Ascendis Pharma A/s · NASDAQ:ASND
Ascendis Pharma A/s — Investor Day (November 2020)
57 slides from Ascendis Pharma A/s's investor day presentation, Nov 20, 2020
Slide 1: Virtual Oncology R&D Day
Ascendis Pharma A/S Virtual Oncology R&D Day November 20, 2020 Exhibit 99.1
Slide 2: Cautionary Note On Forward-Looking Statements
Cautionary Note On Forward-Looking Statements This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, such as statements regarding our future results of operations and financial position, including our business s
Slide 3: Virtual Oncology R&D Day Agenda
Virtual Oncology R&D Day Agenda Welcome & Agenda Overview Scott T. Smith, SVP, CFO Vision 3x3 Jan Møller Mikkelsen, President & CEO TransConTM Platform & Product Innovation Kennett Sprogøe, Ph.D., SVP, Head of Innovation and Research 9:01-9:05 a.m. 9:00 a.m. 9:05-9:20 a.m. TransCon TLR7/8 Agonist &
Slide 4: Vision 3x3
Vision 3x3 Jan Møller Mikkelsen President & CEO
Slide 5: Company Overview
Company Overview Create best-in-class products addressing unmet medical needs by applying TransCon™ technologies to parent drugs with clinical proof-of-concept Endocrinology rare disease TransCon hGH: pediatric GHD BLA (PDUFA June 25, 2021) and MAA submitted; adult GHD phase 3 trial ongoing TransCon
Slide 6: Vision 3x3: Building a Leading BioPharma Company
Vision 3x3: Building a Leading BioPharma Company Our Goal is to Achieve Sustainable Growth through Multiple Approaches Obtain regulatory approval for three independent Endocrinology Rare Disease products TransCon Growth Hormone for pediatric growth hormone deficiency TransCon PTH for adult hypoparat
Slide 7: TransCon Technology Platform & Product Innovation
TransCon Technology Platform & Product Innovation Kennett Sprogøe, Ph.D. SVP, Head of Innovation and Research
Slide 8: The Evolution of TransCon Technology
The Evolution of TransCon Technology Precise release of active drug, from a prodrug, without changing the molecule’s biology TransCon technology reversibly conjugates a drug to a carrier and predictably releases the unmodified drug under physiological conditions Vision of Ascendis Founding Scientist
Slide 9: Transient Conjugation: A Powerful, Flexible Platform
Transient Conjugation: A Powerful, Flexible Platform Parent Drug Soluble Carriers Insoluble Carriers Antibodies, Antibody Fragments, Proteins, Peptides and Small Molecules Aromatic Cyclic Imide DKP Carbamate Bicin AEG Pyroglutamate TransCon Carrier TransCon Prodrug: 3 components TransCon Linker
Slide 10: TransCon Technology: The TransCon Linker
TransCon Technology: The TransCon Linker Cleaves in an enzyme-independent fashion, ensuring reproducible drug release; in vitro to in vivo correlation with high predictability TransCon linkers remain covalently bound to the carrier molecule after release of the unmodified parent drug Enables tunable
Slide 11: TransCon Technology: Sustained Systemic Release
TransCon Technology: Sustained Systemic Release Parent drug is transiently bound to a TransCon linker-soluble carrier moiety, which inactivates and shields parent drug from clearance Designed to distribute released molecule like the parent drug; linker-carrier is cleared renally Following injection,
Slide 12: TransCon Technology: Sustained Localized Release
Parent drug is transiently bound to TransCon linker-hydrogel carrier, which inactivates, shields parent drug and prevents clearance Designed to provide sustained high local drug levels with low systemic exposure; hydrogel degrades into small polymers that are renally cleared Following injection, the
Slide 13: TransCon IT: Potential Paradigm Shift in Intratumoral Delivery
