Slide 1: Virtual R&D Program Update
Exhibit 99.1 ASCENDIS PHARMA A/S Virtual R&D Program Update December 14, 2021
Slide 2: Welcome & Agenda Overview
Welcome & Agenda Overview Scott T. Smith Senior Vice President, Chief Financial Officer
Slide 3: 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 4: Virtual R&D Program Update Agenda
Virtual R&D Program Update Agenda 9:00-9:05 a.m. E.T. 9:55–10:35 a.m. E.T. TransCon CNP Welcome & Agenda Overview Kennett Sprogøe, Ph.D. Scott T. Smith SVP, CFO SVP, Head of Innovation and Research 9:05–9:10 a.m. E.T. Marie-Louise C. Hartoft-Nielsen, M.D., Ph.D. Opening Comments Senior Medical Direc
Slide 5: Opening Comments
Opening Comments Jan Møller Mikkelsen President & Chief Executive Officer
Slide 6: Introduction to Ascendis Pharma
Introduction to Ascendis Pharma An expanding global footprint • Founded in 2007 in Copenhagen, Denmark Global HQ • Publicly listed on NASDAQ since 2015 Ascendis Pharma A/S Hellerup, Denmark (ASND) Research Site • TransCon™: Innovative technology US Commercial Redwood City, CA platform utilized in al
Slide 7: Vision 3x3: Building a Leading Global BioPharma Company
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 hypopa
Slide 8: Diverse Pipeline of Independent Product Candidates
Diverse Pipeline of Independent Product Candidates 7 7 8 1 Received positive CHMP opinion on November 12, 2021. Final EC decision expected within 67 days, or by end of January 2022. 2 In development in Greater China through strategic investment in VISEN Pharmaceuticals. 3 Japanese riGHt Trial. 4 Glo
Slide 9: TransCon PTH Clinical Update
TransCon PTH Clinical Update Aimee D. Shu, M.D. VP, Clinical Development, Endocrine Medical Sciences
Slide 10: Hypoparathyroidism: Insufficient Parathyroid Hormone
Hypoparathyroidism: Insufficient Parathyroid Hormone • An intact PTH axis maintains normal serum calcium and phosphate – By acting on bone, kidney, and intestine – Promoting normal nerve and muscle function • Hypoparathyroidism is a two-hormone deficiency – Resulting in broad systemic dysfunction Hy
Slide 11: Hypoparathyroidism: Multiple Complications
Hypoparathyroidism: Multiple Complications Brain fog Seizures Laryngospasm & Anxiety & depression bronchospasm Infections Heart failure Renal failure Arrhythmias Abnormal skeletal Numbness & tingling dynamics Abnormal tissue Muscle spasms calcifications Fatigue Pain All product candidates are invest
Slide 12: Hypoparathyroidism: Acquired and Inherited Etiologies
Hypoparathyroidism: Acquired and Inherited Etiologies Etiologies as reported by 146 respondents to the Voices of Hypoparathyroidism survey Murphy et. al., Voices of Hypopara survey, poster presented at The Endocrine Society All product candidates are investigational. meeting, 2021. For investor comm
Slide 13: Chronic Hypoparathyroidism: Significant Patient Population
Chronic Hypoparathyroidism: Significant Patient Population Estimated Prevalence: ~400k in these 5 regions South USA Europe Japan China Korea ~70k–112k ~86k–223k ~25k–32k ~12k–13k ~180k–220k • 2013, Powers et. al., • 2013, Underbjerg et. al., • 2017. Shishiba et. • S. Korean ICD-10 codes • 2020, Sui
Slide 14: Conventional Therapy Targets Symptoms, Not Underlying Disease
Conventional Therapy Targets Symptoms, Not Underlying Disease Calcitriol (active vitamin D) Calcium or its analogue alfacalcidol Endogenous production diminished Often requires high pill burden due to insufficient PTH Fails to restore normal PTH physiology and introduces secondary complications • At
Slide 15: Hypoparathyroidism: Goals of an Ideal Therapy
Hypoparathyroidism: Goals of an Ideal Therapy Untreated Ideal therapy hypoparathyroidism Serum calcium ↓ normalize Serum phosphate ↑ normalize Urine calcium ↑ normalize Independence from n/a yes conventional therapy Skeletal health ↓ normalize Quality of life ↓ normalize All product candidates are i
Slide 16: TransCon PTH Designed to Be a Hormone Replacement Therapy
TransCon PTH Designed to Be a Hormone Replacement Therapy TransCon carrier TransCon linker Active PTH Receptor Renal clearance PTH Linker cleavage dependent (inactive) upon pH and temperature • TransCon PTH is a sustained-release prodrug designed to provide stable PTH levels in the physiological ran
