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BSE:532872 NSE: SPARC BLOOMBERG: SPADV@IN REUTERS: SPRC.BO CIN: L73100GJ2006PLC047837 December, 19 2024 Update on Clinical Programs and R&D Pipeline
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01 UPDATE ON STRATEGY AND PRIORITIES ANIL RAGHAVAN 02 SHORT -TERM OPPORTUNITIES: IMMUNOLOGY MUDGAL KOTHEKAR 03 SHORT -TERM OPPORTUNITIES: ONCOLOGY SANDEEP INAMDAR Agenda 3
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PROSEEK data analysis completed Full data set confirms IA findings PROSEEK: Phase 2 study in early Parkinson’s disease patients evaluating the safety and efficacy of Abl tyrosine kinase inhibition using K0706 | IA: Interim Analysis | CSF: Cerebro Spinal Fluid | PK: Pharmacokinetics | MDS-UPDRS: Movement Disorders Society Unified Parkinson’s Disease Rating Scale Study did not meet primary endpoint The placebo response in PR OSEEK appears to be an outlier compared to historical data Target CSF concentrations of Vodobatinib were achieved in both dosing arms Plasma PK consistent with earlier studies and expectations Biomarker data showed mixed and inconclusive trends Part III Score Change in MDS-UPDRS Part III score by week 36 Vodobatinib High Dose Vodobatinib Low Dose Placebo 26 22 24 20 18 Baseline Visit 4, Week 4 Visit 6, Week 8 Visit 7, Week 12 Visit 8, Week 20 Visit 9, Week 28 Visit 10, Week 36 Visit 11, Week 40 Visit SPARC will discuss results with scientific advisory board and publish the results Change in MDS-UPDRS Part III score in long-term extension Part III Score Vodobatinib High Dose Vodobatinib Low Dose Prior Placebo 20 22 24 26 16 18 14 12 Part 2 Baseline, Week 40 Visit 14, Week 44 Visit 15, Week 48 Visit 16, Week 56 Visit 17, Week 64 Visit 18, Week 72 Visit 19, Week 76 Visit Change in CSF α-Synuclein levels by week 36 SAA SD50 Mean (SE +) Visit 10 15 20 5 0 Baseline Week 36 Vodobatinib High Dose (N=9) Vodobatinib Low Dose (N=14) Placebo (N=16) 4
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Turning the page – Post PROSEEK priorities Focus on medium-term clinical PoCs and cash flow TA: Therapy Area | NewCo.: New Company | PoCs: Proof of Concepts Short-term catalysts & costs Multiple levers to drive near-term cash events Cost reduction through reorganization and execution efficiency 4 near-term milestones Business model flexibility Early stage licensing Pivoting to smart deals (NewCo. formation, Equity transactions) 7 strategic & commercial partnerships Portfolio optimization Oncology and Immunology as key T A focus Prioritize resourc ing for SBO-154 & SCD-153 to achieve meaningful value inflection points 10+ assets under development SCD-153 and SBO-154 can become productive platforms upon successful translation 5
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Turning the page – Post PROSEEK priorities Focus on medium-term clinical PoCs and cash flow Short-term catalysts & costs Multiple levers to drive near-term cash events Cost reduction through reorganization and execution efficiency 4 near-term milestones Business model flexibility Early stage licensing Pivoting to smart deals (NewCo. formation, Equity transactions) 7 strategic & commercial partnerships Portfolio optimization Oncology and Immunology as key T A focus Prioritize resourc ing for SBO-154 & SCD-153 to achieve meaningful value inflection points 10+ assets under development SCD-153 and SBO-154 can become productive platforms upon successful translation TA: Therapy Area | NewCo.: New Company | PoCs: Proof of Concepts 6
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mAbs: Monoclonal Antibodies | siRNA: Small Interfering RNA | AA: Alopecia Areata Smart delivery of chemotherapeutics or immune activators using targeting mAbs or small molecule ligands Topical delivery of novel agents providing potentially safer treatment options to patients ONCOLOGY IMMUNOLOGY ONCOLOGY Smart delivery Synthetic lethality Antibody Drug Conjugates DNA Damage Response Small Molecule Drug Conjugates T-cell Engagers New synthetic lethality combinations Nanoparticle based siRNA system IMMUNOLOGY Novel targets Topical formulations Targeting novel antigens and delivery platforms to deliver therapeutic agents Focus on dermatological indications with a potential to work both as monotherapy and in combination with other complementary mechanisms Targeting novel mechanisms for treatment of AA, Vitiligo and other chronic inflammatory dermatological conditions having limited treatment options Developing topical agents to achieve optimal concentration at the site of action without the toxicity challenges associated with systemic agents Narrowing therapeutic area focus 7
