Methods of treatment using IGF-1 chimeric proteins

Abstract

Provided herein are methods of treating a subject in need thereof with an IGF-1 chimeric protein.

Description

Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025METHODS OF TREATMENT USING IGF-1 CHIMERIC PROTEINSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Application No. 63 / 723,024, filed November 20, 2024, and U.S. Provisional Application No. 63 / 903,770, filed October 22, 2025, the entire contents of each of which are incorporated herein by reference.REFERENCE TO SEQUENCE LISTING

[0002] This specification includes a sequence listing submitted herewith, which includes the file entitled 132463-011302. xml having the following size: 37,142 bytes which was created November 19, 2025, the contents of which are incorporated by reference herein.TECHNICAL FIELD

[0003] Aspects of the present disclosure relate generally to pharmaceutical compositions comprising IGF-1 chimeric proteins, and methods for using such IGF-1 chimeric proteins in a subject in need thereof.BACKGROUND

[0004] The insulin-like growth factors (IGFs) constitute a family of proteins having insulinlike and growth stimulating properties.SUMMARY

[0005] Aspects of the disclosure relate to methods of treating a subject in need thereof with an IGF-1 chimeric protein, the method comprising administering a solution comprising an effective amount of dextrose prior to administering an IGF-1 chimeric protein, wherein the administering is over a period of about 48 hours, and administering a pharmaceutical composition comprising an effective amount of the IGF-1 chimeric protein, wherein the effective amount of dextrose supports eugly cemia and wherein half-life of the IGF-1 chimeric protein is from about 6 hours to about 10 hours. In some embodiments, the solution comprising the effective amount of dextrose is administered by infusion to the subject in need thereof. In some embodiments, the method comprises administering the solution comprising the effective amount of dextrose at a starting infusion rate of about 0. 1 mL / kg / h. In some embodiments, the method further comprises adjusting the infusion rate at an incremental rate of +0.05 mL / kg / hr to +2 mL / kg / hr.1ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0006] In some embodiments, the solution comprising the effective amount of dextrose comprises from about 5% to about 10% dextrose (w / v) in water. In some embodiments, the solution comprising the effective amount of dextrose comprises from about 5% to about 10% dextrose (w / v) in saline solution.

[0007] In some embodiments, the method comprises administering the solution comprising the effective amount of dextrose from about 1 min to about 30 min before the administration of the IGF-1 chimeric protein.

[0008] In some embodiments, the IGF-1 chimeric protein comprises a targeting domain comprising human annexin 5 (AnxV) or variant thereof, and an activator domain comprising insulin-like growth factor (IGF-1) or variant thereof. In some embodiments, the IGF-1 chimeric protein further comprising a peptide, wherein the peptide extends the half-life of the chimeric protein. In some embodiments, the targeting domain is a non-intemalizing variant of annexin 5. In some embodiments, the IGF-1 chimeric protein is substantially not internalized by cells. In some embodiments, the IGF-1 chimeric protein comprises a non-intemalizing variant of annexin 5, wherein the non-intemalizing variant of annexin 5 comprises one or more mutations, wherein the one or more mutations comprises a substitution at a position corresponding to C316 and optionally at one or more positions corresponding to R63, K70, K101, E138, D139, N160, and combinations thereof. In some embodiments, the activator domain of chimeric protein is a variant of human insulin-like growth factor IGF-1 comprising one or more mutations, wherein the one or more mutations consist of a substitution at one or more positions corresponding to E3, Y24, Y31, Y60, and combinations thereof. In some embodiments, the IGF-1 chimeric protein further comprises a half-life modulator comprising a variant of human serum albumin (HSA) comprising one or more mutations, wherein the one or more mutations consist of a substitution at one or more positions corresponding to C58 and N527, and combinations thereof. In some embodiments, the IGF-1 chimeric protein comprises or consists of IGF 1 (E3R / Y31 A)_lk7_HS A26-609(C58S / N527Q)_lk7_AnxV2- 320(R63A / K70A / K101A / E138A / D139G / N160A / C316A). In some embodiments, the IGF-1 chimeric protein comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 24.

[0009] In some embodiments, the method comprises administering descending effective amounts of the IGF-1 chimeric protein over a period of 2 days to 14 days or more.

[0010] In some embodiments, the administering of the effective amount of the IGF-1 chimeric protein inhibits apoptosis.2ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0011] In some embodiments, the pharmaceutical composition further comprises at least one physiologically acceptable carrier.

[0012] In some embodiments, the subject in need thereof is a human. In some embodiments, the wherein the subject in need thereof has acute ischemic stroke (AIS).

[0013] Aspects of the disclosure relate to methods of treating a subject having an acute ischemic stroke with an 1GF-1 chimeric protein. In some embodiments, the method comprises administering a pharmaceutical composition comprising an effective amount of the IGF-1 chimeric protein to the subject beyond conventional therapeutic window for treating acute ischemic stroke. In some embodiments, the administering of the pharmaceutical composition is on average about 12 hours after stroke onset. In other embodiments, the pharmaceutical composition is on average about 12 hours up to 24 hours after stroke onset.

[0014] In some embodiments, the administration of the pharmaceutical composition results in one or more of (i) enhanced rate of neurological recovery, (ii) earlier discharge from hospital, (iii) reduced neurological deficit at discharge or day 7, (iv) reduced infarct volume on followup imaging, and / or (v) increased frequency of favorable functional outcomes at 90 days.

[0015] In some embodiments, the administration of the pharmaceutical composition results in increased rate of neurologic recover from 0.1 - 4 points per day. In some embodiments, the administration of the pharmaceutical composition results in earlier discharge by 0.3 - 4 days. In some embodiments, the administration of the pharmaceutical composition results in improved neurologic function at discharge by 1 - 6 points on the National Institutes of Health Stroke Scale (NIHSS). In some embodiments, the administration of the pharmaceutical composition results in reduced volume of infarction by 5 - 40%. In some embodiments, the administration of the pharmaceutical composition results in an increase in the relative proportion of subjects achieving good outcomes (mRS 0 - 2) by 5 - 30%.

[0016] In some embodiments, the pharmaceutical composition further comprises at least one physiologically acceptable carrier.

[0017] In some embodiments, the subject in need thereof is a human.

[0018] In some embodiments, the IGF-1 chimeric protein comprises a targeting domain comprising human annexin 5 (AnxV) or variant thereof, and an activator domain comprising insulin-like growth factor (IGF-1) or variant thereof. In some embodiments, the IGF-1 chimeric protein comprises a non-internalizing variant of annexin 5, wherein the non-internalizing variant of annexin 5 comprises one or more mutations, wherein the one or more mutations comprises a substitution at a position corresponding to C316 and optionally at one or more3ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 positions corresponding to R63, K70, K101. E138, D139. N160, and combinations thereof. In some embodiments, the activator domain of IGF-1 chimeric protein is a variant of human insulin-like grow th factor IGF-1 comprising one or more mutations, wherein the one or more mutations consist of a substitution at one or more positions corresponding to E3, Y24, Y31, Y60, and combinations thereof. In some embodiments, the IGF-1 chimeric protein further comprises a half-hfe modulator comprising a variant of human serum albumin (HSA) comprising one or more mutations, w herein the one or more mutations consist of a substitution at one or more positions corresponding to C58 and N527, and combinations thereof. In some embodiments, the IGF-1 chimeric protein comprises or consists of IGF 1 (E3R / Y31 A) Jk7 HS A26-609(C58S / N527Q) Jk7_AnxV2-320(R63A / K70A / K101 A / E138A / D139G / N160A / C316A). In some embodiments, the IGF-1 chimeric protein comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 24. In some embodiments, the administering comprises administering a first dose of the pharmaceutical composition comprising about 2 mg / kg of the IGF-1 chimeric protein, followed by a second dose of the pharmaceutical composition comprising about 1.8 mg / kg of the IGF-1 chimeric protein about 24 hour after the first dose. In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, a solution comprising an effective amount of dextrose is administered intravenously to maintain levels above 80 mg / dL.DESCRIPTION OF THE SEQUENCE LISTING

[0019] SEQ ID NO: 1 is the amino acid sequence of wild-type human IGF-1 (mature form).

[0020] SEQ ID NO: 2 is the amino acid sequence of a variant of wild-type human IGF-1 variant comprising E3R and Y31A substitutions.

[0021] SEQ ID NO: 3 is the amino acid sequence a variant of human IGF-1 (IGF-1 LONG).

[0022] SEQ ID NO: 4 is the amino acid sequence a variant of human IGF-1 (IGF1 E3R).

[0023] SEQ ID NO: 5 is the amino acid sequence of a variant of human IGF-1 (IGF-1 Des 1-3).

[0024] SEQ ID NO: 6 is the amino acid sequence of a variant of human IGF-1 (IGF-1 LR3).

[0025] SEQ ID NO: 7 is the amino acid sequence a variant of human IGF-1 (IGF1 R37X).

[0026] SEQ ID NO: 8 is the amino acid sequence of a variant of human IGF-1 w ith deletion of residues 68-70 (IGF1 3X).4ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0027] SEQ ID NO: 9 is the amino acid sequence of wild type human annexin A5 (AnxV).

[0028] SEQ ID NO: 10 is the amino acid sequence of a variant of wild-type human annexin 5 comprising the amino acids 2-320 of wild type annexin 5 and the R63A. K70A. KI 01 A, E138A, D139G, N160A and C316A substitutions.

[0029] SEQ ID NO: 11 is the amino acid sequence of non-internalizing variant of human annexin A5 (ni-AnxV).

[0030] SEQ ID NO: 12 is the amino acid sequence of wild type Human Serum Albumin (HS A).

[0031] SEQ ID NO: 13 is the amino acid sequence of Human Serum Albumin variant mHSA (C34S, N503Q substitutions).

[0032] SEQ ID NO: 14 is the amino acid sequence of Human Serum Albumin variant mHSA7 (C34S, N503Q, E505G and V547A substitutions).

[0033] SEQ ID NO: 15 is the amino acid sequence of a variant human serum albumin comprising the amino acids 26-609 of wild ty pe human serum albumin and the C58S and N527Q substitutions.

[0034] SEQ ID NO: 16 is the amino acid sequence of a peptide linker.

[0035] SEQ ID NO: 17 is the amino acid sequence of human transferrin (Tf).

[0036] SEQ ID NO: 18 is the amino acid sequence of Human Alpha Fetoprotein (AFP).

[0037] SEQ ID NO: 19 is the amino acid sequence of Human Vitamin D Binding Protein (VDBP).

[0038] SEQ ID NO: 20 is the amino acid sequence of Human Transthyretin (TTR).

[0100] SEQ ID NO: 21 is the amino acid sequence of a motif PASylati on.

[0101] SEQ ID NO: 22 is the amino acid sequence of the albumin-binding domain human antibody (aldudAB).

[0039] SEQ ID NO: 23 is the amino acid sequence of a peptide linker lk7.

[0040] SEQ ID NO: 24 is the amino acid sequence of chimeric protein scp776.

[0041] SEQ ID NO: 25 is the amino acid sequence of chimeric protein IGF 1 (E3R / Y31 A)_lk7_HS A26-609(C58S / N527Q)_lk7_AnxV2-320(R63 A / K70A / K101 A / E 138 A / D 139G / N 160A / C316S).BRIEF DESCRIPTION OF THE DRAWINGS5ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0042] Figure 1A and Figure IB. Design of the IGF-1 Fusion Protein Scp776 and Selective Targeting of Scp776 to Injured Cells. Figure 1A. Scp776 is comprised of human recombinant IGF-1 fused to a serum albumin backbone that results in an extended half-life. A terminal Annexin V binds phosphatidylserine (PS) on the surface of apoptotic cells, thereby targeting scp776 to injured cells. On healthy cells, phosphatidylserine (PS) is primarily distributed on the inner membrane leaflet. On apoptotic cells, PS is redistributed to the outer leaflet. Scp776 selectively interacts with PS exposed on the outer surface of apoptotic cells, enabling targeting of IGF-1 to IGF-1 receptors (IGF-1R) on injured cells. Figure IB. The activation by scp776 of the IGF-1R pro-survival signaling pathway, as measured by phosphorylation of AKT, is over 100-fold more potent in apoptotic cardiomyocytes than in healthy cells. The selectivity of scp776 for apoptotic CMs is quantified by comparison of the EC50’s in healthy CMs and in apoptotic CMs (82.4 nM vs. 0.77 nM indicated by vertical dotted lines), resulting in a pAKT potency shift of 107-fold.

[0043] Figure 2. Study Design in Scp776 Phase 1 Studies. Cohort and dosing regimen for the phase la sequential single dose study, and the phase lb single and multiple dose study.

[0044] Figures 3A and Figures 3B. Mean Serum Concentration-Time Profiles. Semi-log scale for scp776 concentration versus time following single doses in adult males (Phase la) (Figure 3 A) and following single and multiple doses in adult males and females (Phase lb) (Figure 3B).

[0045] Figure 4A and Figure 4B. Adaptive Dextrose Supplementation in Study lb. Figure 4A: Supplemental dextrose administration over time by Cohort. Figure 4B: Histograms for the frequency of rate adjustments made in Cohorts 1-3 versus 4-6.

[0046] Figure 5A, Figure 5B and Figure 5C. Blood Glucose Levels with and Without IV Dextrose Supplementation After Single or First Doses of 2 and 4 mg / kg scp776. Subjects received either 2 mg / kg (Figure 5A) or 4 mg / kg (Figure 5B) scp776 and blood glucose was monitored every 30 minutes. The first 6 hours of data post-IV dose are shown for individual subjects (colored circles) and group means (connected lines). Blood glucose monitoring results from phase la and phase lb participants are shown in orange and blue, respectively. Figure 5C: Impact of supplemental dextrose infusions on glycemic control during the first 24 hours after 4 mg / kg scp776 administrations. Blood glucose levels in the 24 hours following 4 mg / kg scp776 doses from both studies were compared. The blood glucose area above the 75 mg / dL cutoff was determined for each subject and was defined as the eugly cemic area (area with normal blood6ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 glucose concentrations). Data are depicted as box and whiskers with the box boundaries representing the 1st and 3rd quartiles, the line representing the median, and the whiskers at the minimum and maximum values. Administration of scp776 with adaptive supplemental dextrose infusions significantly increased the median eugly cemic area compared to no dextrose infusions (p=0.0034; Kruskal-Wallis test with Dunn multiple comparisons), indicating improved maintenance of normal blood glucose levels in the phase lb study.

[0047] Figure 6: Flow of healthy participants in phase 1 studies of scp776

[0048] Figure 7A and Figure 7B Dose Proportionality Analysis of Scp776 PK Parameters (phasela and phase lb, Combined Analysis). Figure 7A; AUCO-infas a function of total scp776 dose. Figure 7B: Cmax as a function of single or Day 1 scp776 dose. Best fit slopes and 95% confidence intervals of the slopes are depicted as lines and dotted lines, respectively. Slope (95% confidence intervals) and r-squared values are indicated at the bottoms of the graphs.

[0049] Figure 8: Linear Regression Slopes of Blood Glucose Concentrations Over Time for Placebo and Scp776 Dose groups from the Phasela Study. Blood glucose values over time from the first 3.5 hours following dosing (until mealtime) were fit for each participant by linear regression. Lines shown represent means ± SD for each group. The resultant slopes grouped by cohort and a pooled placebo group were analyzed by one-way ANOVA with multiple comparisons between all groups. No significant differences were observed between the placebo group and 1, 2, and 4 mg / kg single dose groups.

[0050] Figure 9: Blood Glucose Concentrations in Serum. Blood glucose (BG) concentrations for the first 6 hours after saline control or scp776 injections by dose level in the phase la (•, dotted line) and phase lb (A, solid line) studies.

[0051] Figure 10: Individual Dextrose Administration Rates in the Phase lb Study.

[0052] Figure 11: Time-Matched Baseline-Adjusted Blood Glucose Levels Versus Serum Scp776 Concentrations Following Single and Multiple IV Scp776 Doses (Phase lb Study). Linear regression gave a slope of 0.220 (95% CL 0. 129 - 0.311) and an R2 value of 0. 100.

[0053] Figure 12: Time-Matched Baseline-Adjusted Heart Rates Versus Serum Scp776 Concentrations Following Single and Multiple Scp776 Doses (Phase lb Study). Linear regression gave a slope of 0.0666 (95% CL 0.0158 - 0.117) and an R2 value of 0.0328.

[0054] Figure 13: Time-Matched Coagulation Parameters (PT, PT / INR, PTT) Versus Serum Scp776 Concentrations Following Multiple Doses (Phase lb Study, Cohorts 5 and 6).7ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0055] Figure 14: Pharmacokinetic Parameters Following Multiple Scp776 Doses in Adults per Day and Overall (Phase lb, Cohorts 3-6).

[0056] Figure 15: Phase 2 study design, primary objective, Key efficacy endpoints and Key enrollment criteria.

[0057] Figure 16A and Figure 16B: Hot clot lysis assay-Rat whole blood

[0058] Figure 17: Scp776 ± tPA PK in Cynomolgus Monkeys

[0059] Figure 18A and Figure 18B: Phosphatidylserine binding assay.

[0060] Figure 19A is a graph showing blood weight loss. Figure 19B is a graph showing step bleeding time. Figure 19C is a summary table showing experimental conditions.

[0061] Figure 20 is a schematic showing the IGF-1 for apoptotic escape.

[0062] Figure 21 are graphs showing improved outcomes in a Non-Human Primate Clip Model of MCA Stroke.

[0063] Figure 22 is a flowchart of the results of the Phase 2a study.

[0064] Figure 23 is a table showing the overall baseline characteristics.

[0065] Figure 24 is a table show ing the primary safety TEAEs results.

[0066] Figure 25 is a table showing the primary' safety AESIs results.

[0067] Figure 26 is a table showing the primary' safety AESIs results.

[0068] Figure 27 are graphs showing Key Efficacy results NIHSS at Discharge / Day 7.

[0069] Figure 28 are graphs showing Key Efficacy results Final infarct volume.

[0070] Figure 29 is a graph showing Exploratory Efficacy Day 90 mRS.

[0071] Figure 30 is a graph showing the quantification of scp776 localization to rat brain tissue rat tMCAO filament model of ischemic stroke.

[0072] Figure 31A is an image of a histological section of rat brain stained for the presence of apoptotic nuclei with TUNEL staining after 3 hours of tMCAO occlusion and 3 hours of reperfusion at 16x magnification. Figure 31B is a zoomed in view' of the same TUNEL-stained section in figure 31A at 400x magnification. Figure 31C is an image of a histological section of rat brain stained for the presence of scp776 in the same animal shown in figures 31A and 31B. Figure 31D is a zoomed in view of the same anti-scp776 stained section in figure 31C at8ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025400x magnification. The boxes in Figures 31A and 31C indicate the zoomed in regions visible at higher magnification in Figures 31B and 3 ID.

[0073] Figure 32 is a graph showing the longitudinal NIHSS scores over Days 1-7 postrandomization for subjects treated with scp776 (scp776 Selected Dose) and control group (Placebo).DETAILED DESCRIPTION

[0074] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments of the disclosure only and is not intended to be limiting.

[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the disclosure pertains.

[0076] All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.Definitions

[0077] As used in this specification and the appended claims, the singular forms "a, "an" and "the" include plural referents unless the content clearly dictates otherwise.

[0078] The term “peptide,” “polypeptide” and “protein” are used interchangeably to denote a sequence polymer of at least two amino acids covalently linked by an amide bond (also referred herein as peptide bond).

[0079] As used herein the term “target molecule” refers to any molecule that is associated with a tissue (e.g. “at risk”, diseased or damaged tissue). A “target cell” is meant to be a cell to which a protein or targeting domain thereof can specifically bind.

[0080] “Binding” or “specific binding” are used interchangeably herein and indicates that a protein (or the targeting polypeptide domain thereof or the activator domain thereof) exhibits substantial affinity for a specific molecule (e.g., targeting domain exhibits substantial affinity for a target molecule, or an activator domain exhibits substantial affinity for a molecule associated with the surface of a cell such as a growth factor receptor) or a cell or tissue bearing the molecule and is said to occur when the protein (or the targeting polypeptide domain thereof or the activator domain thereof) has a substantial affinity for a specific molecule and is selective in that it does not exhibit significant cross-reactivity with other molecules.9ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0081] "Identity." as known in the art, is a relationship between two or more polypeptide or protein sequences, as determined by comparing the sequences. In the art, "identity" also refers to the degree of sequence relatedness between polypeptides or proteins, as determined by the match between strings of such sequences. "Identity" can be readily calculated by any bioinformational methods known in the art.

[0082] The term "parent polypeptide" refers to a wild-type polypeptide and the amino acid sequence or nucleotide sequence of the wild-type polypeptide is part of a publicly accessible protein database (e.g., EMBL Nucleotide Sequence Database, NCBI Entrez, ExPasy, Protein Data Bank and the like).

[0083] The term "mutant polypeptide" or "polypeptide variant" refers to a form of a polypeptide, wherein its amino acid sequence differs from the amino acid sequence of its corresponding wild-type (parent) form, naturally existing form or any other parent form. A mutant polypeptide can contain one or more mutations, e.g.. substitution, insertion, deletion, addition etc. ..which result in the mutant polypeptide. Generally, variants are overall closely similar, and, in many regions, identical to the reference polypeptide. As used herein, “variant” refers to a polypeptide, differing in sequence from a native protein but retaining at least one functional and / or therapeutic property thereof as described elsewhere herein or otherwise known in the art.

[0084] The term "corresponding to a parent polypeptide" is used to describe a polypeptide of the disclosure, wherein the amino acid sequence of the polypeptide differs from the amino acid sequence of the corresponding parent polypeptide only by the presence of at least one amino acid variation. Typically, the amino acid sequences of the variant polypeptide and the parent polypeptide exhibit a high percentage of identity. In one example, "corresponding to a parent polypeptide" means that the amino acid sequence of the variant polypeptide has at least about 50% identity, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% identity or at least about 99% identity to the amino acid sequence of the parent polypeptide. In another example, the nucleic acid sequence that encodes the variant polypeptide has at least about 50% identity7, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at10ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 least about 95%, at least about 96%. at least about 97%, at least about 98% identity or at least about 99% identity to the nucleic acid sequence encoding the parent polypeptide.

[0085] The term ‘"substantial identity’7or “substantial similarity,” as used herein, when referring to a nucleic acid or fragment thereof, indicates that when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95% to 99% of the sequence. The term “substantial identity” or “substantial similarity,” as used herein, when referring to a protein or fragment thereof, indicates that when optimally aligned there is an amino acid sequence identity in at least about 95% to 99% of the sequence.

[0086] The term “damaged cell” or "damaged tissue," as used herein, means and includes biological cell or tissue; for example, but not limited to, neurons, glia or nervous tissue damaged or injured by, but not limited to, trauma or chemical insult, ischemic tissue, cell or tissue damaged by any means which results in intermption of normal blood flow to the tissue.

[0087] The term “therapeutically effective amount,” as used herein, means the amount of the protein or agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0088] The term “pharmaceutically acceptable,” or “physiologically acceptable” as used herein, means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0089] The term "targeting moiety", “targeting domain,” “targeting polypeptide” or “targeting module” are used herein interchangeably and refer to molecules that selectively localize the chimeric protein in a particular tissue or region of the body. The localization can be mediated by specific recognition of molecular determinants, molecular size of the targeting domain, ionic interactions, hydrophobic interactions and the like. As used herein, the terms "therapeutic moiety," “activator domain,” “activator polypeptide”, “signaling arm” and “effector module” are used herein interchangeably and refers to any agents useful for therapy and that are nontoxic, do not have a cytotoxic effect or are not detrimental to the cells. Such agents can include, but not limited to, growth factors.

[0090] A “patient” or a “subject” is a mammal, preferably a human. The term “treating” (or “treat” or “treatment”) means slowing, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease.11ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0091] The term “therapeutically effective amount’" refers to the amount or dose of chimeric proteins described herein which, upon single or multiple dose administration to a patient, provides the desired treatment.

[0092] As used herein, the term "physiologically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the bi-specific fusion protein is administered. Physiologically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, or sesame oil). Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water and ethanol. The pharmaceutical composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0093] Like insulin, endogenous IGF-1 has known blood glucose lowering effects, which is a demonstrated dose limiting toxicity of exogenously administered IGF-1. Endogenous IGF-1, which shares approximately 50% of the amino acid sequencing of insulin, has broad systemic metabolic and homeostasis effects in the body. Its direct effects on glucose metabolism are mediated through pancreatic insulin secretion and increased glucose uptake by muscle tissue due to increased insulin sensitivity. When administered to severely insulin resistant diabetic patients, IGF-1 improved glucose levels, but also resulted in significant systemic adverse events at doses required for these therapeutic effects.IGF-1 Chimeric Proteins

[0094] Chimeric proteins provided herein are capable of specific binding to two or more different specific molecules. In some embodiments, the chimeric protein comprises a targeting domain having a binding specificity to a first specific target molecule, an activator domain having a binding specificity to a second target molecule, and a half-life modulator.

[0095] In some aspects, the activator domain has a binding specificity to a tyrosine kinase receptor at the cell surface. In some embodiments, the binding of the activator to the tyrosine12ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 kinase receptor activates intracellular signaling pathways associated with cell survival. In some aspects, the activator domain has a binding specificity to a receptor that modulates / promotes tissue regeneration.

[0096] In some embodiments, the targeting domain serves to target the chimeric protein to a target cell or tissue while the activator domain serves to activate the intracellular signaling pathway associated with cell survival.

[0097] In some embodiments, the half-life modulator extends the half-life of the chimeric protein.

[0098] In some embodiments, the chimeric proteins are fusion proteins having a targeting polypeptide connected or linked to a half-life modulator and to an activator polypeptide. In some embodiments, the engineered proteins are chimeric proteins having a targeting polypeptide connected or linked to a half-life modulator and a growth factor or mutated growth factor.

[0099] In some embodiments, the mutated grow th factor (e.g. IGF-1 variant) is engineered to reduce potency while retaining the ability to activate the cognate growth factor receptor. In some embodiments, wild type growth factors can be used as activator domains.

[0100] The targeting domain is generally used to target the chimeric proteins to a target cell. In some embodiments the target cell is undergoing apoptosis. The binding of the targeting domain to its target molecule does not induce a significant biological effect in the target cell. The activator domain binds to a receptor on a cell surface. The binding of the activator domain to its receptor is intended to modulate a specific biological effect, such as, activate the intracellular signaling pathway associated with cell survival. In some embodiments, binding of the activator domain to its receptor is intended the positively regulate survival of the targeted cells or tissue. In particular, the activator domain of chimeric protein can promote survival signaling.

