Ascendis Pharma A/s · NASDAQ:ASND
Ascendis Pharma A/s — Investor Presentation (January 2019)
64 slides from Ascendis Pharma A/s's investor presentation, Jan 7, 2019
Slide 1: Ascendis Pharma A/S January 2019
Ascendis Pharma A/S January 2019 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 Unique algorithm for product innovation has resulted in successful clinical validation of 3 out of 3 product candidates within the endocrino
Slide 4: 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 parent drug like the endogenous compound; linker-carrier is cleared renally Following injecti
Slide 5: TransCon Technology: Sustained Localized Delivery
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
Slide 6: Sustained Localized Delivery: Validated Across Multiple Drugs and Administration Sites
Sustained Localized Delivery: Validated Across Multiple Drugs and Administration Sites Vitreal PK of Fab following intra-vitreous administration in rabbits. TransCon Fab half-life was ~53 days compared to free Fab half-life of ~3.2 days. Plasma PK of Daptomycin following intra-articular administrati
Slide 7: Ascendis Algorithm for Product Innovation
Ascendis Algorithm for Product Innovation Our unique algorithm for product innovation has resulted in clinical validation of 3 out of 3 product candidates in Endocrinology Rare Disease Unmet Medical Need Clinically Validated Parent Drug TransCon Technology Suitability Clearly Differentiated Product
Slide 8: Building a Leading Company in Rare Diseases
PRODUCT CANDIDATE PRIMARY INDICATION DEVELOPMENT STAGE POTENTIAL WW MARKET1 WW COMMERCIAL RIGHTS TransCon Anti-VEGF Ophthalmology Not disclosed >$7 billion TransCon Peptides Diabetes Not disclosed >$1 billion PRODUCT CANDIDATE PRECLINICAL PHASE 1 PHASE 2 PHASE 3 POTENTIAL WW MARKET1 COMMERCIAL RIGHT
Slide 9: TransCon Growth Hormone: Once-Weekly Replacement Therapy
TransCon Growth Hormone: Once-Weekly Replacement Therapy
Slide 10: Growth hormone market primed for disruption by long-acting product
Well-established market primed for disruption by a long-acting growth hormone product The Growth Hormone Market1 ~$3.5 billion in worldwide rhGH2 sales and growing (2.4% CAGR)3 Fragmented market with same undifferentiated hGH molecule competing on differentiated formulations, devices, services and a
Slide 11: Clinical Implications of Untreated GHD
Clinical Implications of Untreated GHD 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. 8. Bex, M
Slide 12: Daily Growth Hormone: The Problem
Increased adherence Improved growth Doses missed per week1 ≥3 2 p< 0.001 p< 0.01 4 3 2 1 0 ≤1 Height velocity SDS Poor adherence with daily hGH therapy is associated with reduced height velocity and impaired quality of life1 Daily Growth Hormone: The Problem 1 PLoS ONE 2011, 6(1): e16223 2 Clinical
Slide 13: TransCon hGH Design
TransCon hGH Design Once-weekly prodrug releases unmodified hGH designed to mimic daily hGH: Tissue distribution Physiological levels Therapeutic effects: efficacy, safety and tolerability TransCon carrier TransCon linker Inactive parent drug Unmodified parent drug Receptor Linker cleavage dependent
Slide 14: TransCon Growth Hormone Target Product Profile
Efficacy Safety (including immunogenicity) Tolerability TransCon Growth Hormone Target Product Profile Comparable to Daily Growth Hormone Weekly subcutaneous administration Small injection volume (31G needle) Room temperature storage Device Easy to use Automatic data capture Empty-all design
Slide 15: Growth Comparable to a Daily hGH in Phase 2
Growth Comparable to a Daily hGH in Phase 21,2 Same weekly dose 11.5 14.5 0.14 mg 0.21 mg 0.30 mg 0.21 mg Dose (GH/kg/week): 1 Intergroup differences not statistically significant 2 J Clin Endocrinol Metab 2017, 102(5): 1673–1682 3 Conducted with a previous lower strength version of TransCon Growth
Slide 16: Dose Proportional IGF-1 Response in Phase 2
Dose Proportional IGF-1 Response in Phase 21 Days (Week 13) IGF-1 SDS (+ SEM) 0 1 2 3 4 5 6 7 Transient values greater than +2.0 observed in a small number of patients primarily at the highest dose level 1 J Clin Endocrinol Metab 2017, 102(5): 1673–1682