Slide 17: PaTH Forward (Phase 2) Trial Design
TransCon PTH PaTH Forward (Phase 2) Trial Design Adults with hypoparathyroidism who required conventional therapy (active vitamin D + calcium) at baseline Blinded Treatment (4 weeks) TransCon PTH 15 µg/day Screening Titration of TransCon PTH and conventional therapy with the TransCon PTH 18 µg/day ≤
Slide 18: PaTH Forward: Mean Serum Calcium and Urine Calcium Through Week 84
PaTH Forward: Mean Serum Calcium and 24-Hour Urine Calcium Through Week 84 Mean Serum Calcium Mean 24-hour Urine Calcium 500 11 All TransCon PTH All TransCon PTH 400 Normal range Mean Mean 10 Calcium 24-hour 300 ULN (men) Corrected Urine for Albumin ULN (women) Calcium mg/dL mg/24hr (± SE) 200 (± SE
Slide 19: PaTH Forward: Mean Active Vitamin D Dose
PaTH Forward: Mean Active Vitamin D Dose Through Week 84 OLE starts 1.8 TransCon PTH 1.6 Placebo 1.4 All TransCon PTH Mean 1.2 Active 1.0 Vitamin D Dose 0.8 µg/day 0.6 (± SE) 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 Weeks TransCon PTH enabled discontinuation of a
Slide 20: PaTH Forward: Mean Calcium Supplement Dose
PaTH Forward: Mean Calcium Supplement Dose Through Week 84 3,000 OLE starts TransCon PTH Placebo 2,500 All TransCon PTH 2,000 Mean Calcium 1,500 Dose mg/day 1,000 (± SE) 500 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 Weeks TransCon PTH enabled rapid and continuous calcium su
Slide 21: Abnormal Skeletal Dynamics in Hypoparathyroidism
Abnormal Skeletal Dynamics in Hypoparathyroidism Hypoparathyroid Normal 1 Representative images above show bone biopsies of the iliac crest as scanned by microcomputed tomography (microCT) Lack of PTH-driven skeletal remodeling results in abnormal bone structure 2 and may be associated with poor bon
Slide 22: PaTH Forward: Serum Markers of Skeletal Dynamics
PaTH Forward: Serum Markers of Skeletal Dynamics Mean P1NP Mean CTx TransCon PTH TransCon PTH Placebo Placebo 110 1,000 All TransCon PTH OLE All TransCon PTH OLE starts starts 90 800 Procollagen Type I 70 600 1N-Terminal Collagen C- Propeptide Telopeptides ng/mL ng/L 50 400 (± SE) (± SE) 30 200 10 0
Slide 23: PaTH Forward: Bone Mineral Density by DXA
PaTH Forward: Bone Mineral Density by DXA 1 Mean Z-scores (n = 43 ) Week 58 change Region Baseline Week 26 Week 58 from baseline Lumbar spine L1-L4 1.6 1.0 0.9 ‒0.7 Femoral neck 1.0 0.5 0.4 ‒0.6 Total hip 1.0 0.6 0.5 ‒0.5 1/3 radius 0.4 0.3 0.3 ‒0.1 With TransCon PTH treatment, Week 58 mean Z-scores
Slide 24: PTH Requirements Change as Skeletal Dynamics Normalize
PTH Requirements Change as Skeletal Dynamics Normalize 2.0 1.6 40 1.5 (Z-score) (mcg/day) 1.0 0.9 30 1.0 0.5 20 0.0 10 -0.5 -1.0 0 0 8 26 58 84 Study Week Mean BMD Z-score (lumbar spine) Mean TransCon PTH Dose • Over time, rates of bone • In hypoparathyroidism, • With physiologic PTH exposure, the t
Slide 25: PaTH Forward: Treatment-Emergent Adverse Events Through Week 84
PaTH Forward: Treatment-Emergent Adverse Events Through Week 84 Week 84 All TransCon PTH (N =59) Subjects With – n (%) Treatment-Emergent Adverse Events (TEAE) 51 (86) Serious TEAE 5 (8) Severity Severe TEAE 3 (5) Moderate TEAE 17 (29) Mild TEAE 31 (53) Related TEAE* 22 (37) Related Serious TEAE 0 T
Slide 26: Summary: PaTH Forward Trial Results Through Week 84
Summary: PaTH Forward Trial Results Through Week 84 1 • 58/59 subjects remain in the trial beyond Week 84 • At Week 84, 93% of subjects were independent from active vitamin D and therapeutic doses of calcium • Mean serum and urine biochemistries continued to be in the normal range • Through Week 58,
Slide 27: PaTHway (Phase 3) Trial Design
TransCon PTH PaTHway (Phase 3) Trial Design Double-blind, placebo-controlled trial with an open-label extension period 1 82 adults with chronic hypoparathyroidism randomized 3:1 (TransCon PTH:placebo) Double-Blind Main period (26 weeks) Open-Label Extension period (156 weeks) Week 26 ¾ TransCon PTH
Slide 28: PaTHway Phase 3 Trial: Baseline Characteristics
