First-in-human Safety Study of Hypoimmune Pancreatic Islet Transplantation in Adult Subjects With Type 1 Diabetes

First-in-human Safety Study of Hypoimmune Pancreatic Islet Transplantation in Adult Subjects With Type 1 Diabetes

The current study tests the hypothesis whether genetically modified Langerhans islet cells containing insulin-producing cells from a deceased organ donor can

1. be transplanted safely and
2. help to regain insulin production in individuals with type 1 diabetes without need in simultaneous treatment with immunosuppressive medicines.

The study is an open, one-armed study where adult subjects with longstanding type 1 diabetes will receive transplantation of Langerhans islet cells (25 000 000-80 000 000) into forearm muscle. Both subjects receive active treatment. Safety is monitored with frquent follow-up visits over a year, including medical examinations, blood tests and MRI scans. Insluin producing cell function is monitored with blood samples and continuous glucose measurement.

Main objective is to to investigate the safety of an intramuscular transplantation of genetically modified allogeneic human islets (study product UP421) in adult subjects diagnosed with type 1 diabetes.

Secondary objectives are to study changes in beta-cell function, metabolic control and immunological response to pancreatic islets during the first year following treatment.

Inclusion Criteria:

1. Signed informed consent for participation in the study

2. Diagnosis of type 1 diabetes mellitus (T1D);

   i) for ≥ 5 years and

   ii) diagnosed before the age of 18 years and

   iii) at least one or more HbA1c documented in the subject's medical journal or Swedish National Diabetes Registry during the last five-year period must be

   ≥70 mmol/mol.

3. The subject must be involved in intensive diabetes management defined as self-monitoring of subcutaneous glucose level by continuous glucose monitoring or by

   intermittent scanning glucose monitoring no less than a mean of three times per day averaged over each week and by the administration of three or more insulin

   injections per day or insulin pump therapy. This management must be under the direction of an M.D specialized in endocrinology and diabetology with support of

   a diabetes nurse at a specialist clinic for Endocrinology and Diabetology or Internal Medicine during the 12 months prior to study enrolment.

4. C-peptide negative (C-peptide < 0.01 nmol/l) in response to a mixed meal tolerance test (MMTT)

5. Positive for antibodies to either GAD or IA2 at screening

6. 30-45 years of age at time of enrollment

7. HbA1c ≥70 mmol/mol

8. Exogenous insulin needs < 1 IU/kg

9. Body weight <80 kg

10. Female subjects of child-bearing potential must agree to using adequate contraception until one year after the administration of UP421, as outlined in

https://www.hma.eu/fileadmin/dateien/Human\_Medicines/01-About\_HMA/Working\_Groups/CTFG/2014\_09\_HMA\_CTFG\_Contraception.pdf

A woman is considered of childbearing potential if she is not surgically sterile or isles than 1 year since last menstrual period.

Adequate contraception is as follows:

1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal)

2. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)

3. intrauterine device (IUD)

4. intrauterine hormone-releasing system (IUS)

5. bilateral tubal occlusion f) vasectomised partner g) sexual abstinence Male subjects must not intend to procreate until one year after the administration of UP241.

   Males must be willing to use effective measures of contraception (condoms) during the whole trial period.

   Exclusion Criteria:

   Any previous organ transplantation;

   2. Any systemic immunosuppressive medication for any other disease;

   3. Any history of malignancy;

   4. Use of any investigational agent(s) within 4 weeks of enrollment;

   5. Use of any anti-diabetic medication, other than insulin, within 4 weeks of enrollment;

   6. Active infections including Tuberculosis, HIV, HBV and HCV;

   7. Liver function test value for AST, ALT, GGT or ALP exceeding the respective reference interval for the clinical assay at Uppsala university hospital;

   8. Serological evidence of infection with HTLVI or HTLVII;

   9. Pregnancy, nursing, intention for pregnancy;

   10. Chronic kidney disease grade 3 or worse (GFR<60 ml/min as estimated by creatine measurement) ;

   11. Medical history of cardiac disease, or symptoms at screening consistent with cardiac disease;

   12. HLA immunization;

   13. MIC A/B immunization;

   14. Known autoimmune disease other than type I diabetes (e.g. Hashimoto disease);

   15. Administration of live attenuated vaccines <6 months before transplant;

   16. Islet antibodies where GADA >2000 IE/ml or IA2A >4000 IE/ml, or positive for ZnT8 auto-antibodies;

   17. Untreated proliferative diabetic retinopathy;

   18. Major ongoing psychiatric illness which the Principal Investigator judges increases the risk of noncompliance or does not allow safe participation in the study;

   19. Ongoing substance abuse, drug or alcohol; or recent history of treatment noncompliance;

   20. Known hypersensitivity to ciprofloxacin, gentamicin, or amphotericin (since these are used in the manufacturing process of UP421);

   21. Any other condition that in the opinion of the Principal Investigator does not allow safe participation in the study.