Ascendis Pharma A/s · NASDAQ:ASND
Ascendis Pharma A/s — Investor Presentation (January 2020)
95 slides from Ascendis Pharma A/s's investor presentation, Jan 13, 2020
Slide 1: Ascendis Pharma A/S January 2020
Ascendis Pharma A/S January 2020 Exhibit 99.1
Slide 2: Cautionary Note On Forward-Looking Statements
Cautionary Note On Forward-Looking Statements This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, such as statements regarding our future results of operations and financial position, including our business s
Slide 3: Company Overview
Company Overview Create best-in-class products addressing unmet medical needs by applying TransCon™ technologies to parent drugs with clinical proof-of-concept Endocrinology rare disease internal pipeline and expected 2020 milestones TransCon hGH for pediatric GH deficiency: BLA and MAA filings expe
Slide 4: Vision 3x3: Building a Leading BioPharma Company
Vision 3x3: Building a Leading BioPharma Company Our Goal is to Achieve Sustainable Growth through Multiple Approaches Obtain regulatory approval for three independent Endocrinology Rare Disease products TransCon Growth Hormone for pediatric growth hormone deficiency TransCon PTH for adult hypoparat
Slide 5: Diverse Pipeline of Independent Product Candidates
Diverse Pipeline of Independent Product Candidates 1 Excludes rights granted to VISEN Pharmaceuticals in Greater China 2 In phase 3 development for pediatric growth hormone deficiency in Greater China through strategic investment in VISEN Pharmaceuticals
Slide 6: Transient Conjugation: Flexible and Versatile Platform
Transient Conjugation: Flexible and Versatile Platform Parent Drug Soluble Carriers Insoluble Carriers Antibodies, Antibody Fragments, Proteins, Peptides and Small Molecules Aromatic Cyclic Imide DKP Carbamate Bicin AEG Pyroglutamate TransCon Carrier TransCon Prodrug: 3 components TransCon Linker
Slide 7: TransCon Technology: Sustained Systemic Delivery
TransCon Technology: Sustained Systemic Delivery Parent drug is transiently bound to a TransCon linker-soluble carrier moiety, which inactivates and shields parent drug from clearance Designed to distribute released drug like the parent molecule; linker-carrier is cleared renally Following injection
Slide 8: TransCon Technology: Sustained Localized Delivery
Parent drug is transiently bound to TransCon linker-hydrogel carrier, which inactivates, shields parent drug and prevents clearance Designed to provide sustained high local drug levels with low systemic exposure; hydrogel degrades into small polymers that are renally cleared Following injection, the
Slide 9: Ascendis Algorithm for Product Innovation
Ascendis Algorithm for Product Innovation Unmet Medical Need Clinically Validated Parent Drug TransCon Technology Suitability Clearly Differentiated Product Established Clinical & Regulatory Pathway Large Addressable Market Higher Value, Lower Risk Pipeline
Slide 10: TransCon Growth Hormone: Once-Weekly Replacement Therapy
TransCon Growth Hormone: Once-Weekly Replacement Therapy
Slide 11: Growth Hormone Supports Overall Endocrine Health
Growth Hormone Supports Overall Endocrine Health Sources: 1. de Boer, H. et al. 1997; 2. Rutherford, O. M. et al. 1991. 3. Colle, M., J. Auzerie.1993. 4. Johannsson, Gudmundur, et al. 1999. 5. Stabler, Brian et al. 1996. 6. Leong, Gary M., Gudmundur Johannsson. 2003. 7. Colao, Annamaria et al. 2002.