Slide 17: Comparable hGH Levels in Phase 2
Comparable hGH Levels in Phase 21 Maximum hGH concentration comparable between equivalent weekly doses of TransCon hGH and a daily hGH Days (Week 13) hGH serum concentration (+SEM, ng/ml) 1 J Clin Endocrinol Metab 2017, 102(5): 1673–1682
Slide 18: Comparable Safety to a Daily hGH in Phase 2
Comparable Safety to a Daily hGH in Phase 21 >1100 TransCon hGH injections administered No reports of lipoatrophy or nodule formation No serious adverse events related to study drug Immunogenic profile comparable to a daily hGH Injection site tolerability comparable to a daily hGH Adverse events con
Slide 19: TransCon hGH Phase 3 Program
TransCon hGH Phase 3 Program FDA and EMA support size and scope of program for pediatric GHD filing Database lock for filing package expected Q3 2019 Switch trial (n=146) Fully enrolled Data expected Q2 2019 Extension trial (n~300) Regulatory Filings Pivotal trial (n=161) Fully enrolled Data expecte
Slide 20: Phase 3 heiGHt Trial Ongoing
Phase 3 heiGHt Trial Ongoing Key Inclusion Criteria Prepubertal children with GHD Height SDS ≤ -2.0 IGF-1 SDS ≤-1.0 2 GH stimulation tests (GH ≤10 ng/mL) Bone age ≥ 6 months behind chronological TransCon hGH (0.24 mg/kg/week) Genotropin (34 µg/kg/d = 0.24 mg/kg/week) Key Endpoints Annualized height
Slide 21: Phase 3 heiGHt Trial Update
Phase 3 heiGHt Trial Update1 161 subjects enrolled 1 discontinued from treatment after unrelated appendectomy 100% of subjects who completed heiGHt Trial enrolled in enliGHten Trial Observed data from the heiGHt Trial continue to indicate a safety profile consistent with the published safety profile
Slide 22: heiGHt Trial: Baseline Demographics and Model Prediction for Daily Arm
heiGHt Trial: Baseline Demographics and Model Prediction for Daily Arm Sponsor Versartis LG Life Sciences Biopartners Daily hGH cohort Genotropin Genotropin Valtropin Humatrope Dose of daily hGH 0.034 mg/kg/d 0.030 mg/kg/d 0.030 mg/kg/d 0.030 mg/kg/d (0.24 mg/kg/wk) (0.21 mg/kg/wk) (0.21 mg/kg/wk) (
Slide 23: Auto-Injector Designed to Improve Adherence
Auto-Injector Designed to Improve Adherence Auto-injector introduction during extension study and for commercial launch Simple operation with few user steps Single low-volume (<0.60 mL) injection for patients ≤60kg Small needle, comparable to daily hGH (31G, 4mm) Room temperature storage No waste du
Slide 24: Improve Adherence Through Feedback & Intervention
Improve Adherence Through Feedback & Intervention Secure Cloud-Based Central Database Integrating with a Connected Healthcare Platform Automated Data Capture of Dose and Injection Time TransCon hGH Auto-Injector Data Analysis
Slide 25: TransCon hGH: Highlights
TransCon hGH: Highlights Potential best-in and first-in-class long-acting hGH in pediatric GHD Trial phase 3 top-line data expected Q1 2019 Trial top-line data expected Q2 2019 Introduction of auto-injector into Trial expected Q2 2019 Clinical database lock for filing package expected Q3 2019 Improv
Slide 26: TransCon PTH: PTH Replacement Therapy for Hypoparathyroidism
TransCon PTH: PTH Replacement Therapy for Hypoparathyroidism
Slide 27: Hypoparathyroidism: Serious Unmet Medical Need
Hypoparathyroidism: Serious Unmet Medical Need Parathyroid hormone (PTH) regulates calcium/phosphate homeostasis Hypoparathyroidism (HP) is a rare disease characterized by deficient or absent PTH Low serum calcium, increased serum phosphate and urine calcium levels Most common cause (~75%) is inadve
Slide 28: Diverse Clinical Manifestations of HP
Diverse Clinical Manifestations of HP Central nervous system Seizures Calcifications Parkinsonism or dystonia Respiratory system Laryngospasm Renal system Nephrocalcinosis* Kidney stones* Chronic kidney disease* Peripheral nervous system Paresthesia Muscle cramps Tetany Neuropsychiatric system Anxie
Slide 29: Burden of Illness Despite Treatment: The Patients' View
