International Stroke Conference 2023: ARPEGGIO Study Design

Rescue cells. Change Lives. Scp776 A first-in-class Smart Growth Factor ™ Selective Delivery of IGF-1 to Damaged Tissues ▪ IGF-1 inhibits apoptosis and promotes cerebroprotection ▪ Central albumin scaffold extends half-life ▪ Annexin V binds phosphatidylserine on the surface of apoptotic cells Preclinical Efficacy in NHP tMCAO Model ▪ Improved BBB Integrity during acute phase ▪ Lesion size reduced by > 30% at 72 hrs ▪ Improved neurologic function ▪ Mortality decreased five-fold in scp776 treatment group Silver Creek Pharmaceuticals, Inc. 409 Illinois Street | San Francisco, CA 94158 [email protected] Cerebroprotective effect and safety of scp776, an IGF-1 fusion protein targeted to damaged tissues, in large vessel ischemic stroke patients undergoing thrombectomy without thrombolysis A single ascending dose, first in human Phase 1A trial, of scp776 was conducted in healthy volunteers to evaluate its safety , tolerability , and pharmacokinetic (PK) profile in humans. The study enrolled 24 healthy adult male subjects in 3 cohorts (6 active : 2 placebo per cohort). Serum concentration curves are shown for the three dose levels investigated in this study . In healthy human participants, the circulating half-life of scp776 is 10.6 ± 1.4 hours. Results demonstrated that scp776 is safe and well tolerated in healthy human subjects. Our Mission: Targeted Intervention During Acute Injury Can Change the Destiny of Injured Cells and Preserve Tissue Function Scp776 Inhibits the Apoptotic Pathway and Promotes Escape from Apoptosis with Greater Potency than Natural Growth Factors Phase 1A — SCP-CL-0001 Study Design Phase 1B — SCP-CL-0002 ARPEGGIO is a Phase 2 randomized, placebo-controlled, double-blind study that will be conducted in 2 parts: sequential dose escalation in Part A, followed by dose expansion in Part B.  In Part A, approximately 40 evaluable subjects will be assigned 1:1:2 overall to Cohort 1, Cohort 2, or placebo. Doses of scp776 will be tested sequentially in 2 cohorts, each in parallel with a volume-matched placebo, randomized as 1:1 scp776:placebo within each cohort, to maintain the overall 1:1:2 ratio. Subjects will receive 2 doses of either normal saline (placebo) or scp776 approximately 24 hours apart. In Part B, approximately 40 subjects will be assigned 1:1 to the best therapeutic dose from Part A or placebo. On Day 1, subjects who meet the eligibility criteria will begin administration of study drug at a stroke center with an endovascular suite on-site. The qualifying brain imaging scan and Alberta stroke program early CT (ASPECT) score must be performed within 4 hours before the planned EVT . Study drug is intended to be administered within 1 hour of the baseline/qualifying scan, if possible, but no more than 4 hours after the qualifying scan. Study drug should be administered before the first pass with the EVT device, if possible, but before restoration of vessel flow. Preferably , at least 5 minutes should elapse after the end of the study drug administration before the opening of the vessel during the EVT procedure. The study drug will be administered via slow IV injection over two minutes. The second dose of study drug will be administered 24 hours after the first dose. Subjects will remain hospitalized for at least 48 hours; data collected through Day 7 if still hospitalized. Subjects will return for follow up visits on Days 30 and 90. Because of the modified insulin-like growth factor signaling arm, scp776 can decrease blood glucose levels. Before administration of study drug, all subjects will begin an IV infusion of 10% dextrose in water (D10) started at a rate of 0.1 mL/kg/h. Dextrose administration will continue through at least 48 hours and managed per the protocol blood glucose management plan (BGMP). The Phase 1B study was a randomized, double-blind, placebo-controlled study of the safety and PK of single ascending and multiple doses of IV scp776 in healthy adults receiving a continuous infusion of dextrose. The study enrolled 44 healthy adult male and female subjects in 6 cohorts. The supplemental dextrose infusion was implemented to limit the known blood glucose (BG) lowering effect of IGF-1. Comparison of the areas above 70 mg/dL (euglycemia) in the Phase 1A and Phase 1B is shown. Supplemental dextrose in the Phase 1B significantly increased the euglycemic area, maintaining BG levels post administration of scp776. Additional results indicate that multidose regimens of scp776 were safe and well tolerated when administered with a continuous infusion of supplemental dextrose. Preclinical Efficacy of Scp776 in an NHP Model of Acute Ischemic Stroke Scp776 was studied in a blinded non-human primate (Macaca fascicularis) transient middle cerebral artery occlusion (tMCAO) model of AIS. In this surgical model, the MCA was occluded by placing two microvascular clips, one at the proximal MCA trunk and the other at the distal to orbito-frontal branch. The clips were removed after four hours ischemia time, creating a large infarct, small penumbra injury .  