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Potential first-in-class assets as anchors Prioritized resourcing for SBO-154 and SCD-153 Both products offer significant product extensions once the primary tenets of the hypothesis get clinically validated Delivers proven payload with a novel epitope of tumor targeting antibody and a validated linker Key elements of the hypothesis validated in preclinical studies Topical agent for treatment of AA and Vitiligo Low potential for systemic AEs confirmed in Phase 1a study in healthy volunteers SBO-154 SCD-153 AEs: Adverse Events 8
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SBO-154 leverages the broad success of the modality 15 ADCs approved by USFDA Notable progress in the development of new ADCs in oncology, making up 9% of the oncology pipeline in 2023 ADCs have transformed the treatment landscape with their ability to deliver payloads with precision directly to tumor cells providing better cell kill and avoiding off-target side-effects Advanced linker technology allows use of both covalent and non-covalent methods to retain the conjugates in circulation while permitting antibody function and cellular internalization *Markets and Markets; Antibody Drug Conjugates (ADC) Market Published Date: Oct 2023 | #Surge in ADC Deals Drives Oncology Dealmaking; Lucy Haggerty and Taskin Ahmed; September 2024 | Global trends in R&D 2024: Activity, Productivity and Enablers; IQVIA Institute for Human Data Science; Feb 2024 | ADC: Antibody Drug Conjugate | USFDA: United States Food and Drug Administration | CAGR: Compound Annual Growth Rate 15.2% $300 Bn $20 BnEstimated revenue by 2028 CAGR from 2023-2028 Cumulative deal value in last 5 years Preclinical Phase 1 Phase 2 Phase 3 Approved 13% 46% 13% 19% 9% ADC deals by development phase#ADC market global forecast to 2028* 9
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SBO-154 offers a distinctive advantage in dynamic ADC space Binds to a novel epitope of a cancer associated antigen MUC1 expression confirmed across multiple tumor types providing development opportunities to target several patient sub-types SBO-154 has successfully established SEA binding hypothesis in preclinical studies and can be used for multiple constructs using different payloads and linkers MUC1-SEA domain is an unexplored ADC target ADC field centered around select antigens ~65% of pipeline assets targeting 5 antigens *https://njbio.com/antibody-drug-conjugates/ | SEA: Sea urchin sperm protein, Enterokinase, Agrin Number of ADCs under development by target* 20 0 40 60 80 100 120 106 HER-2 48 TROP-2 29 EGFR 26 CLDN 18.2 25 B7-H3 21 Nectin-4 17 Folate Receptor Alpha 17 HER-3 16 C-MET 13 CD30 12 CD19 12 ROR1 11 5T4 11 Tissue factor Number of ADCs under development ADC targets 10
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SCD-153 expands pathway & modality options Expensive biologic treatments are reserved for more severe patients who constitute a much smaller proportion of treated patients Adverse events associated with current oral SoC for dermatological indications warrant a different modality for reduced side effects The field is expected to evolve towards use of mechanistically independent combinations enhancing effectiveness and provide more comprehensive management of disease *Graph adapted from Dermatology Drives Autoimmune Market Growth; IQVIA; Aug 2022 | SoC: Standard of Care | The non-biologic patient proportions reach over 100% because patients often take more than one prescription drug over the course of a year. This is not the case for biologic treatments, which are not used in combination. Addressing the need for safer and convenient alternatives in Immunology Non-biologic Biologic Patient Proportion by Biologics vs Non-Biologics treatments in 7 major markets* Urticaria 0% 50% 100% 150% 200% 250% 300% Ulcerative colitis Rheumatoid arthritis Psoriatic arthritis Psoriasis Crohn’s disease Atopic dermatitis 11
