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6-K

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

FORM 6-K

 

 

REPORT OF FOREIGN PRIVATE ISSUER

PURSUANT TO SECTION 13a-16 OR 15d-16

UNDER THE SECURITIES EXCHANGE ACT OF 1934

For the month of May, 2023

Commission File Number: 001-36815

 

 

Ascendis Pharma A/S

(Exact Name of Registrant as Specified in Its Charter)

 

 

Tuborg Boulevard 12

DK-2900 Hellerup

Denmark

(Address of principal executive offices)

 

 

Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F.

Form 20-F  ☒            Form 40-F  ☐

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(1):  ☐

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(7):  ☐

 

 

 

Ascendis Pharma A/S (the “Company”) is hereby furnishing as Exhibit 99.1 the attached presentation relating to the latest developments in the Company’s Oncology programs, including clinical data updates and a review of clinical development strategy for the Company’s two immuno-oncology product candidates, TransCon TLR7/8 Agonist and TransCon IL-2 ß/g.

The furnishing of the attached presentation is not an admission as to the materiality of any information therein. The information contained in the presentation is summary information that is intended to be considered in the context of more complete information included in the Company’s filings with the Securities and Exchange Commission (the “SEC”) and other public announcements that the Company has made and may make from time to time. The Company undertakes no duty or obligation to update or revise the information contained in this report, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing or furnishing of other reports or documents with the SEC or through other public disclosures.

Exhibit

 

99.1    Company Presentation.

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

    Ascendis Pharma A/S
Date: May 31, 2023     By:  

/s/ Michael Wolff Jensen

      Michael Wolff Jensen
      Executive Vice President, Chief Legal Officer
EX-99.1

Slide 1

Ascendis Pharma A/S Oncology Program Update May 31, 2023 Exhibit 99.1

Slide 2

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 prospective product candidates; clinical trial results; the expected timing of future clinical trial results; the scope, progress, results and costs of developing our product candidates or any other future product candidates; timing and likelihood of success; plans and objectives of management for future operations; and future results of current and anticipated products and product candidates are forward-looking statements. These forward-looking statements are based on our current expectations and beliefs, as well as assumptions concerning future events. These statements involve known and unknown risks, uncertainties and other factors that could cause our actual results to differ materially from the results discussed in the forward-looking statements. These risks, uncertainties and other factors are more fully described in our reports filed with or submitted to the Securities and Exchange Commission, including, without limitation, our most recent Annual Report on Form 20-F filed with the SEC on February 16, 2023 particularly in the sections titled “Risk Factors” and “Operating and Financial Review and Prospects.” In light of the significant uncertainties in our forward-looking statements, you should not place undue reliance on these statements or regard these statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified timeframe, or at all. Any forward-looking statement made by us in this presentation speaks only as of the date of this presentation and represents our estimates and assumptions only as of the date of this presentation. Except as required by law, we assume no obligation to update these statements publicly, whether as a result of new information, future events, changed circumstances or otherwise after the date of this presentation. This presentation concerns product candidates that are or have been under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration, European Medicines Agency or other foreign regulatory authorities. These product candidates are currently limited by U.S. Federal law to investigational use, and no representations are made as to their safety or effectiveness for the purposes for which they are being investigated. Ascendis, Ascendis Pharma, the Ascendis Pharma logo, the company logo, TransCon, and SKYTROFA are trademarks owned by the Ascendis Pharma group. © May 2023 Ascendis Pharma A/S. .

Slide 3

Oncology R&D Day Agenda Welcome & Agenda Overview Scott T. Smith, EVP, CFO Vision 3x3 Jan Møller Mikkelsen, President & CEO TransCon™ Platform & Product Innovation Kennett Sprogøe, Ph.D. EVP, Head of Innovation and Research 10:05-10:20 a.m. 10:00 a.m. 10:20-10:35 a.m. Clinical Development Strategy & Clinical Updates Stina Singel, M.D., Ph.D. EVP, Head of Clinical Development, Oncology Investigator Perspectives Diwakar Davar, M.D. Associate Professor; Clinical Director of Melanoma & Skin Cancer Program, University of Pittsburgh Medical Center (UPMC), Hillman Cancer Center 11:10-11:30 a.m. 10:35-11:10 a.m. 11:30-12:00 p.m. Closing Remarks Jan Møller Mikkelsen, President & CEO Q&A Moderated by Scott T. Smith, EVP, CFO

Slide 4

Vision 3x3 Our Vision for Oncology Jan Mikkelsen President & Chief Executive Officer

Slide 5

Vision 3x3: Building a Leading Global Biopharma Company Our goal is to achieve sustainable growth through multiple approaches Obtain regulatory approval for three independent Endocrinology Rare Disease products TransCon hGH for pediatric growth hormone deficiency TransCon PTH for adult hypoparathyroidism TransCon CNP for achondroplasia Grow Endocrinology Rare Disease pipeline through Global clinical reach Pursuing 9 total indications, label optimization, and life cycle management New endocrinology products Establish global commercial presence for our Endocrinology Rare Disease area Build integrated commercial organization in North America and select European countries Establish global commercial presence through partners with local expertise and infrastructure Advance a high-value oncology pipeline with one IND or similar filing each year Create a third independent therapeutic area with a diversified pipeline Ascendis Pharma’s 2020 - 2025 strategic roadmap

Slide 6

Why Oncology? Very large unmet medical need Large number of clinically validated pathways which are limited by toxicity, efficacy, and ease of administration Suitable for use with the TransCon Technology platform Systemic delivery Localized delivery Potential to address all the aspect of the cancer immunity cycle Opportunity to expand pipeline to impact multiple aspects of anti-tumor response

Slide 7

Interleukin 2 Overview First immunologic compound in cancer FDA approved for the treatment of metastatic renal cell carcinoma (1992) FDA approved for the treatment for metastatic melanoma (1998) Interleukin shown to be effective in approximately 15% of patients Number of Responding Patients (response rate) Median Response Duration in Months (range) CR’s 17 (7%) 80+* (7 to 131+) PR’s 20 (8%) 20 (3 to 126+) PR’s + CR’s 37 (15%) 54 (3 to 131+) Clinical response data - Metastatic renal cell carcinoma Number of Responding Patients (response rate) Median Response Duration in Months (range) CR’s 17 (6%) 59+* (3 to 122+) PR’s 26 (10%) 6 (1 to 111+) PR’s + CR’s 43 (16%) 9 (1 to 122+) Clinical response data - Metastatic melanoma Proleukin (aldesleukin) product label (+) sign means ongoing * Median duration not yet observed; a conservative value is presented which represents the minimum median duration of response.

Slide 8

TransCon™ Technology Platform & Product Innovation in Oncology Kennett Sprogøe, Ph.D. EVP, Head of Innovation and Research

Slide 9

TransCon platform is uniquely suited for amplified and durable immune activation, with the aim for addressing significant unmet medical need TransCon: An Innovative Technology Platform TransCon technologies combine the benefits of prodrug and predictable release technologies. TransCon soluble prodrug technology validated within endocrinology with a high success rate in multiple clinical programs; SKYTROFA® approved in the EU and US.  TransCon hydrogel technology applied as a long-acting intratumoral (IT) delivery platform of small molecules, peptides, proteins, antibody fragments and antibodies. TransCon IL-2 b/g is using same soluble prodrug technology as SKYTROFA, enabling sustained released of potent non-alpha IL-2. TransCon TLR7/8 Agonist is using our hydrogel technology for sustained intratumoral immune activation, with minimal systemic exposure.