Scp776 (n = 10) or placebo (n = 12) was administered 30-minutes prior to reperfusion. All animals received supplemental dextrose. Endpoints included MRI imaging, neurologic function, and survival. Injury Cell Injured Cell Survival Full Recovery Treatment with Scp776 Cell Death Apoptosis Necrosis Apoptosis Escape ▪ IGF-1 is rapidly captured by IGFBPs ▪ Healthy cells greatly outnumber injured cells ▪ Increasing the dose to reach injured tissue results in off-target effects The Challenge How to deliver IGF-1 only to the injury? ▪ Avoid binding proteins and reach sites of injury ▪ Effective targeting to injured cells to limit side effects ▪ Efficient delivery to mitigate damage as paracrine pro-survival factor The Solution Scp776 is a first-in-class targeted IGF-1 therapy Scp776 is engineered to drive pro-survival signaling in injured cells Scp776 is administered intravenously and has a circulating half-life of ~10 hours in healthy subjects Long lasting therapeutic precisely delivers pro-survival signals to injured tissues IGF-1 Serum Albumin AnxV ▪ Aged 18 years or older . ▪ Acute ischemic stroke (AIS) intended for immediate endovascular treatment. ▪ Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) greater than or equal to 6 at the time of randomization. ▪ Confirmed symptomatic intracranial occlusion, based on qualifying imaging, at one or more of the following locations: Intracranial carotid artery and/or M1 middle cerebral artery (MCA). Onset AIS (last-seen-well) time to randomization time < 16 hours. ▪ Pre-AIS (24 hours prior to stroke onset) independent functional status in activities of daily living with modified Rankin Score of 0 or 1. Subject must be living in their own home, apartment, or seniors lodge where no nursing care is required. ▪ Evidence of acute intra-cerebral hemorrhage on qualifying imaging, per radiology lab manual. ▪ Poor/no collateral circulation (e.g. collateral score of 0 or 1). ▪ ASPECT score of 0-4. ▪ Current AIS is being treated with IV thrombolytic therapy or the subject has received thrombolytic therapy within the previous 24 hours. ▪ Intent to use any endovascular thrombectomy device that is not FDA-approved. ▪ Planned use of intra-arterial thrombolytic therapy . ▪ Clinical history , past imaging or clinical judgment suggests that the intracranial occlusion is chronic or there is suspected intracranial dissection such that there is a predicted lack of success with endovascular intervention. Inclusion Criteria: Exclusion Criteria: Enrollment Criteria The ARPEGGIO Trial is Now Enrolling Study Information  Protocol Number: SCP-CL-0003 Clinicaltrials.gov Identifier: NCT05585606 Study Status Patient enrollment is active at multiple sites with additional US sites expected to begin enrollment in February 2023. Site selection is ongoing.   Objectives Associated Endpoints Objectives Associated Endpoints Primary To measure the neuroprotective capacity of scp776 Secondary To evaluate scp776 safety and tolerability  To evaluate the  effect on other assessments  of efficacy Exploratory To evaluate the exploratory efficacy and pharmacodynamics of scp776 Pharmacokinetic (PK) To evaluate the pharmacokinetic profile of scp776 ▪ Change in NIHSS from baseline to Day 7/discharge ▪ Frequency of TEAEs, SAEs, and drug-related AEs ▪ Proportion of subjects experiencing each of the following AESIs: ◦ Hypoglycemia ◦ Tachycardia ◦ Bleeding Events ▪ Change in NIHSS from baseline to Day 3 ▪ Proportion of subjects with Modified Rankin Scale score 0–2 at Day 7 /discharge, and of 0–1 and 0–2 at Day 90 ▪ Change in Modified Rankin Scale score at Days 30 and 90 from baseline ▪ Day 30 survival ▪ Change in NIHSS from baseline to Days 1 and 2 ▪ Proportion of subjects with Barthel Index between 90-100 on Day 90 ▪ Change in Barthel Index score from baseline to Day 90 ▪ Day 90 Survival ▪ Total dextrose infusion ▪ Change