Slide 12: TransCon hGH Design
TransCon hGH Design TransCon carrier TransCon linker hGH (inactive) Unmodified hGH Receptor Linker cleavage dependent upon pH and temperature Renal clearance Once-weekly prodrug releases unmodified hGH designed to mimic daily hGH: Tissue distribution Physiological levels Therapeutic effects: efficac
Slide 13: Growth Comparable to a Daily hGH in Phase 2
Growth Comparable to a Daily hGH in Phase 21,2 1 Intergroup differences not statistically significant 2 J Clin Endocrinol Metab 2017, 102(5): 1673–1682 3 Conducted with a bioequivalent version of TransCon hGH Same weekly dose Dose hGH (mg/kg/week): 11.5 0.14 0.21 0.30 0.21 TransCon hGH3 Genotropin®
Slide 14: TransCon hGH Phase 3 Program in Pediatric GHD
TransCon hGH Phase 3 Program in Pediatric GHD Subjects previously treated (n=143) and treatment-naïve (<3 years, n=3) Extension trial (N=296) Expected Regulatory filings (BLA Q2 2020, MAA Q4 2020) Treatment-naïve subjects N=146 N=161
Slide 15: Phase 3 heiGHt Trial
Phase 3 heiGHt Trial 161 treatment-naïve children with GHD dosed (2:1 randomization) TransCon hGH (0.24 mg/kg/week) Genotropin (34 µg/kg/day = 0.24 mg/kg/week) Long-Term Extension Trial Week 1 Week 5 Week 13 Week 52 Week 26 Week 39 Screening ≤6 weeks Key Endpoints Annualized height velocity (AHV) at
Slide 16: Demographics and Baseline Characteristics Comparable Between Arms
Demographics and Baseline Characteristics Comparable Between Arms TransCon hGH (n=105) Mean Genotropin (n=56) Mean Age (years) 8.51 8.48 Male (%) 81.9 82.1 Height SDS -2.89 -3.00 ∆ Average Parental Height SDS -2.32 -2.55 IGF-1 SDS -2.08 -1.96 Peak Stimulated GH (ng/mL) 5.89 5.48 BMI (kg/m2) 16.1 16.
Slide 17: TransCon hGH Met Primary Objective of Non-inferiority and Superiority in AHV
TransCon hGH Met Primary Objective of Non-inferiority and Demonstrated Superiority in AHV at Week 52 TransCon hGH 0.24 mg/kg/week (n=105) Genotropin® 0.24 mg/kg/week (n=56) Estimate of Treatment Difference P-value LS Mean AHV at Week 52 (cm/year) 11.2 10.3 0.86 0.0088 Standard Error 0.23 0.30 0.33 9
Slide 18: AHV Consistently Favors TransCon hGH Across All Subgroups
AHV Consistently Favors TransCon hGH Across All Subgroups at Week 52 Treatment Difference (TransCon hGH – Genotropin) cm/year ANCOVA Model Age < 6 years 24% 25% ³ 6 years 76% 75% Sex Male 82% 82% Female 18% 18% Baseline GH-Stimulation £ 5ng/mL 35% 38% > 5 ng/mL 65% 63% Etiology and Extent of GHD Iso
Slide 19: AHV Poor Responders: Post-hoc Analysis
AHV Poor Responders: Post-hoc Analysis Poor responders defined as AHV <8.0 cm/year1 1 Bakker et. al. J Clin Endocrinol Metab 93: 352–357, 2008 2 Excludes one subject per group with missing Week 52 data (98.8% subjects completed study) At Week 522 TransCon hGH (n=104) n (%) Genotropin (n=55) n (%) Re
Slide 20: IGF-1 Profile Over Week
IGF-1 Profile Over 1 Week TransCon hGH (0.24 mg/kg/week) (n=11) Days (Week 13) 1 2 3 0 5 4 7 6 Baseline 13th Dose Mean SDS (±SE)
Slide 21: AHV Paralleled the Difference in Average IGF-1
AHV Paralleled the Difference in Average IGF-1 Baseline Week 13 Week 26 Week 39 Week 52 -5 -4 -3 -2 -1 0 1 2 3 4 Model-derived Average IGF-1 SDS IGF-1 SDS AHV* (cm/year) LS Mean AHV (±SE) TransCon hGH Genotropin TransCon hGH preserved the balance between direct and indirect effects of daily hGH P-va
Slide 22: Phase 3 fliGHt Trial Design
Phase 3 fliGHt Trial Design 1 Primary outcome measure was safety and tolerability of TransCon hGH over 26 weeks 146 children with GHD (143 treatment-experienced) TransCon hGH (0.24 mg/kg/week) Long-Term Extension Trial Week 1 Week 4* (±1 Week) Week 26 (±1 Week) Week 13 (±1 Week) Screening Up to 4 We
Slide 23: fliGHt Baseline Demographics
fliGHt Baseline Demographics Top-line results from phase 3 fliGHt Trial. Baseline Mean (N=146) Male (%) 75.3 Age (years) 10.6 Age Range (years) 1 to 17 Height SDS -1.42 BMI (kg/m2) 17.5 ∆ Average Parental Height SDS -1.14 IGF-1 SDS +0.9 IGF-1 SDS Range -1.9 to +4.0 Caucasian (%) 84.9 Recruited in No
