Ascendis Pharma A/s · NASDAQ:ASND
Ascendis Pharma A/s — Investor Day (September 2016)
144 slides from Ascendis Pharma A/s's investor day presentation, Sep 30, 2016
Slide 1: Ascendis Pharma A/S R&D Update September 30, 2016
Ascendis Pharma A/S R&D Update September 30, 2016 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
Slide 3: Vision 20/20
Vision 20/20 Jan Mikkelsen, President & CEO
Slide 4: Today's Agenda
Today’s Agenda 8:30-8:45 a.m.Vision 20/20 & TransCon Technology (Jan Mikkelsen) 8:45-9:00 a.m.Pediatric Growth Hormone Deficiency (Barbara Lippe, M.D.) 9:00-9:20 a.m. TransCon Growth Hormone Program (Jonathan Leff, M.D.) 9:20-9:40 a.m. Q&A 9:40-9:45 a.m. TransCon Treprostinil (Kennett Sprogøe, Ph.D.
Slide 5: Vision 20/20: Building a Leading Rare Disease Company
Vision 20/20: Building a Leading Rare Disease Company Create best-in-class rare disease products addressing unmet medical needs by applying TransCon technology to parent drugs with clinical proof-of-concept Improve efficacy, safety and/or convenience Expected higher development success rate compared
Slide 6: TransCon Technology
TransCon Technology Predictable release of parent drug in the body Parent Drug Parent Drug TransCon carrier TransCon linker Inactive Prodrug Predictable release of unmodified parent drugs Parent drugs can be proteins, peptides or small molecules TransCon carrier enables both systemic and localized d
Slide 7: TransCon Linker
TransCon Linker Self-cleaving linkers that autohydrolyze at a predictable rate Linker release only dependent on pH and temperature (in vitro / in vivo correlation) Linkers are stable under storage conditions (low pH and temperature or lyophilized) Sustained release of drug initiated upon injection T
Slide 8: Patent Filing Strategy
Patent Filing Strategy Protection of TransCon Technology Layered Protection of Product Concepts Broad patent portfolio covering reversible linkers, carriers and processes in major markets Linker claims directed at both chemical and functional aspects Linker families cover most drug classes and help
Slide 9: Multi-level Patent Portfolio Protection
Multi-level Patent Portfolio Protection 69 Issued Patents > 200 Patent Applications Pending Product Concepts TransCon Linkers Dose Regimen Process Composition of Matter Device TransCon Carriers
Slide 10: Ascendis' Approach to Product Innovation
Ascendis’ Approach to Product Innovation 1 Totals from FDA and EMA Orphan List, public & proprietary databases, advisors and conferences Unmet Medical Need Clinically Validated Parent Drug TransCon Technology Suitability Clearly Differentiated Product Established Clinical & Regulatory Pathway Large
Slide 11: Expected Synergies of Therapeutic Focus
Expertise in endocrinology (clinical, regulatory, medical affairs) Concentrated prescriber audience Small, focused sales force Patient-centric support system Reimbursement and payor knowledge Distribution networks TransCon CNP TransCon Growth Hormone Expected Synergies of Therapeutic Focus TransCon
Slide 12: Building a Leading Company in Rare Diseases
Product Candidate Primary Indication Development Stage Potential WW Market1 WW Commercial Rights TransCon Growth Hormone Growth hormone deficiency Phase 3 > $3 billion TransCon PTH Hypoparathyroidism Pre-IND > $2 billion2 TransCon CNP Achondroplasia Pre-IND > $1 billion TransCon Ranibizumab Ophthalm
Slide 13: Today's Agenda
Today’s Agenda 8:30-8:45 a.m.Vision 20/20 & TransCon Technology (Jan Mikkelsen) 8:45-9:00 a.m.Pediatric Growth Hormone Deficiency (Barbara Lippe, M.D.) 9:00-9:20 a.m. TransCon Growth Hormone Program (Jonathan Leff, M.D.) 9:20-9:40 a.m. Q&A 9:40-9:45 a.m. TransCon Treprostinil (Kennett Sprogøe, Ph.D.
Slide 14: Recombinant Human Growth Hormone
Recombinant Human Growth Hormone Life cycle progress toward the future Barbara Lippe, MD Professor Emerita of Pediatrics David Geffen School of Medicine at UCLA
Slide 15: What is GH deficiency and why do we treat it?