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Turning the page – Post PROSEEK priorities Focus on medium-term clinical PoCs and cash flow Short-term catalysts & costs Multiple levers to drive near-term cash events Cost reduction through reorganization and execution efficiency 4 near-term milestones Business model flexibility Early stage licensing Pivoting to smart deals (NewCo. formation, Equity transactions) 7 strategic & commercial partnerships Portfolio optimization Oncology and Immunology as key T A focus Prioritize resourc ing for SBO-154 & SCD-153 to achieve meaningful value inflection points 10+ assets under development SCD-153 and SBO-154 can become productive platforms upon successful translation TA: Therapy Area | NewCo.: New Company | PoCs: Proof of Concepts 12
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Openness to explore partnering options at multiple inflection points including IND Explore preclinical program/ platform collaborations Beyond traditional licensing arrangements including asset specific NewCos and potential spin-outs Opportunities to leverage capability based partnering EXPAND PARTNERING INTENT EXPLORE NEW STRUCTURES Our collaboration with the UCSF and the formation of Tiller Therapeutics illustrates this approach IND: Investigational New Drug | UCSF: University of California San Francisco Business model flexibility to advance assets and leverage capabilities 13
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Case in point - A NewCo. to advance Joint IP Developed in collaboration with UCSF R esearch collaboration with the University of California San Francisco (UCSF) for development of oncology assets F ast-track development Lead c ompound identified within 2 years of initiation of the project T erms finalization and LOI execution within 6 months of NewCo (Tiller Therapeutics) formation LOI: Letter of Intent | IP: Intellectual Property 2017 2020 2022 2024 Master agreement signed Task Order signed Lead candidate identified Binding LOI executed with UCSF and Tiller Therapeutics Inc. 14
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SCO-155 enables preferential delivery using a small molecule ligand Offers potential advantages over RLTs SCO-155 is a Small Molecule Drug Conjugate (SMDC) delivering cytotoxic agent targeting prostate-specific membrane antigen (PSMA) as a potential treatment for metastatic Castration Resistant Prostate Cancer (mCRPC) PSMA is specifically and highly expressed in prostate cancer Oppor tunities with PSMA directed SMDCs SCO-155 has potential to become standard of care for treatment of Prostate Cancer Durable tumor penetration Designed for repeat administration and co-administration with other therapies Convenient administration in community-based infusion centers RLT: Radioligand Therapy 15
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SCO-155 improves the therapeutic window Preclinical PoC established SCO-155 showed selective killing of PSMA over- expressing prostrate cancer cells in vitro with around 1000x selectivity over PSMA null cells SCO-155 showed selective tumor growth inhibition of PSMA over-expressing tumors in vivo PC3-PIP cells (PSMA over-expressing) PC3-FLU cells (vector control) IC50(nM) 0.09 90.76 PC3-FLU cells (vector control) – SCO-155 60 µg/kg PC3-FLU cells (vector control) – Vehicle PC3-PIP cells (PSMA over- expressing) – SCO-155 60 µg/kg PC3-PIP cells (PSMA over- expressing) – Vehicle 150 100 50 0 0.001 0.01 0.1 1 10 100 1000 10000 Relative Cell Numbers (%) 965x Concentration (nM) 1500 1000 500 0 0 5 10 15 20 25 Tumor volume (mm³) Days after Treatment SCO-155 treated 2000 In vitro cytotoxicity in PC3 Prostate cancer cells In vivo efficacy in Prostate Cancer PC3 Xenograft model 16
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Tiller Therapeutics explores smart delivery with a novel approach SMDCs leveraging synthetic ligands of cancer specific antigens Upon grant of license, SPARC will receive 55% equity stake in the fully diluted securities of Tiller. The equity will be issued to SPARC in two tranches within 6 months of execution of license agreement IND filing expected in FY26 SPARC and UCSF have signed binding LOI with Tiller Therapeutics Inc. (Tiller) granting exclusive worldwide license to Tiller for preclinical oncology asset along with associated IP 17