Slide 24: Previous Daily hGH Use
Previous Daily hGH Use Top-line results from phase 3 fliGHt Trial. Baseline (N=146) Daily hGH Dose Prior to Trial (mg/kg/week), mean (range) 0.29 (0.13 – 0.49) Treatment-Experienced, n (%) 143 (97.9%) <6 Months 40 (27.4%) ≥6 to <12 Months 32 (21.9%) ≥12 to <18 Months 28 (19.2%) ≥18 Months 43 (29.5%)
Slide 25: Mean AHV at Week 26 by Subgroups
Mean AHV at Week 26 by Subgroups Top-line results from phase 3 fliGHt Trial. AHV at Week 26 (cm/year) TransCon hGH (N=146) Arithmetic Mean Age <3 years 16.2 ≥3 and <6 years 10.0 ≥6 and <11 for girls; ≥6 and <12 for boys 8.2 ≥11 for girls; ≥12 for boys 9.0 Gender Male 9.0 Female 9.1 Peak Stimulated G
Slide 26: Key Learnings from TransCon hGH Clinical Trials
Key Learnings from TransCon hGH Clinical Trials TransCon hGH demonstrated an adverse event and immunogenicity profile comparable to that of a daily hGH TransCon hGH demonstrated superior height velocity1 to a daily hGH through a PK profile of released hGH that may be more efficiently utilized by tar
Slide 27: Adverse Event Profile of TransCon hGH in the Phase 3 Program
Adverse Event Profile of TransCon hGH in the Phase 3 Program1 heiGHt Trial fliGHt Trial enliGHten Trial2 TransCon hGH 0.24 (n=105) n (%) Genotropin 0.24 (n=56) n (%) TransCon hGH 0.24 (N=146) n (%) TransCon hGH 0.24 (N=296) n (%) Treatment-emergent Adverse Events (TEAEs) 81 (77) 39 (70) 83 (57) 161
Slide 28: TransCon hGH Sustained Improvement in Height SDS
TransCon hGH Sustained Improvement in Height SDS Change from Baseline LS Mean (+SE) heiGHt Trial subjects rolled over into enliGHten Trial (long-term extension) 1 Based on results from phase 3 heiGHt Trial at 52 week endpoint *Treatment difference resulted in a nominal p-value <0.05 ANCOVA model hei
Slide 29: Linear Relationship Between Dose and IGF-1 Response
Linear Relationship Between Dose and IGF-1 Response Demonstrated in Clinical Program 1 Average IGF-1 at Week 13 was used given availability of measured data over one week for the phase 2 trial 2 Average IGF-1 during Week 13 for phase 3 heiGHt Trial TransCon hGH subjects is model-derived average 3 Co
Slide 30: Relationship Between Average IGF-1 SDS and Height SDS
Relationship Between Average IGF-1 SDS and Height SDS from Phase 2 and Phase 3 Trials 1 Average IGF-1 at week 13 was used given availability of measured data over one week for the phase 2 trial 2 Average IGF-1 during week 13 for phase 3 heiGHt Trial TransCon hGH subjects is model-derived average 3 C
Slide 31: Auto-Injector Designed to Improve Adherence
Auto-Injector Designed to Improve Adherence Room temperature storage Small needle, comparable to daily hGH (31G, 4mm) Single low-volume (<0.60mL) injection for patients ≤60kg Simple operation No waste due to empty-all design Device lifespan at least 4 years Easy to titrate Bluetooth® connectivity en
Slide 32: Global Clinical Reach
Global Clinical Reach * Ethnobridging is required before initiation of phase 3 ** Phase 3 being conducted by Visen Pharmaceuticals Region US EU Japan South Korea China Nonclinical packet acceptable for regulatory filing Regulatory concurrence with proposed clinical development plan Planned phase 3 i
Slide 33: On-track towards Filing TransCon hGH BLA Q2 and MAA Q4
On-track towards Filing TransCon hGH BLA Q2 and MAA Q4 Completed both the fliGHt and heiGHt Trials, including rollover into enliGHten, and completed two-year follow-up for 46 subjects on TransCon hGH Completed manufacturing of PPQ batches and development of the auto-injector Proprietary Auto-Injecto
Slide 34: TransCon hGH: Raising the Bar
TransCon hGH: Raising the Bar Phase 3 heiGHt Trial demonstrated superior height velocity of TransCon hGH in pediatric GHD, with comparable safety and tolerability as compared to a daily hGH BLA filing expected Q2 2020 and MAA filing expected Q4 2020 Create further growth: China: Pediatric GHD phase
Slide 35: TransCon PTH: PTH Replacement Therapy for Hypoparathyroidism