Slide 10

Transient Conjugation: A Powerful, Flexible Platform Aromatic Cyclic Imide DKP Carbamate Bicin AEG Pyroglutamate Parent Drug TransCon Carrier TransCon Platform: 3 components TransCon Linker Antibodies, Antibody Fragments, Proteins, Peptides and Small Molecules Soluble Carriers Insoluble Carriers Local TransCon TLR7/8 Agonist Systemic TransCon IL-2 β/γ Leveraging the breath of TransCon platform to design pipeline of immuno-oncology drugs

Slide 11

Stimulating Local Immunity to Achieve Systemic Effect TransCon IL-2 b/g and TransCon TLR7/8 Agonist have been designed mechanistically for monotherapy and synergistic combination effects TransCon TLR7/8 Agonist for long-acting IT delivery Turns the tumor hot Enhances education of T cells Recruits systemic cytotoxic immune cells APC: Antigen presenting cell, TRM: Resident memory T cell, CTL: Cytotoxic T cell, NK: Natural killer cell TransCon IL-2 b/g for long-acting systemic delivery Expands & activates CD8+ T and NK cell population Activates tumor resident effector cells locally Innate immune stimulator Adaptive immune stimulator

Slide 12

The Immune System in Normal Compared to Inflamed Tissue Tissue resident immune cells survey all organs and act as first responders in response to threats Local chemokines attract effector cells from blood and surrounding tissue Local cytokines such as IL-2 proliferate, activate and potentiate the immune response Tcirc: Circulating T cells, NK: Natural killer cells, APC: Antigen presenting cell, TRM: Tissue resident T cell (effector & memory), CTL: Cytotoxic T cell (CD8+), Tmem: Memory T cell (CD4+), Th1: T helper 1 cell, M1: M1 macrophage Normal tissue Inflamed tissue

Slide 13

The Immune System in Cold versus Hot Tumors Tcirc: Circulating T cells, NK: Natural killer cells, APC: Antigen presenting cell, TRM: Tissue resident T cell (effector & memory), CTL: Cytotoxic T cell (CD8+), Tmem: Memory T cell (CD4+), Th1 & Th2: T helper 1 or 2 cell, M1 & M2: M1- or M2-like macrophage Innate activators like TLR7/8 Agonist can turn a cold tumor hot In cold tumors, there is no inflammation and no recruitment of effector cells In hot tumors, the tissue resident immune cells fight the cancer and may recruit effector cells from circulation Cold tumors Hot tumor

Slide 14

Optimal Product Design Parameters Ideal TLR agonist Design Sustained high local concentration Potent pro-inflammatory TLR agonist Pharmacology / PD Sustained inflammation in the tumor, with high cyto- and chemokine release Convenient dosing Clinical Clinical activity in injected and non-injected tumor (abscopal) Well-tolerated systemic AE profile Ideal IL-2 agonist Design Long systemic half-life with low Cmax IL-2 biased to b/g with high potency and similar size to native IL-2 Pharmacology / PD Expansion of CD8+ T and NK cells, with no expansion of EOS and Tregs Convenient dosing Clinical  Broad clinical activity Well-tolerated (no grade 3/4 CRS, VLS) Administered as outpatient Innate immune system Adaptive immune system TLR: Toll-like receptor; Treg: regulatory T cells;  EOS: eosinophils; ALC absolute lymphocytes count (blood); CRS: cytokine release syndrome; VLS: vascular leak syndrome

Slide 15

TransCon TLR7/8 Agonist: Using TransCon Hydrogel Technology for Targeted Intratumoral Exposure TransCon TLR7/8 Agonist

Slide 16

pH and temperature dependent linker cleavage Local depot of drug loaded TransCon hydrogel carrier Sustained Local Intratumoral Release of Resiquimod Using TransCon hydrogel enables high local concentration of resiquimod with low systemic exposure

Slide 17

TransCon TLR7/8 Agonist: Turning the Tumor Hot TransCon TLR7/8 Agonist is designed for high intratumoral exposure over several weeks with minimal systemic exposure and to turn the tumor hot using a potent TLR agonist1 Local and abscopal effect expected via increased antigen presentation in tumor & draining lymph nodes2 TransCon TLR7/8 Agonist is designed to activate the antigen presenting cells locally and make tumors hot regardless of immune status Increase antigen presentation Production of chemokines Increase intratumoral proinflammatory cytokines CXCL-10 creates homing of Teff and NK cells from tissue and blood. 1 Cellular Immunology 243 (2006) 48–57 2 Cancer Cell International (2022) 22:286

Slide 18

TransCon IL-2 b/g: Sustained Release of Non-alpha IL-2 Using Validated Prodrug Technology TransCon IL-2 b/g

Slide 19

TransCon IL-2 b/g Best-in-Class Design Rosen D, et al. AACR annual meeting. 2020; Poster 4507. TransCon linker slowly releases IL-2 b/g TransCon carrier IL-2 b/g TransCon linker TransCon IL-2 b/g (Prodrug) Active IL-2 b/g % Release of IL-2 b/g TransCon IL-2 b/g in vitro release kinetics TransCon IL-2 b/g is designed to provide sustained expansion of circulating CD8+ T and NK cells. Released IL-2 b/g  can distribute to tumor tissue to active resident immune cells. pH and temperature dependent linker cleavage

Slide 20

TransCon IL-2 β/γ: Built on 30 Years of Learnings TransCon IL-2 b/g is designed to enhance both local and systemic immune responses and synergize with hot tumor biology 1Data on file 2Bioconjugate Chem. 2004, 15, 6, 1304–1313 Variant β/γ Bias Potency reduction1 Size2 (Radius) IL-2 No n/a 2 nm IL-2 β/γ 5 kDa Yes ~4-fold 3 nm IL-2 β/γ 10 kDa Yes ~6-fold 4 nm IL-2 β/γ 30 kDa Yes ~20-fold 6 nm Selectively expand reservoir of cytotoxic T- and NK cells over Tregs Low Cmax, of released biased IL-2 β/γ molecule, retaining native-like size Locally activate tissue-resident cytotoxic T-cells Designed for desired receptor binding, potency, and exposure β/γ bias obtained with small 5 kDa PEG, retaining native-like size and high potency to preferentially expand and activate cytotoxic T- and NK cells over Tregs Long half-life prodrug and low Cmax widen therapeutic index to deliver tolerable and sustained expansion of effector cell

Slide 21

Two Products Designed for Monotherapy Effects and Synergistic Mode of Action Tcirc: Circulating T cells, NK: Natural killer cells, APC: Antigen presenting cell, TRM: Tissue resident T cell (effector & memory), CTL: Cytotoxic T cell (CD8+), Tmem: Memory T cell (CD4+), Th1: T helper 1 cell, M1: M1 macrophage TransCon IL-2 b/g designed to robustly expand and activate immune effector cells in tumor and circulation TransCon TLR7/8 Agonist designed to increase tumor recognition for local and systemic tumor clearance