What is GH deficiency and why do we treat it? ...7 years later following treatment Tom Thumb 16 Months
Slide 16: Background on GHD
Absence of any pituitary GH secretion from infancy results in a normally proportioned “little person” ~ 70% of his/her expected adult height ~ 1/4000 children are born with or acquire GH deficiency Continuous treatment from early childhood can restore height to near or at genetic potential and corre
Slide 17: Where does GH come from? How does it work?
Adapted from: Roelfsema V, et al. J Am Soc Nephrol. 2001. IGF-1: insulin-like growth factor-1 SRIF: somatostatin, GHRH; growth hormone-releasing hormone Where does GH come from? How does it work?
Slide 18: What causes failure to secrete enough GH?
Most common cause is “idiopathic” = we’re idiots because it’s really pathologic Absence of a gene or genes in the pathway to GH synthesis or secretion Combination of congenital malformations of the brain Pituitary tumor (i.e. craniopharyngioma) Radiation to the head as therapy for other conditions H
Slide 19: Key Milestones in GH treatment
Key Milestones Milestones in GH treatment 1947 UCSF scientists isolate GH from pituitary Injections in dwarf children were “successful” Some physicians provided pituitary extracted GH GH extraction centralized at the NHPP; sent to hundreds of US endocrinologists ~ 7,700 children were treated Creutzf
Slide 20: Key Milestones in GH treatment (cont'd)
Key Milestones Milestones in GH treatment (cont’d) 1985 -1998 Progression to SC administration Efficacy with daily dosing Multiple companies enter market Improved body comp in GH deficient adults Liquid formulations, small needles and devices New indications for pediatric and adult patients (e.g., T
Slide 21: Why do we still need innovation?
Why do we still need innovation? To optimize adherence and compliance so that maximum growth can be achieved with the least amount of “mental” stress and “physical inconvenience”
Slide 22: What are causes of patient non-adherence?
Rosenfeld and Bakker. Endocr Pract. 2008; 14, 143-154 What are causes of patient non-adherence? Compliance means conforming Compliance Survey for GH How often…. ? Forgot to take it Forgot to renew prescription Forgot to order the next refill Experience side effects Not able to pay for it Away from h
Slide 23: Drugs don't work in patients who don't take them
“Drugs don’t work in patients who don’t take them” C. Everett Koop, MD Former Surgeon General
Slide 24: Previous and current approaches to long-acting GH
Depot formulations (e.g., Nutropin Depot, LB03002) Covalent pegylation (e.g., Pfizer, Ambrx, Novo, GenSci’s “Jintrolong”) Hybrid molecules/fusion proteins (e.g., TEVA TV-1106, Versartis VRS-317, Novo somapacitan, LAPSrhGH/HM10560A [Hamni Pharma], GX-H9 [Handok, Genexine, Inc.) Prodrug/sustained rele
Slide 25: Characteristics of an effective long-acting GH
Provides all the benefits of naturally secreted hGH Free GH molecule reaches all the target tissues Small volume administered with a very small needle Easy to administer with a user friendly device Room temperature stability Pain “free” (comparable safety/tolerability to daily GH) Lack of immunogeni
Slide 26: What is the preferred dosing regimen?
Frequency Pros Cons Twice Monthly Fewer injections Confusing week on/off schedule Larger injection volumes, which may result in 2 shots/dose Less clinical experience Weekly Easy regimen to schedule Less frequent injections Less clinical experience than daily Daily Long track record of safety/efficac
Slide 27: The goal
And this is how the child measures it The goal Everyone should be able to reach the bar
Slide 28: TransCon Growth Hormone: Once-Weekly Replacement Therapy
TransCon Growth Hormone: Once-Weekly Replacement Therapy Jonathan Leff, M.D. Chief Medical Officer
Slide 29: Poor Compliance Reduces Treatment Outcomes
Higher compliance Improved growth response Doses missed per week ≥3 2 p< 0.001 p< 0.01 4 3 2 1 0 ≤1 Height Velocity SDS Poor compliance with daily growth hormone therapy is associated with reduced height velocity and impaired quality of life1 Poor Compliance Reduces Treatment Outcomes 1 PLoS ONE 201
Slide 30: Desired Target Product Profile