TransCon PTH: PTH Replacement Therapy for Hypoparathyroidism
Slide 36: Hypoparathyroidism: Severe Short-term Complications
Hypoparathyroidism: Severe Short-term Complications 1 Endo Pract. 2017, 20(7);671-679 2 2019 Ascendis Pharma HP Patient Experience Research Hypocalcemia Paresthesias, muscle cramps, tetany, laryngospasm, seizures, coma 85% Report inability to perform household activities1 Brain fog 76% Either unable
Slide 37: Hypoparathyroidism: Severe Long-term Complications
Hypoparathyroidism: Severe Long-term Complications 1 J Bone Miner Res 2013, 28: 2570-2576; J Clin Endocrinol Metab 2012, 97(12): 4507-4514; J Bone Miner Res 2013, 28: 2277-2285 Long-term Complications1 4-fold increased risk of renal disease (nephrocalcinosis, nephrosclerosis, kidney stones & renal i
Slide 38: Majority of Patients Remain Unsatisfied with Current Management
“ I find that doctors don't know much about this and...I have to educate them. I ordered these booklets from the hypoparathyroidism organization…The endocrinologist that I see he does have some patients that have hypoparathyroidism, but it's not the majority of his practice. Majority of Patients Rem
Slide 39: Vast Majority of Patients Unable to Work or Less Productive
Vast Majority of Patients Unable to Work or Less Productive Due to HP Symptoms1 1 Poster presented at ISPOR 2019 and 2019 Ascendis Pharma HP Patient Experience Research. Work-Related Impacts Interference with work productivity No longer able to work due to HP symptoms 76% % of patients (n=42) Among
Slide 40: Chronic Hypoparathyroidism: Significant Patient Population
~86k-223k 2013, Underbjerg et. al., Cardiovascular and Renal Complications to Postsurgical Hypoparathyroidism: A Danish Nationwide Controlled Historic Follow-up Study 2015, The Epidemiology of Nonsurgical Hypoparathyroidism in Denmark: A Nationwide Case Finding Study 2016, Astor et. al., Epidemiolog
Slide 41: Constant Normal Level of PTH is Optimal - FDA Perspective
Constant Normal Level of PTH is Optimal - FDA Perspective1,2 Continuous infusion of PTH demonstrated3,4: Normalization of serum calcium and phosphate Complete removal of current standard of care (vitamin D and calcium supplements) Normalization of urinary calcium 1,2 FDA presentation: Natpara Adviso
Slide 42: TransCon PTH Design
TransCon PTH Design Renal clearance Receptor TransCon carrier TransCon linker PTH (inactive) Active PTH Linker cleavage dependent upon pH and temperature TransCon PTH is a sustained-release prodrug designed to provide stable PTH levels in the physiological range for 24 hours/day TransCon PTH designe
Slide 43: Phase 1: PK Data Support Infusion-like Profile
Phase 1: PK Data Support Infusion-like Profile over 24 Hours 1 PTH measured as Free PTH(1-34) and Free PTH(1-33) Analyses from TransCon PTH Phase 1 trial; data not shown for doses <12 µg/day, as levels of Free PTH are BLQ. Poster presented at ECTS 2019 TransCon PTH daily dosing provided a flat infus
Slide 44: Dose-Dependent Increase of Serum Calcium
Dose-Dependent Increase of Serum Calcium Analyses from TransCon PTH Phase 1 trial; doses <12 µg/day not shown as no significant increase in calcium at these doses. Poster presented at ECTS 2019 Change in Albumin-adjusted Serum Calcium over 10 Days of TransCon PTH TransCon PTH daily dosing for 10 day
Slide 45: Control of Urinary Calcium Despite Mild Hypercalcemia
Control of Urinary Calcium Despite Mild Hypercalcemia with Multiple Doses 1 J Clin Endocrinol Metab 2001, 86(4): 1525-1531 Poster presented at ECTS 2019 Spot FECa with daily doses of TransCon PTH for 10 days Mean albumin-adjusted sCa at Day 11: Placebo: 9.6 mg/dL 12 µg: 9.85 mg/dL 16 µg: 10.18 mg/dL
Slide 46: Phase 1: Adverse Event and Immunogenicity Summary
Phase 1: Adverse Event and Immunogenicity Summary Generally well-tolerated 2 placebo subjects (vs. 0 active subjects) discontinued due to SAEs 4 subjects experienced SAEs, all of which were unrelated to study drug or placebo SAD: 1 placebo subject (“bacteremia”) (withdrew) 1 active (12 µg) subject (
