Clinical Trial Protocol: ASBI 603 A Multicenter, Randomized, Double- Blind, Placebo-Controlled, Parallel- Group Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of SUN13837 Injection in Adult Subjects with Acute Spinal Cord Injury

Primary Objective: Evaluate the efficacy of SUN13837 injection versus placebo in acute spinal cord injury (ASCI) subjects by a comparison of the proportion of SUN13837-treated subjects and placebo-treated subjects who are defined as responders.

Responder definition A subject who has reached the following outcome at Day 112, either : For cervical AIS A subjects at baseline – an improvement of 2 or more motor levels from baseline on either the right or left side. For cervical AIS B or C subjects at baseline – a total Lower Extremity Motor Score (LEMS) of 40 or more points.

Study information Phase 2 About 60 sites. Initially at an acute care hospital, and can continue at an inpatient rehabilitation facility or an outpatient rehabilitation therapy clinic. Some facilities had participated in both the trauma and rehabilitation phases, but most, such as Genesis, were involved in only one phase. Other renowned rehabilitation facilities were Craig, Kessler, and Rusk/University of Missouri.

SUN13837 A novel small molecule under development that exerts neuroprotective and neuroregenerative properties similar to basic fibroblast growth factor (bFGF) through modulation of the signal transduction pathway of the fibroblast growth factor receptor. However, SUN13837 does not possess the same proliferative effects as bFGF.

SUN13837 A smaller, lipid soluble, molecule that makes it more likely to cross the blood-brain barrier. Two phase 1 studies were conducted in the US with the first having 48/64 subjects, and the second having 24/32 subjects. IV infusions given were safely tolerated. Various strength doses were given. SUN13837, 2-([5-Amino-4, 6-dimethylpyrimidin- 2-yl] oxy)-N-(1-benzylpiperidin-4-yl)-N- methylacetamide

Study Design Administration of the first dose of the study must occur within 12 hours of injury after informed consent obtained. In order to standardize dosing time, at least 5 hours but no more than 24 hours should elapse between the first and second doses of the study drug, including missed doses.

Study Design Daily dosing with the study drug was standardized to 9 AM (1 hour) for each subject after he/she received 1-2 doses of the study drug initially. For each subject, daily IV injections were given by a peripheral IV catheter (eventually PICC lines were allowed). The study drug administration period was days with 28 total doses of the study drug to be given IV push.

Study Design 22 weeks of post-dose follow-up were planned. Pharmacokinetics, EKG, and motor/sensory testing were done, along with a standard history taking and physical examination. Looked at ISNCSCI levels A (C4-7) through B and C (C3-8). Ages

Study Design Placebo was an isotonic solution containing sterile water for IV push injection matching in appearance to SUN SUN13837 treatment was 1.0 mg per kg daily for 28 doses.

Our experience Worked with the University of Iowa Department of Neurosurgery, which was the primary acute care trauma facility and enrolled each patient. Dr. Patrick Hitchon, MD, was the principal investigator there. Patients were planned to come to GMC anywhere from 5 to 20 days post-ASCI. Involved extensive interaction with the Genesis IRB, Genesis clinical research coordinators, pharmacists, rehabilitation nurses, rehabilitation therapists, and physical medicine & rehabilitation physicians.

Our experience Had turnover in staff that did not interfere with the study implementation. Company that initially started the study of SUN13837 (Asubio) was merged to another company (Daiichi- Sankyo). Study closed with 62 subjects enrolled from five different countries: USA, United Kingdom, Czech Republic, France, and Spain. Canada and Norway did not enroll any subjects. Genesis Medical Center was one of two community hospitals that participated in this study.

My Thanks Dr. Blaine Washington, MD, who was my associate. Dr. Ben Levinson, MD, who is the lead physician investigator. Maite Gomez-Lopez at DP Clinical, who educated and trained us for their study, and helped us stay in compliance. Dr. Patrick Hitchon, MD, who chose Genesis Medical Center as his inpatient rehabilitation facility of choice to continue patients with the study after UIHC was finished with them.

My Thanks Genesis IRB to allow us to participate in this study with UIHC. Genesis Inpatient Rehabilitation unit and the Genesis Day Rehabilitation clinic for their staffs providing the time and energies, as well as their excellent patient care. Genesis Clinical Research team with Desyree Weakley, Molly Frazier, Yvonne Bonick, Sarah Castro, and their previous colleagues for their tireless efforts, extreme patience and understanding, and words of encouragement.