[0101] In some embodiments, the in vivo activity of the chimeric protein can be assessed by detecting signaling changes in molecules that are regulated by the activator domain, including but not limited to cell surface receptor phosphorylation status or downstream mediators such as phospho-AKT or phospho-ERK (as detected by flow cytometry, immunofluorescence, ELISA, phospho-labeling, Western analysis of treated tissues, or any other methodology known in the art.) In some embodiments, a chimeric protein functions in13ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 vivo if it induces a significant (e.g.. at least 10%. at least 20%, at least 30%, at least 40%, at least 50% or more) change in the level, functional activity, or phosphorylation of the regulated molecule detected by the assay.Activator Domain

[0102] The activator domain can be any polypeptide that detectably modulates the activity of a cellular network. In some embodiments, the activator domain is capable of activating signal transduction pathways by binding to a receptor at the surface a cell. In some embodiments, certain activator domains are growth factor polypeptides, or any agonist of the receptor. It will be apparent that such modulation may be an increase in the activity of the cellular network such as induction of proliferation of cells, induction of cell growth, promotion of cell survival and / or inhibition of apoptosis.

[0103] During acute injury, cells have 3 fates: survival, apoptosis, or necrosis. Some injured cells can naturally avoid cell death via a mechanism called apoptosis escape. Enhancement of apoptosis escape after an acute injury’ leads to improved cell survival and preserved organ function. Growth factors have the potential to promote cell and tissue survival by enhancing apoptosis escape.

[0104] An activator domain for a particular application may be selected based on the desired therapeutic outcome. For example, to increase survival and neuroprotection, activator domains that comprise IGF-1 (or variant or fragment thereof) can be used.

[0105] In some embodiments, the activator domain comprises a change in the amino acid sequence, the three-dimensional structure of the protein, and / or the activity' of the protein, relative to the wild-type form of the protein.

[0106] In some embodiments, the activator domain comprises or consists of a growth factor having amino acid sequence modification relative to the wild-type growth factor (e.g. IGF-1) to decrease its binding to its natural receptor (e.g. IGF-1 receptor), to decrease its binding to binding proteins (e.g. IGF binding proteins) and / or decrease its activation of its natural receptor (e.g. IGF-1 receptor). In some embodiments, the activator domain is a growth factor having amino acid sequence modification that reduce (e.g., for about 1- 5%, 5-10%, 10%-20%, about 20%-40%, about 50%, about 40%-60%, about 60%-80%, about 80%-90%, 90-95%) the binding to its natural receptor (e.g. IGF-1 receptor).14ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0107] A growth factor polypeptide detectably modulates activation of a growth factor receptor. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retains at least about 0.01 % of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retain at least about 0.1 %, at least about 1%, at least about 10%, of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retains between about 0.01% to about 0.1% of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retains between about 0.01% to about 1% of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retains between about 0.01% to about 10% of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retains between about 0. 1% to about 1% of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a growth factor, variant or fragment thereof that retains betw een about 0.1% to about 10% of wild-type biological activity. In some embodiments, the activator domain of the bi-specific protein is a grow th factor, variant or fragment thereof that retains between about 01% to about 10% of wild- type biological activity. Biological activity in some embodiments can be determined by measuring activation of the corresponding growth factor receptor in appropriate cells. In some embodiments, activation may be assessed, for example, by measuring phosphorylation of receptor kinase or downstream effector proteins, such as, but not limited to, AKT, S6, ERK, JNK. mTOR, etc.Insulin-like growth factors (IGFs) and derivatives thereof

[0108] The insulin-like growth factors (IGFs) constitute a family of proteins having insulin-like and growth stimulating properties. The IGFs Human IGF-1 is a 70 amino acids basic peptide having the protein shown in SEQ ID NO: 1, respectively. IGF-1 and extracellular tyrosine kinase receptor (e.g. IGF-1 receptor) are important for cellular processes such as cell proliferation and survival. Binding of IGF-1 or variant thereof to the IGF-1 receptor stimulates kinase activity, leading to phosphorylation of multiple substrate, thereby initiating signaling cascades. The chimeric proteins disclosed herein can maintain the ability to signal through the extracellular receptor, for example IGF-1 receptor. The activator domain IGF-1 stimulates cell15ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 proliferation and survival through activation of the AKT pathway. Upon binding of IGF -I to the IGF-1 receptor, a tyrosine kinase, phosphorylates tyrosine residues on two major substrates, IRS-1 and She, which subsequently signal through the Ras / Raf and PI 3-kinase / AKT pathways.

[0109] The interaction of IGF-1 (and IGF-2) with the IGF-1 receptor is regulated by IGF binding Proteins (IGFBPs). All six IGFBPs (particularly IGFBP5) have been shown to inhibit IGF action, but in some instances a stimulatory' effect has been observed. At least 99% of the IGF in the circulation is normally bound to IGFBPs.

[0110] In some embodiments, the activator domain is a variant of the human IGF-1 or fragment thereof. In some embodiments, the variant of IGF-1 or fragment thereof is capable of maintaining selectivity to the IGF-1 receptor.

[0111] In some embodiments, the IGF-1 variant is modified to reduce binding to IGF- 1 binding proteins (IGFBPs) relative to wild-tj pe IGF-1 while maintaining its ability to activate the AKT pathway. In some embodiments, the IGF-1 variant can activate the IGF-1 receptor with a decreased potency for non-target cells, as assessed by pAKT EC50. EC50 is defined as the concentration needed to achieve the half maximal level of pAKT signaling.

[0112] In some embodiments, the IGF-1 variant comprises a substitution at one or more of the tyrosine residues. In some embodiments, the IGF-1 variant comprises one or more substitutions at position Y24, Y31 and Y60. In an exemplar} embodiment, the IGF-1 variant can comprise a single tyrosine substitution at position Y31, or Y24, or Y60. In an exemplary embodiment, the IGF-1 variant can comprise a single tyrosine substitution at position Y24 and Y31, Y24 and Y60, Y31 and Y60, or Y24 and Y60. In another exemplary embodiment, the IGF-1 variant can comprise one or more of the following substitutions, Y24L, Y31 A, and Y60L relative to w ild type IGF-1. For example, the IGF-1 variant can comprise the Y24L substitution and the Y31 A substitution or the IGF-1 variant can comprise the Y24L substitution, the Y31 A substitution and the Y60L. In some embodiments, one or more tyrosine residues (Y24. Y31, Y60 or combinations thereof) can be substituted for a short aliphatic amino acid. In some embodiments, one or more tyrosine residues (Y24, Y31, Y60 or combinations thereof) can be substituted for a polar amino acid. In some embodiments, one or more tyrosine residues (Y24, Y31, Y60 or combinations thereof) can be substituted for leucine, alanine, isoleucine, serine, threonine or any other amino acid.

[0113] In some embodiments, the IGF-1 variant comprises a substitution replacing Arg for a Glu, Lys, Met, Vai, Ala, Leu, He, Gly, Ser, or Thr at the 3 position of the polypeptide. In16ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 some embodiments, the IGF-1 variant comprises a substitution replacing Arg for a Glu at the 3 position of the polypeptide (E3R).

[0114] In some embodiments, the IGF-1 variant comprises a substitution at the position 3 and 31. For example, the IGF-1 variant comprises E3R and Y31A substitutions. In some embodiments, the activator domain has an amino acid sequence having SEQ ID NO: 2.

[0115] In some embodiments, the activator domain is a derivative of the human IGF-1 comprising one or more of the following modifications: a N-terminal 13-residue extension (IGF-1 LONG), a deletion of amino acids 1-3 (Des-1-3), a substitution replacing Arg for a Glu at the 3 position of the polypeptide (E3R), no Arginine at position 37 (R37X), a deletion of amino acids 68-70 (3X), an N-terminal 13-residue extension and a substitution replacing Arg for a Glu at the 3 position of the wild -type polypeptide (LR3), substitutions of one or more of tyrosine residues (Y24, Y31, Y60 or combinations thereof (e.g. Y24L, Y31A, Y60L substitutions or combinations thereof).

[0116] In some embodiments, the activator domain is variant of the human IGF-1 comprising a mutation (e.g. substitution, deletion) at one or more residues 24 to 37.

[0117] In some embodiments, the activator domain is a derivative of the human IGF-1 and comprises an N-terminal 13-residue extension (also referred as IGF-1 LONG, SEQ ID NO: 3), a mutation E3R (SEQ ID NO: 4) or a combination thereof (LONG E3R, also referred as LR3, SEQ ID NO: 6). In some embodiments, the IGF-1 variant comprises the E3R substitution, an N-terminal 13-residue extension, deletion of amino acids 1-3 ((Desl-3), SEQ ID NO: 5) or a combination thereof to decrease the binding of the activator domain to the IGF binding proteins which are present in the serum and other body fluid.

[0118] In some embodiments, the activator domain is a derivative of the human IGF-1 and comprises one or more of the following modifications: an N-terminal 13-residue extension (SEQ ID NO: 3), a deletion of amino acids 1-3 (SEQ ID NO: 5), a substitution replacing Arg for a Glu at the 3 position of the polypeptide (SEQ ID NO: 4), no Arginine at position 37 (R37X, SEQ ID NO: 7), a deletion of amino acids 68-70 (3X, SEQ ID NO: 8), or an N-terminal 13-residue extension and a substitution replacing Arg for a Glu at the 3 position of the wild - ty pe polypeptide (SEQ ID NO: 6).

[0119] It is believed that the bi-specific proteins that contain the variant of IGF-1 described herein (e.g. E3R, IGF-1 LONG, IGF-1 LONG E3R (referred to as IGF-1(LR3)) or17ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025IGF1 Desl-3), have decreased affinity for IGF binding proteins relative to wild-type IGF-1. In some embodiments, the IGF-1 variants of the bi-specific proteins described herein can activate the signaling pathway while having a substantially decreased interaction with the IGF-1 binding proteins relative to wild-type IGF-1.

[0120] In some embodiments, the IGF-1 variant can be modified by glycosylation of one or more glycosylation site present in the IGF-1 variant.

[0121] In some embodiments, the chimeric proteins that contain the IGF-1 variants described herein have a potency for non-target cells that is less than wild-type IGF-1 for nontarget cells.

[0122] Certain activator domains that bind to growth factor receptors are provided herein in SEQ ID NOs: 1-8.

[0123] Additional peptide sequence modifications can be included, such as variations, deletions, substitutions or derivatizations of the amino acid sequence of the sequences disclosed herein, so long as the peptide has substantially the same activity or function as the unmodified peptides. Notably, a modified peptide will retain activity' or function associated with the unmodified peptide, the modified peptide will generally have an amino acid sequence “substantially homologous” with the amino acid sequence of the unmodified sequence.

[0124] In some embodiments, the IGF-1 variant can have an amino acid sequence having at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 97%, at least about 98% identity or at least about 99% identity to the amino acid sequence provided in SEQ ID NOs: 1- 8. In some embodiments, the IGF-1 variant can have an amino acid sequence having from about 85% to about 90%, from about 90% to about 95%, from about 95% to about 98%, from about 98% identity' to about 99% identity' to the amino acid sequence provided in SEQ ID NOs: 1-8. In some embodiments, the IGF-1 variant can comprise 10, 20, 30, 40, 50, 60 or more consecutive amino acids of any one of amino acids in SEQ ID NOs: 1-8. In some embodiments, the IGF-1 variant can have an ammo acid sequence recited in any one of SEQ ID NOs: 1-8. In some embodiments, the IGF-1 variant can have an amino acid sequence recited in any one of SEQ ID NOs: 2-8 In some embodiments, the IGF-1 variant can have an amino acid sequence recited in SEQ ID NO: 2.18ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0125] In some embodiments, the bi-specific protein comprises an activator domain having a growth factor variant such as an IGF-1 variant that is selected to give the bi-specific protein at least an order of magnitude lower EC50 in damaged tissue than in healthy tissue. For example, the bi-specific protein domain comprises a growth factor variant such as an IGF-1 variant and has an EC50 in damaged tissue that is at least 10 times lower, at least 15 times lower, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times low er, at least 65 times low er, at least 70 times lower, at least 75 times lower, at least 80 times lower, at least 85 times lower, at least 90 times lower, at least 95 times lower, at least 100 times lower, at least 110 times lower than the EC50 in healthy tissue.

[0126] In some embodiments, the bi-specific proteins that contain the IGF-1 variants have a half maximal effective concentration (EC50) that is lower in damaged tissue than in healthy tissue. In some embodiments, the bi-specific proteins that contain the IGF-1 variants have a half maximal effective concentration (EC50) that is at least 10 times lower, at least 15 times low er, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times lower, at least 65 times lower, at least 70 times lower, at least 75 times lower. at least 80 times lower. at least 85 times lower, at least 90 times low er, at least 95 times low er, at least 100 times lower, at least 110 times lower in damaged tissue than in healthy tissue.

[0127] In some embodiments, the chimeric proteins provided herein having such variant growth factors have a higher specificity to the damaged tissue targeted.Target molecules

[0102] In some aspects, target molecules are exposed or enriched on the exterior of a target cell. In some embodiments, the target molecule is associated with a damaged cell, early apoptotic or apoptotic cell, the target molecule being intracellular in a viable or undamaged cell and being exposed to the extracellular space in a damaged cell. Such molecules include, for example, molecules that are exposed in cells that undergo necrosis (such as DNA) or apoptosis (e.g., phosphatidylserme), myosin (including the tissue type-specific subtypes thereof), ICAM-1 or P-selectin. Yet in other embodiments, the target molecule is a molecule that is present or enriched at the surface of a diseased or dysfunctional cell or tissue as19ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 compared to the level detected in a healthy or functional cell or tissue. In some embodiments, the target cell is not a tumor or cancerous cell.

[0103] Cells are bounded by a plasma membrane (or cell membrane) comprising a lipid bilayer. The cell membrane may be considered to have a surface facing the cytosol (cytosolic side or interior of the cell) and a surface facing the exterior of the cell, or the extracellular space. Trans-bilayer movement of anionic phospholipids from the inner to the outer leaflet of the plasma membrane occurs during apoptosis. The anionic phospholipid-binding protein, such as Annexin A5, synaptotagmin I or lactadherin can be used to detect the presence of phosphatidyl serine on the outer leaflet of the cell membrane. Phosphatidyl serine is a phospholipid, that is usually restricted to the cytosolic side of the membrane in viable or undamaged cells, and that becomes exposed on the outer cell surface or to the extracellular space in damaged cells or apoptosis.

[0104] In some embodiments, the target molecule is an "‘ischemia-associated molecule7’. An "ischemia-associated molecule" is any molecule that is detected at a level that is significantly higher (e.g., at least 1.5 higher, at least 2-fold higher, at least 3-fold higher, at least 4-fold higher, at least 5-fold higher) following ischemia (which results in hypoxia) or hypoxia than in a cell of the same tissue that has not undergone an ischemic event (i.e., the molecule is specific to or enriched in the post-ischemic tissue). Ischemia occurs when there is insufficient blood flow to provide adequate oxygenation, which results in tissue hypoxia (reduced oxygen) or anoxia (absence of oxygen) as the most severe form of hypoxia, and ultimately tissue necrosis, and apoptosis.Targeting Domain

[0105] In some embodiments, the targeting domain has a specific binding affinity to a target molecule associated with a tissue (for example, an ischemia-associated molecule). In some embodiments, the targeting domain has a specific binding affinity for a target molecule presented on the surface of early apoptotic cells. The targeting domain may be any polypeptide sequence that serves this function. In some embodiments, binding of the targeting domain to the target molecule does not have or does not modulate a biological activity. As used herein, “biological activity” refers to a defined, known activity performed by exposure of a molecule to a domain of the protein.

[0106] In some embodiments, the targeting domain can be a non-antibody polypeptide, fragment thereof or variant thereof having a binding affinity' to the target molecule. Yet in 20ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 other embodiments, the targeting polypeptide domain comprises one or more antibody variable regions (e.g. scFv).Annexin A 5 and variants thereof

[0128] In some embodiments, the targeting domain comprises annexin, a variant thereof or a fragment thereof. The term "annexin" refers to any protein capable of binding to phospholipids, especially phosphatidylserine (PS), and member of the annexin family. In some embodiments, the annexin is Annexin A5 but other annexins can equally be used. In some embodiments, the targeting domain is human Annexin A5, a functional fragment thereof, or a variant thereof. A variant of Annexin A5 comprises at least one amino acid in at least one position in which this amino acid is not found in the parent wild type Annexin A5 polypeptide (SEQ ID NO: 9). The annexin variants according may comprise one or more amino acid substitutions, deletions, additions, or combinations thereof wherein the amino acid substitutions, deletions, or additions do not substantially affect the ability of the Annexin A5 variant of the chimeric protein to bind to at least one phospholipid, such as PS. In some embodiments, the Annexin A5 variant can have an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 98% identity or at least about 99% identity to the amino acid sequence provided in SEQ ID NO: 9. In some embodiments, the Annexin A5 variant can comprise 50, 80, 100, 110, 200, 300, or more consecutive amino acid having at least about 85%, at least about 90%, at least about 95%, at least about 98% identity or at least about 99% identity to the amino acids in SEQ ID NO: 9.

[0129] In some embodiments, the variant of Annexin A5 is modified to substitute cysteine at position 315 (corresponding to C316) with serine or alanine to reduce dimer formation. For example, the cysteine can be substituted to an alanine or a serine. As used herein, the term "corresponding to" is used to designate the position / identity of an amino acid residue in a polypeptide (e.g., Annexin A5). Those of ordinary skill will appreciate that, for purposes of simplicity, a canonical numbering system (based on wild-type Annexin A5) is utilized herein, so that an amino acid "corresponding to" a residue at position 316, for example, need not actually be the 316th amino acid in a particular amino acid chain but rather corresponds to the residue found at position 316 in a for example Annexin A5 before the post- translational removal of the N-terminal methionine; those of ordinary7skill in the art readily appreciate how to identify corresponding amino acids. In particular, it is noted that the amino21ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 acid sequence of wild-type Annexin A5 (SEQ ID NO: 9) do not start with a Methionine as the Methionine residue is cleaved during processing.

[0130] In some embodiments, the variant of Annexin A5 has an amino acid sequences that has been mutated to reduce internalization of Annexin A5 or the chimeric protein comprising the variant of Annexin A5 into a cell while maintaining binding affinity7to phosphatidylserine (PS). In some embodiments, the variant of Annexin A5 or the chimeric protein comprising the variant of Annexin A5 has a binding affinity to phosphatidylserine, and is not internalized into a cell or is internalized at a slower rate than wild-type annexin A5. In some embodiments, the targeting domain is a non-intemalizing variant of Annexin A5, (also referred as ni-Annexin A5 or ni-AnxV, SEQ ID NO: 11). In some embodiments, the variant of Annexin A5 has an amino acid set forth in SEQ ID NO: 10. In some embodiments, the non- intemalizing mutant of Annexin A5 has an ammo acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 98% identity or at least about 99% identity to the amino acid sequence provided in SEQ ID NO: 11. In some embodiments, the noninternalizing mutant of Annexin A5 can have an amino acid sequence having from about 85% to about 90%, from about 90% to about 95%, from about 95% to about 98%. from about 98% to about 99% identity to the amino acid sequence provided in SEQ ID NO: 11. In some embodiments, the Annexin A5 variant can comprise 50, 80, 100, 110, 200, 300, or more consecutive amino acid of any one of amino acids in SEQ ID NO: 11. Any variation of Annexin A5 that results in substantially no internalization is envisioned.

[0131] It should be appreciated that the non-intemalizing variant of annexin A5 can confer an extended half-life to the chimeric protein as compared to a chimeric protein that contains wild-type A5. In some embodiments, the variants of annexin A5 that results in substantially no internalization, or chimeric proteins containing variants of annexin A5 that results in substantially no internalization, can have an extended half-life of 1.1 to 1.2, 1.1 to 1.3, 1.1. to 1.4, 1.1 to 1.5. 1.1 to 1.6, 1.1 to 1.7, 1.1 to 1.8, 1.1 to 1.9, 1.1 to 2 or greater as compared to wild-type annexin A5, or chimeric proteins containing wild-type annexin A5.

[0132] The terms “non-intemalizing” and "substantially no internalization." as used herein, refer to alack of internalization of a substantial amount of the chimeric protein disclosed herein. For example, the phrase "substantially no internalization" will be understood as less than 50% of the chimeric protein being internalized by a cell to which the chimeric protein is bound, or less than 25% of the chimeric protein being internalized by a cell to which the22ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 chimeric protein is bound, or less than 10% of the chimeric protein being internalized by a cell to which the chimeric protein is bound, or less than 5% of the chimeric protein being internalized by a cell to which the chimeric protein is bound, or less than 3% of the chimeric protein being internalized by a cell to which the chimeric protein is bound, or less than 1 % of the chimeric protein being internalized by a cell to which the bi-specific protein is bound.

[0133] In some embodiments, the non-internalizing mutant of Annexin A5 can have an amino acid sequence having at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% identity7or at least about 99% identity to human Annexin A5. In some embodiments, the non-intemalizing variant of Annexin A5 comprises a substitution at position 315 (corresponding to C316) wherein the cysteine residue is substituted with serine (Ser), alanine (Ala), leucine (Leu), phenylalanine (Phe), methionine (Met) or tryptophan (Trp). In some embodiments, the non-intemalizing mutant of Annexin A5 can have an amino acid sequence having at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%. at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% identity7or at least about 99% identity7to human Annexin A5. In some embodiments, the non-intemalizing variant of Annexin A5 comprises a substitution at position 315 (corresponding to C316) wherein the cysteine residue is substituted with serine (Ser) or alanine (Ala). In some embodiments, the non-intemalizing mutant of Annexin A5 can have an amino acid sequence having at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% identity7or at least about 99% identity to human Annexin A5 modified to substitute cysteine at position 315 (corresponding to C316) with serine or alanine.

[0134] In some embodiments. Annexin A5 or Annexin A5 variants (for example variant having a substitution at position C316) are modified to comprise one or more substitutions at the following positions: R62, K69, K.100, E137, D138, N159, L313 (corresponding to R63, K70, K101, E138, D139, N160, L314 relative to wild type human Annexin A5).

[0135] In some embodiments, the Annexin A5 variant comprises:23ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025R62A, R62E, R62D, R62M. R62L, R62I, R62Y (corresponding to R63A. R63E, R63D, R63M, R63L, R63I, R63Y relative to wild type human Annexin A5);K69A, K69E, K69D, K69M, K69L, K69I, K69Y (corresponding to K70A, K70E, K70D, K70M, K70L, K70I, K70Y relative to wild type human Annexin A5);E137A. E137K, E137R, E137M, E137L, E137I, E137Y (E138A, E138K, E138R, E138M, E138L, E1381, E138Y relative to wild type human Annexin A5);D138G, D138K, D138R, D138M, D138L, D138I, D138Y (corresponding to D139G, D139K, D139R, D139M, D139L, D139I, D139Y relative to wild type human Annexin A5)N159A, N160M, N160L, N160I, N160V, N160Y (corresponding to N160A, N160M, N 160L, N 1601, N 160V, N 160Y relative to wild type human Annexin A5)L313E L313D, L313K, L313R, L313H, L313Q, L313N, L313Y (corresponding to L314E L314D, L314K, L314R, L314H, L314Q, L314N, L314Y relative to wild type human Annexin A5); or any combinations of the foregoing.

[0136] In some embodiments. Annexin A5 or Annexin A5 variants comprise one or more substitutions at position D143 and / or E227. In some embodiments, Annexin A5 variant comprises:D142G, D142A, D142K, or D142R (corresponding to D143G, D143A, D143K, or D143R) substitution, and / orE226G, E226A, E226K, or E226R (corresponding to E227G, E227A, E227K, E227R) substitution.

[0137] In some embodiments, Annexin A5 or Annexin A5 variants (for example having a substitution at C316, D143 and / or E227) are modified to comprise one or more of the following substitutions R62A, K69A, K100A, E137A, D138G, N159A, L313E (corresponding to R63A, K70A, K101A, E138A, D139G, N160A, L314E). For example, Annexin A5 having SEQ ID NO: 9 can be modified to have C315A or C315S substitution (corresponding to C316A or C316S relative to wild type Annexin A5) and one or more of the following substitutions R62A, K69A. K100A, E137A. D138G. N159A, L313E (corresponding to R63A, K70A. K101 A, E138A, D139G, N160A, L314E relative to wild type Annexin A5).

[0138] In some embodiments, human Annexin A5 (SEQ ID NO: 9) are modified to comprise one or more of the following substitutions R62A, K69A, K100A, E137A, D138G, N159A, D143N, E227A, C315S or C315A (corresponding to R63A, K70A, K101A, E138A, D139G, D144N, N160A, E228A, C316S or C316A relative to wild type Annexin A5).24ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0139] In some embodiments, the targeting domain is Annexin A5 which has been engineered to have R63A, K70A, K101A, E138A, D139G, N160A and C316A or C316S substitutions relative to wild type Annexin A5. For example, the targeting domain can have the amino acid sequence of SEQ ID NO: 10.

[0140] In some embodiments, the Annexin A5 variant comprises one, two, , three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen nineteen, twenty or more substitutions in different regions, in order to further decrease the internalization of the annexin in a cell. For example, the Annexin A5 variants may comprise R62A and K69A, R62A and KI 00 A, R62A and E137A, R62A and D138G, R62A and N159A, R62A and K69A and K100A, R62A and K69A and E137A, R62A, K69A and K100A, R62A, K69A, K100A, and E137A etc...

[0141] The annexin variants according may further comprise one or more amino acid substitutions, deletions, or additions, wherein the amino acid substitutions, deletions, or additions do not substantially affect the ability of the Annexin A5 variant of the chimeric protein to bind to at least one phospholipid, such as PS.

[0142] Native polypeptide can be used as targeting domains. It will be apparent, however, that portions of such native sequences and polypeptides having altered sequences may also be used, provided that such polypeptides retain the ability to bind the target molecule with an appropriate binding affinity (Kd) as described in more details below.Antibody targeting domain:

[0143] In some embodiments, an anti-phosphatidylserine antibody can be used as a targeting domain. As used herein, term ‘'antibody’’ includes but is not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) F(ab)2 and F(ab')2 fragments, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a scFv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Such antibodies may be produced from intact antibodies using methods known in the art, or may be produced recombinantly, using standard recombinant DNA and protein expression technologies.Binding of Targeting domain25ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0144] In some embodiments, the chimeric protein binds to the target molecule with a Kd of less than 10'6M, preferably less than 10'7M, 10‘8M, 10'9M or IO'10M.Half-Life Modulator

[0145] One skilled in the art would appreciate that proteins used in therapeutic applications may not exhibit optimal serum half-lives due to their relatively low molecular weight. In some therapeutic applications, it may therefore be desirable to extend the half-life of the proteins. In some embodiments, to achieve accumulation of the chimeric protein to the diseased injured or damaged area of an organ, the chimeric protein is conjugated operatively associated or fused with a half-life modulator. Preferably, the half-life modulator is non- immunogenic polypeptide.

[0146] For example, short half-life is the most limiting attribute of wild-type growth factors as therapeutics. Intravenous administered IGF-1 has a serum half-life in humans of less than 1 hour. The extended half-life of chimeric proteins disclosed herein compared to IGF- 1, for example, allows for 1) equivalent efficacy with less frequent dosing; 2) equivalent exposure at a lower dose; 3) lower Cmax at an equivalent exposure level, reducing the risk of Cmax-related toxicity.