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Turning the page – Post PROSEEK priorities Focus on medium-term clinical PoCs and cash flow Short-term catalysts & costs Multiple levers to drive near-term cash events Cost reduction through reorganization and execution efficiency 4 near-term milestones Business model flexibility Early stage licensing Pivoting to smart deals (NewCo. formation, Equity transactions) 7 strategic & commercial partnerships Portfolio optimization Oncology and Immunology as key T A focus Prioritize resourc ing for SBO-154 & SCD-153 to achieve meaningful value inflection points 10+ assets under development SCD-153 and SBO-154 can become productive platforms upon successful translation TA: Therapy Area | NewCo.: New Company | PoCs: Proof of Concepts 18
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Execute on short-term catalysts which can provide non-dilutive capital to reduce external funding R educe cash burn through better alignment of objectives and cost PURSUE PROGRAMS WITH CASH VISIBILITY OPTIMIZE CASH BURN Clinical capability base and execution cost targeted for optimization Opportunities with a spectrum of probabilities of success, which will be resolved mostly by end of this financial year Focus on near-term catalysts & cost efficiency 19
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Near-term cash generating milestones Delivering on actionable drivers of identified milestones is a top operational priority PRV: Priority Review Voucher | NDA: New Drug Application Approval of NDA Q2 FY27 Update of PRV litigation with USFDA Q4 FY25 Partnering & Licensing Q4 FY25 Potential removal of unapproved products Q3 FY26 Sezaby Vodobatinib (SCO-088) Sezaby PDP - 716 20
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Sezaby’s eligibility for PRDV Exploring all available options to ensure PRDV resolution USFDA denied SPARC PRDV based on its interpretation of PRDV statute and its requirements SPARC believes the agency’s interpretation led to an unfair denial of PRDV SPARC is committed to exploring all available remedies including litigation in search of a final resolution PRDV: Pediatric Rare Disease Review Voucher Priority review vouchers have recently been traded for value in excess of $100 mn Acadia Pharmaceuticals Enters Into an Agreement to Sell its Rare Pediatric Disease Priority Review Voucher for $150 Million November 06, 2024 04:05 PM Eastern Standard Time Approval USFDA approves Sezaby without PRV SPARC approached US District Court for the District of Columbia USFDA did not provide any feedback. SPARC sued USFDA for resolution of matter 2024 Q2In-person meeting In-person meeting with USFDA for sharing its position and seeking a review of decision 2024 Q1 Court opinion2022 Q4 Ipsen announces sale of Priority Review Voucher for $158m Partnering * 27 August 2024 If granted, PRV can provide an income in excess of $100 mn for SPARC 21 Q1 2025
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Enforcing Sezaby’s orphan drug exclusivity Unapproved phenobarbital injectable formulations may cause serious adverse events in neonates Significant efforts ongoing to potentially secure the removal of unapproved injectable formulations from the market Sezaby is the only approved phenobarbital injectable formulation by the USFDA USFDA stated in a recent guidance that excipients with known toxicity should not be used in neonates (e.g.propylene glycol, benzyl alcohol) Unapproved phenobarbital injectable formulations currently marketed contain propylene glycol and benzyl alcohol that presents specific safety concerns for neonates Filed Citizen’s Petition with USFDA. National coalition of Infant Health provided support to Citizen Petition Ongoing communication with the USFDA for acting on manufacturers’ unapproved injectable formulations Sent notification letters to voluntarily withdraw the unapproved injectable formulation Sent cease & desist letters Communication with USFDA Engaged manufacturers of unapproved injectable formulation 22