Slide 22

Optimal Product Design Parameters Ideal TLR agonist Design Sustained high local concentration Potent pro-inflammatory TLR agonist Pharmacology / PD Sustained inflammation in the tumor, with high cyto- and chemokine release Convenient dosing Clinical Clinical activity in injected and non-injected tumor (abscopal) Well-tolerated systemic AE profile Ideal IL-2 agonist Design Long systemic half-life with low Cmax IL-2 biased to b/g with high potency and similar size to native IL-2 Pharmacology / PD Expansion of CD8+ T and NK cells, with no expansion of EOS and Tregs Convenient dosing Clinical  Broad clinical activity Well-tolerated (no grade 3/4 CRS, VLS) Administered as outpatient Innate immune system Adaptive immune system TLR: Toll-like receptor; Treg: regulatory T cells;  EOS: eosinophils; ALC absolute lymphocytes count (blood); CRS: cytokine release syndrome; VLS: vascular leak syndrome

Slide 23

Clinical Development Strategy & Clinical Updates Stina Singel, M.D., Ph.D. EVP, Head of Clinical Development, Oncology

Slide 24

Removing the Immune Brakes Is Not Sufficient for Majority of Tumors Hirsch et al. 2019 British Journal of Cancer 120:3–5, Reproduced with permission from Springer Nature Primary and acquired resistance to immune checkpoint inhibitors limit the benefit from checkpoint inhibitors Response rate (ORR) of checkpoint inhibitors (CPIs) % Reprinted from Cancer Cell 37:443-455, Schoenfeld and Hellmann, 2020, with permission from Elsevier Copyrighted Image Copyrighted Image

Slide 25

Melanoma is the First Solid Tumor to Demonstrate Benefit from Checkpoint Inhibitors Reprinted from Eur J Cancer, Vol /edition number, Ugurel et al., Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019, 2020; 130:126-138, with permission from Elsevier. Checkpoint inhibitors and targeted therapies have made significant impact on melanoma survival Copyrighted Image

Slide 26

Many Patients Do Not Benefit Sufficiently from Checkpoint Inhibitors in Melanoma Adapted from Ugurel et al. Eur J Cancer 2020; 130:126-138 Unmet Need Anti-CTLA4 + anti-PD-1 Anti-PD-1 Anti-CTLA4

Slide 27

Novel Approaches Are Needed in Melanoma Checkpoint inhibition is not sufficient here Adapted from Ugurel et al. Eur J Cancer 2020; 130:126-138 Unmet Need Anti-CTLA4 + anti-PD-1 Anti-PD-1 Anti-CTLA4

Slide 28

Product Candidates in Oncology TransCon TLR7/8 Agonist

Slide 29

Resiquimod: TLR7/8 Agonist 1,2 Small molecule agonist of both TLR7 and TLR8 TLR7: mainly expressed in dendritic cells (DCs), to some extent in B cells, monocytes, macrophages TLR8: primarily expressed in DCs, monocytes, macrophages Potent activator of the innate immunity Elevates proinflammatory cytokines Enhances antigen presentation Enhances anti-tumor immunity 1 Vasilakos J and Tomai M. Exp Rev Vaccines, 2013; 12:809-819. 2 Rook A, et al. Blood. 2015;126(25):2765. Resiquimod activates dendritic cells, key antigen-presenting cells

Slide 30

transcendIT-101 Oral Presentation at SITC 2022 Intratumoral TransCon TLR7/8 Agonist RP2D declared at 0.5mg/lesion Generally well-tolerated with 1 DLT (grade 3 injection site reaction) from 23 patients treated in dose escalation cohorts, as monotherapy or in combination with pembrolizumab PK data showed low systemic exposure and sustained release of resiquimod over weeks after a single injection  Biomarker data showed target engagement in injected and non-injected tumors along with sustained systemic immune response  Clinical activity observed with monotherapy anti-tumor response including abscopal effect RP2D=recommended phase 2 dose DLT=dose limiting toxicity

Slide 31

TransCon TLR7/8 Agonist Has Monotherapy Anti-Tumor Activity Locally and Systemically Datacut 21 Sept 2022 Clinical activity observed with partial response (PR) with monotherapy, including abscopal effect in non-injected lesions, which we continue to see in additional patients

Slide 32

Product Candidates in Oncology IL-2 Selective for the IL-2Rb/g TransCon IL-2 b/g

Slide 33

Aldesleukin – Higher Lymphocyte Count Correlated with Better Efficacy Rosenberg 1998 Ann Surg 228(3):307-19. 600,000 IU/kg (0.037 mg/kg) IV every 8 hours by for max 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a max of 28 doses per course, as tolerated. -Proleukin Product Insert Clinical experience with aldesleukin suggests: Normal lymphocyte count range (adult):1000-4800 cells per mm3 Hospitalization required for administration: Parameters Significantly Associated with Complete Response to Treatment with High-Dose IL-2 * Applying the Hochberg correction, these p values are significant at the 0.05 level. Toxicity: vascular leak and severe cytokine release syndrome requiring vasopressors and oxygen support due to IL-2Ra binding to eosinophils, endothelial cells Total IL-2 in first course (mean ± SEM, IU/kg): Complete responders: 11,171±624 Noncomplete responders: 9,710 ± 183 (P2* = 0.024) Maximum lymphocytes (mean ± SEM, per mm3) Complete responders: 8,048 ± 900 Noncomplete responders: 6,514 ± 668 (P2* = 0.017) More Drug Sustained Lymphocyte Exposure Better Efficacy

Slide 34

Maximizing IL-2 Therapy Has So Far Been Limited by Toxicity or Insufficient Lymphocyte Expansion and Short Drug Exposure Aldesleukin Reprinted from Blood, 107(6):2409, Ahmadzadeh and Rosenberg , IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients, Copyright 2006, with permission from Elsevier IV three times daily , 7-11 doses/pt, n=8 Recent clinical programs with IL-2 variants demonstrate improved tolerability and improved PK properties with aim to have better efficacy, but actual extent (both magnitude and duration) of lymphocyte expansion has not clearly surpassed that of aldesleukin Dutcher et al. Journal for ImmunoTherapy of Cancer 2014, 2:26 Absolute Lymphocyte Count “The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity.” High dose interleukin-2 (Aldesleukin) – expert consensus on best management practices -2014 Copyrighted Image

Slide 35

Sustained Immunological Activation Potentially Increases Effectiveness While Lowering Toxicity Risk IV three times a day in ICU for 5 days, rest 9 days, repeat for max 28 doses as tolerated (Proleukin product insert) IV outpatient once every 3 weeks until progressive disease or unacceptable toxicity

Slide 36

IL-Believe Phase 1/2 Trial Design and Next Steps Study designed to define maximum tolerated dose and assess preliminary anti-tumor efficacy Dose Escalation (“3+3” Design) Ph2 Dose Expansion at RP2D Combination with pembrolizumab: Ongoing Cohort 3 TransCon IL-2 b/g + chemo  PROC Cohort 4 TransCon IL-2 b/g + TC TLR 7/8 Agonist Post anti-PD-1 Melanoma Cohort 5 TransCon IL-2 b/g + TC TLR 7/8 Agonist 2L+ Cervical Cancer  Cohort 6a* TransCon IL-2 b/g monotherapy Neoadjuvant Melanoma Cohort 6b* TransCon IL-2 b/g + pembro Neoadjuvant Melanoma Cohort 6c* TransCon IL-2 b/g + TC TLR 7/8 Agonist Neoadjuvant Melanoma Cohort 7 TransCon IL-2 b/g + chemo + pembro Neoadjuvant NSCLC *monotherapy arm will only open if either of combination arms passes futility PROC = platinum resistant ovarian cancer; NSCLC = non-small cell lung cancer Monotherapy: Completed Combination with pembrolizumab: Ongoing Study status as of 18 May 2023 20 mg/kg + pembro 40 mg/kg + pembro 80 mg/kg + pembro 120 mg/kg + pembro 20 mg/kg 40 mg/kg 80 mg/kg 160 mg/kg 120 mg/kg