Desired Target Product Profile Efficacy Safety (including immunogenicity) Tolerability Comparable to Daily Growth Hormone = Weekly subcutaneous administration Single injection/dose Convenience 31G needle Room temperature storage Device Easy to use Empty-all design (controlled substance)
Slide 31: Mode of Action of TransCon Growth Hormone
Mode of Action of TransCon Growth Hormone Predictable release of parent drug in the body hGH hGH TransCon carrier TransCon linker Inactive Prodrug Creation of TransCon Prodrug Designed as a sustained-release prodrug that releases native human growth hormone with once-weekly administration Releases n
Slide 32: Optimal Therapeutic Range
Optimal Therapeutic Range Acromegaly Growth Hormone Deficiency Short stature Metabolic abnormalities Cardiovascular abnormalities Cognitive deficiencies Poor quality of life High Low THERAPEUTIC RANGE DAILY hGH PHYSIOLOGICAL RANGE Tissue overgrowth Diabetes Heart disease, stroke Risk of colon cancer
Slide 33: Distribution and Effects of hGH and IGF-1
ADIPOSE TISSUE hGH directly stimulates the breakdown of fat counteracting the adipogenic effect of IGF-1 MUSCLE hGH stimulates muscle growth via direct stimulation of GH receptors in muscle and through IGF-1 Distribution and Effects of hGH and IGF-1 TransCon Growth Hormone therapy designed to achiev
Slide 34: Growth Hormone: Penetration of Growth Plate
Growth Hormone: Penetration of Growth Plate Associated with Optimal Growth1-4 1 J Clin Endocrinol Metab 2007,12: 4529-4535 2 J Clin Endocrinol Metab1997, 82(2): 629-633 3 Endocr Rev 1989, 10 (1): 68-91 4 Dev Biol 2001, 229: 141-162
Slide 35: Phase 2 Pediatric Study Design: Inclusion Criteria
Phase 2 Pediatric Study Design: TransCon GH in Treatment-Naïve Pre-Pubertal Growth Hormone Deficiency Age 3-11 years (girls) or 3-12 years (boys) hGH treatment naïve Height (HT) SDS ≤ -2.0 Height Velocity (HV) SDS ≤ -1.0 IGF-1 SDS ≤ -1.0 Two GH stimulation tests; peaks ≤ 10 ng/mL Bone age below chro
Slide 36: Phase 2 Pediatric Study Design: Treatment Groups
Phase 2 Pediatric Study Design: TransCon GH in Treatment-Naïve Pre-Pubertal Growth Hormone Deficiency Randomized Treatment Groups (n=53) TransCon Growth Hormone Cohort 1 0.14 mg hGH/kg/week Cohort 2 0.21 mg hGH/kg/week Cohort 3 0.30 mg hGH/kg/week Genotropin® Cohort 4 0.21 mg hGH/kg/week (0.03 mg/kg
Slide 37: Growth Comparable to Daily hGH in Phase 2 Study
Growth Comparable to Daily hGH in Phase 2 Study1 Same weekly dose 11.5 14.5 0.14 mg 0.21 mg 0.30 mg 0.21 mg TransCon Growth Hormone2 Genotropin® Dose hGH/kg/week: 1 Intergroup differences not statistically significant. 2 Conducted with a previous lower strength version of TransCon Growth Hormone.
Slide 38: Dose Proportional IGF-1 Elevation in Phase 2 Study
Dose Proportional IGF-1 Elevation Observed into the Normal Range in Phase 2 Study Days (Week 13) IGF-1 SDS (+ SEM) 0 1 2 3 4 5 6 7 Transient point values of IGF-1 SDS > +2.0 have been observed in a small number of patients primarily at the highest dose level
Slide 39: Comparable hGH Levels in Phase 2 Study
Comparable hGH Levels for TransCon Growth Hormone and Daily hGH in Phase 2 Study Maximum hGH blood concentration comparable between equivalent weekly doses of TransCon Growth Hormone and daily hGH Days (Week 13) hGH Serum Concentration (+SEM, ng/ml)
Slide 40: Comparable Safety to Daily hGH in Phase 2
Comparable Safety to Daily hGH in Phase 2 >1100 TransCon Growth Hormone injections administered in the Phase 2 pediatric study No reports of lipoatrophy or nodule formation No Serious Adverse Events (SAEs) related to study drug Immunogenic profile comparable to daily hGH Injection site tolerability
Slide 41: The heiGHt Trial
The heiGHt Trial www.heighttrial.com
Slide 42: Key Learnings from Phase 2 Informed Phase 3
Key Learnings from Phase 2 Informed Phase 3 Targeting ~100 sites in multiple countries (US, CAN, EU, EE, Australia/NZ, North Africa) Simplified inclusion criteria to facilitate enrollment Selected 0.24 mg/kg/week dose within range acceptable worldwide Established engaged network of European investig
Slide 43: Phase 3 Study - heiGHt Trial