TransCon IT: Potential Paradigm Shift in Intratumoral Delivery TransCon Intratumoral (IT) addresses the problems of conventional IT administration including rapid clearance from the tumor, high systemic exposure and toxicity Data on file. TransCon IT is designed to stay in the tumor and slowly relea
Slide 14: Algorithm Used in Endocrinology Used to Build Oncology Pipeline
Algorithm Used in Endocrinology Used to Build Oncology Pipeline Unmet Medical Need Clinically Validated Parent Drug TransCon Technology Suitability Clearly Differentiated Product Established Clinical & Regulatory Pathway Large Addressable Market Higher Value, Lower Risk Pipeline Our unique algorithm
Slide 15: TransCon Enables Multi-level Patent Protection
TransCon Enables Multi-level Patent Protection As of December 31, 2019. TransCon prodrugs eligible for new composition of matter IP TransCon prodrugs are new chemical entities Enables new patent life for prodrugs of parent drugs A multi-layered patent strategy is applied to protect our assets Compos
Slide 16: TransCon: An Innovative Technology Platform
Our vision is to leverage TransCon technologies to turn the body’s immune system into the therapeutic – to improve patient outcomes TransCon: An Innovative Technology Platform TransCon technologies combine the benefits from prodrug and predictable release technologies with the known biology of the p
Slide 17: Oncology
Oncology Juha Punnonen, M.D., Ph.D. SVP, Head of Oncology Stina Singel, M.D., Ph.D. Head of Clinical Development, Oncology
Slide 18: TransCon Positioned to Transform Cancer Therapy
TransCon Positioned to Transform Cancer Therapy TransCon systemic and IT therapies designed to enhance anti-tumor responses by Providing sustained modulation of tumor microenvironments Activating cytotoxic immune cells Tumor cells Immune-suppressing cells Cytotoxic T cells and other cancer fighters
Slide 19: Oncology Portfolio Strategy
Oncology Portfolio Strategy Create best-in-class oncology therapies by applying TransCon systemic and IT technologies to parent drugs addressing clinically validated pathways Improve outcomes with parent drugs that are currently limited by suboptimal efficacy and systemic toxicity Apply Ascendis’ un
Slide 20: Intratumoral Treatment Has Been Challenging
Intratumoral Treatment Has Been Challenging 1 Example: STING agonist “plasma half-life ranging from 8 to 28 min” Meric-Bernstam F, et al. ASCO annual meeting, 2019; Oral presentation: Abstract 2507. Treatment of cancer via IT administration of oncolytic virus has achieved clinical proof of concept w
Slide 21: TransCon IT Aims to Transform Intratumoral Treatments
TransCon technology provides potential for sustained modulation of tumor microenvironments with infrequent dosing and minimized systemic toxicity TransCon IT Aims to Transform Intratumoral Treatments Slow IT release allows for potential activity in tumor and draining lymph nodes for weeks or months,
Slide 22: Two Near-term IND Candidates
Two Near-term IND Candidates - Potential to Expand Pipeline to Address All Steps of the Immunity Cycle TransCon IL-2 b/g Designed to aid T cell and NK cell expansion, priming and activation as well as infiltration of immune cells in tumors (steps 3 and 5). Additional TransCon Candidates in Preclinic
Slide 23: Product Candidates in Oncology: TransCon TLR7/8 Agonist
Product Candidates in Oncology TransCon TLR7/8 Agonist
Slide 24: Opportunity for TransCon TLR7/8 Agonist in Solid Tumors
Efficacy Each injection designed to provide sustained exposure in the tumor for months to enhance immune activation Reduce risk of reaching super-high “ablative”, non-immunogenic levels Safety Low systemic toxicity expected to reduce dose-limiting adverse events Infrequent dosing designed to improve
