World Stroke Conference 2023: Implementation of a Blood Glucose Management Plan for Scp776

Scp776 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 targeting the drug to damaged tissue 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] Implementation of an adaptive blood glucose management plan for a novel, targeted IGF-1 fusion protein in a Phase 1 study in healthy adults A First-in-Class Smart Growth Factor™ Scp776 is a three-part fusion protein, which includes a modified IGF-1 signaling arm that is targeted to injured cells to enhance apoptosis escape and preserve healthy tissue. By targeting injured cells, scp776 can be administered at higher doses than IGF-1; however , glucose lowering effects of scp776 have been observed both in preclinical toxicity studies and in the clinical first-in-human single ascending dose study . A strategy of supplemental dextrose infusion and responsive glucose monitoring following scp776 dosing was developed in a multiple ascending dose study in healthy male and female participants. This blood glucose management strategy is now being deployed in the current Phase 2 study of scp776 in acute ischemic stroke patients undergoing thrombectomy (SCP-CL-0003 ARPEGGIO, ClinicalTrials.gov ID NCT05585606). 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 sub- jects Long lasting therapeutic precisely delivers pro-survival signals to injured tissues IGF-1 Serum Albumin AnxV IGF-1 AnxV Serum Albumin Keys to Successful Implementation in Phase 2 ARPEGGIO Study In the stroke setting, there will be variability in the timing of most recent meals and baseline blood glucose levels. Blood glucose decreases are most likely to occur within the first 6 hours following scp776 administration and in subjects with lower baseline levels. Supplemental dextrose infusion should be started at a low rate shortly before administration of scp776. Responsive and incremental adjustments to the dextrose infusion rate are more effective than delayed or large rate adjustments. Oral feeding of well-balanced meals should be encouraged. Scp776 Phase 1 Experience Phase 1b MAD Study Scp776 Dose Levels Phase 1a SAD Study Scp776 Dose Levels Day 1 Day 1 Day 2 Day 3 Day 4CohortCohort 1 mg/kg 4 mg/kg — — —11 2 mg/kg 4 mg/kg — — —22 4 2 mg/kg 2 mg/kg 2 mg/kg — 5 2 mg/kg 2 mg/kg 1.75 mg/kg 1.5 mg/kg 6 2 mg/kg 1.8 mg/kg 1.4 mg/kg 1.2 mg/kg 4 mg/kg 33 3 mg/kg — 3 mg/kg — The Phase 1a SAD study enrolled only males. The Phase 1b MAD study enrolled males and females. Blood glucose levels were monitored at 30 minute intervals. Scheduled meals included: Breakfast (8 am), Lunch (12 pm), Dinner (5 pm), Snack (8 pm). In the Phase 1a study , decreases in blood glucose were treated with oral glucose (e.g., juice). In the Phase 1b study , IV dextrose was supplemented and changes in blood glucose were treated by modulation of the infusion rate. Abbreviations: SAD=Single Ascending Dose, MAD=Multiple Ascending Dose Our Solution: Supplemental Dextrose Infusion Based on experience in the first in human study of scp776 (SCP-CL-0001), a stringent Blood Glucose Management Plan (BGMP) was implemented in the Phase 1b MAD study (SCP-CL-0002). Continuous glucose monitoring devices and bedside point-of-care measurements were used to monitor BG levels in all subjects, they received supplemental IV dextrose, with  rates of infusion adjusted to maintain euglycemia.  The experiences in both Phase 1 studies have informed the design of the BGMP that is currently deployed in the Phase 2 study of scp776 in acute ischemic stroke patients. If BG levels are stabilized, and/or the subject is tolerating oral feedings or is not tolerating 2-hour glucose checks within the 48-hour window, the checks may be modified to SOC (e.g., every 4 hours). BG Level ARPEGGIO Blood Glucose Management Plan Overview Infusion Adjustment Clinical ActionFingerstick Frequency Adjustment <60 mg/dL or symptomatic Increase D10 infusion by 1 mL/kg/h Recheck BG every 15 minutes until stable and > 80 mg/dL Administer 1 amp of 50% dextrose injection intravenously 60-69 mg/dL Increase D10 infusion by 0.5 mL/kg/h Recheck BG every 15 minutes until stable and > 80 mg/dL May administer 1/2 amp of 50% dextrose injection intravenously at the discretion of the treatment team 70-79 mg/dL Increase D10 infusion by 0.2 mL/kg/h Recheck BG every 15 minutes until stable and > 80 mg/dL 80-180 mg/dL Continue current D10 infusion rate Continue BGMP per protocol >180 mg/dL Discontinue D10 infusion and consider insulin drip per hospital protocol for hyperglycemia Continue BGMP per protocol Abbreviations: BG = Blood Glucose, BGMP = Blood Glucose Management Plan, D10 = 10% Dextrose in water, SOC = Standard of Care Terry O'Reilly, Kristopher Kuchenbecker, Lakhmir Chawla, Sam Pfaff, Yan Zhang; Silver Creek Pharmaceuticals, Inc., San Francisco, CA, United States of America ARPEGGIO Key Enrollment Criteria Phase 2 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 24 hours ▪ ASPECTS ≥ 5 ▪ NIHSS ≥ 6 ▪ Pre-event mRS 0 – 2 ▪ 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 IGF-1 Based Therapies Can Decrease Blood Glucose Insulin-like Growth Factor-1 (IGF-1) is structurally related to insulin and has widespread receptor binding throughout the body . IGF-1 is a hormone of clinical interest due to a broad range of important physiologic effects, including roles in neonatal growth and development, with primary postnatal targeting to skeletal muscle, as well as bone development, inhibition of apoptosis, and glucose