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Vodobatinib in Chronic Myelogenous Leukemia Phase 3 design agreed with the agency Significant activity in last line CML patients demonstrated in Phase 2 study Registration study requirement was reset by USFDA; aligned with new requirements State of readiness for initiation of Phase 3 Registration path Initial outreach completed through an Investment banker Expected to close by end of FY25, however, CML being niche area, licensing process may require longer time Licensing Screening Stratification MCyR Vs No MCyR Previously treated with ponatinib and/ or asciminib: Yes/No Vodobatinib versus Bosutinib monotherapy 1:1:1 randomization N~ 250 Bosutinib monotherapy Continuation of bosutinib study arm Vodobatinib monotherapy Continuation of dose arm agreed with USFDA for Phase 3 study Vodobatinib monotherapy N= 20 at 200 mg Vodobatinib monotherapy N= 20 at 130 mg Bosutinib monotherapy N= 200 at 500 mg Population CML-CP previously treated with ≥ 1 2nd G or later TKI Randomized Phase 2 component of the Phase 2/3 study Randomized Phase 2 dose finding FDA agreement on dose for Phase 3 study MCyR: Major Cytogenetic Response | CML-CP: Chronic Myelogenous Leukemia - Chronic Phase | TKI: Tyrosine Kinase Inhibitor 23
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Vibozilimod Phase 2 outcomes later this year Both studies achieved enrolment closure in Q2 FY25 240 patients across three dose levels and placebo Primary endpoint – Proportion of patients with EASI-75 response at week 16 Enrolment completed: Jul 2024; 250 patients enrolled Topline (16-week) results: Q4 FY25 240 patients across three dose levels and placebo Primary endpoint – Proportion of patients with PASI-75 response at week 16 Enrolment completed: Aug 2024; 263 patients enrolled Topline (16-week) results: Q1 FY26 EASI = Eczema Area and Severity Index | PASI = Psoriasis Area and Severity Index 24
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Leaner organization to drive cost optimization Manpower expense expected to be reduced by ~30% Reorganized teams based on current stage of pipeline assets 21% reduction in manpower Available debt and cost optimization measures can provide runway upto May 2025 Expected milestones defer the imminent need of fundraise Scaled down ex-India headcount to optimize resource allocation FY24 Head Count - 409 Biologics Clinical Development Drug Discovery & Preclinical Development 17 28 168 57 54 16 92 59 60 182 FY25 HC as on 30th Sep 2024 | FY24 HC as on 31st Mar 2024 FY25 Head Count - 324 400 372 317 200 0 Organization Strength (India) 40 37 7 30 20 10 0 Organization Strength (Ex-India) FY 23-24 FY 24-25 Number of Employees Number of Employees Year Year OthersDrug Delivery Systems 25
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Key execution priorities for next 24 months SBO-154 Phase 1a Initiation Vibozilimod SOLARES-Pso-1 topline data Sezaby Potential removal of unapproved products SCD-153 Phase 2 IND filing PDP-716 Refiling of NDA Q4 FY25 Q1 FY26 Q2 FY26 Q3 FY26 Q4 FY27Q3 FY27 Vodobatinib (SCO-088) Partnering & Licensing SCD-153 Phase 1b FPI SBO-154 IND filing Sezaby PRV litigation outcome Vibozilimod SOLARES-AD-1 topline data SCO-155 Execution of definitive agreement SBO-154 Phase 1b Initiation AD: Atopic Dermatitis | Pso: Plaque Psoriasis 26
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SCD-153 For treatment of Alopecia Areata 27
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Alopecia Areata: Autoimmune disease causing spontaneous hair loss Current approved oral drugs carry risk of long-term serious side effects # Sibbald C. J Cutan Med Surg. 2023 May-Jun;27(3):241-259. | * Adapted from Nature Reviews. Disease Primers. 3:17011, 2017 | JAK: Janus Tyrosine Kinase | CD8+: Cell Differentiation 8+ | APC: Antigen Presenting Cells | MHC: Major Histocompatibility Complex Alopecia Areata affects 2% of global population After first episode ~50% patients spontaneously recover in one year. Relapse rate is up to 85%, reaching 100% in long-term Chronic treatments are needed; disease relapses on withdrawal of treatment Approved oral JAK inhibitors and off-label steroids carry significant risk on long-term use Clinical manifestations of AA# In AA, CD8+ T cells at the base of follicle secrete inflammatory cytokines, leading to hair loss Sebaceous gland Dermal papillaBulb Hair shaft Inner root sheath Healthy Alopecia Areata APC CD4+ T cell CD8+ T cell MHC class I and class II Perifollicular infiltrations of inflammatory cells in AA patients* 28