[0147] In some embodiments, the half-life modulators can increase the in vivo half-life of the chimeric proteins. For example, the half-life of the chimeric proteins comprising the half-life modulator is about 1 hour, 2 hour, 3 hours, 4 hours, 5 hours, 6 hours or greater. For example, the half-life of the chimeric proteins can be about 8 hours or more when tested in cynomolgus monkey. In some embodiments, the half-life of the chimeric proteins comprising the half-life modulator is about 24 hours, or greater. In some embodiments, the half-life of the chimeric proteins comprising the half-life modulator is about a week or greater.

[0148] In some embodiments, the half-life modulator is non-immunogenic in humans.

[0149] In some embodiments, the half-life modulator is a polypeptide that interacts with cellular machinery' that promote evasion of lysosomal degradation pathways (e.g. - FcRn receptor-mediated recycling).

[0150] In some embodiments, the half-life modulator is designed to extend the half-life of the chimeric protein through binding to serum components such as Human Serum Albumin (HSA). HSA is the most abundant protein in the blood and has a demonstrated safety' in humans.26ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0151] In some embodiments, the half-life modulator is an HSA variant. In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wild type human serum albumin amino acid sequence (wtHSA, SEQ ID NO: 12). In some embodiments, the half-life modulator comprises at least 200 consecutive amino acids that are at least 70%. 80%. 85%. 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%. 98%. or 99% identical to wild type human serum albumin amino acid sequence. In some embodiments, the half-life modulator comprises at least 300 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wild type human serum albumin amino acid sequence. In some embodiments, the half-life modulator comprises at least 400 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wi Id type human serum albumin amino acid sequence. In some embodiments, the half-life modulator comprises at least 500 consecutive amino acids that are at least 70%. 80%. 85%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wild type human serum albumin amino acid sequence.

[0152] In some embodiments, the HSA variant can have one of more of the following substitutions: cysteine C58 can be substituted, for example, with serine (C58S), alanine (C58A), asparagine (C58N), leucine (C58L), or glutamine (C58Q), lysine K420 can be substituted for example, with glutamic acid (K420E), aspartic acid (K420D), a leucine (K.420L) or methionine (K410M). asparagine N527 can be substituted for example, with glutamine (N527Q), aspartic acid (N527D), histidine (N527H), or tyrosine (N527Y), glutamic acid E505 can be substituted for example, with glycine (E505G), alanine (E505A), leucine (E505L), lysine (E505K), valine (E505V), isoleucine (E505I), methionine (E505M), or glutamine (E505Q), valine V547 can be substituted for example, with alanine (V547A). glycine (V547G), leucine (V547L), lysine (V547K), isoleucine (V547I), methionine (V547M), asparagine N503 can be substituted for example, with a Glutamine (N527Q), aspartic acid (N503D), histidine (N503H), or ty rosine (N503Y), or glutamine (V547Q).27ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0153] In some embodiments, the HSA variant can have amino acids 26-609 and have one of more of the following substitutions: cysteine C58 can be substituted for example, with serine (C58S), alanine (C58A), asparagine (C58N), leucine (C58L), or glutamine (C58Q), lysine K420 can be substituted for example, with glutamic acid (K420E), aspartic acid (K420D), a leucine (K420L) or methionine (K410M). asparagine N527 can be substituted for example, with glutamine (N527Q), aspartic acid (N527D), histidine (N527H), or tyrosine (N527Y), glutamic acid E505 can be substituted for example, with a glycine G (E505G), alanine (E505A), leucine (E505L), lysine (E505K), valine (E505V), isoleucine (E505I), methionine (E505M), or glutamine (E505Q), valine V547 can be substituted for example, with an alanine (V547A), glycine (V547G), leucine (V547L), lysine (V547K), isoleucine (V547I), methionine (V547M), asparagine N503 and / or N527 can be substituted for example, with Glutamine (N503Q and / or N527Q), aspartic acid (N503D and / or N527D), histidine (N503H and / or N527H), or tyrosin (N503Y and / or N527Y).

[0154] In some embodiments, the HSA variant (referred herein as mHSA) has the following substitutions: C34S, N503Q (SEQ ID NO: 13). In some embodiments, the HSA variant (referred herein as mHSA7) has the following substitutions C34S, N503Q, E505G and V547A (SEQ ID NO: 14). In some embodiments, the HSA variant has amino acids 26-609 and the following substitutions C58S and N527Q (SEQ ID NO: 15).

[0155] In some embodiments, the asparagine at position 503 and / or 527 of HSA, which may be deamidated and decrease half-life, can be removed by the N503Q substitution and / or the N527Q. In some embodiments, the cysteine C34 of HSA may be substituted to serine or alanine (S or A) to remove the free cysteine and minimize alternate disulfide-bond formation. In some embodiments, the half-life modulator is a modified version of the domain III (mHSA dlll) of a modified HSA with the N503Q substitution and an additional terminal glycine. Such a modified version retains the HSA property of binding to FcRn and increased serum half-life.28ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0156] In some embodiments, the half-life modulator is an Fc domain of an antibody or a single chain constant fragment. In some embodiments, the half-life modulator comprises Fc regions of an immunoglobulin molecule (e.g. IgG). In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a human Fc amino acid sequence. The Fc domain of an antibody has a natural capability to bind FcRn. resulting in an extended half-life. In some embodiments, the Fc domain of an antibody is engineered not to bind Fc(gamma)R. In an exemplary7embodiment, the Fc domain is engineered to substitute N297 with Q (N297Q variant). In some embodiments, the half-life modulator is a monomeric variant form of Fc (scFc). For example, the subset of IgG heavy chain which naturally dimerizes to form Fc is hinge-CH2-CH3. In some embodiments, the Fc domain is engineered to form a single chain by linking the hinge-CH2-CH3 with a flexible linker such as GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 16) to create a hinge-CH2-CH3-linker-hinge- CH2-CH3 chain. In an exemplary7embodiment, the single chain Fc (scFc) is engineered to substitute N297 with Q and C220 with S (N297Q, C220S).

[0157] In some embodiments, the half-life modulator is a single chain variable fragment (scFv) of an antibody targeted to albumin or other circulating protein. In some embodiments, the half-life modulator comprises an amino acid sequence that is at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to scFv amino acid sequence directed to a specific antigen, such as, but not limited to, albumin. In some embodiments, the half-life modulator comprises at least 50, at least 100, at least 150, at least 200, at least 250 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a scFv amino acid sequence directed to a specific antigen, such as, but not limited to, albumin.

[0158] In some embodiments, the half-life modulator is transferrin such as human transferrin (Tf, SEQ ID NO: 17). In some embodiments, the half-life modulator comprises an amino acid sequence that is at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to human transferrin amino acid sequence. In some embodiments, the half-life modulator comprises at least 100, at least 200, at least 300, at least 400, at least 500, at least 600. at least 650 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a human transferrin amino acid sequence.29ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0159] In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wild type human alpha-fetoprotein amino acid sequence (AFP, SEQ ID NO: 18). In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are about 70%, 80%, 85%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wild type human alpha-fetoprotein (AFP) amino acid sequence. In some embodiments, the N-linked glycosylation site of the AFP is removed by the N251Q substitution.

[0160] In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. or 99% identical wild-type vitamin D-binding protein amino acid sequence (VDBP, SEQ ID NO: 19). In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical wild-type vitamin D-binding protein (VDBP) amino acid sequence. In some embodiments, the N-linked glycosylation site of the VDBP can be removed by the N288Q or N288T substitution.

[0161] In some embodiments, the half-life modulator comprises at least 100 consecutive ammo acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to wild-type human transthyretin amino acid sequence (TTR, SEQ ID NO: 20). In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to wild type human transthyretin (TTR) amino acid sequence. In some embodiments, the transthyretin is modified to remove the Ni l 8 N- glycosylation site. In some embodiments, the half-life modulator is a monomeric form of TTR.

[0162] In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a PASylation amino acid sequence. PASylation are proline-, alanine-, and / or serine-rich sequences that mimic PEGylation (see WO / 2008 / 155134). In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a PASylation amino acid sequence. PASylation are proline-, alanine-, and / or serine- rich sequences that mimic PEGylation. Polypeptide stretches of proline, alanine, and / or serine30ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 form semi-structured three-dimensional domains with large hydrodynamic radius, thereby reducing clearance of fusion proteins. In some embodiments, the PASylation amino acid sequence is about 200, 300, 400, 500 or 600 amino acids long. For example, the PASylation is a 20 times repeat of the amino acid sequence ASPAAPAPASPAAPAPSAPA (SEQ ID NO: 21).

[0163] In some embodiments, the half-life modulator comprises the attachment of polyethylene glycol (PEG) chain or chains to the fusion proteins through chemical attachment either to the N- and / or C-terminus and / or to an amino acid side chain (e.g., PEG-maleimide attachment to cysteines). PEG chains form semi-structured three-dimensional domains with large hydrodynamic radius, thereby reducing clearance of fusion proteins.

[0164] In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%. 98%. or 99% identical to an albumin-binding domain human antibody (albudAb) amino acid sequence (SEQ ID NO: 22). In some embodiments, the half-life modulator comprises at least 100 consecutive amino acids that are about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an albumin-binding domain human antibody (albudAb) amino acid sequence. Albumin-binding domain antibodies can increase the fusion protein half-life by binding non-covalently to serum albumin (see W02008 / 096158 which is incorporated herein by reference in its entirety). In some embodiments, the albuminbinding domain human antibody is engineered to remove the C-terminal arginine to remove the Lys-Arg Kex2 protease site.

[0165] Representative such half-life modulators include those recited in any one of SEQ ID NOs: 12-15. 17-22.

[0166] In some embodiments, the half-life modulators can be modified to substitute the cysteine residues to serine or alanine residues to reduce the ability to form disulfide bonds.

[0167] In some embodiments, the targeting domain and activator domain can be joined via a half-life modulator. Accordingly, the half-life modulator can have two termini, an N- terminus and a C-terminus. In some embodiments, the half-life modulator is joined at one terminus via a peptide bond to the targeting polypeptide domain and is joined at the other terminus via a peptide bond to the activator domain. In certain embodiments, the half-life modulator is joined at the N-terminus to the C-terminus of the targeting polypeptide domain and at the C-terminus to the N-terminus of the activator domain. In other embodiments, the 31ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 half-life modulator is joined at the C-terminus to the targeting polypeptide domain and at the N-terminus to the activator domain. Yet, in other embodiments, the half-life modulator is joined at one of the termini of the bi-specific protein. For example, in some embodiments, the half-life modulator is joined at the C-terminus to the N-terminus of the activator domain. In other embodiments, the half-life modulator is joined at the N-terminus to the C-terminus of the targeting domain. In other embodiments, the half-life modulator can be joined at the N- terminus to the C-terminus of the activator domain. Yet in other embodiments, the half-life modulator can be joined at the N-terminus to the C-terminus of the targeting domain.Peptide Linkers

[0168] In some embodiments, the activator domain, half-life modulator, and targeting domain are linked by peptide linker (e.g., from 2 to 40, 2-50, 2-100 amino acid residues) such that upon target recognition and engagement by the targeting domain, the presentation of the activator domain is optimized for binding to and activation of extracellular receptors on the surface of cells that present the target at a given surface density (e.g. - 5 xlO2molecules / 1,000 A2).

[0169] Targeted delivery of the activator domain for example IGF-1 for the activation of receptors on cells or tissues displaying a specific target requires appropriate presentation of both the activator domain and the targeting domain. In some embodiments, the flexibility of the linker is optimized for proper geometry of the engaged chimeric protein. Some of the principal determinants of the geometric constraints are the distances from the cell surface for the target and the receptor.

[0170] Additional optimization can be driven by the relative number of receptors and target molecules. At high ratios of Receptor: Target molecule, the engagement of both domains is reaction-limited. When the target molecule is more abundant than the receptor, the occupancy of both domains is diffusion-limited. Under the reaction-limit, optimal delivery of the activator domain is attained via short and rigid linkers. Under the diffusion limit, long and flexible linkers allow the activator domain to access a larger surface area. For cells with complex shapes (i.e. - bodies and neuronal processes) and receptor distributions, appropriate design of linker flexibility can enable precise targeting to sub-cellular regions.

[0171] In some embodiments, the peptide linker is present at the N-terminus, at the C- terminus or at both the N-terminus and the C-terminus of the half-life modulator at one or both ends. Suitable short connector polypeptides for use at the N-terminal end of the linker include,32ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 for example, dipeptides such as -Gly-Ser- (GS), -Gly-Ala- (GA) and -Ala-Ser- (AS). Suitable peptide linkers for use at the C-terminal end of the linker include, for example, dipeptides such as -Leu-Gin- (LQ) and -Thr-Gly- (TG). In some embodiments, the peptide linkers are longer than 2 amino acids. For example, the peptide linkers are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids long or longer. In some embodiments, the peptide linkers are 20 or more 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more amino acids long. Preferably, such peptide linkers are flexible (for example glycine-rich) or structured (e.g., alpha-helix rich). In some embodiments, the linker comprises or consist of amino acids - Gly-Ser-Gly-Gly-Gly-Ser-Gly (SEQ ID NO: 23).

[0172] It will be apparent that elements in addition to those described above may optionally be included in the proteins provided herein. Such elements may be present for a variety of purposes, including to facilitate expression, preparation or purification of the bi- specific fusion protein, or to perform targeting functions.Representative chimeric protein

[0173] In some embodiments, a representative bi-specific fusion proteins comprise (from N-terminal to C-terminal):(a) a targeting polypeptide domain comprising or consisting of a non-internalizing human annexin V variant (e.g., comprising or consisting of amino acids 2-320 of wt human Annexin 5 and a substitution at C316, R63, KAO, K101. E138, D139, N160);(b) a linker peptide (e.g., - Gly-Ser-Gly-Gly-Gly-Ser-Gly):(c) a half-life modulator (e.g., HSA variant comprising or consisting of amino acids 26- 609 of \\1 human HSA and comprising substitutions at C58 and N527);(d) linker peptide (e.g., - Gly-Ser-Gly-Gly-Gly-Ser-Gly);(e) an activator domain comprising or consisting of an IGF-1 variant (e.g., comprising a substitution at E3 and Y31.

[0174] In some embodiments, the chimeric protein comprises or consists of IGFl(E3R / Y3IA)_lk7_HSA26-609(C58S / N527Q)_lk7_AnxV2- 320(R63A / K70A / K101A / E138A / D139G / N160A / C316A) (also referred herein as scp776). In some embodiments, the chimeric protein has an amino acid sequence as set forth in SEQ ID NO: 24.33ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0175] In some embodiments, the chimeric protein comprises or consists of IGFl(E3R / Y31A)_lk7_HSA26-609(C58S / N527Q)_lk7_AnxV2- 320(R63A / K70A / K101A / E138A / D139G / N160A / C316S). In some embodiments, the chimeric protein has an amino acid sequence as set forth in SEQ ID NO: 25.Nucleic acids

[0176] Provided herein are polynucleotides encoding the chimeric proteins that may be in the form of RNA or in the form of DNA, which DNA includes cDNA and synthetic DNA. The DNA may be double-stranded or single-stranded. The coding sequences that encode the variants of the present disclosure may vary as a result of the redundancy or degeneracy of the genetic code.Pharmaceutical Compositions-Methods of Treatment

[0177] Pharmaceutical compositions comprising a therapeutically effective amount of at least one chimeric protein as described herein, together with at least one physiologically acceptable carrier, are provided. Such compositions may be used for treating patients who are suffering from, or at risk for, tissue damage, in order to prevent tissue damage, or to repair or regenerate damaged tissue.

[0178] In some embodiments, the subject in need thereof has acute CNS injury’, acute cardiovascular injury (e.g., STEMI, Cardiac Arrest), acute radiation sickness (e.g., acute radiation syndromes (ARS) of the gastrointestinal (GI-ARS) and hematopoietic (H-ARS) systems), chemical inhalation injury’ (e.g., sulfur mustards exposure), dermatologic injuries (e.g., wound healing), traumatic injuries (e.g., bum. crush, laceration, contusion, avulsion, concussion, fracture, amputation), or chronic neurodegenerative diseases (e.g., synucleinopathies, amyloidoses). In some embodiments, the subject in need thereof is undergoing a procedure with risk of iatrogenic injury (e.g., transcatheter aortic valve replacement, percutaneous coronary intervention, coronary artery7bypass grafting). In some embodiments, the subject in need thereof is undergoing an organ transplantation procedure (e.g., skin, kidney, liver, heart, lung). In some embodiments, the subject is undergoing cosmetic dermatologic treatments (e.g., laser resurfacing).

[0179] In some embodiments, the pharmaceutical composition is a liquid formulation formulated for intravenous (IV) injection. In some embodiments, the composition is formulated for IV bolus injection.34ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0180] In some embodiments, the pH of the pharmaceutical composition is from about 7 to about 8, for example about 7.5. In some embodiments, the pharmaceutical composition comprises in an alkalinizing agent, such as tromethamine or dibasic sodium phosphate. In some embodiments, the alkalinizing can be at a concentration of about 10 to about 50 mM, for example about 20 mM. In some embodiments, the pharmaceutical composition comprises a surfactant. In some embodiments, the surfactant is a non-ionic surfactant such as polysorbate 80 or polysorbate 20 may be present in a concentration of about 0.01%, 0.02%. 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% (w / v) or any concentration therebetween. In some embodiments, the pharmaceutical composition comprises sucrose. In some embodiments, the sucrose may be present in a concentration of about 1%, 2%. 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% (w / v) or any concentration therebetween.

[0181] In some embodiments, the pharmaceutical composition comprises from about 1 to about 100 g / 1 chimeric protein, from about 10 mM to about 50 mM tromethamine, from about 2 to about 15 % (w / v) sucrose, from about 0.001% to about 0.04% (w / v) Polysorbate 80, at pH 7.5.

[0182] In some embodiments, the chimeric protein (from about 1 to about 100 g / 1) is formulated in about 20 mM tromethamine, about 7.5% sucrose, and about 0.02% polysorbate 80 at pH 7.5 (via addition of HC1). In some embodiments, about 20 mg / ml of the chimeric protein is formulated in about 20 mM tromethamine, about 7.5% sucrose, and about 0.02% polysorbate 80 at pH 7.5 (via addition of HC1).

[0183] In some embodiments, the pH of the pharmaceutical composition is from about4.5 to about 6.5, from about 4.5 to about 5, from about 5 to about 5.5, from about 5.5 to about 6. from about 6 to about 6.5. about 4.5. about 5. about 5.5. about 6. about 6.6. In some embodiments, the pharmaceutical composition comprises acetate, phosphate, citrate, histidine, for example at a concentration of 10 to 50 mM. In some embodiments, the pharmaceutical composition comprises acetate. In some embodiments, the citrate can be at a concentration of about 10 to about 50 mM. for example about 20 mM. In some embodiments, the pharmaceutical composition comprises sucrose. In some embodiments, the sucrose may be present in a concentration of about 1%, 2%. 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or any concentration therebetween (w / v).

[0184] In some embodiments, the pharmaceutical composition comprising the chimeric protein comprises citrate, sucrose or a combination thereof.35ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0185] In some embodiments, the pharmaceutical composition comprises less than 2% (w / v) sucrose, less than 1.5 % (w / v) sucrose, less than 1% (w / v) sucrose, less 0.5% (w / v) sucrose, less than 0.1% (w / v) sucrose, less than 0.01% (w / v) sucrose. In some embodiments, the pharmaceutical composition is free of sucrose.

[0186] In some embodiments, the pharmaceutical composition comprises from about 1 to about 25 g / 1 chimeric protein or any value therebetween.

[0187] In some embodiments, the pharmaceutical composition has a pH of from about 5 to about 7, for example about 5, about 5.5, about 6, about 6.5, about 7.

[0188] In some embodiments, the pharmaceutical composition comprises from about 100 mM to about 150 mM sodium chloride and sterile water. In some embodiments, the pharmaceutical composition is a preservative-free formulation. In some embodiments, the pharmaceutical composition is sterile.

[0189] In some embodiments, the pharmaceutical composition comprises excipients that are such as, but not limited, to histidine, histidine monohydrochloride, histidine hydrochloride, methionine, succinic acid, trehalose dihydrate, polysorbate 20, and polysorbate 80.

[0190] In some embodiments, the pharmaceutical composition has an osmolality of about 45-140 mOsmol / kg, or any value therebetween, for example 45-75 mOsmol / kg, 74-110 mOsmol / kg or 110-140 mOsmol / kg.

[0191] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the chimeric protein, about 20 mM sodium citrate, about 122 mM sodium chloride and has a pH of about 6.5. In some embodiments, the pharmaceutical composition consists essentially of a therapeutically effective amount of the chimeric protein, about 20 mM sodium citrate, about 122 mM sodium chloride and has a pH of about 6.5. In some embodiments, the pharmaceutical composition consists of a therapeutically effective amount of the chimeric protein, about 20 mM sodium citrate, about 122 mM sodium chloride and has a pH of about 6.5.

[0192] In some embodiments, the pharmaceutical composition comprises from about 1 to about 25 g / 1 chimeric protein, from about 2 to about 15 % (w / v) sucrose, at pH 5.

[0193] In some embodiments, the chimeric protein (from about 1 to about 10 g / 1) is formulated in about 20 mM citrate, about 7.5% sucrose, at pH 5. In some embodiments, about 5 mg / ml of the chimeric protein is formulated in about 20 mM citrate, about 7.5% sucrose, at pH 5.36ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0194] In some embodiments, the pharmaceutical composition comprising the chimeric protein comprises alkalinizing agent, a surfactant, sucrose or a combination thereof.

[0195] The pharmaceutical compositions of the disclosure may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, preservatives and the like. In some embodiments, the liquid composition is sterilized by conventional sterilization techniques, or sterile filtered. In some embodiments, the liquid composition is in a vial.

[0196] In some embodiments, the pharmaceutical composition is administered intravenously or intraarterially to a subject in need thereof via bolus injection. A bolus injection comprises, e.g., fast intravenous injection, for example less than 10 seconds (or less than 20, 30, 40. 50. 60 second), or intravenous infusion over less than approximately 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes or 10 minutes. In some embodiments, the pharmaceutical composition is administered intravenously to a subject in need thereof. In some embodiments, the composition is administered as an I.V. push. In some embodiments, the administration is over 5 min. or less, 4 min. or less, 3 min. of less, 2 min. or less, 1 min or less (for example 50 s, 40 s, 30 s, 20 s or any administration time therebetween). In other embodiments, the composition is administered as a slow I.V. injection.

[0197] In some embodiments, the pharmaceutical composition is administered intravenously to a subject using a syringe injection pump at a rate of 0.5 - 25 mL / min. For example, the pharmaceutical composition is administered intravenously to a subject using a syringe injection pump at a rate of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4. 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9. 9.5. 10. 10.5. 11. 11.5. 12. 12.5. 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5. 17. 17.5. 18. 18.5. 19.19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5 or 25 mL / min. In some embodiments, the pharmaceutical composition is administered intravenously to a subject using a syringe injection pump al a rate of 0.5-1, 1- 1.5, 1.5-2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5- 5, 5- 5.5, 5.5-6, 6-6.5, 6.5-7. 7-7.5, 7.5-8, 8-8.5. 8.5- 9, 9-9.5. 9.5-10. 10-10.5, 10.5-11. 11-11.5, 11.5-12, 12-12.5, 12.5-13, 13-13.5, 13.5-14, 14-14.5, 14.5-15, 15- 15.5, 15.5-16, 16-16.5, 16.5-17, 17-17.5, 17.5- 18, 18-18.5, 18.5-19, 19-19.5, 19.5-20, 20-20.5, 20.5-21, 21-21.5, 21.5-22, 22- 22.5, 22.5-23, 23-23.5, 23.5-24, 24-24.5 or 24.5-25 mL / min

[0198] In some embodiments, the pharmaceutical composition is administered intraarterially to a subject using a syringe injection pump at a rate of 0.05 - 10 mL / min. For 37ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 example, the pharmaceutical composition is administered intraarterially to a subject using a syringe injection pump at a rate of 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 rnL / min. In some embodiments, the pharmaceutical composition is administered intraarterially to a subject using a syringe injection pump at a rate of 0.05-0.1, 0.1-0.2. 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6. 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-1.5, 1.5- 2, 2-2.5, 2.5-3, 3-3.5. 3.5-4, 4-4.5, 4.5-5. 5-5.5. 5.5-6, 6-6.5, 6.5-7. 7-7.5, 7.5-8, 8-8.5. 8.5-9, 9- 9.5, 9.5- lO mL / min.

[0199] In some embodiments, the pharmaceutical composition is administered intrathecally to a subject using techniques known in the art.

[0200] In some embodiments, a therapeutically effective amount generally is in the range of about 0.01 mg / kg to about 100.0 mg / kg per dose. In some embodiments, a therapeutically effective amount of a protein disclosed herein ranges from about 0.01 mg / kg to about 0.05 mg / kg per dose, about 0.01 mg / kg to about 0.1 mg / kg per dose, 0.01 mg / kg to about 1 mg / kg per dose, 0.01 mg / kg to about 10 mg / kg per dose, 0.01 mg / kg to about 100.0 mg / kg per dose, 0.1 mg / kg to about 0.5 mg / kg per dose, 0.1 mg / kg to about 1 mg / kg per dose, 0.1 mg / kg to about 5 mg / kg per dose, 0.1 mg / kg to about 10 mg / kg per dose, 0.1 mg / kg to about 20 mg / kg per dose, 0. 1 mg / kg to about 30 mg / kg per dose. 0. 1 mg / kg to about 40 mg / kg per dose, 0. 1 mg / kg to about 50 mg / kg per dose. 0. 1 mg / kg to about 60 mg / kg per dose, 0. 1 mg / kg to about 70 mg / kg per dose, 0.1 mg / kg to about 80 mg / kg per dose, 0.1 mg / kg to about 90 mg / kg per dose, 0.1 mg / kg to about 100 mg / kg per dose, 1 mg / kg to about 5 mg / kg per dose, 1 mg / kg to about 10 mg / kg per dose, 1 mg / kg to about 20 mg / kg per dose, 1 mg / kg to about 30 mg / kg per dose, 1 mg / kg to about 40 mg / kg per dose, 1 mg / kg to about 50 mg / kg per dose, 1 mg / kg to about 60 mg / kg per dose, 1 mg / kg to about 70 mg / kg per dose, 1 mg / kg to about 80 mg / kg per dose, 1 mg / kg to about 90 mg / kg per dose, 1 mg / kg to about 100 mg / kg per dose, 10 mg / kg to about 20 mg / kg per dose, 10 mg / kg to about 30 mg / kg per dose, 10 mg / kg to about 40 mg / kg per dose, 10 mg / kg to about 50 mg / kg per dose, 10 mg / kg to about 60 mg / kg per dose, 10 mg / kg to about 70 mg / kg per dose, 10 mg / kg to about 80 mg / kg per dose, 10 mg / kg to about 90 mg / kg per dose, or 10 mg / kg to about 100 mg / kg per dose.