Burden of Illness Despite Treatment: The Patients’ View Sources: Endocrine Practice 2014, 20: 671-679; results of Paradox survey of patients (n=374) I am concerned with the long-term complications of my HP medications 75% strongly agree I am satisfied with the effectiveness of my medications to trea
Slide 30: Treatment Contributes to Risk of Renal Disease
Treatment Contributes to Risk of Renal Disease 4.8-fold increased risk of renal stones 31% had renal calcifications (renal stones or nephrocalcinosis) Sources: J Bone Miner Res 2013, 28: 2277-2285; J Clin Endocrinol Metab 2012, 97(12): 4507-4514 5.0-fold increased risk of renal insufficiency 41% had
Slide 31: HP Treatment Strategies Are Evolving
HP Treatment Strategies Are Evolving TransCon PTH is designed to address all aspects of the disease by restoring physiological levels of PTH throughout the day 1 Front. Endocrinol. 2017, 7: 172 2 Nature Reviews 2017, 3: 1-20 3 Natpara/Natpar label Conventional treatment by calcium and vitamin D can
Slide 32: FDA Perspective on Optimal PTH PK Profile
FDA Perspective on Optimal PTH PK Profile1 1 FDA presentation: Natpara Advisory Committee, September 12, 2014 Natpara QD provides dose-dependent increases in serum calcium for ~24 hours Natpara QD effect on urinary calcium excretion is short-lived (10-12 hours) as kidney reabsorption of calcium foll
Slide 33: Continuous PTH Infusion Led to Improved Outcomes
Continuous PTH Infusion Led to Improved Outcomes Desired Treatment Outcomes in HP Natpara Once-daily1, 2 PTH (1-34) Infusion3-9 Increase serum calcium Reduce pill burden Normalize urinary calcium excretion X Reduce clinical hypercalcemia X Reduce clinical hypocalcemia X Normalize serum phosphate (hi
Slide 34: TransCon PTH Design
TransCon PTH Design TransCon PTH is a sustained-release prodrug designed to provide stable PTH levels in the physiological range for 24 hours/day TransCon PTH designed to normalize blood and urinary calcium levels, serum phosphate and bone turnover Renal clearance Receptor TransCon carrier TransCon
Slide 35: Single Dose PK Data Support Infusion-Like Profile
Single Dose PK Data Support Infusion-Like Profile with Daily Administration Free PTH Exposure After Single Doses of TransCon PTH (n=4-8) TransCon PTH phase 1 data reproduced PK profile from preclinical studies and showed t1/2 of ~60 hours (versus Natpara t1/2 ~3 hours) 1 PTH measured as free PTH(1-3
Slide 36: PK Data Support Infusion-like Profile over Hours
PK Data Support Infusion-like Profile over 24 Hours Lower limit of normal for PTH(1-34) ‘normal range’ PTH Exposure After Multiple Doses of TransCon PTH (n=7-8) TransCon PTH daily dosing for 10 days provided a flat infusion-like profile with low PTH peak-to-trough ratio at day 10 1 PTH measured as f
Slide 37: Multiple Doses Provided Dose-Dependent Increase of Serum Calcium
Multiple Doses Provided Dose-Dependent Increase of Serum Calcium Albumin- adjusted Calcium (mg/dL) (Mean ± SE) Change in Albumin-adjusted Serum Calcium over 10 Days of TransCon PTH (n=8/group) TransCon PTH daily dosing for 10 days provided dose-dependent increase of serum calcium
Slide 38: Multiple Doses Provided Dose-Dependent Suppression of Endogenous PTH(1-84)
Multiple Doses Provided Dose-Dependent Suppression of Endogenous PTH(1-84) Suppression of PTH(1-84) over 10 Days of TransCon PTH (n=8/group) TransCon PTH daily dosing for 10 days provided dose-dependent down regulation of endogenous PTH(1-84)
Slide 39: Control of Urinary Calcium with Multiple Doses
Control of Urinary Calcium with Multiple Doses FECa in normal healthy volunteers clamped to calcium of 10.3 mg/dL1 Mean albumin-adjusted.sCa at day 10: Placebo: 9.6 mg/dL 12 µg: 9.9 mg/dL 16 µg: 10.2 mg/dL 20 µg: 10.6 mg/d Spot morning FECa (%, Mean ± SE) FECa upper limit of normal Spot FECa with da
Slide 40: Market Research Validates Unmet Medical Need for TransCon PTH
Market Research Validates Unmet Medical Need for TransCon PTH Market research with 108 U.S. endocrinologists treating HP1 Variety of clinical settings, geographies, patient volumes, disease severity, and short-acting PTH use Endocrinologists’ views on current short-acting PTH: Reduces hypocalcemia,
Slide 41: TransCon PTH: Highlights