PaTHway Phase 3 Trial: Baseline Characteristics Characteristics Total Randomized (N=82) Age, mean years 49 years Female sex, % 78% Geographic region, % North America 62% Europe 38% Postmenopausal, % 28% Duration of hypoparathyroidism, mean years 12 years Post-surgical etiology of hypoparathyroidism,
Slide 29: PaTHway Trial Includes Diverse Etiologies
PaTHway Trial Includes Diverse Etiologies Idiopathic Autoimmune polyglandular syndrome 1 (APS-1) Autosomal dominant hypocalcemia (ADH1) DiGeorge syndrome HDR syndrome (hypoparathyroidism, deafness, renal disease) Acquired from Neck Surgery All product candidates are investigational. For investor com
Slide 30: Potential New Treatment Paradigm for Hypoparathyroidism
Potential New Treatment Paradigm for Hypoparathyroidism TransCon PTH has the potential to be the first hormone replacement therapy for hypoparathyroidism addressing major unmet medical need for a large rare disease patient population Anticipated near-term milestones for global reach and indication e
Slide 31: Three Patient Journeys from the PaTH Forward Trial
Three Patient Journeys from the PaTH Forward Trial Aliya Khan MD, FRCPC, FACP, FACE, FASBMR Clinical Professor of Medicine Director, Calcium Disorders Clinic Director, Fellowship in Metabolic Bone Disease McMaster University 31
Slide 32: Aliya Khan MD, FRCPC, FACP, FACE, FASBMR
Aliya Khan MD, FRCPC, FACP, FACE, FASBMR • Professor of Clinical Medicine at McMaster University • Director of the Calcium Disorders Clinic • Director of Fellowship in Metabolic Bone Disease at McMaster University • Graduated from the University of Ottawa Medical School with honors • Completed postg
Slide 33: Disclosure
Disclosure •For profit • Research grants from Amgen, Ascendis, Alexion, Radius, Takeda, Ultragenyx •Not for profit • Chair, Rapid Response Committee, Osteoporosis Canada • Co-Chair, Knowledge Translation Committee, Osteoporosis Canada • Chair, International Osteonecrosis of the Jaw (ONJ) Taskforce •
Slide 34: Calcium Disorders Clinic at McMaster University Medical Centre
Calcium Disorders Clinic at McMaster University Medical Centre • Specialized Calcium Disorders Clinic (CDC) was established at St Joseph's Healthcare in Hamilton in 2005. • CDC has serves as a Center of Excellence for the diagnosis and management of complex calcium disorders. • Tertiary referral cen
Slide 35: Patient 1: History
Patient 1: History • 57-year-old male • Employment history • Automobile painter, but • Past medical history of: took early retirement • Hypertension due to complications of • Parathyroid adenoma with hypoparathyroidism subsequent total parathyroidectomy • Contractor: was able to • Thyroid nodule and
Slide 36: Hypoparathyroidism Patient Experience Scale: Patient 1 Clinical Course
Hypoparathyroidism Patient Experience Scale (HPES) Patient 1: Clinical Course 80 60 40 20 0 Baseline Week 58 Baseline Week 58 • Prior to trial HPES-Impact Score HPES-Symptom • Very symptomatic with significant muscle cramps and Score paresthesias daily as well as tetany Note: lower is better • Laryn
Slide 37: Patient 1: Laboratory Data
Patient 1: Laboratory Data Albumin-Adjusted Serum Calcium (mg/dL) 24-Hour Urine Calcium (mg/day) 13 3.25 1000 25 800 20 11 2.75 600 15 9 2.25 400 10 7 1.75 200 5 5 1.25 0 0 0 2 4 26 58 84 0 26 58 84 Study Duration (Weeks) Study Duration (Weeks) Serum Phosphate (mg/dL) Active Vitamin D and Calcium Su
Slide 38: Patient 2: History
Patient 2: History • 62-year-old female • Church organist and pianist • Past medical history of: • Hypertension • Goiter, total thyroidectomy- Nov 2012 • Asthma • Hypoparathyroidism Etiology: postsurgical 38
Slide 39: Patient 2: Clinical Course
Patient 2: Clinical Course • Prior to trial • Daily feet cramps and peri-oral numbness and tingling 3-4x/week • Afraid to hold her grandchild due to muscle cramping • Post TransCon PTH • Improved energy and sleep • Able to play the organ again as the finger cramping resolved • Able to enjoy her time
Slide 40: Patient 2: Laboratory Data
Patient 2: Laboratory Data Albumin-Adjusted Serum Calcium (mg/dL) 24-Hour Urine Calcium (mg/day) 13 3.25 1000 25 800 20 11 2.75 600 15 9 2.25 400 10 7 1.75 200 5 5 1.25 0 0 0 2 4 26 58 84 0 26 58 Study Duration (Weeks) Study Duration (Weeks) Serum Phosphate (mg/dL) Active Vitamin D and Calcium Suppl