Phase 3 Study - heiGHt Trial TransCon Growth Hormone (0.24 mg/kg/week) Genotropin® (34µg/kg/d = 0.24 mg/kg/week) Screening ≤ 6 weeks Long-Term Extension Study Week 1 Week 5 Week 13 Week 52 Week 26 Week 39 VISIT SCHEDULE Prepubertal children with GHD Height SDS ≤ -2.0 IGF-1 SDS ≤ -1.0 GHD with 2 GH s
Slide 44: Phase 3 Study - heiGHt Trial Endpoints
Phase 3 Study - heiGHt Trial Annualized height velocity (HV) at 52 weeks (cm/year) Non-inferiority design Primary Efficacy Endpoint Annualized HV over 52 weeks Change in height standard deviation score (SDS) over 52 weeks Change in serum IGF-1 and IGFBP-3 levels Change in IGF-1 SDS and IGFBP‑3 SDS N
Slide 45: heiGHt Trial - Recent Achievements & Future Plans
heiGHt Trial - Recent Achievements & Future Plans No AEs observed in toxicology studies FDA End-of-Phase 2 meeting conducted EMA Scientific Advice completed CRO selected and kick-off meeting conducted Site selection underway US IND update submitted Site submissions ongoing Update to be provided on r
Slide 46: Easy to Use Device with Optimal Product Features
Easy to Use Device with Optimal Product Features Auto-injector for commercialization to be used in extension study Simple operation with few user steps A single low-volume injection for all patients (<0.6 mL) Small needle comparable to daily hGH (31G, 4mm) Room temperature storage No waste due to em
Slide 47: 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 Single injection/dose Convenience 31G needle Room temperature storage Device Easy to use Empty-all design (controlled substan
Slide 48: Highlights: TransCon Growth Hormone
Highlights: TransCon Growth Hormone First of our platform programs that leverages clinically-validated parent drugs with our TransCon platform to develop a best-in-class growth hormone product Supply chain established, commercial scale manufacturing ongoing Phase 3 heiGHt Trial initiated and gaining
Slide 49: ascendis LA
ascendis LA
Slide 50: TransCon Treprostinil: Opportunities for Pulmonary Arterial Hypertension
TransCon Treprostinil: Opportunities for Pulmonary Arterial Hypertension Kennett Sprogøe, PhD Senior Vice President, Product Innovation
Slide 51: TransCon Treprostinil Program Status
TransCon Treprostinil Program Status Pulmonary arterial hypertension (PAH) is a rare, progressive and often fatal lung disorder characterized by increased pressure in the pulmonary artery Prostacyclin administered as continuous infusion, or multiple daily oral or inhaled administrations, dependent o
Slide 52: TransCon Treprostinil: Phase 1 in Healthy Volunteers
TransCon Treprostinil: Phase 1 in Healthy Volunteers Flat infusion-like profile with low intra-patient variability; PK profile supports daily SC injections Injection site reactions (including redness and pain) were consistent with exposure to free treprostinil PK of free treprostinil after a single
Slide 53: TransCon Treprostinil SC: Proof-of-Concept
TransCon Treprostinil SC: Proof-of-Concept A double prodrug (phosphorylated treprostinil) designed to reduce exposure to free treprostinil at the injection site and to de-phosphorylate in the blood compartment Phosphorylated treprostinil liberated at the injection site is not active No local tolerab
Slide 54: TransCon Treprostinil Inhale: Proof-of-Concept
TransCon Treprostinil Inhale: Proof-of-Concept Free Treprostinil [pg/mL] LLOQ 45 pg/ml TransCon Treprostinil can be inhaled, providing local sustained release of treprostinil and low systemic exposure Leading product Tyvaso® (inhaled treprostinil) has short therapeutic coverage and requires up to 9
Slide 55: Treprostinil Programs Opportunity
Treprostinil Programs Opportunity TransCon Treprostinil demonstrated for the first time steady treprostinil concentrations in humans with daily injections Two new formulations demonstrate in preclinical models the potential to improve standard of care: TransCon Treprostinil SC demonstrated infusion-
Slide 56: Hypoparathyroidism: Clinical Impact of the Disorder
Hypoparathyroidism: Clinical Impact of the Disorder and Its Treatment on Patients’ Lives Dolores Shoback, MD Professor of Medicine University of California, San Francisco
Slide 57: Key Actions of Parathyroid Hormone (PTH)