[0201] In some embodiments, a therapeutically effective amount generally is in the range of about 0.01 mg / kg to about 20.0 mg / kg per dose. In some embodiments, a therapeutically effective amount ranges from about 0.01 mg / kg to about 10.0 mg / kg per dose.38ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0202] In some embodiments, a therapeutically effective amount of a protein disclosed herein ranges from about 0.01 mg / kg to about 0.02 mg / kg per dose, about 0.01 mg / kg to about 0.03 mg / kg per dose, about 0.01 mg / kg to about 0.04 mg / kg per dose, about 0.01 mg / kg to about 0.05 mg / kg per dose, about 0.01 mg / kg to about 0.06 mg / kg per dose, about 0.01 mg / kg to about 0.07 mg / kg per dose, about 0.01 mg / kg to about 0.08 mg / kg per dose, about 0.01 mg / kg to about 0.09 mg / kg per dose, about 0.01 mg / kg to about 0. 1 mg / kg per dose, about 0.01 mg / kg to about 0.2 mg / kg per dose, about 0.01 mg / kg to about 0.3 mg / kg per dose, about 0.01 mg / kg to about 0.4 mg / kg per dose, about 0.01 mg / kg to about 0.5 mg / kg per dose, about 0.01 mg / kg to about 0.6 mg / kg per dose, about 0.01 mg / kg to about 0.7 mg / kg per dose, about 0.01 mg / kg to about 0.8 mg / kg per dose, about 0.01 mg / kg to about 0.9 mg / kg per dose, about 0.01 mg / kg to about 1 mg / kg per dose, about 0.01 mg / kg to about 2 mg / kg per dose, about 0.01 mg / kg to about 3 mg / kg per dose, about 0.01 mg / kg to about 4 mg / kg per dose, about 0.01 mg / kg to about 5 mg / kg per dose, about 0.01 mg / kg to about 6 mg / kg per dose, about 0.01 mg / kg to about 7 mg / kg per dose, about 0.01 mg / kg to about 8 mg / kg per dose, about 0.01 mg / kg to about 9 mg / kg per dose, about 0.01 mg / kg to about 10 mg / kg per dose, about 0.01 mg / kg to about 11 mg / kg per dose, about 0.01 mg / kg to about 12 mg / kg per dose, about 0.01 mg / kg to about 13 mg / kg per dose, about 0.01 mg / kg to about 14 mg / kg per dose, about 0.01 mg / kg to about 15 mg / kg per dose, about 0.01 mg / kg to about 16 mg / kg per dose, about 0.01 mg / kg to about 17 mg / kg per dose, about 0.01 mg / kg to about 18 mg / kg per dose, about 0.01 mg / kg to about 19 mg / kg per dose, about 0.01 mg / kg to about 20 mg / kg per dose.

[0203] In some embodiments, a therapeutically effective amount of a protein disclosed herein ranges from about 0.01 mg / kg to about 0.05 mg / kg per dose, about 0.05 mg / kg to about 0.1 mg / kg per dose, about 0.1 mg / kg to about 0.5 mg / kg per dose, about 0.05 mg / kg to about 1 mg / kg per dose, about 1 mg / kg to about 2 mg / kg per dose, about 2 mg / kg to about 3 mg / kg per dose, about 3 mg / kg to about 4 mg / kg per dose, about 4 mg / kg to about 5 mg / kg per dose, about 5 mg / kg to about 6 mg / kg per dose, about 6 mg / kg to about 7 mg / kg per dose, about 7 mg / kg to about 8 mg / kg per dose, about 8 mg / kg to about 9 mg / kg per dose, about 9 mg / kg to about 10 mg / kg per dose, about 10 mg / kg to about 11 mg / kg per dose, about 11 mg / kg to about 12 mg / kg per dose, about 12 mg / kg to about 13 mg / kg per dose, about 13 mg / kg to about 14 mg / kg per dose, about 14 mg / kg to about 15 mg / kg per dose, about 15 mg / kg to about 16 mg / kg per dose, about 16 mg / kg to about 17 mg / kg per dose, 17 mg / kg to about 18 mg / kg per dose, about 18 mg / kg to about 19 mg / kg per dose, about 19 mg / kg to about 20 mg / kg per dose.39ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0204] In some embodiments, a therapeutically effective amount of a protein disclosed herein is about 0.01 mg / kg per dose, about 0.02 mg / kg per dose, about 0.03 mg / kg per dose, about 0.04 mg / kg per dose, about 0.05 mg / kg per dose, about 0.06 mg / kg per dose, about 0.07 mg / kg per dose, about 0.08 mg / kg per dose, about 0.09 mg / kg per dose, about 0.1 mg / kg per dose, about 0.2 mg / kg per dose, about 0.3 mg / kg per dose, about 0.4 mg / kg per dose, about 0.5 mg / kg per dose, about 0.6 mg / kg per dose, about 0.7 mg / kg per dose, about 0.8 mg / kg per dose, about 0.9 mg / kg per dose, about 1 mg / kg per dose, about 1.1 mg / kg per dose, about 1.2 mg / kg per dose, about 1.3 mg / kg per dose, about 1.4 mg / kg per dose, about 1.5 mg / kg per dose, about 1.6 mg / kg per dose, about 1.7 mg / kg per dose, about 1.8 mg / kg per dose, about 1.9 mg / kg per dose, about 2 mg / kg per dose, about 2. 1 mg / kg per dose, about 2.2 mg / kg per dose, about 2.3 mg / kg per dose, about 2.4 mg / kg per dose, about 2.5 mg / kg per dose, about 2.6 mg / kg per dose, about 2.7 mg / kg per dose, about 2.8 mg / kg per dose, about 2.9 mg / kg per dose, about 3 mg / kg per dose, about 3.1 mg / kg per dose, about 3.2 mg / kg per dose, about 3.3 mg / kg per dose, about 3.4 mg / kg per dose, about 3.5 mg / kg per dose, about 3.6 mg / kg per dose, about 3.7 mg / kg per dose, about 3.8 mg / kg per dose, about 3.9 mg / kg per dose, about 4 mg / kg per dose, about 4. 1 mg / kg per dose, about 4.2 mg / kg per dose, about 4.3 mg / kg per dose, about 4.4 mg / kg per dose, about 4.5 mg / kg per dose, about 4.6 mg / kg per dose, about 4.7 mg / kg per dose, about 4.8 mg / kg per dose, about 4.9 mg / kg per dose, about 5 mg / kg per dose, about 5.1 mg / kg per dose, about 5.2 mg / kg per dose, about 5.3 mg / kg per dose, about 5.4 mg / kg per dose, about 5.5 mg / kg per dose, about 5.6 mg / kg per dose, about 5.7 mg / kg per dose, about 5.8 mg / kg per dose, about 5.9 mg / kg per dose, about 6 mg / kg per dose, about 6.1 mg / kg per dose, about 6.2 mg / kg per dose, about 6.3 mg / kg per dose, about 6.4 mg / kg per dose, about 6.5 mg / kg per dose, about 6.6 mg / kg per dose, about 6.7 mg / kg per dose, about 6.8 mg / kg per dose, about 6.9 mg / kg per dose, about 7 mg / kg per dose, about 7.1 mg / kg per dose, about 7.2 mg / kg per dose, about 7.3 mg / kg per dose, about 7.4 mg / kg per dose, about 7.5 mg / kg per dose, about 7.6 mg / kg per dose, about 7.7 mg / kg per dose, about 7.8 mg / kg per dose, about 7.9 mg / kg per dose, about 8 mg / kg per dose, about 8. 1 mg / kg per dose, about 8.2 mg / kg per dose, about 8.3 mg / kg per dose, about 8.4 mg / kg per dose, about 8.5 mg / kg per dose, about 8.6 mg / kg per dose, about 8.7 mg / kg per dose, about 8.8 mg / kg per dose, about 8.9 mg / kg per dose, about 9 mg / kg per dose, about 9.1 mg / kg per dose, about 9.2 mg / kg per dose, about 9.3 mg / kg per dose, about 9.4 mg / kg per dose, about 9.5 mg / kg per dose, about 9.6 mg / kg per dose, about 9.7 mg / kg per dose, about 9.8 mg / kg per dose, about 9.9 mg / kg per dose, about 10 mg / kg per dose, about 11 mg / kg per dose, about 12 mg / kg per dose, about 13 mg / kg per dose, about 14 mg / kg per dose, about 15 mg / kg per dose, about40ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 202516 mg / kg per dose, about 17 mg / kg per dose, about 18 mg / kg per dose, about 19 mg / kg per dose, about 20 mg / kg per dose.

[0205] In some embodiments, a therapeutically effective amount generally is in the range of about 1 mg / kg to about 10.0 mg / kg per dose. In some embodiments, an effective amount of a protein disclosed herein can be, e.g., about 1 mg / kg to about 10 mg / kg per dose, 1 mg / kg to about 9 mg / kg per dose, 1 mg / kg to about 8 mg / kg per dose, 1 mg / kg to about 7 mg / kg per dose. 1 mg / kg to about 6 mg / kg per dose, 1 mg / kg to about 5 mg / kg per dose, 1 mg / kg to about 4 mg / kg per dose, 1 mg / kg to about 3 mg / kg per dose or 1 mg / kg to about 2 mg / kg per dose.

[0206] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For instance, treatment of a nervous system disorder may comprise a one-time administration of an effective dose of the pharmaceutical composition disclosed herein. As a non-limiting example, an effective dose of the composition disclosed herein can be administered once to a patient, e.g., as a single injection or bolus. Alternatively, treatment of a nervous system disorder may comprise multiple administrations of an effective dose of the pharmaceutical composition disclosed herein carried out over a range of time periods, such as. e.g., four times daily, three times daily, twice daily, daily, once every few days, weekly, monthly or yearly. As a non-limiting example, a combination disclosed herein can be administered once or twice weekly to a patient. The timing of administration can upon such factors as the severity of the patient’s symptoms. For example, an effective dose of the composition disclosed herein can be administered to a patient once a month for an indefinite period of time, or until the mammal no longer requires therapy.

[0207] In some embodiments, a therapeutically effective amount generally is in the range of about 0.01 mg / kg to about 200.0 mg / kg per day. In some embodiments, an effective amount of a protein disclosed herein ranges from about 0.01 mg / kg to about 0.1 mg / kg per day, 0.01 mg / kg to about 1 mg / kg per day, 0.01 mg / kg to about 10 mg / kg per day, 0.01 mg / kg to about 100.0 mg / kg per day, 0.01 mg / kg to about 200.0 mg / kg per day, 0.1 mg / kg to about 1 mg / kg per day. 0. 1 mg / kg to about 10 mg / kg per day. 0. 1 mg / kg to about 100 mg / kg per day, 0. 1 mg / kg to about 200 mg / kg per day, 1 mg / kg to about 100 mg / kg per day, 1 mg / kg to about 200 mg / kg per day, 10 mg / kg to about 100 mg / kg per day or 10 mg / kg to about 100 mg / kg per day.41ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0208] In some embodiments, a therapeutically effective amount generally is in the range of about 0.01 mg / kg to about 20.0 mg / kg per day. In some embodiments, a therapeutically effective amount generally is in the range of about 0.01 mg / kg to about 10.0 mg / kg per day. In some embodiments, a therapeutically effective amount generally is in the range of about 1 mg / kg to about 20.0 mg / kg per day. In some embodiments, a therapeutically effective amount generally is in the range of about 1 mg / kg to about 10.0 mg / kg per day. In some embodiments, an effective amount of a protein disclosed herein can be, e.g., about 1 mg / kg to about 10 mg / kg per day, 1 mg / kg to about 9 mg / kg per day, 1 mg / kg to about 8 mg / kg per day, 1 mg / kg to about 7 mg / kg per day. 1 mg / kg to about 6 mg / kg per day, 1 mg / kg to about 5 mg / kg per day, 1 mg / kg to about 4 mg / kg per day. 1 mg / kg to about 3 mg / kg per day or 1 mg / kg to about 2 mg / kg per day.

[0209] In some embodiments, a therapeutically effective amount of a chimeric protein disclosed herein ranges from about 0.01 mg / kg to about 0.02 mg / kg per day, about 0.01 mg / kg to about 0.03 mg / kg per day, about 0.01 mg / kg to about 0.04 mg / kg per day, about 0.01 mg / kg to about 0.05 mg / kg per day, about 0.01 mg / kg to about 0.06 mg / kg per day, about 0.01 mg / kg to about 0.07 mg / kg per day. about 0.01 mg / kg to about 0.08 mg / kg per day, about 0.01 mg / kg to about 0.09 mg / kg per day, about 0.01 mg / kg to about 0.1 mg / kg per day, about 0.01 mg / kg to about 0.2 mg / kg per day, about 0.01 mg / kg to about 0.3 mg / kg per day, about 0.01 mg / kg to about 0.4 mg / kg per day, about 0.01 mg / kg to about 0.5 mg / kg per day, about 0.01 mg / kg to about 0.6 mg / kg per day, about 0.01 mg / kg to about 0.7 mg / kg per day, about 0.01 mg / kg to about 0.8 mg / kg per day, about 0.01 mg / kg to about 0.9 mg / kg per day, about 0.01 mg / kg to about 1 mg / kg per day, about 0.01 mg / kg to about 2 mg / kg per day, about 0.01 mg / kg to about3 mg / kg per day, about 0.01 mg / kg to about 4 mg / kg per day, about 0.01 mg / kg to about 5 mg / kg per day, about 0.01 mg / kg to about 6 mg / kg per day, about 0.01 mg / kg to about 7 mg / kg per day, about 0.01 mg / kg to about 8 mg / kg per day, about 0.01 mg / kg to about 9 mg / kg per day, about 0.01 mg / kg to about 10 mg / kg per day, about 0.01 mg / kg to about 11 mg / kg per day, about 0.01 mg / kg to about 12 mg / kg per day, about 0.01 mg / kg to about 13 mg / kg per day, about 0.01 mg / kg to about 14 mg / kg per day, about 0.01 mg / kg to about 15 mg / kg per day, about 0.01 mg / kg to about 16 mg / kg per day. about 0.01 mg / kg to about 17 mg / kg per day, about 0.01 mg / kg to about 18 mg / kg per day, about 0.01 mg / kg to about 19 mg / kg per day, or about 0.01 mg / kg to about 20 mg / kg per day.42ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0210] In some embodiments, a therapeutically effective amount of a chimeric protein disclosed herein ranges from about 0.01 mg / kg to about 0.05 mg / kg per day, about 0.05 mg / kg to about 0.1 mg / kg per day, about 0.1 mg / kg to about 0.5 mg / kg per day, about 0.05 mg / kg to about 1 mg / kg per day, about 1 mg / kg to about 2 mg / kg per day, about 2 mg / kg to about 3 mg / kg per day. about 3 mg / kg to about 4 mg / kg per day, about 4 mg / kg to about 5 mg / kg per day, about 5 mg / kg to about 6 mg / kg per day, about 6 mg / kg to about 7 mg / kg per day, about 7 mg / kg to about 8 mg / kg per day, about 8 mg / kg to about 9 mg / kg per day, about 9 mg / kg to about 10 mg / kg per day, about 10 mg / kg to about 11 mg / kg per day, about 11 mg / kg to about 12 mg / kg per day, about 12 mg / kg to about 13 mg / kg per day, about 13 mg / kg to about 14 mg / kg per day. about 14 mg / kg to about 15 mg / kg per day, about 15 mg / kg to about 16 mg / kg per day, about 16 mg / kg to about 17 mg / kg per day, 17 mg / kg to about 18 mg / kg per day, about 18 mg / kg to about 19 mg / kg per day, or about 19 mg / kg to about 20 mg / kg per day.

[0211] In some embodiments, a therapeutically effective amount of a chimeric protein disclosed herein ranges about 0.01 mg / kg per day, about 0.02 mg / kg per day, about 0.03 mg / kg per day, about 0.04 mg / kg per day, about 0.05 mg / kg per day, about 0.06 mg / kg per day, about 0.07 mg / kg per day, about 0.08 mg / kg per day, about 0.09 mg / kg per day, about 0. 1 mg / kg per day, about 0.2 mg / kg per day, about 0.3 mg / kg per day, about 0.4 mg / kg per day, about 0.5 mg / kg per day, about 0.6 mg / kg per day, about 0.7 mg / kg per day, about 0.8 mg / kg per day, about 0.9 mg / kg per day, about 1 mg / kg per day, about 1.1 mg / kg per day, about 1.2 mg / kg per day, about 1.3 mg / kg per day. about 1.4 mg / kg per day, about 1.5 mg / kg per day, about 1.6 mg / kg per day, about 1.7 mg / kg per day, about 1.8 mg / kg per day, about 1.9 mg / kg per day, about 2 mg / kg per day, about 2. 1 mg / kg per day, about 2.2 mg / kg per day, about 2.3 mg / kg per day, about 2.4 mg / kg per day, about 2.5 mg / kg per day, about 2.6 mg / kg per day, about 2.7 mg / kg per day, about 2.8 mg / kg per day. about 2.9 mg / kg per day, about 3 mg / kg per day, about 3.1 mg / kg per day, about 3.2 mg / kg per day, about 3.3 mg / kg per day, about 3.4 mg / kg per day, about 3.5 mg / kg per day, about 3.6 mg / kg per day, about 3.7 mg / kg per day, about 3.8 mg / kg per day, about 3.9 mg / kg per day, about 4 mg / kg per day, about 4.1 mg / kg per day, about 4.2 mg / kg per day, about 4.3 mg / kg per day, about 4.4 mg / kg per day, about 4.5 mg / kg per day, about 4.6 mg / kg per day, about 4.7 mg / kg per day, about 4.8 mg / kg per day, about 4.9 mg / kg per day, about 5 mg / kg per day, about 5.1 mg / kg per day, about 5.2 mg / kg per day, about 5.3 mg / kg per day, about 5.4 mg / kg per day, about 5.5 mg / kg per day, about 5.6 mg / kg per day, about 5.7 mg / kg per day, about 5.8 mg / kg per day, about 5.9 mg / kg per day, about 6 mg / kg per day, about 6.1 mg / kg per day, about 6.2 mg / kg per day, about 6.3 mg / kg per day,43ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 about 6.4 mg / kg per day, about 6.5 mg / kg per day, about 6.6 mg / kg per day. about 6.7 mg / kg per day, about 6.8 mg / kg per day, about 6.9 mg / kg per day, about 7 mg / kg per day, about 7. 1 mg / kg per day, about 7.2 mg / kg per day, about 7.3 mg / kg per day, about 7.4 mg / kg per day, about 7.5 mg / kg per day, about 7.6 mg / kg per day, about 7.7 mg / kg per day, about 7.8 mg / kg per day, about 7.9 mg / kg per day, about 8 mg / kg per day, about 8. 1 mg / kg per day, about 8.2 mg / kg per day, about 8.3 mg / kg per day, about 8.4 mg / kg per day, about 8.5 mg / kg per day, about 8.6 mg / kg per day, about 8.7 mg / kg per day, about 8.8 mg / kg per day, about 8.9 mg / kg per day, about 9 mg / kg per day, about 9.1 mg / kg per day, about 9.2 mg / kg per day, about 9.3 mg / kg per day, about 9.4 mg / kg per day, about 9.5 mg / kg per day, about 9.6 mg / kg per day, about 9.7 mg / kg per day, about 9.8 mg / kg per day, about 9.9 mg / kg per day, about 10 mg / kg per day, about 11 mg / kg per day, about 12 mg / kg per day, about 13 mg / kg per day, about 14 mg / kg per day, about 15 mg / kg per day, about 16 mg / kg per day, about 17 mg / kg per day, about 18 mg / kg per day, about 19 mg / kg per day, or about 20 mg / kg per day.

[0212] In some embodiments, the effective dose is administered daily to the subject in need thereof over a period of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days. 11 days, 12 days, 13 days, 14 days or more. In some embodiments, the effective dose is administered daily to the subject having an acute CNS injury over a period of a minimum 2 days to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered daily to the subject having an acute cardiovascular injury (e.g., STEMI, Cardiac Arrest) over a period of a minimum 2 days to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered daily to the subject having an acute kidney injury over a period of a minimum 2 days to a period of 14 days, for example4, 5, 6, 7 days. In some embodiments, the effective dose is administered daily to the subject experiencing acute radiation sickness (e.g., GI-ARS, H-ARS) over a period of a minimum 2 days to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered daily to the subject experiencing chemical inhalation injury (e.g., sulfur mustards exposure) over a period of a minimum 2 days to a period of 14 days, for example 4,5, 6, 7 days. In some embodiments, the effective dose is administered daily to the subject undergoing a procedure with risk of iatrogenic injury (e.g., transcatheter aortic valve replacement, percutaneous coronary intervention, coronary artery bypass grafting) over a period of a minimum 1 day to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered to the subject undergoing an organ transplantation procedure (e.g., skin, kidney, liver, heart, lung) over a period of a minimum 144ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 day to a period of 14 days, for example 4, 5. 6, 7 days. In some embodiments, the effective dose is administered to the subject undergoing cosmetic dermatologic treatments (e.g., laser resurfacing) over a period of a minimum 1 day to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered to the subject being treated for dermatologic injuries (e.g., wound healing) over a period of a minimum 1 day to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered to the subject being treated for traumatic injuries (e.g., bum, crush, laceration, contusion, avulsion, concussion, fracture, amputation) over a period of a minimum 1 day to a period of 14 days, for example 4, 5, 6, 7 days. In some embodiments, the effective dose is administered to the subject experiencing chronic neurodegenerative diseases (e.g., synucleinopathies, amyloidoses) in an intermittent repeat dosing regimen as a life-prolonging treatment.

[0213] In some embodiments, the effective dose is a descending regimen that is sequentially administered daily to the subject in need thereof over a period of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or more. In some embodiments, descending regimen decreases the requirement for the supplemental dextrose infusion.

[0214] In some embodiments, the effective dose is administered daily to the subject having neurovegetative disease over a period of a minimum 2 days to at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12, years, 13 years, 14 years, 15 years, 16, years, 17 years, 18 years, 19 years or 20 years.

[0215] Provided herein are methods of treating a subject having an acute ischemic stroke with an IGF-1 chimeric protein, the method comprising administering a pharmaceutical composition comprising an effective amount of the IGF-1 chimeric protein to the subject beyond conventional therapeutic window for treating acute ischemic stroke with pharmacological therapeutic agents. In some embodiments, the administration of the pharmaceutical composition results in (i) an enhanced rate of neurological recovery, (ii) an earlier discharge from hospital, (iii) a reduced neurological deficit at discharge or day 7, (iv) a reduced infarct volume on follow-up imaging, and / or (v) an increased frequency of favorable functional outcomes at 90 days. In some embodiments, the administering of the pharmaceutical composition is after 4.5 hours, after 5 hours, after 6 hours, after 7 hours, after 8 hours, after 945ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 hours, after 10 hours, after 11 hours, after 12 hours, after 13 hours, after 14 hours, after 15 hours, after 16 hours, after 17 hours, after 18 hours, after 19 hours, after 20 hours, after 21 hours, after 22 hours, after 23 hours and up to 24 hours after stroke onset. In some embodiments, the administering of the pharmaceutical composition is between 5 hours and 24 hours, between 6 hours and 24 hours, between 7 hours and 24 hours, between 8 hours and 24 hours, between 9 hours and 24 hours, between 10 hours and 24 hours, between 11 hours and 24 hours, between 12 hours and 24 hours, between 13 hours and 24 hours, between 14 hours and 24 hours, between 15 hours and 24 hours, between 16 hours and 24 hours, between 17 hours and 24 hours, between 18 hours and 24 hours, between 19 hours and 24 hours, between 20 hours and 24 hours, between 21 hours and 24 hours, between 22 hours and 24 hours, between 23 hours and 24 hours after stroke onset. In some embodiments, the administering of the pharmaceutical composition is on average about 12 hours after stroke onset. In other embodiments, the pharmaceutical composition is on average about 12 hours up to 24 hours after stroke onset.

[0216] In some embodiments, the administration of the pharmaceutical composition results in (i) increased rate of neurologic recover from 0.1 - 4 points per day, (ii) earlier discharge by 0.3 - 4 days, (iii) improved neurologic function at discharge by 1 - 6 points on the NIHSS scale, (iv) reduced volume of infarction by 5 - 40%, and / or (v) increase in the relative proportion of subjects achieving good outcomes (mRS 0 - 2) by 5 - 30%.

[0217] In some embodiment, the administration of the pharmaceutical composition results in an increased rate of neurologic recover from 0.1 - 4 points per day (e.g. 0.1, 0.5, 1, 1.5, 2, 2.5, 3. 3.5. 4 points or any value therebetween). In some embodiment, the administration of the pharmaceutical composition results in earlier discharge by 0.3 - 4 days (e.g. 0.3, 0.5, 1 . 1.5. 2. 2.5, 3, 3.5, 4 points or any value therebetw een). In some embodiment, the administration of the pharmaceutical composition results an improved neurologic function at discharge by 1 - 6 points on the NIHSS scale (e.g. 1, 2, 3, 4. 5, or 6 points or any value therebetween). In some embodiment, the administration of the pharmaceutical composition results in a reduced volume of infarction by 5 - 40% (e.g. 5, 10, 15, 20, 25, 30, 35, 40% or any value therebetween). In some embodiment, the administration of the pharmaceutical composition results in an increase in the relative proportion of subjects achieving good outcomes (mRS 0 - 2) by 5 - 30% (e.g. 5, 10, 15, 20, 25, 30% or any value therebetween).46ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0218] In some embodiments, the administering comprises administering a first dose of the pharmaceutical composition comprising about 2 mg / kg of the IGF-1 chimeric protein, followed by a second dose of the pharmaceutical composition comprising about 1.8 mg / kg of the IGF-1 chimeric protein about 24 hour after the first dose. In some embodiments, pharmaceutical composition is administered intravenously. In some embodiments, a solution comprising an effective amount of dextrose is administered intravenously to maintain levels above 80 mg / dL.

[0219] In some embodiments, the effective amount is administered once a day (or every24 hours) to the subject in need thereof. In some embodiments, the effective amount is administered once a day to the subject in need thereof over a period of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days. 12 days, 13 days, 14 days or more. In some embodiments, the effective amount is administered once a day to the subject in need thereof over a period of up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, up to 7 days, up to 8 days, up to 9 days, up to 10 days, up to 11 days, up to 12 days, up to 13 days, up to 14 days. In some embodiments, the effective amount is administered once a day to the subject in need thereof over a period of 7 days. In some embodiments, the effective amount is administered two, three or more times a day to the subject in need thereof. In some embodiments, the effective amount is administered two, three or more times a day to the subject in need thereof over a period of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or more. In some embodiments, the effective amount is administered two, three or more times a day to the subject in need thereof over a period of up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, up to 7 days, up to 8 days, up to 9 days, up to 10 days, up to 11 days, up to 12 days, up to 13 days, up to 14 days. In some embodiments, the effective amount is administered two, three or more times a day to the subject in need thereof over a period of 7 days.

[0220] In some embodiments, a total dose of about 5 to 100 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 100 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 90 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 90 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some47ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 embodiments, a total dose of about 5 to 80 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 80 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 70 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 70 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 60 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 60 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 50 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments a total dose of about 5 to 50 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 40 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 40 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 30 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days. 6 days, or 7 days. In some embodiments, a total dose of about 5 to 30 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 20 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 5 to 20 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 5 to 20 mg / kg of the chimeric proteins described herein is administered over a period of 4 days.