Slide 41: Patient 3: History
Patient 3: History •44-year-old female •Occupation: Operating Room Nurse •Past medical history of: • Colorectal cancer • Goiter • Papillary thyroid cancer • Thyroidectomy- Jan 2016 • Myalgia •Hypoparathyroidism Etiology: postsurgical 41
Slide 42: Hypoparathyroidism Patient Experience Scale: Patient 3 Clinical Course
Hypoparathyroidism Patient Experience Scale (HPES) Patient 3: Clinical Course 80 60 40 20 0 Baseline Week 58 Baseline Week 58 • Prior to trial HPES-Impact Score HPES-Symptom Score • Very symptomatic with overwhelming fatigue and headaches , brain fog , irritability and depression Note: lower is bett
Slide 43: Discussion: Impacts on Overall Health
Discussion: Impacts on Overall Health • Through my lenses • Psychosocial aspects • Impacts on family • Pill burden and adherence to conventional therapy 43
Slide 44: Science and Biology of CNP as a Treatment for Achondroplasia
Science and Biology of C-type Natriuretic Peptide (CNP) as a Treatment for Achondroplasia Kennett Sprogøe, Ph.D. SVP, Head of Innovation and Research
Slide 45: Growth Hormone Deficiency and Achondroplasia Differ at the Growth Plate
Growth Hormone Deficiency and Achondroplasia Differ at the Level of the Growth Plate Growth Hormone Deficiency Achondroplasia (ACH) Pituitary gland malfunction Constitutive hyperactive FGFR3 Cause Insufficient endogenous GH signaling caused by receptor mutation Untreated growth plate Normal organiza
Slide 46: Target Cells (Chondrocytes) Are in The Growth Plate
Target Cells (Chondrocytes) Are in The Growth Plate Achondroplasia caused by heterozygous mutation Different conformations of the FGFR3 G380R mutated dimer Constitutive hyperactive FGFR3 signaling in the growth plate blocks growth Constitutive hyperactive FGFR3 signaling occurs in the presence and a
Slide 47: Hyperactive FGFR3 Signaling and the Effect of CNP on Achondroplasia
Hyperactive FGFR3 Signaling and the Effect of CNP on Achondroplasia Are Well-Described CNP inhibits hyperactive FGFR3 signaling to counteract the block of growth plate function Copyrighted Image Wild-type ACH ACH (Normal) +CNP Adapted from Laederich MB, et al. Curr Opin Pediatr. 2010;22(4):516-523.
Slide 48: TransCon CNP Design
TransCon CNP Design CNP TransCon linker (active) TransCon carrier Receptor Renal clearance CNP Linker cleavage (inactive) dependent upon pH and temperature • TransCon technology is designed to provide effective shielding of CNP: – From neutral endopeptidase degradation in subcutaneous tissue and blo
Slide 49: Stages for TransCon CNP to Promote Growth in Achondroplasia
Stages for TransCon CNP to Promote Growth in Achondroplasia TransCon CNP designed to promote growth in three sequential stages Copyrighted Image TransCon CNP provides Continuous free CNP Continuous CNP continuous plasma plasma exposure enables exposure in growth plate exposure of free CNP CNP exposu
Slide 50: TransCon CNP Designed to Provide Continuous Free CNP Exposure
TransCon CNP Designed to Provide Continuous Free CNP Exposure • Continuous exposure – Steady-state exposure is achieved within weeks • Dose-proportionality – Predictable continuous plasma exposure of free CNP • Low C max 1,2 – C targeted well below levels reported to induce hypotension in humans max
Slide 51: Continuous Free CNP Plasma Exposure Enables Growth Plate Exposure
Continuous Free CNP Plasma Exposure Enables CNP Exposure to the Growth Plate • Growth Plate Characteristics – Avascular – Hydrophilic and negatively charged matrix CNP penetration • Molecular penetration to target area to target area 1 restricted by size and charge • CNP-38 properties facilitate gro
Slide 52: Continuous Free CNP Exposure Inhibits Hyperactive FGFR3 Signaling
Continuous Free CNP Exposure Inhibits Constitutive Hyperactive FGFR3 Signaling • FGFR3 hyperactive signaling in ACH is constitutive • CNP mode-of-action in ACH was revealed with sustained CNP 1-2 exposure Copyrighted Image • CNP over-expression in humans results 3-4 in increased linear growth Wild-t
Slide 53: TransCon CNP Designed to Address Key Manifestations of Achondroplasia