Slide 47: TransCon PTH Phase 2 Trial Design
TransCon PTH Phase 2 Trial Design * PRO = patient-reported outcome ~40 adult subjects with HP currently receiving standard of care (active vitamin D + calcium) Primary Composite Endpoint (4 weeks) Proportion of subjects with: Normal serum calcium; and Normal FeCa (or at least 50% decrease from basel
Slide 48: Expanded Phase 2 Trial and Open-label Extension Trial
Expanded Phase 2 Trial and Open-label Extension Trial Implemented addendum to protocol to expand and expedite enrollment in the U.S. for subjects affected by the NATPARA® recall Subjects from fixed-dose PaTH Forward Trial roll over to the open-label extension with individually optimized TransCon PTH
Slide 49: PaTH Forward Update
PaTH Forward Update Sites in Canada, Denmark, Germany, Italy, Norway and U.S. Addendum implemented in the U.S. Screening completed with expected enrollment of ~55 subjects To date, no dropouts in the double-blind portion of PaTH Forward Preliminary data on first 8 subjects completing 4 weeks follow-
Slide 50: Simple Pen Injector in Phase 2
Simple Pen Injector in Phase 2 Simple operation Three multi-use pens with three different strengths (6, 9, 12 µg; 15, 18, 21 µg; 24, 27, 30 µg) Ready-to-use liquid formulation, room temp stability for 14 days Low injection volume (≤0.1 mL) Small (31G), short (5 mm) safety pen needle Key Features Pen
Slide 51: TransCon PTH: Developing a "True" Replacement Therapy
TransCon PTH: Developing a “True” Replacement Therapy Phase 1 data support infusion-like profile of TransCon PTH as a “true” replacement therapy for HP, building on established approach to treat short-term symptoms and long term complications Screening completed for PaTH Forward phase 2 trial in adu
Slide 52: TransCon CNP: The New Frontier of Growth Biology
TransCon CNP: The New Frontier of Growth Biology
Slide 53: TransCon CNP: The New Frontier of Growth Biology
TransCon CNP: The New Frontier of Growth Biology TransCon CNP may provide benefit in several growth disorders — as monotherapy, and potentially in combination with TransCon hGH C-type natriuretic peptide (CNP) is a promising therapeutic pathway for treating growth failure and dwarfism Inhibits the o
Slide 54: Achondroplasia: High Morbidity
Achondroplasia: High Morbidity The Application of Clinical Genetics, 2014:7117-125 Up to 85% of patients require intervention for obstructive sleep apnea and respiratory insufficiency 25% of children have hearing loss increasing to > 50% in adulthood 22% have osteotomy 15-30% have fixed kyphotic def
Slide 55: Achondroplasia: Higher Mortality
Achondroplasia: Higher Mortality Analysis courtesy of Trinity Partners: Trinity Partners Medicare Analysis. Results are preliminary and achondroplasia vs overall Medicare patients have not been risk adjusted. Preliminary analysis shows among achondroplasia patients a median age of death of 60 years
Slide 56: Achondroplasia: Autosomal Dominant Mutation in FGFR3
Achondroplasia: Autosomal Dominant Mutation in FGFR3 1 Adapted from: PLoS ONE, 2008, 3(12), e3961 2J. Biological Chemistry, 285 pp 30103-30113 Downstream inhibition required to inhibit ligand-independent signaling Mutations leading to different Skeletal Dysplasias1 Different Conformations of the FGF
Slide 57: Achondroplasia Signaling Defect is Well Understood
Achondroplasia Signaling Defect is Well Understood1 1Adapted from Current Opin Pediatrics 2010; 22:516-523 TransCon CNP continuously inhibits abnormal FGFR3 signaling, restoring proliferation and differentiation of chondrocytes to rebalance bone growth CNP does not alter the function of FGF receptor
Slide 58: TransCon CNP Design
TransCon CNP Design TransCon technology is designed to provide effective shielding of CNP: From neutral endopeptidase degradation in subcutaneous tissue and blood compartment Minimize binding of TransCon CNP to the NPR-C receptor Reduce binding of TransCon CNP to the NPR-B receptor in vasculature to