Phase 1 data support TransCon PTH as a true replacement therapy for HP Initiation of phase 2 trial in adult HP subjects expected Q1 2019 Randomized placebo-controlled study for approximately four weeks with fixed TransCon PTH doses and titration regimen for complete withdrawal of SoC (i.e., active v
Slide 42: TransCon CNP: Once-Weekly CNP for Achondroplasia
TransCon CNP: Once-Weekly CNP for Achondroplasia
Slide 43: Achondroplasia – Not Only a Skeletal Disease
Achondroplasia – Not Only a Skeletal Disease Autosomal dominant genetic disorder Patients suffer numerous comorbidities No FDA-approved therapy Only option to improve height is surgical limb lengthening Most common form of human dwarfism Approximately 250,000 patients worldwide1 80% born to average-
Slide 44: Balanced Growth Depends on Balanced Pathways
Balanced Growth Depends on Balanced Pathways TransCon CNP is designed to provide continuous exposure to CNP to optimize efficacy with a well-tolerated and convenient once-weekly dose CNP Activity FGFR3 Activity Normal growth Achondroplasia growth CNP FGFR3 FGFR3 CNP
Slide 45: Achondroplasia Signaling Defect is Well Understood
Achondroplasia Signaling Defect is Well Understood FGFR3 negatively regulates chondrocyte proliferation and differentiation and hence bone growth Achondroplasia results from a mutation in FGFR3 which leaves the receptor constitutively activated CNP inhibits the FGFR3 pathway and thereby promotes pro
Slide 46: TransCon CNP Design
TransCon CNP Design TransCon technology provides effective shielding of CNP: From neutral endopeptidase degradation in subcutaneous tissue and blood compartment Minimize binding of TransCon CNP to the NPR-C clearance receptor Reduce binding of TransCon CNP to the NPR-B receptor in vasculature to avo
Slide 47: Juvenile Healthy Monkey Growth Study
Percentage change from baseline (Mean +SD) Juvenile Healthy Monkey Growth Study Demonstrated dose-proportional tibial linear growth; ulnar growth consistent Compared to untreated control, growth increased >70% with highest TransCon CNP dose vs. 35% with CNP analogue* at a higher weekly dose 1 Poster
Slide 48: TransCon CNP in Achondroplasia Disease Model
TransCon CNP/ Vehicle Vehicle TransCon CNP may ameliorate most disabling achondroplasia traits, including stenosis of the foramen magnum TransCon CNP in Achondroplasia Disease Model (Fgfr3Y367C/+)1 Preventing Premature Fusion of Synchondroses of Foramen Magnum Linear and Skeletal Growth in Achondrop
Slide 49: TransCon CNP: Phase 1 Trial
TransCon CNP: Phase 1 Trial A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Tolerability and Pharmacokinetics of Subcutaneous Single Doses of TransCon CNP in Healthy Adult Male Subjects
Slide 50: Phase 1 Trial Design
Phase 1 Trial Design Primary Endpoint Frequency of adverse events (AEs) reported after administration of TransCon CNP Secondary/Exploratory Endpoints Safety parameters and local tolerability assessment Pharmacokinetic parameters Other exploratory endpoints 3.0 µg/kg 10 µg/kg 25 µg/kg 75 µg/kg 150 µg
Slide 51: Sustained CNP Exposure Over One Week
Sustained CNP Exposure Over One Week1 A single dose of TransCon CNP provided continuous CNP exposure over the entire week with low inter-subject variability CNP2 (pM) (Mean ±SEM) Hours 1 Preliminary data 2 CNP measured as CNP-38 TransCon CNP 25 µg/kg (n=8)
Slide 52: Dose-related Increase in CNP Exposure
Dose-related Increase in CNP Exposure1 Dose CNP (µg/kg) Dose-related increase in CNP exposure and low inter-subject variability suggests ability to titrate and individualize dosing; observed free CNP t1/2 of ~ 90 hours (versus native CNP t1/2 of 2-3 minutes) Hours CNP2 (pM) (Mean ±SEM) 1 Preliminary
Slide 53: Mean Resting Blood Pressure Unchanged from Predose
Mean Resting Blood Pressure Unchanged from Predose1 1 Preliminary data. 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 54: Mean Resting Heart Rate Unchanged from Predose
Mean Resting Heart Rate Unchanged from Predose1 Change in heart rate 1 Preliminary data. 3.0 and 10 μg/kg dose levels are not represented. Data from these cohorts are consistent with placebo.