[0221] In some embodiments, a total dose of about 100 to 500 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 100 to 500 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 100 to 400 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments a total dose of about 100 to 400 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 100 to 300 mg / kg of the chimeric proteins described herein48ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 100 to 300 mg / kg of the chimeric proteins described herein is administered over aperiod of 7 days. In some embodiments, a total dose of about 100 to 200 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 100 to 200 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 100 to 150 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 100 to 150 mg / kg of the chimeric proteins described herein is administered over a period of 7 days. In some embodiments, a total dose of about 140 mg / kg of the chimeric proteins described herein is administered over a period of 4 days, 5 days, 6 days, or 7 days. In some embodiments, a total dose of about 140 mg / kg of the chimeric proteins described herein is administered over a period of 7 days.

[0222] In some embodiments, the treatment regimen comprises a descending dosage regimen. In descending dosage regimen, the amount of the dose of the chimeric protein of the disclosure administered in the subject is reduced over the course of the duration of the treatment. In some embodiments, the dose administered on the second day is lower than the dose administered the second day. In other embodiments, the dose administered on the second day is the same than the dose administered the second day, and the dose administered the third day is lower than the dose administered the second day. In some embodiments, the treatment regimen provides for a total dose of about 2 mg / kg to about 200 mg / kg, of about 2 mg / kg to about 20 mg / kg, of about 2 mg / kg to about 10 mg / kg, of about 100 mg / kg to about 200 mg / kg, of about 100 mg / kg to about 150 mg / kg over a predetermined period of time (e.g. 4, 5, 6, or 7 days). In some embodiments, the treatment regimen provides for a total dose of about 5 mg / kg, of about 10 mg / kg, or of about 20 mg / kg over a predetermined penod of time (e.g. 4, 5, 6, or 7 days).

[0223] In some embodiments, a first daily dose is administered the first day, a second daily dose that comprises from about 85% to about 95% of the amount of the chimeric protein present in the first dose is administered on day 2, a third daily dose that comprises from about 65% to about 85% of the amount of the chimeric protein present in the second dose and an amount that is lower than the second dose is administered on day 3, a fourth dose that comprises from about 45% to about 65% of the amount of the chimeric protein present in the first dose49ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 and an amount that lower than the third dose is administered on day 4, a fifth dose that comprises from about 35% to about 45% of the amount of the chimeric protein present in the first dose and an amount that lower than the fourth dose is administered on day 5, a sixth dose that comprises from about 25% to about 35% of the amount of the chimeric protein present in the first dose and an amount that lower than the fifth dose is administered on day 6, and a seventh dose that comprises from about 15% to about 25% of the amount of the chimeric protein present in the first dose and an amount that lower than the sixth dose is administered on day 7. In some embodiments, the descending treatment regimen comprises administering a first daily dose on day 1, a second daily dose corresponding to about 90% of the first daily dose on day 2. a third daily dose corresponding to about 70% of the first daily dose on day 3, a fourth daily dose corresponding to about 50% of the first daily dose on day 4, a fifth daily dose corresponding to about 40% of the first daily dose on day 5, a sixth daily dose corresponding to about 30% of the first daily dose on day 6 and a seventh daily dose corresponding to about 20% of the first daily dose on day 7.

[0224] In some embodiments, a first daily dose is administered the first day, a second daily dose that comprises from about 85% to about 95% (e.g. about 90%) of the amount of the chimeric protein present in the first dose is administered on day 2, a third daily dose that comprises from about 65% to about 85% (e.g. about 70%) of the amount of the chimeric protein present in the second dose and an amount that is lower than the second dose is administered on day 3, a fourth dose that comprises from about 45% to about 65% (e.g. about 50%) of the amount of the chimeric protein present in the first dose and an amount that lower than the third dose is administered on day 4.

[0225] In some embodiments, a first daily dose administered the first day and the second daily dose administered on the second day are the same, a third daily dose comprising from about 65% to about 90% (e.g. about 75%) of the amount of the chimeric protein present in the first dose is administered on day 3, a fourth daily dose that comprises from about 45% to about 65% (e.g. about 50%) of the amount of the chimeric protein present in the second dose and an amount that is lower than the second dose is administered on day 4.

[0226] In some embodiments, the treatment regimen or descending treatment regimen provides a total dose of from about 2 mg / kg to about 20 mg / kg over a period of 7 days. In some embodiments, the treatment regimen provides a total dose of from about 2 mg / kg to about 20 mg / kg over a period of 4 days. In some embodiments, the treatment regimen or descending50ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 treatment regimen provides a total dose of from about 2 mg / kg to about 10 mg / kg over a period of 7 days. In some embodiments, the treatment regimen or descending treatment regimen provides a total dose of from about 2 mg / kg to about 10 mg / kg over a period of 4 days. In some embodiments, the treatment regimen or descending treatment regimen provides a total dose of about 5 mg / kg, about 10 mg / kg, or about 20 mg / kg over a period of 7 days. In some embodiments, the treatment regimen or descending treatment regimen provides a total dose of about 5 mg / kg, about 10 mg / kg, or about 20 mg / kg over a period of 4 days.

[0227] In some embodiments, the treatment regimen comprises a 5-day course of intravenous administration of the chimeric protein, such as scp776. In some embodiments, the treatment regimen comprises a 7-day course of intravenous administration of the chimeric protein, such as scp776. In some embodiments, the treatment regimen comprises a 4-day course of intravenous administration of the chimeric protein, such as scp776. In some embodiments, the treatment regimen comprises a 3-day course of intravenous administration of the chimeric protein, such as scp776. In some embodiments, the treatment regimen comprises a2-day course of intravenous administration of the chimeric protein, such as scp776. In some embodiments, the treatment regimen comprises administering intravenously a first dose at from about 2 mg / kg to about 6 mg / kg on day 1 , and one dose of about 1 mg / kg to about 2 mg / kg one each of the following days. In some embodiments, the first and second dose are the same (e.g. 2 mg / kg), and the third dose is lower than the first dose. For example, the first dose can be 2 mg / kg, the second dose can be 2 mg / kg, the third dose can be 1.5 mg / kg and the fourth dose can be 1 mg / kg, in a 4-day treatment course. In some embodiments, the second dose is lower than the first dose and the third dose is lower than the second dose etc... For example, the first dose can be 2 mg / kg, the second dose can be 1.8 mg / kg, the third dose can be 1.4 mg / kg and the fourth dose can be 1 mg / kg. in a 4-day treatment course. In some embodiments, the second dose is lower than the first dose and the third dose is the same as the second dose, etc... For example, the course can comprise a first dose of about 5.2 mg / kg on day I, and one dose of about 1.3 mg / kg on day 2, day 3, day 4 and day 5, if the course is a 5 day course.

[0228] In some embodiments, the course of treatment comprises administration of the effective amount over 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days. 9 days. 10 days, 11 days, 12 days, 13 days, 14 days or more. In some embodiments, the course of treatment comprises administration of the effective amount over 7 days. In some embodiments, the course51ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 of treatment comprises administration of the effective amount over 4 days. In some embodiments, the course of treatment comprises administration of the effective amount over consecutive days. In some embodiments, the course of treatment comprises administration of the effective amount every day, every 2nd day, every 3rd day or every74th day.

[0229] In some embodiments, the human dose regimen can be calculated based on allometric scaling of the Non-Human Primate to Human dose regimen.

[0230] An estimate of the human equivalent dose (HED) to the efficacious dosing regimen can be obtained via allometric scaling (USDHHS, FDA, CDER, Guidance for Industry, 2005). Allometric scaling treats the problem of differential metabolic rates between species by applying a correction factor based on body surface area to the dose of interest in a given species. Allometric scaling is most frequently used in estimating safe starting doses for first-in-human studies, but it is also commonly applied in translating effective doses from animals to man. The FDA-recommended correction factor for converting dosages in 3 kg rhesus monkeys to humans is 3.1 (USDHHS, FDA, CDER, Guidance for Industry7, 2005). In some embodiments, the estimated HED of the efficacious dose regimen comprises an initial dose of 5.2 mg / kg. followed by additional doses at 24 hour intervals of 1.3 mg / kg.

[0231] In some embodiments, the pharmaceutical compositions described herein can further include one or more additional bioactive or therapeutic agents or components to aid in the treatment of damaged tissue or cells and / or facilitate the tissue regenerative process.

[0232] In some embodiments, the method comprises administering two or more (e.g. two. there or more) pharmaceutical compositions. The different pharmaceutical compositions may be administered to the subject in any order and in any suitable interval. For example, in some embodiments, the one or more pharmaceutical compositions are administered simultaneously or near simultaneously. In some embodiments, the method comprises a staggered administration of the two or more pharmaceutical compositions, where a first composition is administered and a second pharmaceutical composition is administered at some later time point. Any suitable interval of administration which produces the desired therapeutic effect may be used.

[0233] In certain embodiments, the method has an additive effect, wherein the overall effect of the administration of a combination of therapeutic agents or procedures is approximately equal to the sum of the effects of administering each therapeutic agent or procedure alone. In other embodiments, the method has a synergistic effect, wherein the overall52ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 effect of administering a combination of therapeutic agents or procedures is greater than the sum of the effects of administering each therapeutic agent or procedure alone.

[0234] In some embodiments, a therapeutically effective amount of the pharmaceutical composition comprising the chimeric protein reduces at least one symptom associated with a disorder by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In some embodiments, a therapeutically effective amount of the chimeric protein reduces at least one symptom associated with a nervous system disorder by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In some embodiments, a therapeutically effective amount of the chimeric protein disclosed herein reduces at least one symptom associated with a nervous system disorder by. e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%. about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. In some embodiments, a therapeutically effective amount of the chimeric protein reduces at least one symptom associated with a disorder for, e.g., at least one week, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.Dextrose supplementation

[0235] Administration of IGF-1 or IGF-1 chimeric proteins (also referred herein as chimeric protein or fusion proteins or IGF-1 containing fusion proteins) has the off-target effect of decreasing blood glucose levels. Aspects of the disclosure relate to the administration of variable rate intravenous infusion of dextrose solutions in normal saline (i.e., 0.9%), half normal saline (i.e.. 0.45%), Ringer’s Lactate or Hartmann’s Solution (i.e., 130-131 mM NaCl, 4-5 mM KC1, 2-3 mM CaCk, 28-29 mM CsHsNaCh), 0.2% Saline, or water to buffer against the blood glucose lowering effect. In some embodiments, eugly cemic maintenance is achieved by continuous intravenous dextrose infusion following administration of IGF-1 or IGF-1 containing fusion proteins. In some embodiments, at low rates of dextrose infusion, normal53ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 blood sugar levels can be maintained following therapeutic doses of IGF-1 or IGF-1 containing fusion proteins. In some embodiments, in the event that blood glucose levels decrease following therapeutic doses of IGF-1 containing fusion proteins, transient hypoglycemia can be reversed by increasing the rate of the supplemental dextrose infusion. For subjects that receive multi-day doses of IGF-1 or IGF-1 containing fusion proteins, the rate of supplemental dextrose infusion can be slowly decreased and discontinued in the 24 to 48 hours following the last therapeutic dose of IGF-1 or IGF-1 containing fusion proteins. The eugly cemic buffering potential of supplemental dextrose following administration of IGF-1 containing fusion proteins does not depend on the exact amino acid sequence of the IGF-1 variant contained within the IGF-1 containing fusion protein or the composition of other domains in the fusion protein (as the blood glucose lowering potential is attributable to the IGF-1 domain).

[0236] Provided herein are method for dextrose supplementation to support eugly cemia and / or prevent prolonged hypoglycemic excursions.

[0237] In some embodiments, the method comprises administering to a subject in need thereof a dextrose solution prior to, during, and / or after administering the IGF-1 or IGF-1 chimeric protein (or the or pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein) or any combination of the foregoing to sustain euglycemia. In some embodiments, the administration of dextrose solution mitigates the adverse hypoglycemic effect of the administration of IGF-1 or IGF-1 chimeric protein. In some embodiments, the administering of the dextrose solution is by intravenous infusion. In other embodiments, the administering of the dextrose solution is by intravenous bolus injection.

[0238] In some embodiments, the dextrose solution is administered about 30 min, about 25 min, about 20 min, about 15 min, about 10 min, about 5 min prior to administering the IGF- 1 or IGF-1 chimeric protein or the pharmaceutical composition comprising the IGF-1 or IGF- 1 chimeric protein. In some embodiments, the dextrose solution is administered from about 25 min to about 30 min, about 20 min to about 25 min, about 15 min to about 20 min, about 10 min to about 15 min, about 5 min to about 10 min, prior to administering the IGF-1 or IGF-1 chimeric protein or the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein. In some embodiments, the subject in need thereof treated with the IGF-1 or IGF-1 chimeric protein or pharmaceutical compositions described herein is continuously infused with a dextrose solution to support euglycemia. In some embodiments, the subject in need thereof is continuously infused with a dextrose solution over a period of about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours. In some embodiments, the subject in54ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 need thereof is continuously infused with a dextrose solution over a period of from about 24 hours to about 120 hours, from about 24 hours to about 96 hours, from about 24 hours to about 72 hours, from about 24 hours to about 48 hours, from about 48 hours to about 120 hours, from about 48 hours to 96 hours, from about 48 hours to 72 hours, from about 72 hours to 120 hours, from about 72 hours to about 96 hours, or from about 96 hours to about 120 hours. In some embodiments, the subject in need thereof is infused with a dextrose solution about 30 min, about 25 min, about 20 min, about 15 min, about 10 min, about 5 min prior to administering the IGF-1 or IGF-1 chimeric protein and is continuously infused with a dextrose over a period of about 24 hours, about 48 hours, about 72 hours, from about 24 hours to 72 hours, from about 24 hours to 48 hours, from about 48 hours to 72 hours. In some embodiments, infusion is over a period of about 48 hours.

[0239] In some embodiments, the subj ect is infused with the dextrose solution for about 48 hours. In some embodiments, the subject is infused with the dextrose solution up to the end of the treatment with the IGF-1 or IGF-1 chimeric protein. In some embodiments, the subject is infused with the dextrose solution up to about 24 hours after the end of the treatment with the IGF-1 or IGF-1 chimeric protein.

[0240] For example, the subject can be treated for 4 days with the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein and the subject can be infused for up to 4 or 5 days with the dextrose solution. Alternatively, the subject can be treated for 1, 2, or 3 days with the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein and the subject can be infused for up to 2, 3, or 4 days with the dextrose solution. Alternatively, the subject can be treated daily for up to 5 days with the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein and the subject can be infused with the dextrose solution for up to 1 or 2 days following the last treatment of the pharmaceutical composition that comprises the IGF-1 or IGF-1 chimeric protein.

[0241] In some embodiments, the subject in need thereof is administered the IGF-1 or IGF-1 chimeric protein or pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein via bolus injection and is administered a dextrose solution by continuous intravenous infusion. In some embodiments, the subject in need thereof is administered the IGF-1 or IGF-1 chimeric protein or pharmaceutical composition comprising the IGF-1 or lGF- 1 chimeric protein intrathecally and is administered a dextrose solution by continuous intravenous infusion. In some embodiments, the administering of the dextrose solution by continuous infusion is about 1 min to about 30 min prior to administering the IGF-1 or IGF-155ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 chimeric protein. In some embodiments, the administering of the dextrose solution by continuous infusion is about 30 min, about 25 min, about 20 min, about 15 min, about 10 min, about 5 min, about 4 min, about 3 min, about 2 min, about 1 min prior to administering the IGF-1 or IGF-1 chimeric protein. In some embodiments, the administering of the dextrose solution by continuous infusion is during the administration of the IGF-1 or IGF-1 chimeric protein or the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein. In some embodiments, the administering of the dextrose solution by continuous infusion is during and after the administration of the IGF-1 or IGF-1 chimeric protein or the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein. In some embodiments, the pharmaceutical composition comprising the IGF-1 or IGF-1 chimeric protein does not contain dextrose.

[0242] In some embodiments, the method comprises starting the dextrose infusion is started with a slow rate of infusion (i.e., 0.1 mL / kg / h) shortly before administration (t < 30 minutes) of the IGF-1 or IGF-1 containing fusion protein. In some embodiments, the method further comprises adjusting the infusions rate to support euglycemia.

[0243] In some embodiments, the infusion can be at a rate ranging from 0.01 mL / kg / hr to 5 mL / kg / hr. For example, the infusion can be at a rate of about 0.1 mL / kg / h. In some embodiments, the infusion can start at a rate of about 0.1 mL / kg / h and then be adjusted at an incremental rate of +0.05 mL / kg / hr to +2 mL / kg / hr (for example +0.05 mL / kg / hr. +0.1 mL / kg / hr, +0.2 mL / kg / hr, +0.3 mL / kg / hr, +0.4 mL / kg / hr, +0.5 mL / kg / hr, +0.6 mL / kg / hr, +0.7 mL / kg / hr, +0.8 mL / kg / hr, +0.9 mL / kg / hr, +1 mL / kg / hr, +1.1 mL / kg / hr, +1.2 mL / kg / hr, +1.3 mL / kg / hr, +1.34 mL / kg / hr, +1.5 mL / kg / hr, +1.6 mL / kg / hr, +1.7 mL / kg / hr, +1.8 mL / kg / hr, +1.9 mL / kg / hr, +2 mL / kg / hr). In some embodiments, the infusion can be at a rate of about 2 mL / kg / hr and then be adjusted at a decremental rate of -0.05 mL / kg / hr to -1 mL / kg / hr (for example -0.05 mL / kg / hr, -0.1 mL / kg / hr, -0.2 mL / kg / hr, -0.3 mL / kg / hr, -0.4 mL / kg / hr, -0.5 mL / kg / hr, -0.6 mL / kg / hr, -0.7 mL / kg / hr, -0.8 mL / kg / hr, -0.9 mL / kg / hr, -1 mL / kg / hr).

[0244] In some embodiments, the dextrose solution is in sterile water or normal saline solution. In some embodiments, the dextrose solution comprises from about 5% (w / v) dextrose to about 50% (w / v) dextrose to support euglycemia. In some embodiments, the dextrose solution is in sterile water or normal saline. In some embodiments, the subject in need thereof can be administered from 5% dextrose to 40% dextrose (w / v). In some embodiments, the subject in need thereof can be administered from 5% dextrose to 35% dextrose (w / v). In some embodiments, the subject in need thereof can be administered from 5% dextrose to 30%56ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 dextrose (w / v). In some embodiments, the subject in need thereof can be administered from 5% dextrose to 25% dextrose (w / v). In some embodiments, the subject in need thereof can be administered from 5% dextrose to 20% dextrose (w / v). In some embodiments, the subject in need thereof can be administered from 5% dextrose to 15% dextrose (w / v). In some embodiments, the subject in need thereof can be administered from 5% dextrose to 10% dextrose (w / v).

[0245] In some embodiments, the dextrose solution comprises about 5% (w / v) dextrose, about 6% (w / v) dextrose, about 7% (w / v) dextrose, about 8% (w / v) dextrose, about 9% (w / v) dextrose, about 10% (w / v) dextrose, about 11% (w / v) dextrose, about 12% (w / v) dextrose, about 13% (w / v) dextrose, about 14% (w / v) dextrose, about 15% (w / v) dextrose, about 16% (w / v) dextrose, about 17% (w / v) dextrose, about 19% (w / v) dextrose, about 20% (w / v) dextrose.

[0246] In some embodiments, the dextrose solution comprises from about 5% (w / v) dextrose to about 6% (w / v) dextrose, from about 6% (w / v) dextrose to about 7% (w / v) dextrose, from about 7% (w / v) dextrose to about 8% (w / v) dextrose, from about 8% (w / v) dextrose to about 9% (w / v) dextrose, from about 9% (w / v) dextrose to about 10% (w / v) dextrose, from about 10% (w / v) dextrose to about 11% (w / v) dextrose, from about 11% (w / v) dextrose to about 12% (w / v) dextrose, from about 12% (w / v) dextrose to about 13% (w / v) dextrose, from about 13% (w / v) dextrose to about 14% (w / v) dextrose, from about 14% (w / v) dextrose to about 15% (w / v) dextrose, from about 15% (w / v) dextrose to about 16% (w / v) dextrose, from about 16% (w / v) dextrose to about 17% (w / v) dextrose, from about 17% (w / v) dextrose to about 18% (w / v) dextrose, from about 18% (w / v) dextrose to about 19% (w / v) dextrose or from about 19% (w / v) dextrose to about 20% (w / v) dextrose.

[0247] In some embodiments, the subject in need thereof is continuously supplemented with from about 5% dextrose to about 20% dextrose (w / v), about 5% dextrose to about 15% dextrose (w / v), about 5% dextrose to about 10% dextrose (w / v), about 5% (w / v), about 10% dextrose (w / v).

[0248] In some embodiments, for rapid adjustment, a 50% (w / v) solution of dextrose can be administered as IV bolus.

[0249] In some embodiments, blood glucose is monitored during the administration of the dextrose solution. In some embodiments, blood glucose is monitored before the administration of the dextrose solution. In some embodiments, blood glucose is monitored after the administration of the dextrose solution. In some embodiments, the blood glucose is57ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 monitored every 60 min + / - 20 min during the administration of the dextrose solution. In some embodiments, the blood glucose is monitored every 60 min + / - 20 min during the first 24 hours of the dextrose supplementation. In some embodiments, the blood glucose is monitored every 120 min + / - 20 min from 24 hours to 48 hours or more after the start of the dextrose supplementation. In some embodiments, the blood glucose is monitored according to the standard of care from 48 hours after the start of the dextrose supplementation. In some embodiments, the rate of dextrose supplementation is lowered or discontinued if a subject’s blood glucose measures > 150 mg / dL. In other embodiments, the rate of dextrose supplementation is lowered or discontinued if a subject’s blood glucose measures > 180 mg / dL.

[0250] In some embodiments, the Blood Glucose Management Plan (BGMP) is in accordance with current American Heart Association (AHA) / American Stroke Association (ASA) guidance for blood glucose management in acute ischemic stroke (Powers et al, Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association / American Stroke Association. Stroke. 2019).

[0251] In some embodiments, the subject in need thereof is monitored for blood glucose levels. In some embodiments, blood glucose (BG) monitoring is for a minimum of 48 hours under the following guidelines:

[0252] BG levels are utilized to determine the rate of dextrose supplementation based on Table below.ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Abbreviations: BG=blood glucose; BGMP=Blood Glucose Management Plan; D10=10% dextrose in water.

[0253] Following each administration of the IGF-1 or IGF-1 chimeric protein, the blood glucose level of the subject is checked at 30 minutes (±15 minutes), and hourly thereafter (±20 minutes) through 8 hours postdose. After 8 hours, if blood glucose levels are stable, glucose checks may be modified to every 2 hours (±20 minutes). Stable blood glucose levels are defined as blood glucose greater than 100 mg / dL for 4 consecutive hours without requiring increase to the rate of dextrose infusion.

[0254] Any change in clinical status suggesting a decrease in blood glucose levels (e.g., altered mental status post-dose) warrants an immediate glucose check, and if no longer stable, a return to hourly checks and dextrose rate adjustments until stabilized. If blood glucose levels were stabilized but are no longer stable: o If BG < 80 mg / dL, recheck BG every 15 minutes and adjust / administer dextrose per Table 5 until BG confirmed > 80 mg / dL. o When BG confirmed > 80 mg / , resume hourly glucose checks if within 8 hours postdose.ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 o If later than 8 hours postdose, resume hourly glucose checks again until BG is stabilized (BG > 100 mg / dL for 4 consecutive hours without increased dextrose administration), then glucose checks may again be modified to every 2 hours.

[0255] In some embodiments, the BG level is measured by a central laboratory test, bedside test (e.g., i-STAT® system, arterial blood gas), or by fingerstick.

[0256] In some embodiments, before administration of IGF-1 or IGF-1 chimeric protein, an IV infusion of dextrose solution (e.g. D10) is started at a rate of 0. 1 mL / kg / h.

[0257] In some embodiments, administration of the dextrose solution begins no more than 30 minutes before injection of the IGF-1 or IGF-1 chimeric protein.

[0258] In some embodiments, administration of the dextrose solution continues through at least Hour 48, unless BG levels are greater than 150 mg / dL on 2 consecutive readings separated by 30 minutes or more, then the dextrose administration is discontinued or the rate of administration of dextrose is decreased.

[0259] In some embodiments, if BG levels are decreasing or less than 80 mg / dL, the rate of administration of dextrose solution is increased.

[0260] In some embodiments, the dextrose solution can be 10% dextrose in water. In some embodiments, the dextrose solution can be switched to 5% dextrose in normal saline if there are clinical concerns for excess free water administration at the discretion of the site investigation team.