TransCon CNP Designed to Address Key Manifestations of Achondroplasia Continuous Exposure Growth Promotion Growth Plate Penetration Copyrighted Image TransCon CNP CNP properties and exposure CNP effect • Dose-Proportionality • Continuous exposure • Inhibits constitutive hyperactive FGFR3 • C targete
Slide 54: TransCon CNP for Achondroplasia
TransCon CNP for Achondroplasia Marie-Louise C. Hartoft-Nielsen, M.D., Ph.D. Senior Medical Director, Clinical Development
Slide 55: Achondroplasia – Most Frequent Skeletal Dysplasia
Achondroplasia – Most Frequent Skeletal Dysplasia • Achondroplasia is the most common cause of short- 1 limbed short stature • Autosomal dominant gain-of-function mutation of the 2,3,4 FGFR3 gene 5,6 • Estimated prevalence of ~ 4 per 100,000 births • 80% spontaneous mutations, 20% inherited 1 • A
Slide 56: Primary Skeletal Manifestations and Key Related Complications
Primary Skeletal Manifestations and Key Related Complications 1-10 Lifelong Disease Burden Manifestations Complications Interventions • Short stature • Foramen magnum • Cervicomedullary • Short limbs & rhizomelia stenosis decompression • Narrowing of foramen • Spine deformities • Grommets magnum • S
Slide 57: TransCon CNP Investigational Drug Characteristics
TransCon CNP Investigational Drug Characteristics • Dose proportionality with continuous exposure over one week and low C max • Utilizes wild-type CNP peptide sequence • Designed to provide meaningful impact on clinical manifestations and burden of achondroplasia Designed to continuously inhibit hyp
Slide 58: Non-Clinical Data Support Safety and Efficacy
Non-Clinical Data Support Safety and Efficacy 2 Synchondroses of Foramen Magnum in ACH Model y367C/+ Tibial growth in young cynomolgus monkeys Fgfr3 mice 1 at 6 months (n=4/group) 7 6 Placebo 5 corrected 4 percentage change from 3 baseline 2 1 0 TransCon CNP Vehicle TransCon CNP CNP Analogue* Daily
Slide 59: Integrated & Patient-Focused Clinical Development Program
Integrated & Patient-Focused Clinical Development Program • Global natural history study in children with • Provided first achondroplasia ACHieve TransCon CNP study safety and PK in humans ACcomplisH, ACcomplisH Phase 1 China and ACcomplisH • Focus on identifying Infant • Global clinical program in
Slide 60: Phase 1 Pharmacokinetics
Phase 1 Pharmacokinetics • Dose proportional 50 increase in Free CNP 150 µg/kg 45 exposure 75 µg/kg 40 25 µg/kg • Continuous exposure 10 µg/kg 35 and apparent T of 1/2 30 ~ 120 hours in adults * Free CNP (pM) 25 (Mean ±SEM) 20 15 10 5 0 0 24 48 72 96 120 144 168 Hours Continuous and dose-dependent e
Slide 61: TransCon CNP Was Well-Tolerated in Phase 1
TransCon CNP Was Well-Tolerated Up to 150 µg/kg in Phase 1 • Mean resting blood pressure 40 60 and heart rate were unchanged from pre-dose 40 30 • Mean orthostatic changes in 20 Mean plasma Mean orthostatic vital signs appear unrelated to concentration change in BP 20 0 (mmHg) of free CNP-38 CNP exp
Slide 62: Clinical Development Program
Clinical Development Program ONGOING • Natural history study • Age 0-8 years • N=234 • 14 countries IND or equivalent submission ONGOING ONGOING planned for Q2 2022 • China, multiple dose • Global, multiple dose, • Global, multiple dose study early intervention study study • Age 2-10 years • Age 2-1
Slide 63: TransCon CNP: Phase 2 Trial Design
TransCon CNP: Phase 2 Trial Design Up to 60 children (ages 2–10 years) with achondroplasia Open Label 12 subjects randomized in each dose cohort in a blinded manner TransCon CNP Extension vs. placebo (3:1 Period to 6 µg/kg 20 µg/kg 50 µg/kg 100 µg/kg >100 µg/kg randomization) evaluate long-term Data
Slide 64: Baseline Characteristics ACcomplisH - Enrollment Complete
Baseline Characterics ACcomplisH - Enrollment Complete Demographics Cohort 1 (N = 13) Cohort 2 (N = 15) Cohort 3 (N = 14) Cohort 4 (N = 15) Age (years) Mean (SD) 6.4 (2.82) 6.2 (3.13) 5.6 (2.91) 5.5 (2.51) Age Group (years), n (%) 2–5 years 5 (38.5) 7 (46.7) 6 (42.9) 6 (40.0) 5–8 years 4 (30.8) 5 (3
Slide 65: Baseline Characteristics ACcomplisH - Enrollment Complete