Slide 37

Monotherapy: Completed Combination with pembrolizumab: Ongoing TransCon IL-2 b/g Dose Escalation n=4; no DLTs TransCon IL-2 b/g Phase 1 Trial Dose Escalation Status n=4; no DLTs n=5, 1 DLT n=3; no DLTs n=5; no DLTs n=5; no DLTs n=8, no DLTs n=5; no DLTs Study status as of 18 May 2023 enrolling Monotherapy Dose Escalation Demographics Total N=25 Age (years), median (min, max) 64 (37, 82) Prior Anti-PD(L)1 Therapy (n %) 9 (36) Prior lines of systemic therapies Median (min, max) 4 (1,15) Tumor Types HNSCC CRC Ovarian Pancreas Triple-negative breast cancer Endometrial SCLC Esophageal Cholangiocarcinoma Invasive ductal carcinoma (breast) Leiomyosarcoma Renal Uterine leiomyosarcoma Rectal 5 3 3 3 2 1 1 1 1 1 1 1 1 1 HNSCC=head and neck squamous cell carcinoma; CRC=colorectal cancer; SCLC=small cell lung cancer 20 mg/kg + pembro 40 mg/kg + pembro 80 mg/kg + pembro 120 mg/kg + pembro 20 mg/kg 40 mg/kg 80 mg/kg 160 mg/kg 120 mg/kg TransCon IL-2 b/g monotherapy dose escalation portion completed

Slide 38

TransCon IL-2 b/g Phase 1 Preliminary Safety Overview Monotherapy Dose Escalation *Primary reason for study discontinuation in End of Treatment (EOT) is death due to progressive disease **Subject discontinued treatment due to AEs (including CRS, myalgia and worsening cancer pain) Events Dose (mg/kg) Subjects with Any 20 N=4 n (%) 40 N=3 n (%) 80 N=5 n (%) 120  N=8 n (%) 160 N=5 n (%) Dose Limiting Toxicity (DLT) 0 (0) 0 (0) 0 (0) 0 (0) 1 (20) Grade ≥3 TEAEs related to TransCon IL-2 β/γ  1 (25) 0 (0) 0 (0) 0 (0) 4 (80) TEAEs leading to treatment discontinuation 1 (25) 0 (0) 1 (20) 2 (25) 1 (20) TEAEs leading to death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Data cut 28 Apr 2023 TEAE=treatment-emergent adverse event; G=grade; CRS=cytokine release syndrome TransCon IL-2 b/g monotherapy was generally well-tolerated with effective half-life of at least 35 hours 

Slide 39

TransCon IL-2 b/g Phase 1 Preliminary Safety Overview Monotherapy Dose Escalation Events Dose (mg/kg) Subjects with Any 20 N=4 n (%) 40 N=3 n (%) 80 N=5 n (%) 120  N=8 n (%) 160 N=5 n (%) Dose Limiting Toxicity (DLT) 0 (0) 0 (0) 0 (0) 0 (0) 1 (20) (1) G3 Worsening CRS Grade ≥3 TEAEs related to TransCon IL-2 β/γ  1 (25) (1) Non-serious G4 lymphopenia 0 (0) 0 (0) 0 (0) 4 (80) (1) G3 Hypoxia  (2) G3 Worsening CRS (3) G3 Anemia, G3 Thrombocytopenia (4) G3 Neutropenia TEAEs leading to treatment discontinuation 1 (25) (1) G3 Small bowel obstruction not related to study drug 0 (0) 1 (20) (1) G2 CRS* related 2 (25) (1) G1 CRS** related (2) G4 Septic shock not related to study drug 1 (20) (1) G4 Lung infection not related to study drug TEAEs leading to death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Data cut 28 Apr 2023 TEAE=treatment-emergent adverse event; G=grade; CRS=cytokine release syndrome TransCon IL-2 b/g monotherapy was generally well-tolerated with effective half-life of at least 35 hours  *Primary reason for study discontinuation in End of Treatment (EOT) is death due to progressive disease **Subject discontinued treatment due to AEs (including CRS, myalgia and worsening cancer pain)

Slide 40

TransCon IL-2 b/g Phase 1 Preliminary Safety Overview Monotherapy Dose Escalation Events Dose (mg/kg) Subjects with Any 20 N=4 n (%) 40 N=3 n (%) 80 N=5 n (%) 120  N=8 n (%) 160 N=5 n (%) Dose Limiting Toxicity (DLT) 0 (0) 0 (0) 0 (0) 0 (0) 1 (20) (1) G3 Worsening CRS Grade ≥3 TEAEs related to TransCon IL-2 β/γ  1 (25) (1) Non-serious G4 lymphopenia 0 (0) 0 (0) 0 (0) 4 (80) (1) G3 Hypoxia  (2) G3 Worsening CRS (3) G3 Anemia, G3 Thrombocytopenia (4) G3 Neutropenia TEAEs leading to treatment discontinuation 1 (25) (1) G3 Small bowel obstruction not related to study drug 0 (0) 1 (20) (1) G2 CRS* related 2 (25) (1) G1 CRS** related (2) G4 Septic shock not related to study drug 1 (20) (1) G4 Lung infection not related to study drug TEAEs leading to death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Data cut 28 Apr 2023 TEAE=treatment-emergent adverse event; G=grade; CRS=cytokine release syndrome Recommended Phase 2 dose at 120mg/kg IV Q3W showed no G3/4 CRS or vascular leak syndrome Recommended Phase 2 Dose *Primary reason for study discontinuation in End of Treatment (EOT) is death due to progressive disease **Subject discontinued treatment due to AEs (including CRS, myalgia and worsening cancer pain)

Slide 41

Absolute Lymphocyte Count (ALC) and Eosinophils One Week After First Dosing ALC on C1D8 (x1000 cells/mL) 20 mg/kg 40 mg/kg 80 mg/kg 120 mg/kg 160 mg/kg mean 1.4 2.4 3.1 5.2 5.1 median 1.5 2.0 3.4 4.5 4.7 Absolute lymphocyte count Eosinophils EOS on C1D8 (x1000 cells/mL) 20 mg/kg 40 mg/kg 80 mg/kg 120 mg/kg 160 mg/kg mean 0.21 0.07 0.09 0.20 0.13 median 0.13 0.09 0.09 0.13 0.10 ALC=absolute lymphocyte count Demonstrated clear dose-dependent ALC expansion without effect on eosinophils Each dot represents a single patient; bar indicates the mean of the values; error bars indicate standard deviation from the mean EOS=eosinophil count