Slide 59: Juvenile Healthy Monkey Growth Study
Juvenile Healthy Monkey Growth Study * Refers to a synthesized molecule with a half-life of ~20 mins prepared by Ascendis Pharma Placebo corrected percentage change from baseline TransCon CNP 40 µg/kg/week CNP Analogue* Daily Dosing 140 µg/kg/week (20 µg/kg/day) TransCon CNP 100 µg/kg/week Tibial gr
Slide 60: Phase 1 Trial Design
Phase 1 Trial Design 1 300 µg CNP/kg cohort was deemed not clinically relevant based on emerging pharmacokinetic data from previous cohorts and therefore not dosed. 45 healthy adult male subjects TransCon CNP vs. placebo (4:1 randomization) 3 µg/kg 10 µg/kg 25 µg/kg 75 µg/kg 150 µg/kg Up to 10 subje
Slide 61: Dose Proportional CNP Exposure For One Week
Dose Proportional CNP Exposure For 1 Week 1 CNP measured as CNP-38 Hours CNP1 (pM) (Mean ±SEM) 150 µg/kg 75 µg/kg 25 µg/kg 10 µg/kg AUCt CNP1 (h*pM) Dose CNP (µg/kg) 150 µg/kg 75 µg/kg 25 µg/kg 10 µg/kg Dose proportional increase in CNP exposure suggests ability to titrate dosing Phase 1 showed effe
Slide 62: Dose Dependent cGMP Response Demonstrated Receptor Engagement
Dose Dependent cGMP1 Response Demonstrated Receptor Engagement For 7 Days cGMP is a secondary messenger of NPR-B activation by CNP cGMP levels correlate with TransCon CNP PK profile 1 cGMP=cyclic guanosine monophosphate.. Fold change from baseline
Slide 63: Mean Resting Blood Pressure Unchanged from Predose
Mean Resting Blood Pressure Unchanged from Predose1 1 3.0 and 10 μg/kg dose levels are not represented. Data from these cohorts are consistent with placebo. Change in systolic blood pressure Change in diastolic blood pressure
Slide 64: TransCon CNP: Adverse Event and Immunogenicity Profile
TransCon CNP: Adverse Event and Immunogenicity Profile No serious AEs were reported in the trial TransCon CNP was generally well tolerated at doses up to 150 µg/kg No anti-CNP antibodies detected in any subjects Mean resting blood pressure and heart rate were unchanged from pre-dose at all time poin
Slide 65: ACHieve Ongoing and Enrolling
ACHieve Ongoing and Enrolling A global natural history study of ~200 children <8 years with achondroplasia (ACH): Over 30 subjects enrolled Evaluates height velocity, body proportionality and comorbidities Establishes relationships with study sites worldwide, paving the way for potential future Tran
Slide 66: TransCon CNP: Phase 2 Trial Design
TransCon CNP: Phase 2 Trial Design 1 Dose to be determined. If needed, based on emerging data. Primary Endpoint Annualized height velocity, as measured after 12 months of weekly TransCon CNP treatment Up to 60 children (ages 2 – 10 years) with achondroplasia 6 µg/kg 20 µg/kg 50 µg/kg 100 µg/kg >100
Slide 67: Growth Biology: Rationale for Combination
Growth Biology: Rationale for Combination Effects of Different Pathways Sources: Endocrine Reviews 1987 8 426–438. Endocrine Connections (2018) 7, R212–R222. J Mol Endocrinol. 2014; 53(1): T1–T9. hGH acts directly on pre-chondrocytes in the growth plate, driving differentiation into chondrocytes req
Slide 68: TransCon CNP: Pursuing New Frontier of Growth Biology
TransCon CNP: Pursuing New Frontier of Growth Biology C-type natriuretic peptide (CNP) pathway has demonstrated clinical proof of concept Short half-life of native CNP (2-3 minutes) limits therapeutic use TransCon CNP provides continuous CNP exposure 24 hours a day, seven days a week to balance cons
Slide 69: Oncology
ascendis LA Oncology
Slide 70: Vision in Oncology
Vision in Oncology Create best-in-class oncology therapies by applying systemic and intratumoral TransCon technologies for clinically validated pathways Improve outcomes upon validated mechanisms that are currently limited by suboptimal efficacy and systemic toxicity Apply Ascendis’ unique algorithm
Slide 71: Applying TransCon technologies to clinically validated mechanisms