Baseline Characterics ACcomplisH - Enrollment Complete Demographics Cohort 1 (N = 13) Cohort 2 (N = 15) Cohort 3 (N = 14) Cohort 4 (N = 15) Age (years) Mean (SD) 6.4 (2.82) 6.2 (3.13) 5.6 (2.91) 5.5 (2.51) Age Group (years), n (%) 2–5 years 5 (38.5) 7 (46.7) 6 (42.9) 6 (40.0) 5–8 years 4 (30.8) 5 (3
Slide 66: Baseline Characteristics ACcomplisH - Enrollment Complete
Baseline Characterics ACcomplisH - Enrollment Complete Demographics Cohort 1 (N = 13) Cohort 2 (N = 15) Cohort 3 (N = 14) Cohort 4 (N = 15) Age (years) Mean (SD) 6.4 (2.82) 6.2 (3.13) 5.6 (2.91) 5.5 (2.51) Age Group (years), n (%) 2–5 years 5 (38.5) 7 (46.7) 6 (42.9) 6 (40.0) 5–8 years 4 (30.8) 5 (3
Slide 67: ACcomplisH – Continuous Exposure with Low Cmax
ACcomplisH – Continuous Exposure with Low C max Pharmacokinetics • Continuous exposure over the weekly dosing interval (Free CNP T ~ 110 hours) ½ • Dose proportionality • Steady-state plasma concentration of free CNP reached after four doses Free CNP (pM) • C well below levels reported to induce max
Slide 68: ACcomplisH - Preliminary Safety Profile
ACcomplisH - Preliminary Safety Profile (N=57)* • No withdrawals or discontinuations for any reason • No serious adverse events related to trial drug • 13 AEs related to trial drug or procedures – Of these, eight mild and transient injection site reactions (in over 1900 injections) • Injections gene
Slide 69: Upcoming Trials
Upcoming Trials * • Objectives: Efficacy (AHV at week 52), • Objective: Early intervention to prevent growth safety, PK disorder progression; safety, PK • Design: Randomized, double-blind, • Design: Pending interactions with regulatory placebo-controlled trial agencies • Age: 2-10 years • Age: 0-2 y
Slide 70: The Patient & Caregiver Experience of Achondroplasia
1-6 The Patient & Caregiver Experience of Achondroplasia • Physical signs and symptoms • Functioning and daily life • School participation • Emotional well-being • Social well-being We are committed to understanding achondroplasia beyond growth 1. Bloemeke, J, et al. Qual Life Res 28, 2553–2563 (201
Slide 71: TransCon CNP Clinical Program Is Progressing
TransCon CNP Clinical Program Is Progressing • ACcomplisH enrollment complete (N=57) • Interim blinded data informed dose selection of 50 and 100 mg/kg/week for ACcomplisH China • Preliminary PK and safety data on TransCon CNP suggest continuous CNP is well- tolerated across all doses administered •
Slide 72: TransCon Technology for Intratumoral Administration
™ TransCon Technology for Intratumoral Administration Kennett Sprogøe, Ph.D. SVP, Head of Innovation and Research
Slide 73: TransCon Positioned to Potentially Transform Cancer Therapy
TransCon Positioned to Potentially Transform Cancer Therapy TransCon systemic and intratumoral technologies designed to enhance anti-tumor effects by • Providing sustained modulation of tumor microenvironments • Activating cytotoxic immune cells No Tumor Cold Tumor Hot Tumor Tumor cells X Immune-sup
Slide 74: Two Clinical Candidates – Potential to Address Multiple Steps of the Immunity Cycle
Two Clinical Candidates – Potential to Address Multiple Steps of the Immunity Cycle TransCon IL-2 b/g TransCon TLR7/8 Agonist for IT delivery and enhanced tumor-antigen presentation Designed to enhance antigen presentation and, thereby, promote activation of cytotoxic immune TransCon cells and drive
Slide 75: TransCon IL-2 b/g: Soluble Carrier, as in Endocrine Pipeline
TransCon IL-2 b/g: Soluble Carrier, as in Endocrine Pipeline TransCon carrier TransCon linker IL-2 b/g (active) Receptor TransCon IL-2 β/γ (Prodrug) Renal clearance IL-2 b/g Linker cleavage (inactive) dependent upon pH and temperature TransCon IL-2 b/g is designed to provide sustained, long-lasting
Slide 76: TransCon TLR7/8 Agonist: Sustained Intratumoral Release of Resiquimod
TransCon TLR7/8 Agonist: Sustained Intratumoral (IT) Release of Resiquimod Local depot of drug loaded Linker cleavage under TransCon hydrogel carrier physiological conditions Parent drug is transiently Following injection, the Designed to provide sustained bound to TransCon linker- linker is designe
Slide 77: TransCon IT Represents a Potential Paradigm Shift in Cancer Therapy
