectable viral load per local institutional standard) for the presence of Hepatitis C virus (HCV). Subjects who are positive for anti-HCV antibody are eligible as long as they have a negative undetectable HCV viral load at screening.
- Subjects diagnosed with any history of clinically relevant coagulation or bleeding disorder other than hemophilia A.
- Use of medication(s) that can affect hemostasis (e.g. aspirin, ibuprofen and non-COX-2 selective non-steroid anti-inflammatory drugs).
- Subjects with a history of a malignancy (except surgically resected non-melanoma skin cancer) or subjects with a family history of a known cancer syndrome in a first degree relative.
- Planned surgery within 6 months of enrollment (other than study procedures).
- Treatment with any live vaccines or systemic immunosuppressive agents, not including corticosteroids within 30 days before CD68-ET3-LV CD34+ infusion.
- Treatment with any investigational product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to enrollment.
- History of autoimmune disease (e.g., inflammatory bowel disease, systemic lupus erythematosus, vasculitis).
- Concurrent enrollment in another clinical study, which might interfere with the requirements of this study or have the potential to impact the evaluation of safety and efficacy of CD68-ET3-LV CD34+- unless it is a non-interventional observational study.
- Any condition in the opinion of the Study Investigators that will negatively impact the subject's ability to safely undergo an autologous stem cell transplant.
- Any reason in the opinion of the Study Investigators that will negatively impact the subject's ability to complete the clinical trial per the trial protocol.
Protocol Summary
This study is looking at how safe it is to switch from emicizumab to Mim8, in people with haemophilia A. Mim8 is a new medicine that is used to prevent bleeding episodes in people with haemophilia A. Mim8 works by replacing the function of the missing clotting factor VIII (FVIII). Mim8 will be injected under the skin using a pen-injector either once every week, once every two weeks or once every month. The participants will be trained in using the pen injector. The participants can choose themselves, in collaboration with the study doctor how often they get Mim8 in this study. When the participant will get their first Mim8 injection depends on their current treatment with emicizumab. The participants will get their first Mim8 injection at Visit 2. Participants will have between 6 and 27 Mim8 injections. The total number of injections participants will have depends on their dosing frequency. The study will last for about 6-12 months. While taking part in this study, there are some restrictions about what medicine participant can use. The study doctor will tell the participants more about this. In case the participants experience bleeds, these can be treated with additional haemostatic medicine as agreed with the study doctor. Female participants cannot take part if they are pregnant, breast-feeding or plan to get pregnant during the study period.