regulation. IGF-1 has been evaluated for therapeutic lowering of glucose levels in diabetic patients; however , its therapeutic potential has been limited by the incidence of undesirable side effects in this population including jaw pain, arthralgias and tachycardia1 while its profound effects on glucose metabolism and potential for inducing hypoglycemia have limited its clinical development for other indications. The inherent pharmacology and systemic effects of the IGF-1 component of scp776 can be addressed by dextrose supplementation. Scp776 Targeting To Damaged Tissue Apoptosis Escape Desired Pharmacology Blood Glucose Lowering Effects Off-Target Effects Enhanced Glucose Uptake Inhibition of Gluconeogenesis Insulin Sensitization Glycemic Management in Stroke Hyperglycemia is common in the setting of acute ischemic stroke (AIS), due to both underlying diabetes and as a stress response to the stroke even in patients without diabetes. Conversely , in cases with prolonged time since last know well (LKW), stroke patients may be hypoglycemic due to prolonged fasting. Although hyperglycemia is a concern, studies which have used intensive glucose management via tight insulin control have not demonstrated improved functional outcomes or mortality , instead showing increased morbidity with hypoglycemic events.2 New therapies for the treatment of acute stroke must consider the comorbidity of dysglycemia in these patients and the potential confounding effects of these compounds, while following the AHA guidance on glucose management in AIS.3 ²Ferrari, et al, Neural Reg Res, 2022 Feb; 17(2) ³Powers, et al, Stroke, 2019 Dec; 50(12) Blood Glucose New, Revised, or UnchangedCOR LEO I Ila C-LD C-LD 1. Hypoglycemia (blood glucose <60mg/dL) should be treated in patients with AIS. 2. Evidence indicates that presistent in-hospital hyperglycemia during first 24 hours after AIS is associated with worse outcomes that normypoglycemia and thus, it is reasonable to treat hyperglycemia to achieve glucose levels in a range of 140 to 180 mg/dL and to closely monitor prevent hypoglycemia in patients with AIS. Recommendation and COR unchanged from 2013 AIS Guidances. LOE amended to confirm with ACC/AHA 2015 Recommendation classification System Recommendation and COR unchanged from 2013 AIS Guidances. LOE amended to confirm with ACC/AHA 2015 Recommendation classification System AHA Guidelines abbreviation key: COR=Class of Recommendation, I=strong, IIa=moderate, LOE=Level of Evidence, C-LD=limited data Supplemental Dextrose Decreases Frequency of Hypoglycemic Events In the first-in-human study SCP-CL-0001, subjects received 2 or 4 mg/kg scp776 without constant dextrose supplementation. At matching dose levels in SCP-CL-0002 with IV dextrose supplementation, subjects experienced fewer hypoglycemia events and better maintained normal blood glucose levels in the 6-hour period following dosing. For reference, hypoglycemia events in the Saline Placebo group are also presented. (Note: Meals were scheduled at t = 0 & 4 hours.) Scp776, 2 mg/kg Hypoglycemia Frequency 8 1.33 AEs/subject 0.38 AEs/subject No IV Dextrose (n=6) With IV Dextrose (n=16) 6 Total Hypoglycemia Events 9 1.5 AEs/subject 0.67 AEs/subject No IV Dextrose (n=6) With IV Dextrose (n=9) 6 Scp776, 4 mg/kg 6 1.00 AEs/subject 0.55 AEs/subject No IV Dextrose (n=6) With IV Dextrose (n=11) 6 Saline Placebo Phase 1: Dextrose Infusion Strategy In the Phase 1b study SCP-CL-0002, healthy male and female subjects received supplemental IV dextrose prior to dosing. The blood glucose levels of individual subjects were responsive within standard monitoring intervals (i.e., 0.5 hour) to changes in the rates of dextrose infusion. While some subjects responded more rapidly than others, IV dextrose supplementation was able to successfully reverse episodes of hypoglycemia. During conduct, it was noted that high rates of infusion (i.e., 6 mL/kg/hr) could perpetuate the requirement for supplementation. It is noteworthy that the decreases in blood glucose appeared shortly after scp776 Tmax (~0.5 hour) and stabilized as serum scp776 concentrations decreased and dextrose supplementation was optimized. The tapering of doses combined with low initial dextrose infusion rates and incremental rate adjustments minimized total infusion volumes while providing glycemic control. These dose levels and dextrose supplementation strategies are feasible in a standard clinical setting wherein scp776 will be dosed to patients. In Cohorts 1 – 3, dextrose infusion rates were started high and rate adjustments were large. In Cohorts 4 – 6, the dextrose supplementation strategy was adjusted to initiate at low rates shortly before scp776 dosing and make smaller , incremental rate adjustments in response to glucose monitoring. As evidenced above, significantly less supplemental dextrose was required to maintain euglycemia in Cohorts 4 – 6. 4 mg/kg – x 4 mg/kg – x 3 mg/kg – 3 mg/kg – x 2 mg/kg 2 mg/kg 2 mg/kg – x 2 mg/kg 2 mg/kg 1.75 mg/kg 1.5 mg/kg – x 2 mg/kg 1.8 mg/kg 1.4 mg/kg 1 mg/kg – x Phase 1b – Scp776 IV Dosing Schedule by Cohort (x = end of dextrose infusion) Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 4 mg/kg total 4 mg/kg total 6 mg/kg total 6 mg/kg total 7.25 mg/kg total 6.2 mg/kg total Clemmons, Endocrinol Metab Clin North Am. 2012 June ; 41(2) 2 mg/kg, No IV Dextrose (n = 6) 2 mg/kg, IV Dextrose (n = 16) 4 mg/kg, No IV Dextrose (n = 6) 4 mg/kg, IV Dextrose (n = 9)

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