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SCD-153 induces hair growth in AA disease-relevant C3H/HeJ mouse model Potential first-in-class agent for Alopecia Areata Vehicle Regimen 1 SCD-153, Dose 1, Regimen 1 SCD-153, Dose 2, Regimen 1 SCD-153, Dose 3, Regimen 1 Scd-153, Dose 4, Regimen 2 SEM: Standard Error of Mean SCD-153 treatment shows robust dose-dependent increase in hair growth Hair Growth Index (HGI) Time duration Hair Growth Index (Mean 0 75 150 225 300 Time duration Hair Growth Index (Mean ± SEM; n=7-18/group) Vehicle, Regimen 1 SCD-153, Dose 1, Regimen 1 SCD-153, Dose 2, Regimen 1 Hair Growth Index (HGI) SCD-153, Dose 3, Regimen 1 SCD-153, Dose 4, Regimen 2 * *** *********** ****** * ** * ********* *** SEM; n=7-18/group) 300 225 150 75 0 Hair Growth index (HGI) Spontaneous alopecic female C3H/HeJ mice; treated topically on dorsal side only; DMSO formulation used in study. Data were analyzed using 2 way ANOVA followed by Bonferroni’s multiple comparisons test *p < 0.05, **p < 0.01, ***p < 0.001 vs Vehicle SCD-153, Dose 1, Regimen 1 SCD-153, Dose 4, Regimen 2 Vehicle, Regimen 1 SCD-153, Dose 2, Regimen 1SCD-153, Dose 3, Regimen 1 29
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SCD-153 acts by reducing number of cytotoxic CD8+ T-cells in skin of AA diseased mice CD8+ T-cells are the immune cell type associated with AA In part icular, CD8+ NKG2D+ T-cell is the established disease-causative subtype in AA SCD-15 3 reduces both CD8+ T-cells and CD8+ NKG2D+ T-cells in skin and thereby improves hair growth IHC: Immuno Histo Chemistry Brown stain shows CD8+ T-cells IHC readout Vehicle SCD-153, Dose 2 12 9 6 3 0 **** #### # % of Viable Infiltrating Cells (Mean+ SEM, n=7-15/group) CD8*T-cells 1.2 0.9 0.6 0.3 0.0 ## # #### **** CD8*NKG2D*T-cells Vehicle, Regimen 1 Naive (Healthy) SCD-153, Dose 1, Regimen 1 SCD-153, Dose 2, Regimen 1 SCD-153, Dose 3, Regimen 1 SCD-153, Dose 4, Regimen 2 Flow cytometry readout Data are represented as mean ± SD; n=7–15/group. Data were analyzed using Kruskal-Wallis test with post-hoc Dunn’s multiple comparison test. **** p < 0.0001 vs naïve; # p < 0.05, ## p < 0.01, #### p < 0.0001 vs vehicle 30
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SCD-153 safe & well-tolerated in Phase 1a study Study Title: A Randomized, Double-Blind, Vehicle-Controlled, Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of topically applied SCD-153 in Healthy Volunteers No subject experienced a dose-limiting toxicity The maximum safe dose was not reached SCD-153, at all strengths, is safe and well-tolerated SCD-153 Phase 1a study Cohort 1 (n=8) Cohort 2 (n=8) Cohort 3 (n=8) Cohort 4 (n=8) Cohort 5 (n=8) 31 Measurable concentration detected in dermis and epidermis
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No systemic AEs related to SCD-153 observed in Phase 1a study All AEs were mild in severity and were resolved without treatment Summary of subjects with drug related AEs (N=40) Doses Adverse Events Dose 1 None Dose 2 None Dose 3 None Dose 4 2 (related: Erythema; score 2 and Burning sensation; n=1) Dose 5 3 (related: Erythema; score 2; n=2, Burning sensation ; n=1) 32
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Phase 1b study in Alopecia Areata patients A Randomized, Double-Blind, Vehicle-Controlled Study to Evaluate the Safety, T olerability, Pharmacokinetics, and Efficacy of Topically Applied SCD-153 in Patients With Alopecia Areata (AA) Primary Objective: To determine the maximum safe dose of topical SCD-153 in patients with AA Secondary Objective: To evaluate the safety and local tolerabilit y of multiple ascending doses of topical SCD-153 in patients with AA Screening Double blinded-vehicle controlled Active treatment Safety Follow-up R: Randomization; DE: Dose Escalation; n=12 (active treatments) + 3 (vehicle) Screening Assessments Period 4 12 weeks Period 3 10 weeks Period 2 2 weeks Period 1 1 weeks DE End of Study Assessments (4 weeks) Dose 1 (n=12+3) Dose 1 (n=12+3) Dose 1 (n=12+3) Dose 1 (n=15) Dose 2 (n=12+3) Dose 2 (n=12+3) Dose 2 (n=12+3) Dose 2 (n=15) Dose 3 (n=12+3) Dose 3 (n=12+3) Dose 3 (n=12+3) Dose 3 (n=15) Dose 4 (n=12+3) Dose 4 (n=12+3) Dose 4 (n=12+3) Dose 4 (n=15) R DE DE Safety Review Safety Review Safety Review 33