Applying TransCon technologies to clinically validated mechanisms to develop differentiated and potentially best-in-class products Large number of validated oncology targets with known limitations Applicable for diverse drug classes and mechanisms of action Enable both systemic and intratumoral (IT)
Slide 72: Oncology Product Candidate TransCon IL-2 b/g
Oncology Product Candidate TransCon IL-2 b/g
Slide 73: IL-2: Validated Cytokine with Suboptimal Receptor Binding and PK Properties
IL-2: Validated Cytokine with Suboptimal Receptor Binding and PK Properties Several IL-2 approaches in development To our knowledge, none have fully solved both shortcomings of IL-2 Suboptimal receptor binding Two receptors: IL-2Ra/b/g and IL-2Rb/g a/b/g receptor activates Tregs and endothelial cell
Slide 74: Next Generation IL-2: Designed for Desired Receptor Binding and Exposure
Next Generation IL-2: Designed for Desired Receptor Binding and Exposure Figure adapted from Onur et al., Biomed Intell, 2019 a IL-2 IL-2 IL-2Rα (CD25) β γ β γ Promotes Treg Promotes CD8+ Promote anti-tumor responses Limit anti-tumor responses X Prevent IL-2Rα binding to selectively activate IL-2Rβ/
Slide 75: Design of TransCon IL-2 b/g: Designed for Desired Receptor Binding
Design of TransCon IL-2 b/g: 1) Designed for Desired Receptor Binding Introduction of cysteine at a-binding site of IL-2 (aldesleukin) Site-selective permanent PEG conjugation (5kDa) of introduced cysteine Generation of IL-2 Variant Blocking a-binding IL-2 (gold) with IL-2 alpha-receptor (grey) Opti
Slide 76: Permanently PEGylated IL-2 b/g Demonstrated Low Binding to IL-2Rα
Permanently PEGylated IL-2 b/g Demonstrated Low Binding to IL-2Rα, while Retaining Binding to IL-2Rb IL-2 b/g Binding to IL-2R a-chain Binding to IL-2R b-chain Wild-type IL-2 (aldesleukin seq) Receptor selectivity confirmed in cell-based assays, including primary human Tregs and CD8+ T cells -5 0 5
Slide 77: IL-2 b/g – Desired Receptor Selectivity Demonstrated
IL-2 b/g – Desired Receptor Selectivity Demonstrated ~770-fold reduced potency on primary human Treg cells compared to rhIL-2 while only ~4-fold loss in potency on CD8+ T cells and NK cells
Slide 78: Design of TransCon IL-2 b/g: TransCon Technology to Optimize Exposure
Design of TransCon IL-2 b/g: 2) TransCon Technology to Optimize Exposure Sustained, long-lasting exposure utilizing the TransCon hGH linker and carrier, expected to support every 3 week dosing TransCon carrier TransCon linker IL-2 b/g (inactive) Active IL-2 b/g Linker cleavage at physiological condi
Slide 79: TransCon IL-2 b/g – Prolonged Activity and Receptor Selectivity in Monkeys
1 Rand et al., JCI, 1991; Van Haelst Pisani C et al., Blood, 1991 TransCon IL-2 b/g – Prolonged Activity and Receptor Selectivity Demonstrated in Cynomolgus Monkeys Single dose provided >3-fold and prolonged enhancement of lymphocyte counts supporting Q3W dosing Well tolerated in monkeys with low ri
Slide 80: TransCon IL-2 b/g - Summary
TransCon IL-2 b/g - Summary Designed to fully solve the limitations of IL-2 Optimized receptor binding and exposure Selective activation of IL-2Rb/g observed Potential for best-in-class IL-2 molecule across multiple tumor types Potent expansion and activation of CD8+ T cells and NK cells in vivo Mon
Slide 81: Oncology Product Candidate TransCon TLR 7/8 Agonist
Oncology Product Candidate TransCon TLR 7/8 Agonist
Slide 82: Potential to Transform Efficacy, Safety and Practicality of Intratumoral Treatments
Potential to Transform Efficacy, Safety and Practicality of Intratumoral Treatments Days/Weeks Concentration Long tumor Exposure Systemic Exposure Mins/Hours Concentration Short tumor Exposure Systemic Exposure Transient effect in tumor* Lower systemic toxicity Sustained potent activity in the tumor
Slide 83: Resiquimod Loaded onto TransCon Hydrogel for Intratumoral Sustained Delivery
Resiquimod transiently conjugated to TransCon Hydrogel carrier, designed to provide sustained local release of unmodified parent drug Designed to provide sustained activation of tumoral myeloid lineages driving tumor antigen release/presentation and induction of immune stimulatory cytokines Linker c