Slide 25: TLRs: Innate Immune Sensors of Danger
TLRs: Innate Immune Sensors of “Danger” Associated with Pathogens or Cell Death Toll-like receptors (TLRs): Receptors for Pathogen- or Danger- (cell death) Associated Molecular Patterns Activate innate immunity, antigen presenting cells (APCs) in particular Results in priming and expansion of cytoly
Slide 26: Resiquimod: TLR7/8 Agonist
Resiquimod: TLR7/8 Agonist1,2 Small molecule agonist of both TLR7 and TLR8 TLR7: mainly expressed in plasmacytoid dendritic cells (pDCs), to some extent in B cells, monocytes, macrophages and conventional dendritic cells (DCs) TLR8: primarily expressed in conventional DCs, monocytes, macrophages and
Slide 27: TransCon TLR7/8 Agonist: Sustained Intratumoral Release of Resiquimod
Resiquimod transiently conjugated to TransCon hydrogel carrier, designed to provide sustained local release of unmodified resiquimod Designed to provide sustained activation of intratumoral APCs driving tumor antigen presentation and induction of immune stimulatory cytokines in the tumor Linker clea
Slide 28: 25-fold increased half-life and avoids high Cmax
TransCon technology enables 25-fold increased half-life and avoids high Cmax TransCon TLR7/8 Agonist Resulted in Sustained Release of Resiquimod over Several Weeks Subcutaneous administration in rats Parent Drug (free resiquimod): T1/2 = ~10 h TransCon TLR7/8 Agonist: T1/2 ~10 days TransCon TLR7/8 A
Slide 29: Potent Tumor-growth Inhibition with Low Systemic Cytokines
Potent Tumor-growth Inhibition with Low Systemic Cytokines Lower Systemic Cytokine Release by TransCon TLR7/8 Agonist than Comparable Dose of Resiquimod Single Dose TransCon TLR7/8 Agonist versus Comparable Dose of Resiquimod TransCon TLR7/8 Agonist has the potential to provide more potent anti-tumo
Slide 30: Single-dose Triggered Abscopal Anti-tumor Inhibition
Single-dose of TransCon TLR7/8 Agonist Triggered Abscopal Anti-tumor Inhibition and Enhanced Anti-tumor Effects of IL-2 *IL-2 dosed at 20 mg twice daily on days 0-4, once daily on days 8-12. Zuniga L, et al. SITC annual meeting. 2019; Poster 676. Injected Tumor Non-injected Tumor Single IT Dosing (C
Slide 31: Product Candidates in Oncology: TransCon IL-2 b/g
Product Candidates in Oncology IL-2 Selective for the IL-2Rb/g TransCon IL-2 b/g
Slide 32: Interleukin-2: Validated Cytokine with Suboptimal Properties
Interleukin-2 (IL-2): Validated Cytokine with Suboptimal Receptor Binding and PK Properties Several IL-2 approaches in development To our knowledge, none have fully solved both shortcomings of IL-2 Suboptimal receptor binding Two receptors: IL-2Ra/b/g and IL-2Rb/g a/b/g receptor activates Tregs and
Slide 33: Next Generation IL-2: Designed for Desired Receptor Binding and Exposure
Next Generation IL-2: Designed for Desired Receptor Binding and Exposure Onur B, et al. Biomed Intell. 2019; 149:w14697. a IL-2 IL-2 IL-2Rα (CD25) β γ β γ X Prevent IL-2Rα binding to selectively activate IL-2Rβ/g 1) 2) Generate a product with long-lasting exposure avoiding high Cmax Desired Exposure
Slide 34: Design of TransCon IL-2 b/g: Receptor Binding
Design of TransCon IL-2 b/g: 1) Designed for Desired Receptor Binding Introduction of cysteine at a-binding site of IL-2 (aldesleukin) Site-selective permanent PEG conjugation (5kDa) of introduced cysteine Generation of IL-2 Variant Blocking IL-2Ra-binding IL-2 (gold) with IL-2 alpha-receptor (grey)
Slide 35: Receptor Selectivity Demonstrated in Binding Assays
Receptor Selectivity Demonstrated in Binding Assays Rosen D, et al. AACR annual meeting. 2020; Poster 4507. Binding to IL-2R a-chain Binding to IL-2R b-chain IL-2 b/g Human IL-2 IL-2 b/g demonstrated strong receptor bias with reduced IL-2Rα binding and well-retained IL-2Rb binding