Slide 42

Cytotoxic Immune Cells (CD8+ T and NK cells) and Regulatory T (Treg) Cells One Week After First Dosing Normal range – calculated from normal range of CD4+ T cells: Liotta et al., 2010 - Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma Li et al., 2019 - Increased frequency of regulatory T cells in the peripheral blood of patients with endometrioid adenocarcinoma Normal range: Kokuina et al., 2019 - Normal Values of T, B and NK Lymphocyte Subpopulations in Peripheral Blood of Healthy Cuban Adults Ebbo et al., 2016 - Low Circulating Natural Killer Cell Counts are Associated With Severe Disease in Patients With Common Variable Immunodeficiency Normal range: Bofill et al., 1991 - Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis Kokuina et al., 2019 - Normal Values of T, B and NK Lymphocyte Subpopulations in Peripheral Blood of Healthy Cuban Adults Demonstrated clear dose-dependent response on cytotoxic immune cells without significant effect on Tregs Each dot represents a single patient; bar indicates the mean of the values; error bars indicate standard deviation from the mean

Slide 43

TransCon IL-2 β/γ Changes the Lymphocyte Composition Towards a Majority of Cytotoxic Lymphocytes One Week After First Dosing Average cell count per dose-level - calculated from ALC and Flow Cytometry results *Cell count based on all available data RP2D

Slide 44

TransCon IL-2 b/g Phase 1 Monotherapy Dose Escalation Status of Efficacy-Evaluable Patients Data Cut Apr 28, 2023 HNSCC 3 + MSS CRC 3 - Sigmoid Colon 3 - SCLC 2 + Esophageal 2 - HNSCC 2 + Ovarian 3 - Pancreatic 3 - Ovarian 4 - Breast 9 - Cholangiocarcinoma 4 - RCC 4 + MSI-h CRC 5 + Pancreatic 4 - TNBC 11 + Pancreatic 3 - HNSCC 4 + Endometrial 1 - 0 9 18 27 36 45 54 Weeks SD PR PD Treatment ongoing Discontinue TransCon IL-2 b/g Death Prior CPI Early evidence of clinical benefit in 1 pancreatic cancer with durable stable disease >45 weeks and 1 MSI-h CRC progressed on prior anti-PD1 with PR at first tumor assessment TransCon IL-2 b/g dose levels: 20 mg/kg 40 mg/kg 80 mg/kg 120 mg/kg 160 mg/kg Prior # tx Response by Investigator Assessment per RECIST v1.1 Data cut 28 Apr 2023 # tx= number of lines of systemic treatment; CPI=checkpoint inhibitor; HNSCC=head and neck squamous cell cancer; MSS=microsatellite stable; CRC=colorectal cancer; SCLC=small cell lung cancer; RCC=renal cell carcinoma; MSI-h=microsatellite instability high; TNBC=triple negative breast cancer

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TransCon IL-2 b/g Phase 1 Monotherapy Dose Escalation Status of Efficacy-Evaluable Patients Data Cut Apr 28, 2023 HNSCC 3 + MSS CRC 3 - Sigmoid Colon 3 - SCLC 2 + Esophageal 2 - HNSCC 2 + Ovarian 3 - Pancreatic 3 - Ovarian 4 - Breast 9 - Cholangiocarcinoma 4 - RCC 4 + MSI-h CRC 5 + Pancreatic 4 - TNBC 11 + Pancreatic 3 - HNSCC 4 + Endometrial 1 - 0 9 18 27 36 45 54 Weeks Prior CPI Early evidence of clinical benefit in 1 pancreatic cancer with durable stable disease >45 weeks and 1 MSI-h CRC progressed on prior anti-PD1 with PR at first tumor assessment TransCon IL-2 b/g dose levels: 20 mg/kg 40 mg/kg 80 mg/kg 120 mg/kg 160 mg/kg Prior # tx Response by Investigator Assessment per RECIST v1.1 Data cut 28 Apr 2023 # tx= number of lines of systemic treatment; CPI=checkpoint inhibitor; HNSCC=head and neck squamous cell cancer; MSS=microsatellite stable; CRC=colorectal cancer; SCLC=small cell lung cancer; RCC=renal cell carcinoma; MSI-h=microsatellite instability high; TNBC=triple negative breast cancer Recommended Phase 2 Dose Additional 5 patients not reached efficacy evaluation: 3 ongoing not yet reached assessment timepoint; 2 discontinued due to AE SD PR PD Treatment ongoing Discontinue TransCon IL-2 b/g Death

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TransCon IL-2 b/g Phase 1 Monotherapy Dose Escalation Status of Efficacy-Evaluable Patients Data Cut Apr 28, 2023 HNSCC 3 + MSS CRC 3 - Sigmoid Colon 3 - SCLC 2 + Esophageal 2 - HNSCC 2 + Ovarian 3 - Pancreatic 3 - Ovarian 4 - Breast 9 - Cholangiocarcinoma 4 - RCC 4 + MSI-h CRC 5 + Pancreatic 4 - TNBC 11 + Pancreatic 3 - HNSCC 4 + Endometrial 1 - 0 9 18 27 36 45 54 Weeks Early evidence of clinical benefit in 1 pancreatic cancer with durable stable disease >45 weeks and 1 MSI-h CRC progressed on prior anti-PD1 with PR at first tumor assessment TransCon IL-2 b/g dose levels: 20 mg/kg 40 mg/kg 80 mg/kg 120 mg/kg 160 mg/kg Response by Investigator Assessment per RECIST v1.1 Data cut 28 Apr 2023 # tx= number of lines of systemic treatment; CPI=checkpoint inhibitor; HNSCC=head and neck squamous cell cancer; MSS=microsatellite stable; CRC=colorectal cancer; SCLC=small cell lung cancer; RCC=renal cell carcinoma; MSI-h=microsatellite instability high; TNBC=triple negative breast cancer Recommended Phase 2 Dose Additional 5 patients not reached efficacy evaluation: 3 ongoing not yet reached assessment timepoint; 2 discontinued due to AE Patient 1 Patient 2 SD PR PD Treatment ongoing Discontinue TransCon IL-2 b/g Death Prior # tx Prior CPI

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Patient 1: Heavily Pre-treated Metastatic Colorectal Cancer Patient with metastatic colorectal cancer (CRC): Tumor genetics: Microsatellite Instability High (MSIh); BRAF V600E Prior 5 lines of systemic treatments, including nivolumab, all with Best Overall Response of Stable Disease (SD) Started on TransCon IL-2 b/g monotherapy 120mg/kg every 3 weeks since February 2023, now ongoing after 4 cycles Treatment related adverse events: Grade 2 fever, Grade 2 myalgia, Grade 1 rash, Grade 1 pruritis Tumor assessment at Week 9: Partial Response (PR): Target lesions: peritoneal deposit next to spleen and omental soft tissue nodule Non-target lesions: omentum/peritoneum Diagnosed Januaryà surgery 2018 2019 2020 2021 2022 2023 Metastatic Februaryà surgery Oxaliplatin + capecitabine 2/18-8/18 Nivolumab 7/20-12/20 FOLFIRI (Irinotecan+5FU+leucovorin) + bevacizumab 1/21-10/21 Capecitabine 10/21-12/21 Cetuximab + encorafenib 12/21-1/23 Datacut 28 April 2023 TransCon IL-2 b/g 2/23-ongoing BOR=best overall response; SD=stable disease; PR=partial response BOR Partial Response on monotherapy TransCon IL-2 b/g SD SD SD SD SD PR Visit Sum of Diameters in mm (% change from baseline) Target Lesion Response Non-target Response New Lesion RECIST v1.1 Overall Response Baseline 46 Week 9 31 (-33%) PR Non-CR/Non-PD No uPR