Slide 55: Well-tolerated Safety Profile
Well-tolerated Safety Profile1 No serious AEs were reported in the trial TransCon CNP was generally well tolerated at doses up to 150 µg/kg Mean resting blood pressure and heart rate were unchanged from predose at all time points, in all cohorts Mean orthostatic changes in vital signs appear unrelat
Slide 56: TransCon CNP: Highlights
TransCon CNP: Highlights TransCon CNP phase 1 data reproduced PK profile and cardiovascular safety from preclinical studies Provided continuous CNP exposure over seven days with a single subcutaneous administration, supporting once-weekly dosing Continuous CNP exposure at target levels is important
Slide 57: Vision 3x3: Strategic Roadmap to 2025
Vision 3x3: Strategic Roadmap to 2025
Slide 58: Vision 20/20: Established the Foundation for a Leading Rare Disease Company
Advance our pipeline of three endocrinology rare disease product candidates towards approval Create a leading integrated commercial business primarily focused on the U.S. market with best-in-class products Identify a new rare disease therapeutic area with high-value product opportunities TransCon CN
Slide 59: Vision 3x3: Strategic Roadmap to 2025
Vision 3x3: Strategic Roadmap to 2025 Our Goal is to Achieve Sustainable Growth through Multiple Approaches Obtain regulatory approval for 3 Endocrinology Rare Disease products TransCon hGH for pediatric growth hormone deficiency TransCon PTH for adult hypoparathyroidism TransCon CNP for achondropla
Slide 60: Extending Global Footprint: VISEN Pharmaceuticals
Extending Global Footprint: VISEN Pharmaceuticals Partnership with experienced investors builds presence in second largest pharmaceutical market in the world and expands rare disease clinical programs Develop and commercialize TransCon hGH, TransCon PTH and TransCon CNP in Greater China Right of neg
Slide 61: Why Oncology?
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 Why Oncology? Both TransCon technologies well suited for Oncology: Sustained Systemi
Slide 62: Oncology Pipeline Strategy
Oncology Pipeline Strategy Goal to create at least 3 best-in-class candidates from validated parent drugs – each addressing different aspects of the Cancer Immunity Cycle Impact all aspects of the Cancer Immunity Cycle Stimulators of innate immunity Stimulators of adaptive immunity Modulators of tum
Slide 63: In Vivo Sustained Localized Delivery Proof-of-Concept
In Vivo Sustained Localized Delivery Proof-of-Concept Single IT injection of TransCon TLR Agonist demonstrated superiority to equal IT dose of free TLR Agonist in a syngeneic mouse colon-derived tumor model TransCon TLR Agonist was well tolerated and had no effect on body weights Sustained localized
Slide 64: Selected 2019 Expected Milestones
TransCon PTH: Phase 2 trial top-line data Selected 2019 Expected Milestones TransCon hGH: fliGHt Trial top-line Phase 3 data TransCon hGH: Introduction of auto-injector into enliGHten Trial Research Day: Unveiling oncology pipeline and near-term milestones TransCon hGH: Long-term clinical database l
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