TransCon IT Represents a Potential Paradigm Shift in Cancer Therapy Short tumor exposure Systemic Parent • Transient effect in tumor exposure drug IT • Significant systemic toxicity Days/Weeks Long tumor exposure TransCon IT • Sustained activity in the tumor Low systemic • Minimized systemic toxicit
Slide 78: TransCon IT Designed for Local and Abscopal Anti-Tumor Effects
TransCon IT Designed for Local and Abscopal Anti-Tumor Effects Designed to Enable Immune Activation in the Draining Lymph Nodes Cytotoxic T effector Cells Primed in Lymph Nodes Capable of Targeting Abscopal Tumors All product candidates are investigational. For investor communication only. Not for u
Slide 79: 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 10000.0 Single TransCon IT Dose in Mice 1000.0 Concentration Tumor concentr
Slide 80: Modeled Volume of Hydrogel in Injected Tumor
Modeled Volume of Hydrogel in Injected Tumor Model of Intratumoral Hydrogel M o d e l o f I n t r a t u m o r a l H y d r o g e l Accumulation and Degradation A c c u m u l a t i o n a n d D e g r a d a t i o n 5 Q3W dosing leads to 500 accumulation of 4-5 depots 4 400 within the tumor at steady sta
Slide 81: Algorithm for Product Innovation: Building an Oncology Pipeline
Algorithm for Product Innovation: Building an Oncology Pipeline Clinically Established Higher Value, Unmet TransCon Clearly Large Validated Clinical & Medical Technology Differentiated Addressable Lower Risk Parent Regulatory Need Suitability Product Market Drug Pathway Pipeline We are continuing to
Slide 82: Opportunity for TransCon TLR7/8 Agonist in Solid Tumors
Opportunity for TransCon TLR7/8 Agonist in Solid Tumors Efficacy • Each injection designed to provide sustained exposure in the tumor to enhance immune activation TransCon TLR7/8 Agonist • Systemic immune activation may lead to abscopal tumor effects Safety • Low systemic toxicity expected to reduce
Slide 83: Potential Paradigm Shift in How Cancer Is Treated
Potential Paradigm Shift in How Cancer Is Treated • Oncology pipeline using TransCon technologies that may enable a new treatment paradigm, based on well-known biology • Two clinical-stage product candidates with potentially best-in-class properties using systemic and localized TransCon technology –
Slide 84: TransCon TLR7/8 Agonist Clinical Update
TransCon TLR7/8 Agonist TransCon TLR7/8 Clinical Update Agonist Stina Singel, M.D., Ph.D. Head of Clinical Development, Oncology
Slide 85: 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 • U.S. cancer patients eligible for checkpoint inhibitors (CPI) increased from 1.5% in 2011 to 43.6
Slide 86: Toll-Like Receptors: Well-Validated Targets for Activation of Immunity
Toll-Like Receptors (TLRs): Well-Validated Targets for Activation of 1 Innate and Adaptive Immunity • Activate innate immunity in particular antigen presenting cells (APCs) • Prime and expand cytolytic and helper T cells • Inhibit suppressive mechanisms limiting anti-tumor responses • Resiquimod has
Slide 87: Limitations of TLR Agonists in Clinical Setting
Limitations of TLR Agonists in Clinical Setting 1 • Systemic administration leads to high toxicity such as cytokine release syndrome • Previous IT approaches cannot deliver prolonged exposure of active drug levels needed for anti-tumor activity – Consistent with short exposure, pharmacodynamic effec
Slide 88: Clinical Development Strategy in Oncology
Clinical Development Strategy in Oncology to Take Advantage of the Clinically Validated TransCon Platform BUILD ESTABLISH EXPAND safety and tolerability proof-of-concept to other indications profile while identifying efficacy in indications based on appropriate dose of high unmet medical • Unmet nee
Slide 89: Status Update on transcendIT-101 First-in-Human Trial
Status Update on transcendIT-101: TransCon TLR7/8 Agonist First-in-Human Trial Dose Escalation (“3+3” Design) Dose Expansion Part 1: Part 2: Part 3: Monotherapy Combination with pembro Combination with pembro HNSCC at RP2D Any solid tumor, Indications with known or any line potential pembro activity
Slide 90: Initial Indications of HPV-associated Cancers