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Patient 2: Heavily Pre-treated Metastatic Pancreatic Cancer Patient who progressed after 3 prior lines of systemic treatment Widely metastatic pancreatic cancer including liver and lung involvement TransCon IL-2 b/g monotherapy treated since June 2022 Long stable disease ongoing ~1 year on treatment after 13 cycles Datacut 17 May 2023 Dr. Davar will discuss this patient

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Recommended Phase 2 Dose (RP2D) for TransCon IL-2 b/g Determined from Multiple Observations Aiming to cure more cancer patients safely with amplified and durable immune activation Safety Profile: generally well-tolerated with no DLT out of 8 patients dosed; no vascular leak syndrome; no grade 3 or 4 cytokine release syndrome Long effective half life with low Cmax Expands local and systemic cytotoxic immune effector cells (CD8+ T and NK cells) without clear effect on Tregs and eosinophils Clinical benefit observed with monotherapy in heavily pre-treated patients TransCon IL-2 b/g monotherapy at 120 mg/kg IV Q3W, outpatient

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Next Steps: Phase 2 Indication-Specific Cohorts 1/2L=1st or 2nd line; 2/3L=2nd or 3rd line; HNSCC=head and neck squamous cell cancer; cSCC=cutaneous squamous cell cancer; HPV=human papilloma virus; NSCLC=non-small cell lung cancer; PROC=platinum resistant ovarian cancer Broad clinical development plan aiming to show meaningful clinical activity across various indications First indications selected for speed to meaningful endpoint readout and current treatment landscape Phase 2 dose expansion cohorts currently enrolling in 7 different tumor types; ~40 patients per cohort Melanoma (neoadjuvant and post anti-PD1) cSCC (neoadjuvant) HNSCC (1/2L metastatic) Cervical (2/3L metastatic) Other HPV-associated (1/2L metastatic) NSCLC (neoadjuvant) PROC (metastatic) Randomized Phase 2 trial in neoadjuvant HNSCC to start this year Topline/interim analysis from Phase 2 dose expansion cohorts expected in 2024

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Multiple Combination Opportunities to Optimize Treatment TransCon IL-2 b/g IO combinations Cytotoxics Antibodies Adjuvants Targeted therapies Chemotherapies Bispecifics Antibody-drug conjugates Naked antibodies Cellular therapies Cancer vaccines Innate immune activators (TransCon TLR7/8 Agonist) Checkpoint inhibitors TransCon IL-2 b/g has potential to become a backbone agent in oncology

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Oncology Program Summary and Future Directions TransCon IL-2 b/g Phase 1 monotherapy dose escalation complete with RP2D determined at 120mg/kg IV every three weeks in May 2023 Clinical activity observed with monotherapy anti-tumor response in CRC and long stable disease in pancreatic cancer TransCon IL-2 b/g has the potential to become a backbone agent in oncology with current developments including subcutaneous formulation with goal for adjuvant treatment setting TransCon TLR7/8 Agonist RP2D for monotherapy and combination with anti-PD1 determined at 0.5mg/lesion last fall Clinical activity observed with monotherapy anti-tumor response including abscopal effect TransCon IL-2 b/g and TransCon TLR7/8 Agonist both demonstrated safety and single-agent clinical activity as key attributes for combinability with various other agents and treatment modalities Enrollment in the transcendIT-101 and IL-Believe trials continuing in Phase 2 Dose Expansion at RP2D in indication-specific cohorts Continue to create potential best-in-class differentiated product candidates using TransCon Technologies Aiming to cure more cancer patients with amplified and durable immune activation

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Investigator Perspectives Diwakar Davar, M.D., Associate Professor Clinical Director of Melanoma and Skin Cancer Program, University of Pittsburgh Medical Center (UPMC), Hillman Cancer Center

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Disclosures and Funding – Dr. Davar Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK. Consultant: ACM Bio, Ascendis Pharma, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics CE Speakers’ Bureau: Castle Biosciences. Intellectual Property: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020 US Patent 63/208,719, “Compositions and Methods For Determining Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021

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Metastatic Pancreatic Cancer on TransCon IL-2 b/g Monotherapy NEW SLIDE – PENDING VETTING mm=millimeter; RECIST v1.1=Response Evaluation Criteria for Solid Tumors version 1.1; PR=partial response; CR=complete response; PD=progressive disease; SD=stable disease Datacut 17 May 2023 Diagnosed metastatic 7/20 2020 2021 2022 2023 SD FOLFIRINOX (Irinotecan+oxaliplatin+5FU+leucovorin) +Devimistat 12/20-5/21 Gemcitabine+nab-paclitaxel 6/21-12/21 TransCon IL-2 b/g 6/22-ongoing Irinotecan + 5FU 3/22-4/22 Lung wedge resection 9/20 Case study: 67-year-old male with metastatic pancreatic cancer. Tumor genetics: Microsatellite Stable (MSS); KRAS G12V Prior 3 lines of systemic treatments with Progressive Disease (PD) as Best Overall Response Started on TransCon IL-2 b/g monotherapy 80mg/kg every 3 weeks since June 2022, now ongoing after 13 cycles Dose reduced to 40mg/kg since cycle 5 in September 2022 Tocilizumab added with cycle 8 Encouraging CA19-9 trend shown in blue (tumor marker for pancreatic cancer) Treatment related adverse events: No grade 3 or above Grade 2: cytokine release syndrome, Infusion related reaction, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased` TransCon IL-2 b/g 80 µg/kg 40 µg/kg Treatment hold – Gr 3 sepsis (unrelated) PD PD

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Metastatic Pancreatic Cancer with Long Stable Disease on TransCon IL-2 b/g Monotherapy Visit Sum of Diameters in mm (% change from baseline) Target Lesion Response Non-target Response New Lesion RECIST v1.1 Overall Response Baseline 64.6 Week 9 63.5 (-2%) SD Non-CR/Non-PD No SD Week 18 70.4 (+9%) SD Non-CR/Non-PD No SD Week 27 70.1 (+9%) SD Non-CR/Non-PD No SD Week 36 71.2 (+10%) SD Non-CR/Non-PD No SD Week 45 66.9 (+4%) SD Non-CR/Non-PD No SD mm=millimeter; RECIST v1.1=Response Evaluation Criteria for Solid Tumors version 1.1; PR=partial response; CR=complete response; PD=progressive disease; SD=stable disease Datacut 29 April 2023 Tumor assessments every 9 weeks since first dosing in June 2022 showing Stable Disease (SD), ongoing past Week 45 Target lesions: pancreatic mass, 2 lung lesions Non-target lesions: liver, pancreas, lung, spleen, multiple lymph nodes Heavily pre-treated, widely metastatic pancreatic cancer including liver and lung involvement on TransCon IL-2 b/g monotherapy experiencing long stable disease ongoing ~1 year on treatment