in lesion size from baseline to Day 4 ▪ Change in cerebral blood flow, cerebral blood volume, mean transit time, time to maximum perfusion, and time-to-peak flow, from baseline to Day 4 ▪ PK values and parameter estimates calculated as by noncompartmental analysis as data permits Symptom Onset Timing: Procedures: Screening / Enrollment Study Drug Infusion 1 EVT Study Drug Infusion 2 Discharge / D7 Day 30 Follow Up Day 90 Follow Up IV infusion over  1 – 2 minutes IV infusion over  1 – 2 minutes Brain imaging < 16 hours last seen well ≤ 4 hours before EVT Within 1 – 4 hours of imaging Study drug given before EVT / During first pass 24 hours after study drug infusion 1 At least 24 hours after last study drug administration Following discharge, subject does not return to clinic until Day 30 NIHSS mRS mBI ASPECTS Score Surveillance NCCT NIHSS: Daily until discharge mRS: At discharge NIHSS: Days 30 & 90 mRS: Days 30 & 90 mBI: Day 90 IV Dextrose Infusion / Blood Glucose Monitoring Begin < 30 minutes before study drug administration. Hourly (± 20 minutes) for first 24 hours. Every 2 hours (± 20 minutes) from 24 – 48 hours. SOC thereafter . Patient Flow Interested in Enrolling for ARPEGGIO? To be considered for selection as an enrolling investigator or site, please email [email protected] or visit the webpage at silvercreekpharma.com/ARPEGGIO ARPEGGIO Key Enrollment Criteria Study Objectives ▪ Assess cerebroprotective effect using the NIHSS ▪ Evaluate the safety and tolerability of scp776 in patients ▪ Evaluate additional efficacy endpoints ▪ Last seen well within 16 hours ▪ ASPECTS ≥ 5 ▪ NIHSS ≥ 6 ▪ Pre-event mRS 0 – 1 ▪ No thrombolytics within 24 hrs A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study of the Safety and Neuroprotective Capacity of Scp776 in Subjects Undergoing Endovascular Thrombectomy for Acute Ischemic Stroke Kristopher Kuchenbecker , Lakhmir Chawla, Terry O'Reilly , Brian Byrnes, Richard Landin, Sam Pfaff, Walter Olsen, and Michelle M. Merrigan ARPEGGIO Possible outcomes for an injured cell follow three distinct pathways: 1. Survival and full recovery; 2. Apoptosis with likely cell death; and 3. Necrosis and cell death. Scp776 selectively delivers anti-apoptotic signaling to sites of injury to promote apoptotic escape, survival, and recovery . Escape Apoptosis, Preserve Cellular Function Acute Injury Scp776 Treated* Standard injury progression leads to Impaired Tissue Function Enhanced apoptosis escape with scp776 leads to Preserved Tissue Function Untreated Key: Healthy Cells Early Apoptotic Late Apoptotic Dead / Scar * For illustrative purposes only . These depictions are not quantitative. Following acute injury , cells of the injured core enter apoptosis, which can expand to surrounding cells. In the absence of treatment, the injury spreads to peripheral tissue, further impairing tissue function. Scp776 limits damage from an acute injury by promoting apoptosis escape in viable tissue and preventing the expansion of the injured core. Potency is > 100X higher on injured cells Scp776 strongly interacts with phosphatidylserine (PS) exposed on the outer surface of apoptotic cells. The specific activation of pro-survival signaling pathways in injured cells is over 100-fold more potent than in healthy cells. 4 mg/kg 2 mg/kg 1 mg/kg Mean serum scp776 concentrations are plotted for three cohorts in Phase 1A study SCP-CL-0001. Inset figure shows clearance on semi-log scale. Bedside BG measurements were taken in the 24 hours post scp776 administration. Euglycemic area is calculated as the area under the BG curve above 70 mg/dL. The mean euglycemic area with dextrose supplementation is significantly greater (p = 0.0041). This study compared three groups: Placebo (n = 12), Low Dose (n = 10), and High Dose (n = 10). Dose dependence was noted for all measured parameters. For simplicity, only the vehicle and high dose groups are shown. Multiple comparison of means (ANOVA followed by Fisher’s least significant difference procedure) was performed with all three groups to determine significant differences between group means. Values for monkeys that perished prior to a scheduled assessment were imputed to the maximum observed value. Significant Survival Benefit Preserved BBB Integrity Gadolinium Contrast, p = 0.0325 t = 4 hours Lesion Size Reduced T2 MRI, p = 0.0164 t = 72 hours Functional Improvement Neuro Deficit Score, p = 0.0323 t = 10 days Scp776 Vehicle

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