Initial Indications of HPV-associated Cancers Selected Based on Strong Scientific Rationale 1 TLRs and HPV-associated cancers Dose Expansion Other indications will Combination with CPI be added based on HPV-associated tumors: • Unmet need • HNSCC • Emerging data and • Others (anal, cervical, changin
Slide 91: Interim Status Update on transcendIT-101
Interim Status Update on transcendIT-101: TransCon TLR7/8 Agonist First-in-Human Trial Dose Escalation (“3+3” Design) Dose Expansion Part 1: Part 2: Part 3: Monotherapy Combination with pembro Combination with pembro HNSCC at RP2D Any solid tumor, Indications with known or any line potential pembro
Slide 92: transcendIT-101: Low Systemic Exposure with Half-life of ~7 Days
transcendIT-101: Low Systemic Exposure with Half-life of ~7 Days Resiquimod mean (+SD) plasma concentrations following one intratumoral injection Plasma concentration where cytokine release syndrome has been observed* • Plasma concentrations 15-fold below levels where cytokine release syndrome has b
Slide 93: Demographic and Safety Data
Demographic and Safety Data* Select Demographics Monotherapy (n=5) Combination (n=3) Tumor types Melanoma (n=3) Melanoma (n=1) TNBC (n=1) Basal Cell Carcinoma (n=1) Pancreatic (n=1) Pancreatic (n=1) Median prior anti-cancer treatment regimens 3 2 Prior anti-PD(L)1 4 (80%) 2 (67%) Overview of Safety
Slide 94: Initial Interim Data Indicate TransCon TLR7/8 Agonist Is Well-Tolerated
Initial Interim Data Indicate TransCon TLR7/8 Agonist Is Well-Tolerated as Monotherapy or in Combination with Pembrolizumab • No dose-limiting toxicities observed • Limited safety-evaluable population (n=8) so far indicates no systemic side effects related to TransCon TLR7/8 Agonist ‒ Consistent wit
Slide 95: transcendIT-101: Study Status
transcendIT-101: Study Status N=8 treated with study treatment as of 16 Nov 2021* – 3 efficacy evaluable patients with at least 1 post-baseline tumor assessment – 2 discontinued due to progressive disease (before first tumor assessment at week 9) – 1 discontinued due to physician decision (patient l
Slide 96: Early Signs of Clinical Activity (#1)
Early Signs of Clinical Activity from Efficacy-Evaluable Patients (#1) Best Overall Response per RECIST v1.1 Available On-Treatment Pathology Patient Profile #1 (latest investigator assessment) Tumor Type: Melanoma uPR (week 27) Injected lesion: 3 core biopsies at week 27 after 9 doses showed Prior
Slide 97: Early Signs of Clinical Activity (#2)
Early Signs of Clinical Activity from Efficacy-Evaluable Patients (#2) Best Overall Response per RECIST v1.1 Patient Profile #2 Available On-Treatment Pathology (latest investigator assessment) Tumor Type: Pancreatic Cancer SD (week 9) Injected lesion: 3 core biopsies at week 7 after 1 dose Prior Tr
Slide 98: Early Signs of Clinical Activity (#3)
Early Signs of Clinical Activity from Efficacy-Evaluable Patients (#3) Best Overall Response per RECIST v1.1 Patient Profile #3 Available On-Treatment Pathology (latest investigator assessment) Tumor Type: Basal Cell SD (week 9) Injected lesion: Carcinoma Punch biopsy at week 9 after 3 doses Target
Slide 99: Target Activation of Key Immunological Pathways
Target Activation of Key Immunological Pathways Maintained Through at Least 7 Days Post-Dose in Injected and Non-Injected Lesions Gene Expression at 7 Days After 1 Dose of TransCon TLR7/8 Agonist • Target engagement of TLR7/8 Agonist ‒ Consistent increase of IRF-7 • Innate immune activation IFN-rela
Slide 100: Sustained Upregulation of IFN-Related Genes with Repeat Dosing
Sustained Upregulation of IFN-Related Genes in Tumor Tissue with Repeat Dosing IRF7 STAT1 CXCL10 Injected Lesions Non-injected Lesions * Pembro is administered on C1D8 after biopsy and on C2D1 ** Dose Level 2 (all others at Dose Level 1) • Downstream of TLR7 and TLR8 • Central signaling molecule in
Slide 101: TransCon Represents a Potential Paradigm Shift in Cancer Treatment
TransCon Represents a Potential Paradigm Shift in Cancer Treatment • Early data from ongoing TransCon TLR7/8 Agonist first-in-human trial (transcendIT-101) indicated: – Early signs of activity in three out of three evaluable patients including those previously treated with checkpoint inhibitors – Mo
Slide 102: Q&A Session
Q&A Session Email questions to: IR@ascendispharma.com