Slide 84: Dose-dependent Tumor Growth Inhibition Following a Single IT Injection
Dose-dependent Tumor Growth Inhibition Following a Single IT Injection of TransCon TLR 7/8 Agonist Body Weights: All Doses Well Tolerated Consistent with MOA, local inflammation and some tumor ulcerations observed Single IT Dosing Tumor Growth: Dose-dependent Inhibition
Slide 85: Single Dose Triggered Abscopal Anti-Tumor Inhibition
Single-dose of TransCon TLR7/8 Agonist Triggered Abscopal Anti-Tumor Inhibition and Enhanced Anti-tumor Effects of IL-2 *IL-2 dosed at 20 ug twice daily on days 0-4, once daily on days 8-12 Injected Tumor Non-injected Tumor Single IT Dosing
Slide 86: Potent Tumor Growth Inhibition with Minimal Systemic Cytokine Release
A Single Dose of TransCon TLR7/8 Agonist Mediated Potent Tumor Growth Inhibition with Minimal Systemic Cytokine Release Tumor Growth Inhibition (CT26) with Low Systemic Cytokine Induction Days post-randomization TransCon Vehicle TransCon TLR7/8 Agonist (20 μg IT) Resiquimod (20 μg IT) Absolute tumor
Slide 87: Single Dose with IL-2 Induced Immunological Memory
A Single Dose of TransCon TLR7/8 Agonist with IL-2 Treatment Induced Immunological Memory and Prevented Tumor Grow Upon Rechallenge Absolute tumor volume (mm3) Days post-CT26 rechallenge Control Naïve Mice TransCon TLR7/8 Agonist + rIL-2 CT26 Rechallenge, 2 Months After TransCon TLR7/8 Agonist and I
Slide 88: TransCon TLR 7/8 Agonist - Summary
TransCon TLR 7/8 Agonist - Summary Offers a new treatment paradigm for intratumoral sustained delivery with potential for superior efficacy and safety Single intratumoral dose potentially provides exposure for weeks/months Dramatically altered ratio of anti-tumor vs systemic effects when compared to
Slide 89: Oncology Product Candidate TransCon VEGF-TKI
Oncology Product Candidate TransCon VEGF-TKI
Slide 90: Opportunity for TransCon VEGF-TKI
Opportunity for TransCon VEGF-TKI Efficacy Better tolerated approaches are needed to enable sufficient tumor exposure and new combination approaches Safety Lower systemic exposure expected to enable aggressive multiagent therapies New Indications Patients on poorly tolerated combos Enable intratumor
Slide 91: TransCon VEGF-TKI: Axitinib Loaded onto TransCon Hydrogel
TramsCon VEGF-TKI: Axitinib Loaded onto TransCon Hydrogel for Intratumoral Sustained Delivery Axitinib transiently conjugated to TransCon Hydrogel carrier, designed to provide sustained release of unmodified axitinib Designed to provide sustained modulation of the tumor microenvironment with potenti
Slide 92: Single Dose of TransCon VEGF-TKI Allowed Combination Benefits with anti-PD-1
Single Dose of TransCon VEGF-TKI Allowed for Combination Benefits with anti-PD-1 in Injected and Non-injected Tumors Anti-tumor Activity and Combination Benefits with Anti-PD1 in Injected and Non-injected tumors (MC38 model)
Slide 93: TransCon VEGF-TKI – Summary
TransCon VEGF-TKI – Summary New approach to modulation of tumor microenvironments, with the potential for direct anti-tumor effects TransCon Hydrogels generated for sustained release of axitinib Potent anti-tumor effects in mice observed, including combination benefits with checkpoint blockade Slow
Slide 94: Oncology Summary
Oncology Summary Best-in-class potential using systemic and intratumoral TransCon technologies Preclinical anti-tumor proof-of-concept demonstrated with small molecules, cytokines and antibodies TransCon intratumoral technologies acceptance into the FDA´s Emerging Technology Program Differentiated p
Slide 95: Selected 2020 Expected Milestones
Submit U.S BLA filing Selected 2020 Expected Milestones 1 Results timing +/- two weeks 2 Conducted through strategic investment in VISEN Pharmaceuticals Q1 2020 Q2 2020 Q3 2020 Q4 2020 Six-month data from phase 2 open-label extension Initiate global adult HP phase 3 trial Initiate phase 2 trial for
Ascendis Pharma — Investor Presentation (January 2020) on 6ix