Safety and Dose Ranging Study of Human Insulin Receptor MAb-IDUA Fusion Protein in Adults and Children With MPS I

Stage 1:

Stage one will be a single-dose, dose-escalation study in cohorts of 2 patients with Hurler-Scheie or Scheie syndrome age 18 or greater who have not had ERT for at least 7 days prior to starting treatment. Approximately 3 cohorts will be enrolled sequentially, with safety data from the previous cohort being reviewed prior to escalation to the next higher dose cohort. Patients will be assigned to cohorts on the basis of their order of entry into the study.

The first cohort will be administered a single intravenous infusion of 0.3 mg/kg AGT-181 diluted in D5 normal saline over 4 hours. All patients will be observed for safety for 28 days after dosing. For dose escalation, the decision to proceed to a higher dose of AGT-181 will be made by the Sponsor and the investigator(s) after review of the available safety and tolerability data on or after 7 days post dose from patients who received the previous dose.

Dose escalation to a higher dose cohort can occur providing there are no dose limiting toxicities (DLT), defined as Grade 3 (severe or medically significant but not immediately life threatening) or higher adverse event according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Stage 2:

Assuming safety and tolerability in Stage 1, a second stage will be initiated using a multi-dose, safety, tolerability and proof of concept effect design in children (age 2 or older) with Hurler or Hurler-Scheie with CNS involvement who are either ERT naïve or will have not received ERT for at least 7 days prior to first dose of AGT-181.

This second stage of the study will be conducted in dose groups of up to 5 patients per group who will receive AGT-181; it is planned that up to 10 patients will be enrolled (2 dose cohorts). Additional patients or cohorts may be enrolled in order to evaluate specific safety or PK issues or if it is felt that an active dose has not yet been reached. If an active dose is not achieved, an additional cohort of 5 patients will be enrolled at a higher dose of AGT-181, A maximum of 15 patients will be enrolled in stage 2. These cohorts will be studied in staggered fashion with safety and efficacy data from the previous cohort being reviewed as part of the decision to commence treatment in additional cohorts. Patients will be assigned to cohorts on the basis of their order of entry into the study.

The first cohort will be administered a dose one level below the maximum tolerated (MTD) or maximum administered dose (MAD) from the single dose stage 1 (ie. if the MTD is 3.0 mg/kg from Stage 1 than the starting dose in this stage will be 1.0 mg/kg). AGT-181 will be administered as a once weekly intravenous infusion in D5 normal saline over 4 hours for the first eight infusions. Depending upon tolerability, the rate may be increased to be administered over 1-4 hours. Investigators are permitted to use their clinical judgment and standard protocols in determining whether to administer pre-infusion medications such as antihistamines and antipyretics. In cases where the patient has had a previous infusion reaction(s) to ERT, then premedication should be given prior to each infusion per clinical site standard protocol.

For dose escalation, the decision to proceed to a higher dose of AGT-181 will be made by the Sponsor and the investigator(s) after review of the available safety and tolerability data from patients who received the previous dose.

Dose escalation to a higher dose cohort can occur providing there is no dose limiting toxicity (DLT) in the first 3 patients treated for 28 days or more. If one patient of 3 develops a DLT, then dose escalation may not occur until the remaining 2 patients have completed 28 days of dosing and there have been no further DLTs. A DLT is defined as a Grade 3 (severe or medically significant but not immediately life threatening) or higher adverse event according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

If a Grade 3 or worse event is clearly attributable to a non-treatment event and therefore not a suspected adverse reaction: [21CFR312.32(a)] (for example, trauma secondary to an accident, or spurious lab value not confirmed on repeat) the event will not be considered a DLT for dose escalation purposes after review and agreement by both the Sponsor's Medical Monitor and Principal Investigator.

In addition to adverse events occurring during the first 28 days, late and chronic toxicities will be evaluated and taken into account in determining the safety of each dose level for future studies and the need for additional cohorts in this study.