[0261] In some embodiments, if 50% dextrose injection is given for any reason, BG testing (fingerstick or laboratory glucose) should be conducted every 15 minutes until the BG level is > 80 mg / dL.EXAMPLES

[0262] The following Examples are offered by way of illustration and not by way of limitation. Unless otherwise specified, all reagents and solvents are of standard commercial grade and are used without further purification. Using routine modifications, the procedures provided in the following Examples may be varied by those of ordinary' skill in the art to make and use other bi-specific fusion proteins and pharmaceutical compositions within the scope of the present disclosure.60ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Example 1: Scp776, IGF-1 Fusion Protein for Acute Therapy to Promote Escape from Apoptosis in Tissues Affected by Ischemic Injury: Two Randomized Placebo-Controlled Phase 1 Studies in Healthy Adults

[0263] Abstract

[0264] Apoptosis is a major driver of cell loss and infarct expansion in ischemic injuries such as acute ischemic stroke (AIS) and acute myocardial infarction (AMI). Insulin-like growth factor- 1 (IGF-1) can mitigate cell death and potentiate recovery following acute ischemic injury’, but short half-life and non-specificity limit its therapeutic potential. Scp776 is an IGF- 1 fusion protein designed to target damaged tissue and promote apoptosis escape and is in clinical development as an acute therapy for AIS and AMI. Two phase 1 placebo-controlled studies in healthy volunteers evaluated safety’, tolerability7, pharmacokinetic profile, and pharmacodynamics under single (1, 2, or 4 mg / kg) or multiple dosing regimens (6, 6.2, or 7.25 mg / kg total doses). In addition, a blood glucose management plan was developed and implemented to mitigate hypoglycemia that may develop following scp776 injection. Scp776 was well tolerated in healthy volunteers (n = 51) without serious adverse events. Exposure increased in a near dose-proportional manner with a mean half-life across all doses of 8 hours. Adaptive dextrose infusions maintained normal blood glucose levels with occasional mild hypoglycemic events. These results informed scp776 dose selection and the design of blood glucose monitoring protocols for phase 2 studies.Introduction

[0265] Apoptosis is a major driver of cell loss and infarct expansion in ischemic injuries such as acute ischemic stroke (AIS)1'3and acute myocardial infarction (AMI).4'6The resulting hypoxia from acute occlusion of neural or coronary’ arteries initiates a biochemical cascade that may progress to irreversible cell death. This ischemic cascade includes excitotoxicity, mitochondrial dysfunction, free radical production, and autophagy.3’7,8Current treatment strategies in AIS and AMI focus on blockage removal and revascularization9,10but there are no approved treatments to protect cells from hypoxia-induced apoptosis or improve recovery7from ischemia / reperfusion injury following occlusion and revascularization.11

[0266] Insulin-like growth factor- 1 (IGF-1) is a multifunctional polypeptide that regulates anti-apoptotic and mitogenic pathways in many cell types12and is responsible for context-dependent proliferation, differentiation, growth, and maturation in almost all organs,61ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 including brain and heart.13,14IGF-1 has been shown to mitigate cell death and potentiate recovery following acute ischemic injury [reviewed in15’17] and these protective effects suggest a therapeutic potential in disorders such as AIS and AMI. The protective effects are driven by IGF-1 receptor (IGF-1R) signaling cascades activating MAPK-ERK mitogenic and PI3K-AKT anti-apoptotic pathways17,18that promote tissue growth and repair by increasing anabolic processes. In animal models of stroke and myocardial infarction, intravenous (IV) injected recombinant human IGF-1 can reduce infarct size19,20and protect myocytes from apoptosis.20,21The levels of endogenous plasma IGF-1 levels are positively correlated with clinical outcome after AIS in humans.22,23

[0267] However, the therapeutic application of wild type or recombinant IGF-1 in human disease is hindered by short half-life, interactions with circulating IGF-1 binding proteins, and widespread receptor expression. Administration of IGF-1 can also result in metabolic effects that include decreased blood glucose levels. The IGF-1 fusion protein scp776 was designed to mitigate hypoxic damage and reperfusion injury and is in development as an acute therapy for AIS and AMI. Scp776 is designed to mechanistically target damaged tissue and promote apoptosis escape. Three linked domains comprise scp776 (Figure 1A). The carboxy -terminal annexin V (AnxV, also known as annexin a5) domain drives accumulation of scp776 in target tissues through selective, high-affinity binding to phosphatidylserine (PS) headgroups exposed on the outer leaflet of apoptotic cells24This results in selective delivery of scp776 and signaling in cells presenting PS and IGF-1R in damaged tissue. The aminoterminal IGF-1 domain is the pharmacologic effector arm. It is a sequence variant25that was selected to decrease the likelihood of stimulating IGF-1R on cells that are not presenting PS. A central human serum albumin (HSA) domain serves both as a scaffold and as an extender of drug half-life.

[0268] As a result of ischemia / reperfusion injury, cells of the injured core and adjacent region undergo necrosis, apoptosis, and other forms of cell death, which can expand to surrounding cells. In the absence of treatment, injury' spreads to peripheral tissue, further impairing tissue function.26The working hypothesis for scp776's mechanism of action is that it will limit damage from acute ischemic injury by promoting apoptosis escape in viable tissue and preventing the expansion of the injured core.

[0269] In this paper we assess the targeted activation of pro-survival signaling pathways by scp776 using a cell-based assay measuring phosphory lation of protein kinase B62ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025(i.e., pAKT) in apoptotic cardiomyocytes. We then evaluate scp776 safety, tolerability, pharmacokinetic (PK) profile, and pharmacodynamics (PD) under single ascending or multiple dosing regimens in two phase 1 placebo-controlled studies in healthy volunteers. In addition, a blood glucose management plan was implemented and optimized to reduce the risk of hypoglycemia, which may occur in some individuals following scp776 administration.Methods

[0270] Pro-survival Signaling Activation in vitro Assay

[0271] To quantitate the selectivity of scp776 to activate IGF-1 receptor (IGF-1R) mediated pro-survival signaling in damaged tissues, an in vitro assay measuring phosphorylation of AKT was used. The methods to determine potency (EC50s) of scp776 in activating pAKT in induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) are described in detail in Supplementary7Material: Methods and outcomes to determine pAKT potency (EC50s) of scp776 in induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM). In brief, scp776 stimulation was assayed in iPSC-derived human CMs under 2 conditions: in the absence of doxorubicin (representing control / healthy CMs) and in the presence of doxorubicin (representing injured / apoptotic CMs). The concentration dependencies of scp776 mediated activation of pro-survival signaling in both conditions were determined using a pAKT ELISA. Scp776 EC50 values were determined by fitting 3 -parameter logistic functions to dose-response curves, and the potency shift between healthy and apoptotic cells was calculated as the ratio of their respective EC50 values.

[0272] pAKT potency (EC50) in induced pluripotent stem cell (iPSC)-Derived Cardiomyocytes (CM)

[0273] In cardiomyocytes (CMs), IGF-1 drives pro-survival AKT phosphorylation (pAKT) through the activation of the IGF-1 receptor (IGF-1R) [4], When CMs undergo apoptosis during an insult, the translocation of phosphatidylserine (PS) from the inner leaflet of the cell membrane to the outer surface occurs enabling scp776 to selectively bind to apoptotic CMs through the AnxV targeting arm and activate AKT via the IGF-1 domain. Selective AKT signaling by scp776 in apoptotic CMs was quantitated using an in vitro assay.

[0274] Cell culture and scp776 stimulation

[0275] iPSC-derived human CMs were obtained from Cellular Dynamics International, Inc., plated at 15,000 cells / well onto 0.1% gelatin-coated cell culture microplates and63ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 maintained for 16 days in serum-based maintenance media. On Day 16. media was replaced cultured with low-serum media in the presence of DMSO for healthy CMs and doxorubicin for apoptotic CMs. After 24 hours, 10-fold serial dilutions of scp776 were added to CMs for 10 minutes followed by washing, cell lysis and storage at -80°C until pAKT ELISA. The scp776 assay concentration range was 0.001 - 10,000 nM (0.110 ng / mL - 1.10 mg / mL: scp776 MW = 110.318 g / mol)

[0276] pAKT ELISA

[0277] Black microplates (GREINER-BIO-ONE 781077, PS, F-BOTTOM.FLUOTRAC, HIGH BINDING) were coated with anti-AKT capture antibody (clone SKB1, Millipore Cat # 05-591) and stored overnight. After washing, and blocking, rhAKT controls and samples were added to ELISA plates and incubated for 1.5 hours with pAKT (S473) detection antibody (CST 4060), followed by incubation with anti-Rabbit-IgG-HRP secondary antibody (CST 7074) for 30 minutes. ELISA plate luminescence was read following addition of SuperSignal ELISA Pico chemiluminescent peroxide substrate (Pierce / Thermo Fisher Scientific Cat # 37069) and enhancer.

[0278] Analysis

[0279] pAKT standard curves were plotted, and scp776 EC50 values and potency shifts (equal to healthy pAKT EC50 / apoptotic pAKT EC50) were calculated from 3-parameter best fits for dose-response curves (Figure IB) where

[0280] ELIS As for quantitation of scp776 in human serum in phase 1 studies

[0281] Human serum for the quantitation of scp776 was analyzed using GLP-validated enzyme linked immunosorbent assay (ELISA) methods. An aliquot of human serum containing scp776 was assayed on plates coated with a 1 pg / mL solution of anti-IGF-1 capture antibody (R&D Systems - Part # MAB291). A peroxidase conjugated anti-HSA antibody (Phase la - Abeam, Part # ab24438; Phase lb - Bethyl Laboratories, Part # A280-229P) was the primary detection antibody followed by TMB solution detection. Following phase la the detection antibody was discontinued by the manufacturer, and the assay was revalidated with a replacement antibody.

[0282] Each plate contained 8 scp776 standard levels assayed in duplicate ranging from 0.5 - 20 pg / mL; these values were the lower and upper limits of quantitation, respectively.64ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Standard response versus concentration curves were fit to a 4-parameter logistic model with 1 / y2weighting, which was used to interpolate participant-derived and quality control sample concentrations and back-calculate standard concentrations. Four QC levels were assayed per plate in 6 wells per level. Standards and QCs were rejected if the back-calculated or interpolated values differed by > 20% from their nominal concentrations, or if the coefficient of variation of the signal between wells at a given level was > 20%. Plates were accepted if at least 6 standard levels were accepted, and if more than 2 / 3 of QC samples and 50% of samples at each QC level were accepted. Data from rejected plates was not used in subsequent calculations and the samples were re-assayed.

[0283] Determination of anti-scp776 antibodies in human serum in phase 1 studies

[0284] Anti-drug antibodies (ADA) directed against scp776 in participant serum samples were assayed using a three-tiered testing strategy of screening, confirmation, and titer determination. The basis of each assay tier was a GLP-validated test method described as follows. Participant samples and positive control antibody samples in human serum were treated with 0.3 M acetic acid for 15 minutes, neutralized by the addition of 1 M Tris, pH 10.0, then added to scp776-coated and blocked Meso Scale Discovery (MSD) assay plates. Following incubation and washing, a SULFO-TAG-scp776 conjugate was added as the detection reagent. Read buffer was added to each well and plates were read using an MSD SQ120 Imager. The sensitivity of the screening assay as determined during validation was 14.91 ng / mL (99% confidence level).

[0285] In screening assays, participant samples were deemed positive for ADA if the mean signal across duplicate wells was greater than the plate-specific cut point, as determined by the mean of negative control samples from that plate times the screening correction factor (sCF) determined during assay validation (sCF = 1.1831). Positive samples were tested for specificity of binding to scp776 in confirmatory assays. In confirmatory assays, each participant sample was tested in the presence and absence of an inhibitor solution, 8 jrg / mL scp776. Positivity was confirmed if the percent inhibition upon addition of scp776 was greater than the inhibitory cut point (iCP) determined during validation (iCP = 11.4%). Titers were determined for samples that confirmed positive, by assaying serial 2-fold dilutions of participant samples until signal below the titer cut point (tCP) was measured. An interpolation of the signal between the last dilution above the tCP and the first dilution below the tCP was used to call each sample’s titer.Study Design65ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0286] Both phase 1 studies were randomized, double-blind, placebo-controlled, healthy volunteer studies conducted at a single clinical pharmacology site (Celerion, Tempe, AZ;). SCP-CL-0001 was a phase la first-in-human sequential single ascending dose study. Eligible participants were healthy adult males 35-60 years of age with BMI > 18.5 and < 29 kg / m2. SCP-CL-0002 was a phase lb study comprised of single doses and multiple doses of scp776 in combination with continuous blood glucose monitoring and supplemental intravenous (IV) dextrose infusions. Healthy adult males and females 21-65 years of age with BMI > 18.5 and < 32.0 kg / m2were enrolled. Studies were performed in compliance with the principles of the Declaration of Helsinki. An independent review board (Advarra, Inc. Columbia, MD) approved the protocols, and all participants provided written informed consent.

[0287] Normal physical examinations and the absence of, or no known history of, diabetes, hypoglycemia, bleeding and coagulation disorders, or other significant medical problems were required for enrollment. Only females of non-childbearing potential and males who were vasectomized or who agreed to condom and spermicide use were enrolled. Pregnant or lactating females were excluded from participation.

[0288] Following screening to verify inclusion and exclusion criteria, eligible subjects were randomized to receive single or multiple IV injections of scp776 or normal saline placebo in a 6:2 allocation. In both studies, scp776 and volume-matched normal saline placebo were administered via IV injection or IV infusion pump in the upper extremity at a rate of 2.5 mL / min. The volume administered was adjusted based on dose level and subject weight. In the immediate post-dose period, blood draws were performed in the contralateral upper extremity; however, due to the number of blood draws in both studies and the need for simultaneous dextrose infusion in the phase lb study, blood draws w ere at times performed in the dosing arm after the immediate post-dose period.Dosing Schedule

[0289] Cohort assignments and study interventions are shown in Figure 2. In the phase la study, single doses of 1 mg / kg, 2 mg / kg, or 4 mg / kg scp776 or placebo were administered by IV injection on Day 1 to subjects in Cohorts 1, 2, and 3, respectively. Subjects fasted overnight for at least 10 hours until 20 minutes prior to their initial scheduled morning dose when they received a high-fat / high-calorie breakfast meal. Subjects then fasted for at least 4 hours post dose. Scp776 and placebo were administered no later than 20 minutes after subjects completed the breakfast meal.66ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0290] In the phase lb study, IV dextrose infusion was initiated for all subjects prior to the first dose and continued for 48 hours after the last dose. Cohorts 1 and 2 received a single dose of 4 mg / kg scp776 or placebo injection on Day 1. The remaining cohorts received multiple doses of scp776 or placebo over 3 or 4 days for total doses of 6-7.25 mg / kg:

[0291] Cohort 3 received 3 mg / kg scp776 or placebo on Day 1 and Day 3;

[0292] Cohort 4 received 2 mg / kg scp776 or placebo on Day 1, Day 2, and Day 3;

[0293] Cohort 5 received 2 mg / kg scp776 or placebo on Days 1 and 2, 1.75 mg / kg or placebo on Day 3, and 1.5 mg / kg or placebo on Day 4;

[0294] Cohort 6 received 2 mg / kg, 1.8 mg / kg, 1.4 mg / kg, and 1 mg / kg scp776 or placebo on Days 1, 2, 3, and 4, respectively.

[0295] Cohorts 5 and 6 had descending doses of scp776 over the four days to manage peak exposures and potential decreases in blood glucose levels. Subjects in Cohort 1 of the phase lb study were continuously infused with dextrose 5% in normal saline through 48 hours. For all other cohorts Dextrose 10% in sterile water was used to manage serum glucose levels. The rate of supplemental dextrose administration was adaptively varied to maintain normal blood glucose levels. Scp776 IV injection was administered at 2.5 mL / min.

[0296] Sentinel groups of two subjects in each single-dose cohort in the phase 1 a study were monitored for safety and tolerability after dosing before the remaining subjects in the cohort received study drug. In both studies clinical and laboratory safety data were reviewed for each subject in a cohort to ensure there were no dose limiting toxi cities before proceeding to dose escalation in subsequent cohorts.Safety Assessments and Analyses

[0297] The primary outcomes were the incidence and nature of any treatment-emergent adverse events (TEAEs) and serious adverse events, and any potentially clinically significant abnormalities in physical examinations, clinical laboratory tests, vital signs, 12-lead safety7ECG, and telemetry. Inspection of the site of study drug administration was monitored for injection site reaction pre-dose, at the end of IV injection, and 4, 12, and 24 hours following the end of IV injection.

[0298] Descriptive statistics (n, mean, SD, minimum, median, and maximum) were calculated for quantitative safety data and change from baseline. Frequency counts were67ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 reported for categorical data. Data from subjects who received placebo were pooled across cohorts. Adverse events were assigned using the Medical Dictionary for Regula- tory Activities (MedDRA version 23.1), and severity was assessed using the World Health Organization toxicity grading scale.Pharmacokinetic Assessments and Analyses

[0299] Blood samples for PK analysis were analyzed from subjects receiving scp776 (PK population) pre-dose and after scp776 administration over the first 72 (phase la) or 312 (phase lb) hours and during follow-up through Day 14. Serum concentrations of scp776 used in PK calculations were determined using validated enzyme-linked immunosorbent assay (ELISA) methods developed at Celerion (Lincoln, Nebraska) with an analytical range of 0.5 to 20 pg / mL.

[0300] Serum concentrations of scp776 were summarized by dose level and time point and summary statistics were calculated for all time points. Noncompartmental PK parameters were calculated from the serum scp776 concentration-time data using Phoenix® WinNonlin® Version 8.1 and included maximum concentration observed (Cmax); concentration at the end of injection (Ceoi); time to reach Cmax (Tmax); difference in maximum observed concentration between dosing days (Delta Cmax); time of last measurable concentration (Tlast); the area under the concentration vs time curve (AUC) was calculated using the trapezoidal method until the last measurable concentration (t) (AUCO-t) or during dosing intervals (AUCO-24 or 48); AUC extrapolated to infinity (AUCO-inf); percentage of the AUC extrapolated from the last observed time point (AUC%extrap); apparent terminal elimination rate constant (Kel); apparent terminal elimination half-life (tl / 2); total serum clearance after IV administration (CL); volume of distribution during the terminal elimination phase (Vz).

[0301] SAS® PROC MIXED was used to evaluate dose proportionality' of serum scp776 PK parameters, where a linear relationship between the In-transformed PK parameters and the In-transformed dose was fitted using a regression model with In-transformed dose as a covariate.Pharmacodynamic Assessments and Analyses

[0302] Blood glucose levels and heart rate were determined pre-dose (baseline) and at multiple timepoints up to 144 hours post-dose.68ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0303] Blood glucose was monitored via frequent bedside (capillary or venous) assessments and confirmed by clinical laboratory assessments. Laboratory glucose readings were used when bedside monitoring readings were not available. As part of the blood glucose management plan in the phase lb study, blood glucose levels for all subjects were also continuously monitored via telemetry. The continuous glucose monitoring (CGM) devices were installed from check-in to 48 hours after single dosing or last dose. Cutoffs for defining hypoglycemia varied slightly between studies. For the purpose of comparative analyses, blood glucose levels below the normal (eugly cemic) range were defined as <75 mg / dL.27,28

[0304] Changes in blood glucose levels and heart rate from baseline were calculated by subtracting baseline values from the post-dose values. Blood glucose levels, heart rate, change in blood glucose level from baseline, and change in heart rate from baseline were summarized by dose level and time point.

[0305] During the phase lb study, changes in the dextrose infusion rate were recorded. The total amount of dextrose administered (in grams) was estimated every 6 hours and daily. Summary statistics included n, mean, SD, CV%, SEM, minimum, median, and maximum.

[0306] The PK / PD relationship was explored using scatter plots of blood glucose, heart rate, and coagulation parameters versus time-matched (when possible) serum PK concentration of scp776. A linear regression model estimated slope and its 95% CI, intercept and its 95% CI, r-squared. and p-value for slope.

[0307] Changes in blood glucose between dose levels were compared using slopes derived from blood glucose versus time for each subject and slope values were then compared between dose levels and placebo using one-way analysis of variance (ANOVA).

[0308] The frequencies of low blood glucose events were compared by dose level between phase la subjects (no supplemental IV dextrose) and phase lb subjects (with supplemental IV dextrose). The per subject frequency of low blood glucose events was taken as the number of events over the number of subjects. Odds ratios and 95% confidence intervals representing the likelihood of a low blood glucose event without dextrose supplementation were calculated. As events could occur more than once in each subject, significant odds ratio findings were identified using a Poisson test.Detection of Anti-drug Antibodies and Analysis69ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0309] Blood samples for detection of anti-drug antibodies (ADA) were analyzed pre- first dose and up to 28 days post-dosing. Results from screening and confirmatory ADA assays were listed as positive or negative and titers were determined for samples with a positive confirmatory7assay (Supplemental Methods: Determination of anti-scp776 antibodies in human serum). Frequency counts, percentages (%), and peak titers were calculated by treatment over time.Results

[0310] Pro-survival Signaling Activation by scp776

[0311] Selective activation of the IGF-1R signaling pathway by scp776 was measured in apoptotic iPSC-derived human CMs. Phosphorylation of AKT, a downstream effector in the IGF-1R pathway was quantitated by the pAKT potency shift assay by dividing the EC50 values for scp776 in healthy CMs over apoptotic CMs (Table below ). Scp776 exhibited selective AKT signaling in apoptotic CMs with a much higher pAKT EC50 in healthy CMs than in apoptotic CMs (82.4 nM vs. 0.772 nM) resulting in a pAKT potency shift of 107-fold (Figure IB). The chemiluminescence signals for scp776-treated healthy and apoptotic iPSC-derived cardiomyocytes were interpolated to a pAKT standard curve and the resultant curves were fit to a 3-parameter logistic model. The potency shift was calculated by dividing the Healthy EC50 by the Apoptotic EC50.Best fit values with 95% confidence intervals are show n

[0312] Disposition of Subjects70ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0313] Figure 6 shows the disposition of subjects in both studies. The phase la study enrolled 24 subjects beginning in January 2020 with completion in November 2020. Eight subjects were randomized to each cohort and all 24 completed the study. The phase lb study enrolled 44 subjects beginning in February72021 with completion in November 2021. Eight subjects were randomized to Cohorts 2, 5 and 6, seven to Cohorts 1 and 3, and 6 to Cohort 4, and all 44 completed the study.

[0314] Cohorts were comparable with respect to subject age, race, height, and weight, except for the percentage of females and males in the phase lb study, where there were more males (61%) than females (39%).Demographic of Study PopulationsPhase la Study Phase lb StudyPlacebo Scp776 Placebo Scp776 n=6 Overall n=ll OverallAge 45.8 ± 7.5 45.6 ± 7.3 51.2 ± 5.8 51.2 ± 7.7 mean years ± SD min, max 35, 57 35, 59 43, 62 30, 64Sex n (%)0 06 (55) 13 (39)Female6 (100) 24 (100) 5 (45) 20 (61)Race n (%)White 3 (50) 19 (79) 8 (73) 30 (91)Asian 1 (17) 2 (8) 0 0Black or African American 1 (17) 1 (4) 2 (18) 1 (3)Multiple 1 (17) 2 (8) 1 (9) 2 (6)Ethnicity n (%)Hispanic or Latino 1 (17) 9 (38) 7 (64) 21 (64)Not Hispanic or Latino 5 (83) 15 (63) 4 (36) 12 (36)Wei§ht78.3 ± 11.2 82.3 ± 1 1.0 76.2 10.7 78.4 ± 12.6 mean kg ± SDBMI24.8 ± 2.2 26.0 ± 2.2 27.1 ± 2.3 27.0 ± 2.8 mean kg / m2± SDBMI, body mass index71ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0315] During both studies, the study site made operational adjustments for the COVID- 19 pandemic to ensure personnel and study participant safety without compromising study protocol procedures, data collection, or interpretation of results.

[0316] Safety

[0317] There were no serious adverse events or deaths following scp776 administration and no subject was withdrawn due to an adverse event in either study. Profile and incidence of TEAEs for placebo and scp776 overall are show n for both studies in Table below.Table Adverse Event Profile in Healthy AdultsScp77 6Overa Scp776Placebo 11 Placebo __OverallPhase la Study n=6 n=18 Phase lb Study n=ll n=33Adverse events Subjects (%) Adverse events Subjects (%)Treatment emergent 11 Treatment emergent events 4 (67) (61) events 10 (91) 32 (97)Serious adverse events 0 0 Serious adverse events 1 (9) 0Individual treatment emergent events by system organ class and preferred termsCardiac disorders 0 (0%) 1 (6%) Cardiac disorders 0 (0%) 6 (18%)Ventricular tachyarrhythmia 0 (0%) 1 (6%) Palpitations 0 (0%) 5 (15%)Tachycardia 0 (0%) 2 (6%)Ear and labyrinth Ear and labyrinth disorders 1 (17%) 0 (0%) disorders 1 (9%) 1 (3%)Tinnitus 1 (17%) 0 (0%) Tinnitus 1 (9%) 1 (3%)Eye disorders 0(0%) 2(6%)Diplopia 0 (0%) 1 (3%)Eye irritation 0 (0%) 1 (3%)Vision blurred 0 (0%) 1 (3%)Vitreous floaters 0 (0%) 1 (3%)Gastrointestinal Gastrointestinal disorders 1 (17%) 1 (6%) disorders 3 (27%) 8 (24%)72ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Abdominal pain lower 0 (0%) 1 (6%) Abdominal distension 1 (9%) 0 (0%)Diarrhea 1 (17%) 0 (0%) Abdominal pain 0 (0%) 1 (3%)GERD 0 (0%) 1 (6%) Abdominal pain upper 1 (9%) 2 (6%)Constipation 1 (9%) 1 (3%)Dental discomfort 0 (0%) 1 (3%)Gingival bleeding 1 (9%) 1 (3%)Nausea 1 (9%) 2 (6%)Vomiting 0 (0%) 2 (6%)General disorders and General disorders and administration site 5 administration site conditions 1 (17%) (28%) conditions 6 (55%) 26 (79%)Catheter site irritation 0 (0%) 1 (6%) Asthenia 0 (0%) 3 (9%)Feeling abnormal 0 (0%) 1 (6%) Catheter site pain 1 (9%) 0 (0%)Injection site erosion 1 (17%) 0 (0%) Chest discomfort 0 (0%) 1 (3%)Vessel puncture site bruise 0 (0%) 2 (11%) Chills 0 (0%) 3 (9%)Vessel puncture site pain 0 (0%) 1 (6%) Fatigue 0 (0%) 2 (6%)Vessel puncture site swelling 0 (0%) 1 (6%) Feeling hot 0 (0%) 4 (12%)Hunger 0 (0%) 5 (15%)Infusion site discomfort 0 (0%) 1 (3%)Infusion site erythema 1 (9%) 3 (9%)Infusion site hemorrhage 0 (0%) 1 (3%)Infusion site induration 0 (0%) 1 (3%)Infusion site oedema 1 (9%) 3 (9%)Infusion site pain 4 (36%) 10 (30%)Infusion site reaction 4 (36%) 15 (45%)Localized edema 0 (0%) 1 (3%)Vessel puncture site bruise 2 (18%) 3 (9%)73ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Vessel puncture site ery thema 1 (9%) 0 (0%)Vessel puncture site hemorrhage 1 (9%) 1 (3%)Vessel puncture site hypoesthesia 0 (0%) 1 (3%)Vessel puncture site pain 2 (18%) 3 (9%)Infections and Infections and infestations 0 (0%) 1 (6%) infestations 2 (18%) 2 (6%)AsymptomaticViral infection 0 (0%) 1 (6%) bacteriuria 1 (9%) 0 (0%)Cellulitis 1 (9%) 1 (3%)Oral herpes 0 (0%) 1 (3%)Injury, poisoning and Injury, poisoning and procedural 2 procedural complications 0 (0%) (11%) complications 0 (0%) 2 (6%)Face injury 0 (0%) 1 (6%) Fall 0 (0%) 1 (3%)Skin laceration 0 (0%) 1 (6%) Skin laceration 0 (0%) 1 (3%)6Investigations 1 (17%) (33%) Investigations 1 (9%) 7 (21%)Alanine aminotransferaseBlood glucose decreased 1 (17%) 6 (33%) increased 1 (9%) 1 (3%)Aspartate aminotransferase increased 1 (9%) 0 (0%)Heart rate increased 0 (0%) 7 (21%)Metabolism and Metabolism and nutrition disorders 0 (0%) 1 (6%) nutrition disorders 5 (45%) 18 (55%)Hypoglycemia 0 (0%) 1 (6%) Hypoglycemia 5 (45%) 18 (55%)Musculoskeletal and Musculoskeletal and connective tissue 2 connective tissue disorders 1 (17%) (11%) disorders 1 (9%) 7 (21%)Musculoskeletal pain 0 (0%) 1 (6%) Arthralgia 0 (0%) 1 (3%)74ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Musculoskeletal stiffness 1 (17%) 0 (0%) Back pain 0 (0%) 2 (6%)Joint range of motionPain in extremity 0 (0%) 1 (6%) decreased 0 (0%) 2 (6%)Muscle tightness 0 (0%) 1 (3%)Myalgia 0 (0%) 1 (3%)Neck pain 0 (0%) 1 (3%)Pain in extremity 1 (9%) 2 (6%)Nervous system 2 Nervous system disorders 1 (17%) (11%) disorders 3 (27%) 17 (52%)Headache 1 (17%) 1 (6%) Clumsiness 0 (0%) 1 (3%)Somnolence 0 (0%) 1 (6%) Dizziness 1 (9%) 8 (24%)Dysgeusia 1 (9%) 0 (0%)Headache 2 (18%) 13 (39%)Paresthesia 0 (0%) 1 (3%)Presyncope 0 (0%) 1 (3%)Sensory disturbance 1 (9%) 0 (0%)Somnolence 0 (0%) 6 (18%)Tremor 0 (0%) 4 (12%)Psychiatric disorders 0 (0%) 2 (6%)Confusional state 0 (0%) 1 (3%)Nervousness 0 (0%) 1 (3%)Respiratory, thoracic and mediastinal disorders 0 (0%) 1 (3%)Dyspnea 0 (0%) 1 (3%)Skin and subcutaneous Skin and subcutaneous tissue disorders 1 (17%) 0 (0%) tissue disorders 5 (45%) 8 (24%)Dermatitis contact 1 (17%) 0 (0%) Dermatitis contact 4 (36%) 5 (15%)Ecchymosis 0 (0%) 1 (3%)Erythema 1 (9%) 2 (6%)Pruritus 0 (0%) 1 (3%)75ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Rash papular 1 (9%) 0 (0%)Vascular disorders 0 (0%) 1 (6%) Vascular disorders 1 (9%) 0 (0%)ThrombophlebitisHemorrhage (finger cut) 0 (0%) 1 (6%) superficial 1 (9%) 0 (0%)GERD, gastroesophageal reflux disease

[0318] Phase la study

[0319] TEAEs that were mild or moderate in severity were reported by 61% (11 / 18) of subjects receiving scp776 and 67% (4 / 6) receiving placebo. There were fewer subjects with reported TEAEs in the 1 mg / kg cohort (1 subject) compared to the 2 mg / kg and 4 mg / kg cohorts (5 subjects each). There were no injection site reactions following scp776 administration. The most common TEAE was asymptomatic decreased blood glucose. One subject in the 4 mg / kg dose cohort had an event of symptomatic hypoglycemia that was moderate in severity. The onset of events following scp776 administration ranged from 1.6 hours to approximately 24 hours from dosing and most resolved within 30 minutes. Decreases in blood glucose were treated with oral carbohydrate intake, with one subject in the 4 mg / kg cohort receiving overnight IV dextrose infusion.