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SCD-153 expands pathway & modality options Addressing the need for safer and convenient alternatives in Immunology Topical SCD-153 addresses the limitations of current treatments and offers a class alternative SCD-153 employs a new mechanism of action to address complex pathogenesis and diverse range of clinical manifestations Topical administration of SCD-153 offers possibilities to be used either in combination or as maintenance treatment with SoC Multiple formulation options provide opportunities to expand indications and cater to a large patient pool 34
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Next Steps for SCD-153 FY26 Phase 1b study Initiation FY27 Phase 1b study Interim Readout FY27 Phase 2 IND 35
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SBO-154 For treatment of multiple tumor types 36
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MUC1 offers an excellent opportunity to preferentially target tumor cells MUC1 is normally expressed exclusively on the apical surface of glandular epithelial cells In cancer cells such polar expression is lost and MUC1 expression occurs across the entire membrane Structure of MUC1 in normal and cancer cells Translocation of MUC1 from apical surface (normal cell) to circumferential display (cancer cell)* Normal Mucosa/Epithelium Cancerous Mucosa/Epithelium Aberrantly Extended glycans Truncated glycans MUC1 in normal tissue MUC1 in Cancer tissue Overexpression Loss of polarity VNTR N-glycosylation SEA domain Transmembrane domain Cytoplasmic tail O-glycosylation Tn sTn TF N-terminal (α subunit) C-terminal (ß subunit) 37 *Pathobiological implications of mucin glycans in cancer: Sweet poison and novel targets; Seema Chugh et al; Aug 28, 2015
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Novel targeting approach makes SBO-154 unlikely to be subject to a sink effect in plasma SBO-154 targets the membrane proximal SEA domain of MUC1 MUC1, the glycoprotein antigen on the cell surface consists of two parts - the α & β subunit The junction of α subunit (outside the membrane) & the β subunit (partly embedded) makes the SEA domain Drug targeting at SEA domain has higher potential of therapeutic efficacy compared to MUC1-α subunit SBO-154 may represent a first-in-class MUC1-SEA-targeted therapeutic agent to be developed for use in cancer therapy N C α Subunit β Subunit SEA VNTR 38 MUC1: Structure, Function, and Clinic Application in Epithelial Cancers; Wenqing Chen et al.; Int. J. Mol. Sci. 22 (12), 6567, 2021
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High MUC1-SEA expression level in human tumors of highly prevalent cancers ER: Estrogen Receptor | H score: Histochemical score | TNBC: Triple Negative Breast Cancer | NSCLC: Non-Small Cell Lung Carcinoma High MUC1-SEA expression (IHC-H score > 200) in ER+ breast cancer, non-small cell lung adenocarcinomas, ovarian and pancreatic carcinomas Expression increases as the stage of the tumor advances Preclinical studies further corroborate suitability of MUC1-SEA as an ADC target and establish relevance of antigen expression level Mouse anti-human MUC1-SEA mAb IHC staining in Stage IV cancer 300 250 270 200 205 248 270 293 280 240 H Score 150 ER+ Breast TNBC NSCLC Adeno Pancreatic Ovarian Circumferential/Cytoplasmic Apical n=16 n=20 n=2 n=17 n=4 n=2 n=12 n=12 n=12 n=13 n=13 n=5 39
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SBO-154: Hypothesis validated SEA targeting ADC relatively unaffected by shed antigen, retains function of tumor-targeting VNTR: Variable Number Tandem Repeat Almost all patients with MUC1+ tumors have levels of shed MUC1-VNTR antigen in the plasma This shed MUC1-VNTR binds to therapeutic ADCs, acting as a “sink” in the peripheral blood, and may be responsible for the lack of anti-tumor activity of the 1st generation MUC1 targeting ADCs V ery low levels of MUC1-SEA in plasma of patients with MUC1 expressing tumors, compared to MUC1-VNTR Finding consistent with the hypothesis that SBO-154 may not lose activity due to the “sink” effect MUC1-SEA: sandwich ELISA using MUC1-SEA targeted Ab for coating and detection MUC1 VNTR: ELISA using MUCI-SEA targeted Ab for coating, and MUC1-VNTR Ab for detection 50 40 30 20 10 0 Ovarian Cancer (n=10) Head & Neck Cancer (n=15) Breast Cancer (n=14) MUC1-SEAMUC1-VNTR Concentration in serum (ng/mL) 40
