Ascendis Pharma A/S : TransCon™ TLR7/8 Agonist Initial Results from Dose Escalation Portion of transcendIT-101 Trial

TransCon™ TLR7/8 Agonist

Initial Results from Dose Escalation Portion of transcendIT-101 Trial

November 11, 2022

		TransCon TLR7/8 Agonist is an investigational product candidate.
1		For investor communication only. Not for use in product promotion.
	Not for further distribution.

TransCon TLR7/8 Agonist is an investigational product candidate. For investor communication only. Not for use in product promotion. Not for further distribution.

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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 March 2, 2022 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.

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TransCon TLR7/8 Agonist Design

Local depot of drug loaded

TransCon hydrogel microparticlesUnmodified active resiquimod

TransCon linker

Resiquimod (inactive)	TransCon hydrogel
carrier

Linker cleavage at

physiological conditions

Tumor

Renal

clearance

• TransCon TLR7/8 Agonist is an investigational long-acting prodrug with sustained, localized release of resiquimod in the injected tumor with low systemic exposure1
• Intratumoral delivery of resiquimod using TransCon Hydrogel technology is designed to steadily activate and intensify the body's innate and adaptive immune response systemically over weeks with a single injection

1Zuniga LA, et al. Cancer Cell Int. 2022; 22(1): 286.

3 Davar D. et al., Oral presentation at SITC 2022; Nov. 11, 2022; Boston, U.S.

TransCon TLR7/8 Agonist is an investigational product candidate. For investor communication only. Not for use in product promotion. Not for further distribution.

Toll-Like Receptors Are Well-Validated Targets for Activation of Innate and Adaptive Immunity

• Toll-Likereceptors (TLRs) are potent stimulants of the innate immune system, particularly antigen presenting cells (APCs) such as dendritic cells (DCs) with multiple effects:
• • Induces DC activation and maturation1-5
  • Reprogramming of macrophages and myeloid derived suppressor cells (MDSCs)1
  • APC stimulation produces proinflammatory cytokines  primes and expands cytolytic and helper T cells
• Resiquimod is a potent TLR7/8 agonist
• • In preclinical models, resiquimod amplifies effects of tumor vaccines6,7
• Clinical limitations of TLR agonists:

• Systemic administration may lead to undesired toxicity (ie, cytokine release syndrome)8
• Previous intratumoral (IT) approaches have not demonstrated prolonged exposure of active drug levels in the tumor

Reprinted from Pharmacol Res, 154, Carole Bourquin, et al., 104192, Copyright (2020), with permission from Elsevier.

Sustained IT exposure of resiquimod could provide therapeutic benefit while minimizing systemic toxicity

1Bourquin C, et al.Pharmacol Res.2020;154. 2Baird JR, et al.Int J Radiat Oncol Biol Phys.2017;99(2).3Blasius A, Beutler B.Immunity.2010;32(3). 4Smits, et al.The Oncologist.2008;13. 5Dovedi SJ,et al.Blood.2013;121(2).

6Vasilakos J, Tomai M.Exp Rev Vaccines.2013;12. 7Rook A, et al.Blood.2015;126(25). 8Pockros, et al.J of Hepatology.2007;47.

4 Davar D. et al., Oral presentation at SITC 2022; Nov. 11, 2022; Boston, U.S.

TransCon TLR7/8 Agonist is an investigational product candidate. For investor communication only. Not for use in product promotion. Not for further distribution.

transcendIT-101 Trial Design

Dose Escalation ("3+3" Design)

Part 1:	Dose Level 1				Dose Level 2
Monotherapy
			(0.5 mg/lesion- up
Any solid tumor,	(0.3 mg/lesion-				to 2 lesions
1 lesion injected)
any line					injected)
				RP2D was
					declared-
Part 2:					(0.5 mg/lesion)
Combination	Dose Level 1				Dose Level 2
with CPI	(0.3 mg/lesion-				(0.5 mg/lesion- up
			to 2 lesions
Indications with	1 lesion injected)				injected)
known CPI activity

Objectives:

• Safety and tolerability
• Pharmacokinetics and pharmacodynamics
• Define maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)
• Preliminary anti-tumor efficacy

• Per protocol, injections were allowed: Dose Level 1 in 1 lesion; Dose Level 2 in up to 2 lesions

Phase 1/2, multi-center,open-label trial of TransCon TLR7/8 Agonist alone or in

combination with pembrolizumab

Abbreviations: CPI, check-point inhibitor; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose. ClinicalTrials.gov NCT04799054 Davar D. et al., Oral presentation at SITC 2022; Nov. 11, 2022; Boston, U.S.

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TransCon TLR7/8 Agonist is an investigational product candidate. For investor communication only. Not for use in product promotion. Not for further distribution.