[0320] With the exception of decreased blood glucose, there were no clinically significant trends in the laboratory, physical examination, vital sign, or ECG data. One subject in Cohort 1 experienced mild ventricular tachyarrhythmia approximately 18 hours after dosing with a 4-beat run of wide-complex tachyarrhythmia on telemetry without shortness of breath, dizziness, or sensations in the chest. The event resolved within 1 minute and was considered possibly related to study drug. Slightly elevated prothrombin time (PT) / intemational normalized ratio (INR) and activated partial thromboplastin (aPTT) times were noted in the 24-hour lab results for two individuals that received 4 mg / kg scp776. Values returned to normal ranges within 24-48 hours.

[0321] Phase lb study

[0322] The majority of the 240 TEAEs reported after receiving scp776 were mild (203 / 240, 85%) and the remaining moderate (36 / 240, 15%). One subject receiving placebo experienced two severe events of superficial thrombophlebitis and cellulitis that were considered serious due to in-hospital care.

[0323] The most frequently reported TEAE following scp776 was hypoglycemia and incidence was similar in subjects receiving placebo (See Table Adverse Event Profile in Healthy76ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Adults). All hypoglycemia events following placebo and the majority following scp776 administration (45 / 59, 76%) were asymptomatic. The majority of events occurred within 6 hours of dosing, lasted from 2 minutes to 50 minutes, and resolved within 30 minutes. Hypoglycemia in both placebo and scp776 groups was managed by adjusting IV dextrose infusion rates.

[0324] Hypoglycemia events for subj ects in each study were stratified by blood glucose levels, with cutoffs at <75. <65 and <55 mg / dL. The incidence of events at each cutoff were similar in the placebo and overall scp776 group in the phase lb study (See Table below).Individual Hypoglycemia Events by Blood Glucose Level

[0325] Other TEAEs occurring in more than 5 individuals in the phase lb study were infusion site reaction, headache, infusion site pain, dizziness, and increased heart rate. Incidence of infusion site reaction and infusion site pain were similar in subjects receiving scp776 and placebo. Infusion site reaction and infusion site pain TEAEs occurred at both scp776 injection sites and IV dextrose infusion sites, with the majority of events noted at the dextrose infusion site (placebo n=27, scp776 n=19). None of the infusion site reaction or infusion site pain events were considered related to study drug. Additionally, injection site erythema and edema, vessel puncture site pain and injection site or puncture site bruising / hemorrhage (ecchymosis) were reported with similar frequencies in the placebo group (See Table Adverse Events Profile in Health Adults).

[0326] Mean ECG results remained within normal limits at the post-dose time points across treatments and changes from baseline were generally minimal. Seven individuals 77ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 experienced mild increased heart rate following scp776 dosing. Two (one female in Cohort 5 and one male in Cohort 6) experienced mild intermittent tachycardia after dosing on Day 1, and one experienced 1 minute of supraventricular tachycardia and palpitations. To avoid recurrence of intermittent tachycardia, dosing on Days 3 and 4 were withheld for this individual. All telemetry events resolved without sequelae.

[0327] Mean prothrombin (PT), PT / INR, and PTT times were above reference ranges for subjects receiving multiple doses of scp776 in Cohorts 3 through 6 with maximum values on Day 3. More frequent coagulation assessments were performed in Cohorts 4-6. Multiple participants across Cohorts 3 through 6 (1-6 subjects per cohort at the various time points) had PT, PT / INR, and PTT values that shifted from normal at baseline to above normal post-dose. In general, the shifts were largest shortly after dosing and returned to normal at a rate consistent with the observed clearance of scp776. For subjects receiving multiple doses, this phenomenon was repeated with each subsequent dose. None of these shifts were flagged as clinically significant by the principal investigator and none were associated with an adverse event. Analysis of adverse events related to bleeding or bruising revealed events of mild bruising / hemorrhage (ecchymosis) at IV injection / vessel puncture sites and mild gingival bleeding in both placebo (n=4 events) and scp776 groups (n=7 events) that occurred in 4 participants without reported increases and in 5 participants with reported increased coagulation times. There were no observations of prolonged bleeding at the sites of venipuncture.

[0328] PK Analyses

[0329] Mean serum scp776 concentration versus time data are shown in Figure 3A and Figure 3B. After single scp776 doses in adult males (phase la study), peak mean scp776 concentrations increased with increasing doses from 1 mg / kg to 4 mg / kg (Figure 3A). Serum concentrations of scp776 were below the lower limit of quantitation (0.5 pg / mL) for all subjects by 48 hours, 72 hours, and 144 hours following 1 mg / kg, 2 mg / kg, and 4 mg / kg scp776, respectively. With multiple dosing in the phase lb study, concentrations peaked at or near the end of each injection (Figure 3B, Cohorts 3-6). The mean elimination half-life across all subjects in both studies was 8.00 ± 2.03 hours.

[0330] PK parameters following single doses in adult males are shown in Table 1. Cohort mean t / 2 values increased from 5.5 to 10.6 hours as the dose increased from 1 to 4 mg / kg. Similarly, mean CL values showed a decreasing trend with increasing dose levels. Mean Vz78ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 values were comparable across dose levels (44-57 mL / kg), though lower than expected for an intravenous bolus drug.

[0331] PK parameters after single or first injections for adult males and females in the phase lb study were comparable to those from the Phase la study. Overall PK parameters for the Phase lb study (all cohorts) are shown in Table 2 and parameters per day are presented in Figure 14.

[0332] With multiple scp776 dosing of the same dose in Cohort 3 and Cohort 4 some accumulation was observed in Cmax and AUCO-24 values. In contrast, accumulation was not observed in the multidose cohorts in which doses tapered over 4 days (Cohort 5 and Cohort 6). Total exposure for the multiple dose regimens (AUCO-inf) showed no major deviations from dose proportionality (Figure 7A), while peak exposure (Cmax) versus single or first scp776 reflected dose-proportionality (Figure 7B).

[0333] Pharmacodynamics

[0334] Blood Glucose Levels

[0335] In the phase la study, where subjects received scp776 without continuous IV dextrose supplementation, the mean change from baseline blood glucose levels increased follow ing meals and decreased under fasting conditions for both the placebo and scp776 groups. A dose-dependent relationship between blood glucose levels over time was not observed (Figure 8). However, the low sample size and high-fat / high-calorie meal were confounding factors that prevented definitive conclusions.

[0336] In the phase lb study, dextrose supplementation was begun prior to dosing for all subjects and bedside blood glucose measurements and adaptive supplemental IV dextrose mitigated the magnitude of fluctuations in blood glucose levels. Blood glucose levels stabilized as serum scp776 concentrations declined and dextrose supplementation was established (Figure 9). Table 3 shows the profile of dextrose infusion relative to scp776 PK parameters and incidence of hypoglycemia. In Cohorts 1-3, dextrose infusion was begun at high rates with subsequent large adjustments (Table 3, Figures 4A-4B). High infusion rates (i.e., 6 mL / kg / hr) perpetuated the requirement for supplementation and increased total dextrose infusion volumes. In Cohorts 4-6, low dextrose infusion rates were begun shortly before scp776 dosing and smaller, incremental rate adjustments were made in response to glucose monitoring (Table 3, Figures 4A-4B). Consequently, significantly less supplemental dextrose was required to79ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCT Electronically Filed: November 20. 2025 maintain blood glucose levels in Cohorts 4-6. Dextrose administration rates for individual subjects are shown by phase lb cohort in Figure 10.

[0337] Improved glycemic control with supplemental dextrose infusion was also apparent when comparing matched 2 mg / kg, 4 mg / kg, and placebo groups between the two studies (Figure 5A and 5B, Table below).

[0338] The frequency of low blood glucose events (i.e., blood glucose < 75 mg / dL) was reduced > 2-fold in subjects receiving supplemental dextrose in phase lb compared to dose matched Phase la subjects (Table below). An analysis of the blood glucose versus time curves determined the area above 75 mg / dL for each subject 24 hours post 4 mg / kg scp776. This area, defined as the euglycemic (i.e., normal blood glucose) area was significantly increased with adaptive supplemental dextrose infusions (p=0.0034; Kruskal-Wallis test with Dunn multiple comparisons), indicating improved maintenance of normal blood glucose levels in the phase lb study (Figure 5C).Dextrose Supplementation Decreases the Number and Frequency of Low Blood Glucose Events.< 75 mg / dLACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0339] The consumption of meals immediately prior to dosing caused post-prandial blood glucose elevations that coincided with the high serum concentrations of the early PK time points. This confounding factor impacts interpretation of the relationship between increased blood glucose and increased serum scp776 concentrations, and there was no meaningful correlation between blood glucose level and serum scp776 concentration (Figure 11).

[0340] Heart rate

[0341] Mean change from baseline heart rate tended to be higher following scp776 treatment relative to placebo, but a time-matched comparison of change from baseline heart rates and serum scp776 concentrations indicated no meaningful correlation (Figure 12). Mean heart rates also fluctuated over the sampling period following placebo administration, therefore no definitive conclusions regarding dose-response effect of scp776 on heart rate could be made.

[0342] Coagulation

[0343] Mean PT, PT / INR. and PTT times were above reference ranges for subjects receiving multiple doses of scp776. Time matched comparisons of coagulation parameter values versus scp776 serum concentrations in the phase lb study cohorts 5 and 6 showed positive linear correlations. (Figure 13).

[0344] Immunogenicity

[0345] Scp776 administration was associated with the development of low-titer ADA detectable within 7-28 days of the first dose. For all doses combined, 78% (14 / 18) and 82% (27 / 33) of subjects were confirmed positive for ADA detection in the phase la and phase lb studies, respectively. Scp776 mean concentrations in ADA positive and in ADA negative subjects were similar and scp776 median half-lives were similar across cohorts without regard to ADA status.Discussion

[0346] These studies assessed the first-in-human safety, tolerability, and PK / PD of scp776, an IGF-1 fusion protein in clinical development as a targeted inhibitor of apoptosis following ischemic damage. Activation of pro-survival signals via the IGF-1 receptor pathway can promote apoptosis escape,15'17and scp776 has been engineered to selectively activate IGF- 1 receptor (IGF-1R) mediated pro-survival signaling in damaged tissues containing large numbers of apoptotic cells. When cells undergo apoptosis during an insult, the redistribution of81ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 phosphatidylserine (PS) from the inner leaflet of the cell membrane to the outer surface enables scp776 to selectively bind through the AnxV targeting arm. The selective activation of IGF-1R signaling by scp776 in apoptotic CMs was quantitated by pAKT assay and shown to be 100 times more potent than in non- apopt otic CMs. The AnxV module of scp776 drives selective binding to phosphatidylserine head groups exposed on apoptotic cells and enhances stimulation of 1GF-1R pathways.

[0347] The PK analyses from two phase 1 studies showed that serum concentrations after scp776 IV injections peaked at or near the end of administration at a Cmax value indicative of plasma distribution. The calculated volumes of distribution were lower than typically observed for an IV drug and closely matched plasma volume (—40 mL / kg). Scp776 has also shown Vz values reflecting plasma volume in non-clinical PK studies in rodents and non-human primates (data not shown), and this phenomenon may be attributable to drug binding to circulating IGF-1 binding proteins.29The mean half-life (t! ) of scp776 averaged across all subjects, doses, and days from both studies was 8.00 ± 2.03 hours. AUC and Cmax after single or multiple doses of scp776 were without major deviations from dose proportionality. Infusion site reactions were observed in both placebo and scp776 groups and occurred primarily at the site of dextrose infusions. As expected for a novel biological compound, scp776 administration was associated with the development of low-titer ADA that did not appear to correlate with dose or impact scp776 PK parameters.

[0348] IGF-1 therapeutics include mecasermin (Increlex®), a recombinant human IGF-1 used to treat growth failure in children and adolescents with primary IGF-1 deficiency. Recommended single subcutaneous doses for mecasermin range from 0.04-0.12 mg / kg.30representing a molar dose level of -6-17 pmol / kg (molecular weight 7.6 kDa). The Cmax following a single subcutaneous 0.04 mg / kg dose is 0.121 pg / mL with a half-life of 6 hours31In contrast, 4 mg / kg scp776 represents a molar dose of -36 pmol / kg (molecular weight of 110 kDa) with a Cmax of 118 pg / mL and a half-life of 11 hours after a single injection. Thus, while recognizing the limitation of comparing subcutaneous and intravenous administrations, scp776 can be safely administered at 2-6 times the molar dose, providing a higher Cmax and extended half-life compared to recombinant human IGF-I. In concert with the modifications to IGF-1, the additional bulk provided by fusion with human serum albumin yields an extended half-life relative to native IGF-1.82ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0349] Slightly elevated PT / INR and PTT values above the normal reference range were observed after scp776 administration. None were associated with adverse events or deemed significant by the phase 1 principal investigator. The linear correlations observed between scp776 serum concentrations, and these parameters enable prediction of scp776 dose levels that could lead to abnormal lab values. Mild bruising / bleeding at injection sites, or gingival bleeding, occurred with similar frequencies in individuals with and without above normal coagulation times. Increased coagulation times are consistent with the established binding interaction between the AnxV module of scp776 and phosphatidylserine on the surface of activated platelets that can compete with the prothrombinase complex and increases coagulation times.32While AnxV can inhibit thrombus formation, it has not been found to increase bleeding risk in either ex vivo or in vivo studies.33,34

[0350] Heart rate varied throughout the treatment period following both scp776 and placebo administration. Fast or irregular heart rates may occur due to low blood glucose levels and / or the positive inotropic effect of IGF-1 and have been reported with recombinant human IGF-1 injections.30, 35 Between the two phase 1 studies, 4 subjects had adverse events of tachycardia and 5 had events of palpitation, all of which were mild and self-limiting.

[0351] The most common treatment-related adverse event in both phase 1 studies was decreased blood glucose, in some cases associated with symptomatic hypoglycemia. Most events were mild and resolved within 30 minutes. Decreased blood glucose levels were not unexpected since, as an IGF-1 analogue and structurally related to insulin, scp776 would have potential effects on glucose metabolism. Based on experience in the phase la study, a stringent blood glucose management plan was implemented in the phase lb study. This plan consisted of continuous blood glucose monitoring, bedside point-of-care measurements, and laboratory plasma glucose assessments combined with an adaptive dextrose infusion. Time-matched blood glucose levels determined by either bedside or laboratory assessments were in good agreement across all cohorts. Because the bedside glucose measurements were available more quickly than the laboratory assessments, infusion rate adjustments were more frequently made in response to bedside monitoring.

[0352] Comparing equivalent doses of scp776 in both the phase 1 a and phase 1 b studies showed that the blood glucose management plan implemented in the phase lb study maintained blood glucose levels to a better extent than in the absence of these interventions. There were no hypoglycemic events of moderate severity or higher in the phase lb study. During the study,83ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 the dextrose supplementation strategy was refined to maximize glycemic control and minimize total volume of IV fluids, specifically DIO infusion volume. The limits on DIO infusion volume aimed to avoid potential hyponatremia and other electrolyte imbalances or osmotic changes to avoid complications following ischemic injury to CNS or cardiac tissues. Continuous blood glucose monitoring protocols have been used successfully for individuals post-stroke,36,37and the adaptive dextrose supplementation strategy for administration of scp776 to individuals with acute ischemic injury is expected to be feasible in a standard clinical setting.

[0353] Blood glucose monitoring is especially important in the setting of AIS, since the comorbidity of dysglycemia is common. Hyperglycemia occurs in over 30% of individuals with AIS, including those with no history7of diabetes mellitus. Conversely, prolonged fasting post stroke could predispose patients to hypoglycemia. Increased glucose levels have been associated with larger final infarct volume and w orse clinical outcome, although studies which have used intensive glucose management via tight insulin control have not demonstrated improved functional outcomes or survival, instead showing increased morbidity7with hypoglycemic events.38 The phase 1 study experiences with scp776 dosing and blood glucose monitoring in the healthy participants have informed the design of the monitoring program that is currently being used in a phase 2 study of scp776 for AIS (ARPEGGIO, NCT05585606). Stringent blood glucose monitoring and adaptive dextrose infusions will address the potential confounding hypoglycemic effects of scp776 while following the American Heart Association / American Stoke Association guidance on glycemic control in AIS.9

[0354] The pharmacology of scp776 in the healthy, uninjured human subject is well tolerated and monitorable across all doses tested. In the cell-based assay measuring activation of ART in apoptotic cardiomyocytes, the EC90 w as determined to be ~1 pg / mL. The PK profile of scp776 in healthy normal human subjects demonstrates that following a single dose of 4 mg / kg, the serum concentration remains above the EC90 for approximately 70 hours. With multiple lower doses and blood glucose supplementation, longer durations above the EC90 were achieved with minimal incidence of hypoglycemia and minimal volumes of IV dextrose.Conclusions

[0355] Two phase 1 studies in healthy volunteers have established the safety, tolerability, and PK and pharmacodynamic profiles of scp776 with aggregate data that will inform dosing and adaptive dextrose infusion protocols to help maintain glycemic control.84ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Ongoing and future clinical trials will further assess the cytoprotective potential of scp776 as an acute therapy to promote escape from apoptosis in tissues affected by ischemic injury.References1. Qin C, Yang S, Chu YH, et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022:7:215.2. Lo EH, Moskowitz MA, Jacobs TP. Exciting, radical, suicidal: how brain cells die after stroke. Strode. 2005;36: 189-92.3. Sekerdag E, Solaroglu I, Gursoy-Ozdemir Y. Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. Curr Neuropharmacol. 2018;16: 1396-415.4. Bennett MR. Apoptosis in the cardiovascular system. Heart. 2002;87:480-7.5. Olivetti G, Quaini F, Sala R, et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1996:28:2005-16.6. Saraste A, Pulkki K, Kallajoki M, et al. Apoptosis in human acute myocardial infarction. Circulation. 1997;95:320-3.7. de Zwaan C, Daemen MJ, Hermens WT. Mechanisms of cell death in acute myocardial infarction: pathophysiological implications for treatment. Neth Heart J. 2001;9:30-44.8. Krijnen PA, Nijmeijer R, Meijer CJ, et al. Apoptosis in myocardial ischaemia and infarction. J Clin Pathol. 2002;55:801-11.9. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association / American Stroke Association. Stroke. 2019;50:e344-e418.10. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary’ syndromes. Eur Heart J Acute Cardiovasc Care. 2024:13:55-161.1 1. Mao R, Zong N, Hu Y, Chen Y, Xu Y. Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke. Neurosci Bull. 2022;38: 1229-47.12. Vincent AM, Feldman EL. Control of cell survival by IGF signaling pathways. Growth Horm IGFRes. 2002;12:193-7.13. Obradovic M, Zafirovic S, Soskic S, et al. Effects of IGF-1 on the Cardiovascular System. Curr Pharm Des. 2019;25:3715-25.85ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCT Electronically Filed: November 20. 202514. Benarroch EE. Insulin-like growth factors in the brain and their potential clinical implications. Neurology. 2012;79:2148-53.15. Vincent AM, Mobley BC, Hiller A, Feldman EL. IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis. 2004;16:407-16.16. Kooijman R, Sane S. Michotte Y, De Keyser J. Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke? Stroke. 2009;40:e83-8.17. Macvanin M, Gluvic Z, Radovanovic J, et al. New insights on the cardiovascular effects ofIGF-1. Front Endocrinol (Lausanne). 2023;14:l 142644.18. Bhalla S, Mehan S, Khan A, Rehman MU. Protective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions. Neurosci Biobehav Rev. 2022;142: 104896.19. De Geyter D, De Smedt A, Stoop W, De Keyser J, Kooijman R. Central IGF-I Receptors in the Brain are Instrumental to Neuroprotection by Systemically Injected IGF-I in a Rat Model for Ischemic Stroke. CNS Neurosci Ther. 2016;22:611-6.20. O'Sullivan JF, Leblond AL, Kelly G, et al. Potent long-term cardioprotective effects of single low-dose insulin-like growth factor-1 treatment postmyocardial infarction. Circ Cardiovasc Interv. 2011;4:327-35.21. Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest. 1997; 100: 1991-9.22. Bondanelli M, Ambrosio MR, Onofri A, et al. Predictive value of circulating insulinlike growth factor I levels in ischemic stroke outcome. J Clin Endocrinol Metab. 2006;91:3928- 34.23. Denti L, Annoni V, Cattadori E, et al. Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. Am J Med. 2004;117:312-7.24. Reutelingsperger CP, van Heerde WL. Annexin V, the regulator of phosphatidylserine- catalyzed inflammation and coagulation during apoptosis. Cell Mol Life Sci. 1997;53:527-32.25. Bayne ML, Applebaum J, Chicchi GG, Miller RE. Cascieri MA. The roles of tyrosines 24, 31, and 60 in the high affinity binding of insulin-like growth factor-1 to the t pe 1 insulinlike growth factor receptor. J Biol Chem. 1990;265: 15648-52.26. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology7of ischemia / reperfusion injury7. Int Rev Cell Mol Biol. 2012;298:229-317.86ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 202527. Cryer PE, Axelrod L. Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94:709-28.28. Mathew P, Thoppil D. Hypoglycemia 2022 Dec 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. PMID: 30521262. 2024.29. Mizuno N, Kato Y, Iwamoto M, et al. Kinetic analysis of the disposition of insulin-like growth factor 1 in healthy volunteers. Pharm Res. 2001 ;18: 1203-9.30. Fintini D, Brufani C, Cappa M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin RiskManag. 2009:5:553-9.31. Grahnen A, Kastrup K, Heinrich U, et al. Pharmacokinetics of recombinant human insulin-like grow th factor I given subcutaneously to healthy volunteers and to patients with growth hormone receptor deficiency. Acta Paediatr Suppl. 1993;82 Suppl 391:9-13; discussion 4.32. Andree HA, Stuart MC, Hermens WT, et al. Clustering of lipid-bound annexin V may explain its anticoagulant effect. J Biol Chem. 1992;267: 17907-12.33. van Heerde WL, Sakariassen KS, Hemker HC, et al. Annexin V inhibits the procoagulant activity of matrices of TNF-stimulated endothelium under blood flow conditions. Arterioscler Thromb. 1994;14:824-30.34. Thiagarajan P, Benedict CR. Inhibition of arterial thrombosis by recombinant annexin V in a rabbit carotid artery7injury7model. Circulation. 1997;96:2339-47.35. Vasconez O, Martinez V, Martinez AL, et al. Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I. Acta Paediatr Suppl. 1994;399: 137-9.36. Kersten C, Zandbergen AAM, Fokkert MJ, Slingerland RJ, den Hertog HM. Continuous glucose monitoring in acute ischemic stroke patients treated with endovascular therapy: A pilot study to assess feasibility and accuracy. PLoS One. 2023;18:e0280153.37. Nukui S, Akiyama H, Soga K, et al. Risk of Hyperglycemia and Hypoglycemia in Patients with Acute Ischemic Stroke Based on Continuous Glucose Monitoring. J Stroke Cerebrovasc Dis. 2019;28: 104346.38. Ferrari F, Moretti A, Villa RF. Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity. Neural Regen Res. 2022:17:292-9.87ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025Example 2: Non-Clinical Risk Assessment of co-administration of Thrombolytics and scp776, a targeted IGF-1 neuroprotectant for stroke

[0356] Introduction / Purpose

[0357] Scp776 is a first-in-class targeted growth factor therapeutic in development for treatment of acute ischemic stroke (AIS) patients. The therapeutic hypothesis for scp776 neuroprotection in stroke is targeted deliver}' of a potent growth factor (IGF-1) alongside standard-of-care flow restoration will protect tissue from damage by promoting apoptosis escape. In the ARPEGGIO study of scp776 in patients undergoing endovascular thrombectomy (EVT), those receiving intravenous thrombolytics (IVT) are excluded. Before expanding testing of scp776 into the broader patient population (i.e., including IVT and IVT / EVT patients), we characterized the compatibility of scp776 with IVTs in an array of non-clinical studies. We present tests of compatibility and propose criteria for acceptable test results to allow' the safe introduction of adjuvants (e.g., neuroprotectants) to the significant population of stroke patients receiving thrombolytics.

[0358] Materials / Methods

[0359] The potential for interference with tPA-mediated clot lysis by scp776 was tested in a plate-based assay using clots derived from rat blood.

[0360] The susceptibility of scp776 to proteolysis and / or inactivation by tPA or downstream effectors (e.g., plasmin) was assessed by co-administration pharmacokinetic experiments in monkeys and a binding assay.

[0361] The risk of increased bleeding in animals after co-administration of scp776 and tPA was assessed using a mouse tail snip model.