Slide 36: Receptor Selectivity Confirmed in Primary Human Cells
Receptor Selectivity Confirmed in Primary Human Cells Rosen D, et al. AACR annual meeting. 2020; Poster 4507. Human Treg cells Human CD8+ T cells Human NK cells Substantially reduced potency on primary human Treg cells compared to rhIL-2 with minimal potency loss on CD8+ T cells and NK cells
Slide 37: Design of TransCon IL-2 b/g: Optimize Exposure
Design of TransCon IL-2 b/g: 2) TransCon Technology to Optimize Exposure TransCon linker slowly releases IL-2 b/g TransCon carrier IL-2 b/g TransCon linker TransCon IL-2 b/g (Prodrug) Release Active IL-2 b/g % Release of IL-2 b/g TransCon IL-2 b/g in vitro release kinetics Sustained, long-lasting ex
Slide 38: TransCon IL-2 b/g Resulted in Long-lasting Exposure in NHP
TransCon IL-2 b/g Resulted in Long-lasting Exposure in NHP NHP = non-human primates. 1Rosen D, et al. AACR annual meeting. 2020; Poster 4507. 2Data on file. TransCon IL-2 b/g plasma PK in NHP demonstrated prolonged, sustained release of IL-2 b/g T1/2 of TransCon IL-2 b/g prodrug and released IL-2 b/
Slide 39: Robust Increase in Lymphocyte Count with Minimal Eosinophil Expansion
Robust Increase in Lymphocyte Count with Minimal Eosinophil Expansion in NHP Q3W = every 3 weeks 1Data on file. 2Rosen D, et al. AACR annual meeting. 2020; Poster 4507. 3Rand, et al. J Clin Invest. 1991; 88: 825. 4Van Haelst Pisani C, et al. Blood. 1991;78:1538. Single dose provided >10-fold and pro
Slide 40: Potent CD8+ T Cell and NK Cell Expansion and Activation in NHP
Potent CD8⁺ T Cell and NK Cell Expansion and Activation in NHP *Fold change using cell counts derived from hematology lymphocyte counts and flow cytometry-based frequencies within lymphocytes. Data on file. Expansion and activation of cytotoxic lymphocyte subsets observed following a single dose of
Slide 41: TransCon IL-2 b/g Expands Ratios of CD8+ T Cells and NK Cells Over Treg
TransCon IL-2 b/g Expands Ratios of CD8+ T Cells and NK Cells Over Treg Cells in NHP Data on file. Cell ratios following a single dose of TransCon IL-2 b/g on Day 1 Consistent with observed minimal binding to IL-2Ra, the ratios of CD8+ T cells and NK cells over Treg cells increased following adminis
Slide 42: Lower Systemic Inflammation Markers Than Aldesleukin
TransCon IL-2 b/g IND or similar expected in Q3 2021 Single Dose TransCon IL-2 b/g Induced Lower Levels of Systemic Inflammation Markers in NHP When Compared to Aldesleukin 1Data on file. 2Rosen D, et al. AACR annual meeting. 2020; Poster 4507. Aldesleukin2 (0.4 mg/day x 5) Minimal IL-5 predicts min
Slide 43: Evaluation of Immune Memory and Potential Cross-immunity
Syngeneic CT26 tumor model (colon-derived tumor line) Evaluation of Immune Memory and Potential Cross-immunity Following TransCon IL-2 b/g plus TransCon TLR7/8 Agonist Re-challenge of complete responders with CT26 Challenge of complete responders with different tumor type, EMT6 (mammary-derived) Tre
Slide 44: Durable Complete Tumor Regressions in CT26 Model
The immune activating mechanism of action of TransCon IL-2 b/g plus TransCon TLR7/8 Agonist and complete responses suggests potential for anti-tumor immune memory TransCon IL-2 b/g Plus TransCon TLR7/8 Agonist Resulted in Durable Complete Tumor Regressions in the CT26 Tumor Model Data on file. Buffe
Slide 45: Potent Immune Memory and Cross-reactive Anti-tumor Response
Protection against initial tumor and a new tumor type, suggesting potent anti-tumor memory and cross-reactive anti-tumor immunity Potent Immune Memory and Cross-reactive Anti-tumor Response Against a New Tumor Type Data on file. CT26 re-challenge of CRs (colon-derived tumor line) EMT6 challenge of C