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2nd Generation IL-2 Agonists Aim to Harness T cells and NK cells REF: 1Raker VR, Cells 2020; 2Hashimoto M, Nature 2022; 3Deak LC, Nature 2022 CONFIDENTIAL Augmenting PD-1 Efficacy without Additional Costim (CD28) or Coinhibition (CTLA-4, TIM-3, LAG-3) Interleukin-2 (IL-2) is a T cell growth factor that signals through a complex network of receptors of varying affinity with effects upon Tregs, T effector cells and memory T cells. PD-1+TCF-1+ stem-like CD8+ T cells are not fate-locked. Antigen-specific CD8+ T cells express increased levels of the high affinity IL-2 trimeric receptor; and combination therapy demonstrates synergy in LCMV and cancer models preclinically.2-3 Synergy is dependent upon CD25 engagement,2 but can be overcome by binding of IL-2 to PD-1 and IL-2Rβγ on the same cell in cis.3

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2nd Generation IL-2 Agonists Aim to Harness T cells and NK cells CONFIDENTIAL Drug (Company) Description Phase Indications Nemvaleukin alfa (Alkermes) IL-2-CD25 fusion 3 Ovarian cancer (ARTISTRY-7) Nemvaleukin alfa (Alkermes) IL-2-CD25 fusion 2 Cutaneous and mucosal melanoma (ARTISTRY-6) 1 Single agent dose-escalation and combination with pembro (ARTISTRY-1)1 TransCon IL-2 (Ascendis) PEGylated IL-2 muteins 1/2 Pending AU-007 (Aulos) Anti-IL-2 mAb 1/2 Pending ANV419 (Anaveon) IL-2-anti-IL-2 fusion 1/2 Pending BNT151 (BioNTech) mRNA-encoded IL-2 mutein 1/2 Pending MDNA11 (Medicenna) Albuminated IL-2 mutein 1/2 Pending XTX-202 (Xilio) Masked IL-2 mutein 1/2 Pending CUE-101 (Cue Biopharma) E7-pHLA-IL-2-Fc fusion protein 1 HPV+ tumors2 NL-201 (Neoleukin) IL-2 and IL-15 mimic without CD25-binding interface 1 Pending MK-1484 (Merck) β/γ-selective IL-2 mutein 1 Pending RG6279 (Roche) IL-2–anti-PD-1 fusion protein 1 Pending SHR-1916 (Jiangsu Hengrui) PEGylated IL-2 muteins 1 Pending STK-012 (Synthekine) α/β-selective IL-2 mutein 1 Pending Not included: Bempegaldesleukin (pegylated IL-2 mutein). Negative phase 3 (PIVOT IO-001) in 1L metastatic melanoma (ORR 28% bempeg/nivo vs. 36% nivo).3 SAR444245/THOR-707 (pegylated IL-2 mutein). Phase II (Q3W dosing) combination data reported.4 Program deprioritized and dose-intensification trial announced. REF: 1Vaishampayan UN, ASCO 2022; 2Chung CH, ASCO 2022; 3Diab A, ESMO 2022; 4Falchook G, SITC 2021; 5Atkins MB, J Clin Oncol 1999; 6Klapper JA, Cancer 2012 Trends: POC generation in melanoma and RCC given original indications for aldesleukin.5,6 Expansions in tumor types such as PROC and mucosal melanoma wherein single-agent PD-1 activity is low. Unexplored indications: neoadjuvant settings (melanoma, NSCLC) and other cutaneous tumors where CTLA-4 has not added to PD-1 (cSCC, MCC).

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Overcoming Immune Checkpoint Inhibitor Resistance in Cancer with Innate Agonists1 1Demaria, Nature 2019 Harnessing innate immunity in cancer therapy Targeting anti-microbial immunity for anti-tumor effects (TLR7/8/9, RIG-I, STING, NLRP3) Amplification of immune response (APC activation; co-stimulatory signals; cytokines such as IL-2, IL-12, IL15) Targeting immune suppression within tumor by targeting immune suppressive factors (A2AR, CD39/CD73, IDO, TGFβ, EP4, arginase) or targeting suppressive cells (C5aR1, IL-1β, IL-1α, CXCR2, CCR2, CCR5, ApoE, STAT3, PI3Kγ, CSF-1R) Key cells involved in innate response: NK cells DC Macrophages CONFIDENTIAL

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Toll-Like Receptors (TLRs): Well-Validated Targets for Activation of Innate and Adaptive Immunity1 Activate innate immunity in particular antigen presenting cells (APCs) Prime and expand cytolytic and helper T cells Activate and expand cytotoxic lymphocytes Resiquimod has been clinically evaluated as a potent TLR7/8 Agonist2,3 1. Bourquin C, et al. Pharmacol Res, 2020; 154:104192 2. Vasilakos J and Tomai M. Exp Rev Vaccines, 2013; 12:809-819. 3. Rook A, et al. Blood. 2015;126(25):2765. TLRs activate several key pathways critical in host defense against tumors

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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 myeloid DCs Potent activator of the innate immunity Elevates proinflammatory cytokines: e.g. Type I IFNs, IL-12, TNF-a and chemokines (e.g.CXCL10, CCL2) Enhances antigen presentation: upregulated MHC, costimulatory molecules (e.g. CD80/86) Enhances anti-tumor immunity 1 Vasilakos J and Tomai M. Exp Rev Vaccines, 2013; 12:809-819. 2 Rook A, et al. Blood. 2015;126(25):2765. Resiquimod activates both conventional DCs and pDCs

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transcendIT-101 Trial Open Cohorts Phase 1/2, Open-label, Dose Escalation and Dose Expansion Study of TransCon TLR7/8 Agonist Alone or in Combination with Pembrolizumab in Participants with Locally Advanced or Metastatic Solid Tumor Malignancies (ClinicalTrials.gov: NCT04799054) Part 1: Monotherapy Any solid tumor, any line RP2D Q6W RP2D Q3W X 4 Schedule based on response Dose Optimization (n~6 per cohort) Part 2: Combination Therapy Indications with known CPI activity RP2D Q6W RP2D Q3W X 4 Schedule based on response Part 3: Combination with Pembrolizumaba, Dose-Expansion Indication-specific cohorts Cohort 3a: HNSCC (n~23+25b) Cohort 3b: Other HPV-associated tumor types (n~23+25b) Cohorts 3a and 3b: ≤ 1 line of prior treatment for recurrent metastatic disease Cohort 3c: Neoadjuvant melanoma (n~17+19b) Cohort 3d: Neoadjuvant cSCC (n~23+14b) Cohorts 3c and 3d: no prior treatment for newly diagnosed, resectable disease Dose Expansion RP2D = Intratumoral 0.5 mg/lesion every 3 weeks

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transcendIT-101 Safety and Pharmacokinetics Overview Safety: TransCon TLR7/8 Agonist was generally well-tolerated with a low incidence of DLTs (1 grade 3 injection site reaction) from 23 patients treated in dose escalation cohorts, as monotherapy or in combination with pembrolizumab All TEAEs related to TransCon TLR7/8 Agonist were grades 1 and 2, except 1 grade 3 injection site reaction No TEAEs leading to study drug withdrawal or death Data cut 27Jan23 Pharmacokinetics (PK): Resiquimod plasma concentrations: very low resiquimod Cmax (relative to levels associated with cytokine release syndrome) and no interaction with pembrolizumab Mean systemic half-life ~ 9 days No accumulation of resiquimod on dosing every 3rd week Data cut 21Sep22