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Preclinical efficacy of SBO-154 correlates with MUC1-SEA expression level Carcinoma cell line Expression level (by flow cytometry) SBO-154 ADC IC50 (µg/mL) Anti-CD20 ADC (unrelated ADC) IC 50 (µg/mL) Colo-357 (Pancreatic) +++ 0.05 3.45 MCF7 (ER+ve Breast cancer) ++ 0.07 >10 HT29 (Colon) +/- >10 >10 SBO-154 ADC shows high potency in cells where MUC1 expression is high In vitro cytotoxicity studies IV: Intravenous | IC50: Half-maximal Inhibitory concentration 1 1200 COLO 357 Pancreatic Cancer Tumor volume (mm3) (Mean ± S.E.M, n= 6-8) H Score: 130 Vehicle VehicleSBO-154 (3 mg/kg, IV, Q4D X 4) SBO-154 (3 mg/kg, IV, Q4D X 5) 900 600 300 0 Dosing DosingDays Days 5 9 13 17 1 2000 HT-29 Colon Cancer Tumor volume (mm3) (Mean ±S.E.M, n= 6-8) H Score: 46 1500 1000 500 0 5 9 13 17 21 In vivo mouse xenograft studies SBO-154 ADC shows higher activity in vivo against tumors where MUC1 expression is high 41
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Preliminary NHP Tox suggests SBO-154 is well-tolerated with toxicity profile comparable to other MMAE-based ADCs NHP exploratory 7 week DRF study Doses 1, 3, 6 mpk of SBO-154 Dosing schedule Q3W x 3; Dosing Days: 1, 22 and 43 Results No mortality or clinical signs No effect on body weight and feed consumption at any dose Hematology data showed reduced RBC, WBC and neutrophil count at 3 mpk and 6 mpk. Expected based on known effects of MMAE Histopathology: Minimal to moderate, decreased hematopoietic cellularity (all lineages) in sternal bone marrow was observed in males at 3 mpk and in females at ≥ 3 mpk HNSTD: 6 mg/kg, Q3W x 3, IV; 7-week study Toxicokinetics Dose-proportional increase in exposure with no gender difference and accumulation following Q3W X 2, IV administration Up to 6 mg/kg IV dose was generally well-tolerated (n=1M+1F/group) HNSTD: Highest Non-Severely Toxic Dose | NHP: Non Human Primate | DRF: Dose Range Finding | MMAE: Monomethyl Auristatin E 42
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SBO-154 development update Preparedness for Phase 1 study Pre-IND meeting USFDA response received at the end of Nov 2024 indicates broad agreement with SPARC’s proposed IND data package with no significant barriers to planned IND submission Phase 1 study Global Phase 1 study planned to include the United States and India ≥ 18 years Measurable disease via RECIST 1.1 ECOG 0-1 Life expectancy of ≥ 3 months Pre-existing sensory or motor neuropathy (≥ Grade 2) Uncontrolled CNS metastases Advanced or meta- static solid tumors, relapsed/ not eligible to receive SoC Immunogenicity Anti-tumour activity Key inclusion & exclusion criteria Dose expansion (N=30 per cohort) Endpoints Primary endpoints Safety PK Secondary endpoints Dose escalation (N=30) Cohort 1: ER+ breast cancer Cohort 2: Non small cell lung cancer Cohort 3: Ovarian cancer Phase 1 study design ECOG: Eastern Cooperative Oncology Group | CNS: Central Nervous System 43
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Timelines & Milestones FY25 IND Filing FY26 Phase 1a Initiation FY27 Phase 1b Initiation 44
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Angiogenesis inhibition MUC1-SEA Immune checkpoint inhibition Cytoskeleton disruption DNA damage Immune stimulation Modular platform which can deliver multiple products to the pipeline 45
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Pipeline summary - Multiple first-in-class assets under development Asset / Program MoA Indication Discovery Preclinical Phase 1 Phase 2 Phase 3 Registration Approved Commercialization Partner PDP-716 α2 adrenergic agonist Glaucoma SDN-037 Phospholipase A2 inhibitor Ocular Pain & Inflammation Vodobatinib BCR-ABL Inhibitor Refractory CML Vibozilimod Selective S1PR1 agonist Psoriasis Atopic Dermatitis SCD-153 Itaconate derivative Alopecia Areata SCO-155 Small Molecule Drug Conjugate Prostate Cancer SBO-154 Anti-MUC1 ADC Solid Tumors MoA = Mechanism of Action |S1PR1 = Sphingosine-1-Phosphate Receptor 1 Small Molecules Biologics 46
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