Slide 46: Potential Paradigm Shift to How Cancer is Treated
Potential Paradigm Shift to How Cancer is Treated TransCon technologies may enable a new treatment paradigm building upon well-known biology Two near-term IND candidates demonstrating potentially best-in-class properties TransCon TLR7/8 Agonist designed for intratumoral, long-term sustained release
Slide 47: Clinical Strategy
ascendis LA pharma Clinical Strategy
Slide 48: Unmet Medical Need Remains High Despite Advancements
Unmet Medical Need Remains High Despite Advancements Immunotherapy has given hope for dramatic improvement in cancer treatment… But most cancer patients today are not benefiting from immunotherapy Haslam A and Prasad V. JAMA Netw Open. 2019;2(5):e192535. Immunotherapy has “raised the tail” for multi
Slide 49: Clinical Development Strategy in Oncology
Clinical Development Strategy in Oncology to Take Advantage of the Clinically Validated TransCon Platform Indications with strong scientific rationale Available benchmark data Across various indications As monotherapy and in combination with standard of care In combination with internal pipeline pro
Slide 50: Phase 1/2 Study of TransCon TLR7/8 Agonist
Phase 1/2 Dose Escalation and Dose Expansion Study of TransCon TLR7/8 Agonist Alone or in Combination with CPI MTD: maximum tolerated dose; ORR: overall response rate using RECIST 1.1 Dose Escalation (“3+3” Design) Dose Expansion Part 1: Monotherapy Any solid tumor, any line Part 2: Combination with
Slide 51: Initial Indication Selection: HPV-associated Cancers
Combination with CPI HPV-associated tumors: HNSCC Others (anal, cervical, vulvar, penile, vaginal) Initial Indication Selection Based on Strong Scientific Rationale to Focus on HPV-associated Cancers 1Barros M, et al. J Immunology Res. 2018; 2912671:1-17. 2Mahal B, et al. Cancer Epidemiol Biomarkers
Slide 52: TransCon TLR7/8 Agonist: Potential to Expand to Other Indications
TransCon TLR7/8 Agonist: Potential to Expand to Other Indications HPV-associated: HNSSC, anal, vulvar, penile, vaginal and cervical cancer Melanoma Merkel cell carcinoma Squamous cell carcinoma Gastric cancer Esophageal cancer Hepatocellular carcinoma Non-small cell lung cancer MSI-H/dMMR solid tumo
Slide 53: TransCon TLR7/8 Agonist - Summary
TransCon TLR7/8 Agonist - Summary Sustained IT delivery using the validated TransCon platform offers a new treatment paradigm with potential for superior efficacy and safety IND submission anticipated by year-end 2020 Engaging major academic centers Clinical development strategy aims to: Build saf
Slide 54: Phase 1/2 Study of TransCon IL-2 b/g
Phase 1/2 Dose Escalation and Expansion Study of TransCon IL-2 b/g Alone or in Combination with CPI and TransCon TLR7/8 Agonist Dose Escalation (“3+3” Design) Part 1: Monotherapy Any solid tumor, any line Part 2: Combination with CPI Indications with known CPI activity Part 3a: Combination with CPI
Slide 55: TransCon IL-2 b/g – Potential Backbone Agent in Oncology
TransCon IL-2 b/g – Potential Backbone Agent in Oncology TransCon IL-2 b/g has potential to be the best-in-class IL-2 molecule IND or similar submission anticipated in Q3 2021 Clinical development strategy aims to: Build safety and tolerability profile across multiple indications and with standard
Slide 56: Oncology Summary
Oncology Summary Best-in-class potential using systemic and intratumoral TransCon technologies Differentiated product candidates TransCon TLR7/8 Agonist Potential to improve efficacy and practicality of intratumoral treatments IND expected for TransCon TLR7/8 Agonist by year-end 2020 TransCon IL-2
Slide 57: Q&A Session
ascendis LA pharma Q&A Session