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Patient Status by Investigator Assessment per RECIST v1.1 (by indication) Data cut-off 02February 2023 SD=Stable Disease; PR=Partial Response; PD=Progressive Disease In TransCon TLR7/8 Agonist monotherapy cohorts: 2 of 11 (18%) participants had a partial response (1 confirmed and 1 unconfirmed) and 3 of 11 (27%) participants had complete response (CR) in non-injected lesion(s) (i.e. abscopal responses) First tumor assessment entered after datacut

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Pharmacodynamic Markers Confirm TransCon TLR7/8 Agonist Target Engagement and Mechanism of Action Intratumoral recruitment of Macrophages and CD8+ T cells Induction and sustained elevation of intratumoral TLR7/8 and Type I IFN pathway gene expression CD68+ Macrophages CD8+ T cells

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Main Classes of TLR Agonists in Clinical Development TransCon TLR7/8 agonist Vidutolimod BDB001 4 arm pegylated Resiquimod NKTR-262 Discontinued Intratumoral TLR7/8 agonist Sustained Release Intratumoral TLR7/8 agonist Systemic TLR7/8 agonist Intratumoral TLR9 agonist VLP Salt form Resiquimod TAC-001 Systemic TLR9 agonist mAb conjugate

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TLR agonist and molecule engineering Sustained exposure Schedule Route of administration Limited systemic exposure Early and sustained CXCL10 levels Indications under clinical evaluation and combination treatment Development status TransCon TLR7/8 Agonist ü Q3W or Q6W Intratumoral ü ü transcendIT-101 - HNSCC and other HPV-associated cancers with pembrolizumab - Neoadjuvant melanoma and neoadjuvant cSCC with pembrolizumab IL-Believe - Post anti PD-1 melanoma & 2L cervical cancer with TransCon IL-2b/g - Neoadjuvant melanoma with TransCon IL-2b/g BelieveIT-201 - Neoadjuvant HNSCC with pembrolizumab or TransCon IL-2b/g Phase 1/2 BDB001 (Modified Resiquimod) × Q1W Intravenous × × Advanced solid tumors with atezolizumab and radiation PD-(L)1 refractory tumors Phase 2 Vidutolimod (VLP, TLR9 agonist, CpG oligonucleotide) × Q1W induction (7 weeks) Q3W following cycles Intratumoral ü × Advanced melanoma with nivolumab cSCC, BCC, Merkel, NSCLC with cemiplimab Metastatic castration resistant prostate cancer with nivolumab Phase 2 TAC-001 (TLR9 agonist T-CpG, conjugated with CD22 targeting mAb) × Q2W Intravenous × × Advanced or metastatic solid tumors Phase 1/2 NKTR-262 (Pegylated resiquimod) × Q3W Intratumoral ü × Advanced solid tumors with bempegaldesleukin (NKTR-214) Discontinued Phase 1b/2 Main Classes of TLR Agonists in Clinical Development

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Summary of Investigator Perspective on TransCon IL-2 b/g and TransCon TLR7/8 Agonist Immune checkpoint inhibitors have transformed the management of patients with multiple advanced cancers but have some limitations. PD-1/PD-L1 interaction is utilized by cancer but also self-reactive T cells that escape thymic negative selection à unrestrained self-directed autoimmunity and irAEs. Primary target cells are antigen-experienced T cells expressing PD-1, with minimal activation of NK cells. Effective IO agents are needed beyond checkpoint inhibitors. TransCon platform offers ability to transform active drugs into prodrugs with sustained release properties. Both TLR agonists and IL-2 therapy have potential to benefit from using TransCon technology. Broad development strategy may be needed to explore activity in various indications and with various combination partners or treatment modalities.

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Closing Remarks

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TransCon TLR7/8 Agonist Primes Immune Cells Locally for Systemic Antitumor Effect Intratumoral TransCon TLR7/8 Agonist uses the injected tumor to elicit systemic anti-tumor effects Safety Profile: generally well-tolerated with low systemic side effects Long effective half-life with low Cmax Sustained inflammation in the tumor, with high cytokine and chemokine release Anti-tumor responses observed in injected and non-injected tumors TransCon TLR7/8 Agonist monotherapy at 0.5mg/lesion IT Q3W, outpatient

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TransCon IL-2 b/g Provides a Systemic Immune Boost Aiming to cure more cancer patients safely with amplified and durable immune activation Safety Profile: generally well-tolerated with no DLT out of 8 patients dosed; no vascular leak syndrome; no grade 3 or 4 cytokine release syndrome Long effective half-life with low Cmax Expands local and systemic cytotoxic immune effector cells (CD8+ T and NK cells) without clear effect on Tregs and eosinophils Meaningful clinical benefit observed with monotherapy in heavily pre-treated patients TransCon IL-2 b/g monotherapy at 120 mg/kg IV Q3W, outpatient

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TransCon IL-2 b/g: Potential Best-in-Class IL-2 Therapy TransCon IL-2 b/g1 5-kDa pegylation, TransCon Technology THOR-7072 30-kDa pegylation  Recommended Phase 2 Dose  (monotherapy) 120 mg/kg Q3W 24 mg/kg Q3W3 Retains high potency compared to Aldesleukin Yes No Effective half life > 35 h 9-12 h Non-Alpha Yes Yes Expansion of CD8+ T cells median fold change  5.6 (cycle 1, day 8) 4.0 (peak average) Expansion of NK cells median fold change 20.2 (cycle 1, day 8) 8.4 (peak average) Meaningful increase of Tregs or EOS No No Monotherapy clinical activity at RP2D during dose escalation, indication 1 PR in CRC (n=8 dosed, 3 evaluable as of 28 April, 2023) 1 PR in SCC of unknown primary (n=11) High potency while preventing binding to IL-2Ra Prodrug design enables sustained release of non-alpha IL-2 Selective expansion of CD8+ T and NK cells without effect on Tregs or eosinophils Safety profile compatible with chronic outpatient administration Subjective rankings based on publicly available information. 1Data on file. 2Presented at the European Society of Medical Oncology (ESMO) Annual Meeting 2022, September 9–13, 2022. 3New schedule (QW/Q2W)  NCT04009681. Q3W: every three weeks. TransCon carrier TransCon linker IL-2 b/g Active IL-2 b/g pH and temperature dependent linker cleavage THOR-707 is repositioned as a once-weekly dosing for 6 weeks and maintained with bi-weekly dosing3

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Next Steps for Ascendis’ Immunotherapy Program Heterogeneity across cancers, organs, and patients requires diversity of approaches to achieve benefit for patients  TransCon IL-2 b/g and TransCon TLR7/8 Agonist both showed acceptable safety profile and single-agent clinical activity Optimally positioned for combination, with the potential to become a backbone agent in oncology Topline/interim analysis from Phase 2 dose expansion cohorts expected in 2024 Using TransCon Platform to develop multi-modal approaches for immune-mediated tumor control

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Q&A Session Email questions to: IR@ascendispharma.com ©2023 Ascendis Pharma. Ascendis, Ascendis Pharma, the Ascendis Pharma logo, the company logo, TransCon and Skytrofa are trademarks owned by the Ascendis Pharma Group.