[0362] Results

[0363] In the clot lysis assay, supra-clinical concentrations of scp776 did not affect the rate or extent of clot lysis by tPA (50% Lysis Time, 40 nM tPA = 17.5±0.6 min; 40 nM tPA+ 100 pg / mL scp776 = 16.5±0.6 min), while the inclusion of protease inhibitors abrogated clot lysis.

[0364] Scp776 remained intact, with an unchanged pharmacokinetic profile for 48 hours (~6 half-lives) following co-administration of 4 mg / kg scp776 with 0.9 mg / kg tPA in monkeys. The targeting function of scp776, phosphatidylserine binding, was unaffected by incubation with tPA in an in vitro binding assay (relative binding, 101%; 95% CI, 94-109%).88ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0365] In the tail snip model, mice that received 5. 10, or 20 mg / kg scp776 did not have increased blood loss compared to negative controls, while mice that received 10 mg / kg tPA showed a non-significant increase in blood loss. Mice that received 10 mg / kg tPA with 20 mg / kg scp776 showed a similar non-significant increase in blood loss compared to negative controls. The tPA only and scp776 + tPA groups were not significantly different.

[0366] Conclusion

[0367] We propose a non-clinical testing scheme for the assessment of pharmacocompatibility of novel adjuvant therapies with standard-of-care thrombolytics. Under this paradigm, the proposed neuroprotectant scp776 did not evidence either bidirectional drugdrug interactions or potential synergy in dysregulation of hemostasis. Scp776 did not interfere with tPA-mediated clot lysis in an ex vivo assay. Studies in animals and assay plates revealed that scp776 pharmacokinetics, integrity, and targeting function were not affected by tPA. Together, these results indicate that a drug-drug interaction is unlikely in patients that receive both drugs. Co-administration of scp776 and tPA in mice did not induce significant changes in blood loss compared to mice that received tPA only or saline. These data support future human testing of scp776 in AIS patients receiving thrombolytic therapies.

[0368] Scp776’s Neuroprotective Potential is Being Tested in the Phase 2 ARPEGGIO Study in Acute Ischemic Stroke

[0369] The rationale for scp776 neuroprotection in stroke is based on the role of apoptosis in disease prognosis and the known neuroprotective benefits of IGF- 1.

[0370] Scp776 reduced lesion size and neurologic deficits, and improved survival in a non-clinical model of ischemic stroke in monkeys.

[0371] Subjects undergoing endovascular thrombectomy (EVT) are eligible for participation in ARPEGGIO, while those receiving IV thrombolytics are currently excluded.

[0372] Figure 15 shows the Phase 2 study design.

[0373] Evaluating the Compatibility of Scp776 with Thrombolytics in AIS

[0374] The non-clinical testing paradigm to establish compatibility between scp776 and thrombolytics was focused on 3 types of potential drug-drug interactions.1. Scp776 interference with clot lysis by thrombolytic agents2. Thrombolysis-associated proteolytic degradation of scp77689ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCT Electronically Filed: November 20. 20253. Synergistic interactions affecting patient safety (e.g.. interaction with coagulation pathway due to activated platelets displaying phosphatidylserine)

[0375] Scp776 did Not Interfere with tPA-Mediated Clot Lysis In Vitro

[0376] Rat whole blood clot lysis by tPA was assayed with and without scp776 using the Halo Clot method (Bonnard et al, 2017).

[0377] At a therapeutic concentration of tPA (40 nM), clot lysis was unaffected by the addition of scp776 up to supra-clinical concentrations (50% Lysis Time, 40 nM tPA = 17.5±0.6 min; 40 nM tPA+100 pg / mL scp776 = 16.5±0.6 min).

[0378] High concentrations of scp776 did not modify the rate or extent of clot lysis by tPA in vitro. See Figure 16A and Figure 16B.

[0379] Co-Administration with tPA did Not Modify Scp776 PK

[0380] Cynomolgus monkeys (n = 3 per group) were dosed with 4 mg / kg scp776 IV in addition to tPA (Alteplase, 0.9 mg / kg IV) administered either 3 hours before, 1.25 hours before, or 2 hours after scp776.

[0381] PK analysis showed no significant differences in scp776 exposure due to tPA administration regardless of timing.

[0382] Scp776 is not likely to be cleaved by thrombolytics or their downstream effectors (e.g., plasmin). See Figure 17 and Table below.90ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025AUCo-inf, and Cmaxare presented as Geometric Mean (Geometric CV)Other PK Parameters are presented as ArithmeticMean ± SD

[0383] tPA did not Directly Cleave Scp776 or Inhibit Targeting

[0384] Scp776’s susceptibility7to direct cleavage by tPA was assessed using a functional, in vitro assay of phosphatidylserine (PS) binding. This assay measures the targeting ability of scp776, the key feature of the molecule that enables selective activity in tissues at sites of ischemic injury.

[0385] The PS binding assay requires scp776 to contain a PS binding-capable (i.e., folded and functional) AnxV domain for capture, and a fully intact primary structure to allow for detection by an anti-IGF-1 Ab conjugate (Figure ISA).

[0386] Scp776 samples were assayed with and without pre-incubation with 40 nM tPA for 2 hours at ambient temperature.

[0387] Scp776’s PS binding capacity was unaffected by pre-treatment with tPA (Figure 18B). Relative binding of tPA treated scp776 was 101% of reference (95% CI: 94- 109%).

[0388] Scp776 did Not Affect Bleeding in a Rodent Model- See Figures 19A-19C

[0389] Scp776 (up to 20 mg / kg administered IP), tPA (10 mg / kg administered IV), and the combination were assessed for modification of hemostasis in a mouse tail snip bleeding model.

[0390] Bleed quantity, measured by animal weight loss after bleed (below, left), and bleed time, measured by visual assessment of bleed cessation up to a maximum time of 20 minutes (below, right) were reported after amputation of a 1 cm tail section in C57BL / 6 mice.

[0391] Scp776 up to 20 mg / kg IP showed no effect on bleed quantity or time compared to saline control.91ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0392] Scp776 + tPA and tPA-only bleeding time and bleed quantity were not significantly different. While there was no impact on bleed quantity, the influence of scp776 on tPA induced increase in bleeding time requires further investigation.Example 3: ARPEGGIO Phase 2 Randomized Dose Selection Trial of Novel Cerebroprotectant Scp776 in EVT Treated AIS Patients

[0393] Despite endovascular treatment, nearly half of the patients with large vessel occlusion remain disabled or die by 90 days.

[0394] There is a renewed interest in testing cerebroprotection in setting of endovascular reperfusion to ensure drug delivery to target lesion and / or advance pharmacologic engineering.

[0395] Figure 20 is a schematic showing the IGF-1 for apoptotic escape.

[0396] IGF-1 plays a critical role in brain health. However, IGF-1 has challenges, including but not limited to:Off target effects — IGF-1 affects non-apoptotic cellsShort half-life — IGF-1 half-life is 15 minutesLimited dosing — hypoglycemia

[0397] Scp776 has been shown to improve outcomes in non-human primates clip model of MCA stroke (Figure 21).Abstract

[0398] Background and Aims: Acute ischemic stroke (AIS) patients undergoing EVT are at risk of ischemia-reperfusion injury. Scp776 is a first-in-class novel Insulin-like Growth Factor- 1 engineered to rescue apoptotic cells and protect against injury progression in large vessel occlusion (LVO) stroke. We evaluated the safety and explored cerebroprotective efficacy of scp776 in AIS.

[0399] Methods: ARPEGGIO is a phase 2, placebo-controlled, dose-selection, randomized clinical trial (20 sites, US) that enrolled AIS patients with ICA / M1 / M2 occlusion, NIHSS > 6. intended for EVT within 24 h of LKW, that evaluated, low-, mid-, or high-dose scp776 + standard of care (see Table below). The primary safety endpoint was number of treatment emergent serious adverse events (SAEs) prior to discharge. Top-line efficacy92ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCT Electronically Filed: November 20. 2025 endpoints were NIHSS at discharge (adjusted for baseline) and final infarct volume (adjusted for baseline ASPECTS). Analyses were performed in the modified intent-to-treat (MITT) population.

[0400] Results: We completed enrollment of 119 participants in the MITT. Overall baseline characteristics are outlined in the table at Figure 23. Trial safety’ was reviewed on ongoing basis by the independent Safety Review Committee.

[0401] Conclusions: This two-part Phase 2 study establishes safety and explores early efficacy signals for scp776 adjunctive to EVT. Pending results will guide dose selection, future trials, and potential to improve outcomes in LVO stroke.

[0402] Arpeggio Phase 2a trial design (Table below) is a randomized, placebo- controlled, double-blind study with a primary objective to determine safety and tolerability of scp776 among AIS treated with thrombectomy and a secondary' objective to explore preliminary efficacy of scp776 among AIS treated with thrombectomy.

[0403] Protocolized glucose management plan with IV dextrose to maintain levels above 80 mg / dL.Arpeggio study population

[0404] Key inclusion criteria1. LVO (ICA, Ml and / or M2) intended for endovascular thrombectomy93ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 20252. Pre-EVT NIHSS > 63. LSW to randomization < 24 hrs4. Pre-stroke mRS 0, 1 or 2

[0405] Key exclusion criteria1. Received intravenous thrombolytics2. ASPECTS 0 - 43. Acute intra-cerebral bleed on baseline imaging4. Moderate or severe hypotension or confirmed SBP < 90Study endpoints

[0406] Primary Endpoints1. S AEs and AESIs prior to dischargeAESIs: Hypoglycemia, Tachycardia, Bleeding

[0407] Secondary Key Efficacy Endpoints1 . NIHSS at Discharge / Day 7 (whichever comes first)Adjusted for baseline NIHSS2. Final Infarct Volume (last evaluable imaging study prior to discharge; centrally assessed)Adjusted for baseline ASPECTS

[0408] Exploratory Efficacy Endpoint1. Modified Rankin Scale at Day 90 (all categories)Statistical Analyses

[0409] Primary Outcomes Analysis• Generalized linear model• Adjusted for the following: age, baseline NIHSS, baseline ASPECTS, time from LKW to reperfusion, TICI score

[0410] Secondary Outcome Analysis94ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025• ANCOVA covariates: age. baseline NIHSS, baseline ASPECTS, TICI score, treatment (and imaging modality for FIV)• Statistical power estimated at 81.9% to detect a 2.5-point NIHSS difference between active (n = 40) and control (n = 40) arms• Statistical power estimated at 80.3% to detect a 44% infarct volume difference between active (n = 40) and control (n = 40) arms

[0411] Results of the study are shown in the flowchart of Figure 22. During the Part A dose escalation of the study, an independent safety review committee reviewed blinded safety data prior to advancement to the next dose level. At completion of cohort 3. the highest dose level, the safety review committee reviewed all data and recommended taking the mid-dose level forward to Part B dose expansion. Overall, the safety' profde was most favorable at the mid-dose level, though this may be due to underlying risk enrichment rather than treatment relatedness.

[0412] Figure 23 is a table showing the baseline characteristics.

[0413] Figure 24 is a table showing the primary safety' TEAEs results.

[0414] Figure 25 is a table showing the primary safety7AESIs results.

[0415] Figure 26 is a table showing the primary safety AESIs results.

[0416] The multicenter randomized study was conducted in patients with acute ischemic stroke treated in the late therapeutic window. Efficacy was assessed across three domains: (1) neurological function as measured by theNational Institutes of Health Stroke Scale (NIHSS) at discharge or Day 7. (2) radiographic injury as assessed by final infarct volume (FIV), and (3) functional outcome as measured by the 90-day modified Rankin Scale (mRS).

[0417] NIHSS at Discharge or Day 7

[0418] The National Institutes of Health Stroke Scale (NIHSS) is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. It is a predictor of both short and long term outcomes of persons with stroke.

[0419] In the per-protocol analysis set (PPAS), subjects receiving the investigational cerebroprotective compound, scp776, exhibited a mean reduction in NIHSS of 2.3 points relative to control at discharge or Day 7 (Figure 27). The corresponding statistical analysis yielded a nominal p-value of 0.06.95ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0420] Final Infarct Volume (FIV)

[0421] In the same population, the median final infarct volume in the scp776 treated group was reduced by 9 mL relative to control (Figure 28). The measurement was derived from centrally read and adjudicated imaging-based volumetric assessments of the final infarct core.

[0422] 90-Day Modified Rankin Scale (mRS)

[0423] The mRS is used to evaluate the degree of disability in patients who have suffered a stroke. In the modified intention-to-treat (mITT) population, 62% of subjects in the scp776 treated group achieved an mRS score of 0-2 at 90 days, compared with 54% of control subjects, representing an 8% absolute difference in the proportion of patients attaining functional independence (Figure 29).

[0424] Mixed Model Repeat Measures of NIHSS while Hospitalized (Day 1 - Discharge or Day 7)

[0425] Longitudinal NIHSS scores over Days 1-7 post-randomization are shown for subjects in the per-protocol analysis set (PPAS). The scp776 treated group (Scp776 Selected Dose) recovered neurologic function more rapidly than the control group (Placebo) (Figure 32). Each point represents the mean NIHSS score on that day for a given arm, with error bars denoting standard error (SE). Sample sizes (n) for each timepoint are annotated adjacent to their respective means.

[0426] Subjects in the Scp776 Selected Dose arm demonstrated faster neurologic recovery in the acute hospitalization period compared to placebo, with greater reductions in NIHSS by Day 2 and sustained improvements thereafter. A significant treatment-by-time interaction was detected, indicating differential recovery patterns between arms.

[0427] As revealed in the group counts for participants in the 2 arms, participants receiving scp776 also discharged earlier from the hospital.

[0428] Administration of scp776 in patients treated beyond the conventional therapeutic window7was associated with consistent directional effects across neurological, radiographic, and functional endpoints. The conventional window for administration of pharmacological therapeutic agents such as thrombolytics is within 4.5 hours of symptom onset. The data indicate that compound administration results in (i) enhanced rate of neurological recovery', (ii) earlier discharge from the hospital, (iii) reduced neurological deficit at discharge or day 7, (iv) reduced infarct volume on follow-up imaging, and (v) increased frequency of96ACTIVE 716675072v1Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 favorable functional outcomes at 90 days. For example, the administration of scp776 resulted in (i) increased rate of neurologic recover from 0.1 - 4 points per day, (ii) earlier discharge by 0.3 - 4 days, (iii) improved neurologic function at discharge by 1 - 6 points on the NIHSS scale, (iv) reduced volume of infarction by 5 - 40%, and (v) increases in the relative proportion of subjects achieving good outcomes (mRS 0 - 2) by 5 - 30%. These findings support the use of the compound as a post-reperfusion cerebroprotective agent applicable to late-window stroke patients, a population for which no approved neuroprotective therapies are currently available.Example 3: Localization of Scp776 to Ischemic Brain Tissue Following Transient Middle Cerebral Artery Occlusion in Rats

[0429] The localization of scp776 to ischemic brain tissue was assessed in a rat transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke. Male, Sprague Dawley rats (n = 3 / group) were subjected to 3 hours of filament occlusion of the MCA. Loss of blood flow and subsequent reperfusion was monitored by laser doppler flowmetry. After reperfusion was established, scp776 was dosed IV in 2 dosing regimens, designed to assess dynamics of blood brain barrier integrity in this model. Group A received 3 IV 20 mg / kg doses of scp776 at each of the following times: Reperfusion t = 3 hr, t = 4 hr, and t = 5 hr. Group A animals were sacrificed at 6 hours (3 hours reperfusion time, 1 hour after final scp776 dose.) Group B received 3 IV 20 mg / kg doses of scp776 at each of the following times: t = 21 hr, t = 22 hr, and t = 23 hr. Group B animals were sacrificed at 24 hours (21 hours reperfusion time, 1 hour after final scp776 dose.)

[0430] Brain tissue from both ischemic and remote (contralateral) hemispheres were collected, homogenized, and assayed for scp776 content using an ELISA method. Scp776 localized to the ischemic hemisphere at significantly higher levels after both 3 and 21 hours of reperfusion time in this model (Figure 30). At 3 hours reperfusion time, scp776 was present in the ischemic hemisphere at 2321 ± 352 ppm (ppm = ng scp776 per mg of total protein) compared to 1 15 ± 48.7 ppm in the remote hemisphere (20-fold ischemic / remote ratio; t-test p-value = 0.0008). At 21 hours reperfusion time, scp776 was present at 273 ± 58.5 ppm in the ischemic hemisphere compared to 123 ± 29.3 ppm in the remote hemisphere (2-fold ischemic / remote ratio; t-test p-value = 0.0165).97ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025

[0431] Cross-sectional brain slices from the same animals were fixed in formalin and stained to assess the prevalence of apoptotis (TUNEL staining) and the localization pattern of scp776 (anti-scp776 immunohistochemistry) after ischemic injury. Figure 31A and Figure 3 IB show the results of TUNEL staining in a representative Group A animal 3 hours postreperfusion at different magnifications (16x and 400x). Regions with large populations of TUNEL-positive (brown) apoptotic nuclei were visible in the cerebral cortex and stnatum of the ischemic hemisphere. No comparable apoptotic regions were identified in the remote hemispheres of Group A or Group B animals.

[0432] Figure 31C and Figure 31D show scp776 localization pattern in a neighboring slice from the same representative Group A animal’s brain section. Strikingly, the intense scp776 localization pattern overlays with the regions of enhanced apoptosis identified by TUNEL staining above. This trend was consistent among animals in both Groups A and B, though the Group B animals showed more intense and widespread TUNEL staining and less intense scp776 staining compared to the Group A animals (data not shown).

[0433] Taken together, the ELISA and histological results described above showed that scp776 localized to ischemic brain tissue, specifically to areas with high proportions of apoptotic cells in a rat tMCAO model. Additionally, the reduction in scp776 localization observed between the Group A (3 hour reperfusion) and Group B (21 hour reperfusion) animals suggested a critical window of blood brain barrier integrity loss occurred early after reperfusion allowing passage of scp776 into the brain.

[0434] Specific examples of compositions, methods and kits have been described herein for purposes of illustration. These are only examples. The technology provided herein can be applied to systems other than the example systems described above. Many alterations, modifications, additions, omissions, and permutations are possible within the practice of this invention. This disclosure includes variations on described embodiments that would be apparent to the skilled addressee, including variations obtained by: replacing features, elements and / or acts with equivalent features, elements and / or acts; mixing and matching of features, elements and / or acts from different embodiments; combining features, elements and / or acts from embodiments as described herein with features, elements and / or acts of other technology; and / or omitting combining features, elements and / or acts from described embodiments.98ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025INCORPORATION BY REFERENCE

[0435] All publications, patents and sequence database entries mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.99ACTIVE 716675072v1

Claims

Attorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025CLAIMS1. A method of treating a subj ect having an acute ischemic stroke with an IGF - 1 chimeric protein, the method comprising: administering a pharmaceutical composition comprising an effective amount of the IGF-1 chimeric protein to the subject beyond conventional therapeutic window for treating acute ischemic stroke, wherein administration results in (i) enhanced rate of neurological recovery, (ii) earlier discharge from hospital, (iii) reduced neurological deficit at discharge or day 7, (iv) reduced infarct volume on follow-up imaging, and / or (v) increased frequency of favorable functional outcomes at 90 days.

2. The method of claim 1, wherein the administering of the pharmaceutical composition is on average about 12 hours after stroke onset.

3. The method of claim 1, wherein the administering of the pharmaceutical composition is on average about 12 hours up to 24 hours after stroke onset.

4. The method of any one of claims 1-3, wherein the administering of the pharmaceutical composition results in one or more of (i) enhanced rate of neurological recovery, (ii) earlier discharge from the hospital, (iii) reduced neurological deficit at discharge or day 7, (iv) reduced infarct volume on follow-up imaging, and (v) increased frequency of favorable functional outcomes at 90 days. For example, the administration of scp776 resulted in (i) increased rate of neurologic recover from 0.1 - 4 points per day, (ii) earlier discharge by 0.3 - 4 days, (iii) improved neurologic function at discharge by 1 - 6 points on the National Institutes of Health Stroke Scale (NIHSS), (iv) reduced volume of infarction by 5 - 40%, and (v) increases in a relative proportion of subjects achieving good outcomes (mRS 0 - 2) by 5 - 30%.

5. The method of any one of claims 1-3, wherein the IGF-1 chimeric protein comprises a targeting domain comprising human annexin 5 (AnxV) or variant thereof, and an activator domain comprising insulin-like grow th factor (IGF-1) or variant thereof.

6. The method of any one of claims 1-3, wherein the IGF-1 chimeric protein comprises a noninternalizing variant of annexin 5, wherein the non-internalizing variant of annexin 5 comprises one or more mutations, wherein the one or more mutations comprises a substitution at a position corresponding to C316 and optionally at one or more positions corresponding to R63, K70, K101, E138, D139, N160, and combinations thereof.

7. The method of any one of claims 1-3, wherein the IGF-1 chimeric protein comprises a variant of human insulin-like growth factor IGF-1 comprising one or more mutations, wherein the one100ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 2025 or more mutations consist of a substitution at one or more positions corresponding to E3. Y24, Y31, Y60, and combinations thereof.

8. The method of any one of claims 1-3, wherein the IGF-1 chimeric protein further comprises a half-life modulator comprising a variant of human serum albumin (HSA) comprising one or more mutations, wherein the one or more mutations consist of a substitution at one or more positions corresponding to C58 and N527. and combinations thereof.

9. The method of any one of claims 1-3, wherein the IGF-1 chimeric protein comprises or consists of IGFl(E3R / Y31A)_lk7_HSA26-609(C58S / N527Q)_lk7_AnxV2-320(R63 A / K70A / K101 A / E138A / D 139G / N160A / C316A).

10. The method of any one of claims 1-3, wherein the IGF-1 chimeric protein comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 24.

11. The method of any one of claims 1-3, wherein the administering comprises administering a first dose of the pharmaceutical composition comprising about 2 mg / kg of the IGF-1 chimeric protein, followed by a second dose of the pharmaceutical composition comprising about 1.8 mg / kg of the IGF-1 chimeric protein about 24 hour after the first dose.

12. The method of claim 1 or claim 2, wherein the pharmaceutical composition further comprises at least one physiologically acceptable carrier.

13. The method of any one of claims 1-3, wherein the subject in need thereof is a human.

14. The method of any one of claims 1-3, wherein the pharmaceutical composition is administered intravenously.

15. The method of any one of claims 1-3, wherein a solution comprising an effective amount of dextrose is administered intravenously to maintain levels above 80 mg / dL.

16. A method of treating a subject in need thereof with an IGF-1 chimeric protein, the method comprising: administering a solution comprising an effective amount of dextrose prior to administration of an IGF-1 chimeric protein, wherein the administering is over a period of about 48 hours; and administering a pharmaceutical composition comprising an effective amount of the IGF-1 chimeric protein, wherein the effective amount of dextrose supports eugly cemia, and wherein half-life of the IGF-1 chimeric protein is from about 6 hours to about 10 hours.

17. The method of claim 16, wherein the solution comprising the effective amount of dextrose is administered by infusion to the subject in need thereof.101ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCT Electronically Filed: November 20. 202518. The method of claim 17. comprising administering the solution comprising the effective amount of dextrose at a starting infusion rate of about 0.1 mL / kg / h.

19. The method of claim 16, further comprising adjusting the infusion rate at an incremental rate of +0.05 mL / kg / hr to +2 mL / kg / hr.

20. The method of claim 16 or claim 17, wherein the solution comprises the effective amount of dextrose comprises from about 5% to about 10% dextrose (w / v) in water or saline solution.

21. The method of claim 16 or claim 17, wherein the solution comprises the effective amount of dextrose is administered from about 1 min to about 30 min before the administration of the IGF-1 chimeric protein.

22. The method of claim 16 or claim 17. wherein the IGF-1 chimeric protein comprises a targeting domain comprising human annexin 5 (AnxV) or variant thereof, and an activator domain comprising insulin-like grow th factor (IGF-1) or variant thereof.

23. The method of claim 22, wherein the IGF-1 chimeric protein further comprises a peptide, wherein the peptide extends the half-life of the IGF-1 chimeric protein.

24. The method of claim 22, wherein the targeting domain is a non-intemalizing variant of annexin 5.

25. The method of claim 22, wherein the IGF-1 chimeric protein is substantially not internalized by cells.

26. The method of claim 22, wherein the IGF-1 chimeric protein comprises a non-intemalizing variant of annexin 5, wherein the non-intemalizing variant of annexin 5 comprises one or more mutations, wherein the one or more mutations comprises a substitution at a position corresponding to C316 and optionally at one or more positions corresponding to R63, K70, K101, E138, D139, N160, and combinations thereof.

27. The method of claim 22, wherein the activator domain of IGF-1 chimeric protein is a variant of human insulin-like growth factor IGF-1 comprising one or more mutations, wherein the one or more mutations consist of a substitution at one or more positions corresponding to E3, Y24, Y31, Y60, and combinations thereof.

28. The method of claim 22, wherein the IGF-1 chimeric protein further comprises a half-life modulator comprising a variant of human serum albumin (HSA) comprising one or more mutations, wherein the one or more mutations consist of a substitution at one or more positions corresponding to C58 and N527, and combinations thereof.102ACTIVE 716675072v1Atorney Docket No. 132463-011302 / PCTElectronically Filed: November 20. 202529. The method of claim 22, wherein the IGF-1 chimeric protein comprises or consists of IGFl(E3R / Y31A)_lk7_HSA26-609(C58S / N527Q)_lk7_AnxV2-320(R63 A / K70A / K101 A / El 38A / D 139G / N 160A / C316A).

30. The method of claim 22, wherein the IGF-1 chimeric protein comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 24.

31. The method of claim 16 or claim 17, comprising administering descending effective amounts of the IGF-1 chimeric protein over a period of 2 days to 14 days or more.

32. The method of claim 16 or claim 17, wherein the administering of the effective amount of the IGF-1 chimeric protein inhibits apoptosis.

33. The method of claim 16 or claim 17, wherein the pharmaceutical composition further comprises at least one physiologically acceptable carrier.

34. The method of claim 16 or claim 17, wherein the subject in need thereof is a human.

35. The method of claim 16 or claim 17, wherein the subject in need thereof has acute ischemic stroke (AIS).

36. Use a pharmaceutical composition comprising an effective amount of an IGF-1 chimeric protein in treating a subject having an acute ischemic stroke, comprising: administering the pharmaceutical composition to the subject beyond conventional therapeutic window for treating acute ischemic stroke, wherein administration results in (i) enhanced rate of neurological recovery, (ii) earlier discharge from hospital, (iii) reduced neurological deficit at discharge or day 7, (iv) reduced infarct volume on follow-up imaging, and / or (v) increased frequency of favorable functional outcomes at 90 days.

37. Use a pharmaceutical composition comprising an effective amount of an IGF-1 chimeric protein in treating a subject having an acute ischemic stroke, comprising: administering a solution comprising an effective amount of dextrose prior to administration of an IGF-1 chimeric protein, wherein the administering is over a period of about 48 hours; and administering the pharmaceutical composition comprising an effective amount of the IGF-1 chimeric protein, wherein the effective amount of dextrose supports eugly cemia, and wherein half-life of the IGF-1 chimeric protein is from about 6 hours to about 10 hours.103ACTIVE 716675072v1

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