Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy

The Safety, Tolerability, Pharmacodynamics, and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) in Patients With MNGIE

The purpose of this study is to determine the safety, tolerability, action and effectiveness of repeated doses of Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) for the treatment of patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE).

MNGIE is a rare inherited disease that mainly affects the digestive and nervous system and is caused by a defect in the function of an enzyme called thymidine phosphorylase. This loss of function causes certain molecules (thymidine and deoxyuridine) to accumulate in cells which leads to toxic damage to these cells. The disease can be confirmed by detecting variations (mutations) in the thymidine phosphorylase gene (TYMP). Currently there are no specific treatments for patients with MNGIE, whose effectiveness has been shown through clinical trials. The potential treatment for MNGIE offered in this trial is an enzyme replacement therapy, i.e. replacing functional thymidine phosphorylase. This treatment uses the patients own red blood cells in which thymidine phosphorylase is encapsulated to produce EE-TP (the study drug). EE-TP is created using a machine named a Red Cell Loader (RCL) and is then administered back to the patient.

This is a multi centre, multiple dose, open label study to investigate the safety, tolerability, pharmacodynamics and efficacy of EE-TP in patients with MNGIE. The study will be conducted in an open label manner with all patients receiving EE-TP.

The study will enrol 12 adult treatment naïve patients with MNGIE, aged 18 years or older at Screening. With Independent Data Monitoring Committee (IDMC) approval, a further four juvenile patients (aged 16-17) will be recruited after at least 24 patient-months exposure to treatment. With IDMC approval, a further four juvenile patients (aged 12-15) will be recruited after at least 24 patient-months exposure to treatment in the 16-17 year old patient group.

Screening failures and patients withdrawing from the study may be substituted with IDMC approval. Patients who have previously received EE-TP on a 'compassionate use' basis may be included in the study, if they meet eligibility criteria; these patients will be additional and will not be included in the sample size of 12.

The total sample size of 12 adult treatment naïve patients is not based on a formal statistical assessment, but is dictated by practical considerations mainly due to the rarity of the condition.

All patients will be administered EE-TP by intravenous (IV) infusion. There are 3 planned dose levels:

• Dose Level 1 (low dose): ~58 -65 x10^10 erythrocytes encapsulating 30 to 49 U TP/10^10 erythrocytes
• Dose Level 2 (mid dose): ~58 -65 x10^10 erythrocytes encapsulating 50 to 69 U TP/10^10 erythrocytes
• Dose Level 3 (high dose): ~58 -65 x10^10 erythrocytes encapsulating 70 to 90 U TP/10^10 erythrocytes

All patients will receive infusions at Dose Level 1 (low dose) for the first 2 treatment cycles. If metabolic correction is not achieved, the subsequent 2 treatment cycles will be infusions at Dose Level 2 (mid dose). If metabolic correction is still not achieved, treatment will advance to Dose Level 3 (high dose) for subsequent treatment cycles. If, at any time during this progression, metabolic correction is achieved, the patient will continue at the Dose Level in which metabolic correction has been achieved and there will be no further dose escalation.

Metabolic correction is defined as plasma thymidine <3 µmol/L and deoxyuridine <5 µmol/L (i.e., below the diagnostic levels for MNGIE).

The doses listed represent the planned doses; the starting dose will be Dose Level 1. It is anticipated that the highest dose will not exceed Dose Level 3; however, if metabolic correction is not achieved for an individual patient at this dose level, other modifications of dosing, such as increasing the number of erythrocytes administered in each infusion can be made.

Patients will be administered EE-TP every 3 weeks until the dose level achieving metabolic correction is identified. From Day 78 (or once metabolic correction has been achieved), it is planned that patients will receive EE-TP every 2 to 4 weeks until the end of the study. The interval between doses will not be shorter than 2 weeks ± 2 days. Dose selection will be flexible; continued pharmacodynamic assessment will enable dose optimization and further inform dose response models and establish the therapeutic window for the treatment.

Single doses of EE-TP will be administered on Day 0 then every 3 weeks until metabolic correction is achieved. The starting dose will be Dose Level 1, with potential subsequent dose levels of Dose Level 2 and Dose Level 3 dependent on whether metabolic correction is achieved or not. All doses will be administered IV.

From Day 78 (or once metabolic correction has been achieved), it is planned that patients will receive EE-TP every 2 to 4 weeks until the end of the study. Dose frequency may be reduced (e.g., from every 2 weeks to every 3 to 4 weeks) for individual patients based on ongoing review of emerging safety, tolerability, efficacy, and pharmacodynamic data. The interval between doses will not be shorter than 2 weeks ±2 days.

The dose level from day 78 onward will remain at the dose that achieved metabolic correction during the initial treatment phase (pre-day 78). In the advent of an increase in plasma metabolite levels (i.e. loss of metabolic correction), the frequency of dosing and/or dose level will be reviewed and adjusted accordingly.

Infusions with EE-TP will occur once every 2 to 4 weeks for 24 months.

Planned Enrolment/Screening (Run in) Duration: approximately 28 days (Days 120 to Day 92). Run-in period of 90 days (Days -91 to 0) for repeated evaluations of a number of assessments. Follow up, 90 days post dose. Planned Study Conduct Duration: approximately 31 months including screening, run-in period and post dose follow-up.

Inclusion Criteria:

1. Patients must be male or female, of any race, aged 18 years or older at Screening.

   • Having IDMC reviewed the benefit risk profile and recommended progression to juvenile cohorts the age range will be extended to include patients:

   • aged 16 years or older after at least 24 patient months of exposure in patients aged 18 years or over.
   • aged 12 years or older after at least 24 patient months of exposure in patients aged <18 years at the time of enrolment.

2. Patients must be diagnosed with MNGIE by demonstrating all of the following:

   • <18% normal thymidine phosphorylase activity in the buffy coat;
   • >3 μmol/L plasma thymidine;
   • >5 μmol/L plasma deoxyuridine;
   • Confirmation of the presence of a pathogenic mutation in TYMP by sequencing.

3. Patients must be able to undergo study procedures.

4. Patients must agree to either remain completely true abstinent or to use 2 effective contraceptive methods from Screening until completion of the Follow up Visit

5. Patients must be willing to sign and date the written informed consent form after the benefits and risks of taking part in this study have been explained to them, and to comply with the study restrictions.

Exclusion Criteria:

Patients who meet any of the following criteria will not be eligible to participate in the study:

1. Patients who have received a successful liver or bone marrow transplant.

2. Patients suitable for allogeneic haematopoietic stem cell transplantation (AHSCT).

3. Patients with a matched AHSCT donor.

4. Patients with a known history of human immunodeficiency virus, hepatitis B infection, or an active hepatitis C infection.

5. Patients who are severely disabled (e.g., patient bed bound, incontinent, and unable to carry out any daily activities), or with a life expectancy of less than 12 months at Screening, based on the Investigator's judgment.

6. Female patients who are:

   • pregnant, planning a pregnancy, or are unwilling to use contraception
   • breastfeeding or lactating.

7. Patients who have donated blood in the 90 days prior to Screening.

8. Patients with a confirmed red blood cell count of <3.0 × 10^9 per mL.

9. Patients who have a significant history of alcoholism or drug/chemical abuse within 1 year prior to Screening, as determined by the Investigator.

10. Patients who have an abnormality in heart rate, blood pressure, or body temperature at Screening that, in the opinion of the Investigator, increases the risk of participating in the study.

11. Patients who have an abnormality in the 12 lead electrocardiogram (ECG) at Screening that, in the opinion of the Investigator, increases the risk of participating in the study.

12. Patients who have, or have a history of, any clinically significant neurological, GI, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological, or other major disorder (except for MNGIE, or disorders associated with MNGIE that, in the Investigator's opinion, do not constitute a risk when taking study drug and would not interfere with the study objectives) as determined by the Investigator.

13. Patients with any current malignancy, or a history of malignancy within 5 years prior to Screening, with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.

14. Patients who are currently enrolled in, or are planning to participate in, or discontinued within the last 30 days from a clinical study involving an investigational medicinal product or concurrently enrolled in medical research judged not to be scientifically or medically compatible with EE-TP.

15. Patients with any medical condition, which in the opinion of the Investigator, would make the patient unsuitable for enrolment or could interfere with the patient's participation in, or completion of, the study.