Parathyroid Glands PTH 1,25(OH)2 vitamin D ↑ Bone turnover ↑ Renal Ca2+ reabsorption Renal phosphate clearance Kidney and Bone Serum Calcium é Serum Phosphate ê Key Actions of Parathyroid Hormone (PTH) Parathyroid Glands Hypoparathyroidism PTH ê Serum Calcium ê Serum Phosphate é Serum Magnesium ê Ur
Slide 58: Immediate Impact of Low PTH
Many blood (and urine) tests affected – calcium, phosphate, magnesium How are you doing, feeling, functioning, thinking, and coping when there are fundamental biochemical disturbances in your body Immediate Impact of Low PTH . . . Since PTH regulates serum calcium on a second-by-second time scale
Slide 59: Chronic Impact
Nerve and muscle functions Tetany (repetitive unprovoked/unwanted muscle contractions), cramps, spasms, numbness, tingling, weakness Heart Heart failure, shortness of breath, palpitations, rapid heart beat Intestine Cramps Lungs, larynx Wheezing, throat constriction, shortness of breath Brain – ever
Slide 60: Causes of Hypoparathyroidism
Post-surgical (thyroid – cancer, goiter, hyperthyroidism; parathyroid surgery; head and neck cancers/surgery – larynx, head and neck) Magnesium depletion (gastrointestinal or kidney losses) or excess – usually transient and correctable Tissue destruction: heavy metals (iron and copper overload), rar
Slide 61: Genetic Causes – Hypoparathyroidism and an Example
Many genetic causes – GCM2, PTH, Ca receptor, GNA11 mutations; syndromes - DiGeorge, GATA3 mutations, Kenny-Caffey, Sanjad-Sakati, Kearns-Sayre; mitochondrial DNA mutations Pediatric endocrinologists usually diagnose – but may see for the first time in adulthood Diagnosed 38 year old businessman – W
Slide 62: How Common is Hypoparathyroidism?
Insurance claims database (77 million patients, 75 US health plans) Projected to US population - # neck surgeries and % à hypoparathyroidism1 Denmark: estimated prevalence à 22/100,000 cases of post-surgical hypopara (~1568 cases)2 Hungary: ~1,000 patients3 1Powers J et al. JBMR 2013; 2 Underbjerg e
Slide 63: My Surgery was a Success – Dawn
55 year old woman followed for hypoparathyroidism Surgery for progressively enlarging nodular goiter in 2004 (age 43) She woke up in Recovery Room à “Feeling awful – like I had been run-over by a truck” Her surgeon could not understand it à surgery was a success! Peri-oral numbness/tingling, crampin
Slide 64: Going Forward
Treatment and daily symptom management were challenging She could not keep up with her busy law practice Opted to work part-time and from home Daytime functioning was unpredictable Sleep was routinely interrupted by cramps, palpitations, and “a feeling of doom” After those nights, her mind was not c
Slide 65: Her Regimen
Baclofen 10 mg 3 times a day Cymbalta 20 mg twice a day Thyroxine 0.125 mg Metoprolol 50 mg twice a day Mg oxide 400 mg twice a day Potassium chloride 20 mEq 1000-2000 mg Ca per day (small dose at bedtime) – 5 daily doses! Vitamin D3 1250 IU Calcitriol 0.25 mcg bid (extra before exercise) Hydrochlor
Slide 66: Her Monitoring
Serum calcium – acceptable (symptoms usually controlled except in her hands) Serum magnesium – often low, due to diuretics Serum phosphate – high normal, watch phosp in diet Elevated urinary calcium – up to 500 mg/24 hours eGFR ranges from 50-60 ml/min (normal >90) Renal ultrasound: small non-obstru
Slide 67: Complications – Chronic Therapy
Chart review of 120 pts with chronic hypopara of diverse etiologies – kidney, brain 31% of patients had kidney calcifications 52% of patients with brain imaging had brain calcifications (basal ganglia – movement disorders can result Mitchell DM et al. JCEM 2012;97:4507 Complications – Chronic Therap
Slide 68: Kidney Complications
120 patients 38% of patients had at least one urine calcium determination over 300 mg/24 hours Thiazide diuretics - ~50% of the time did not control urine calcium 0 100 200 300 400 500 600 24-hr urine Ca (mg) Mitchell DM et al. JCEM 2012;97:4507 On thiazide Kidney Complications
Slide 69: Kidney Function
2/120 patients required renal transplantation Rates of CKD stage 3* or higher are 2-17 fold higher than age-appropriate norms (*eGFR 30-59) – regardless of age Mitchell DM et al. JCEM 2012;97:450 normal hypopara Kidney Function Stage 3 Chronic Kidney Disease or Worse
Slide 70: How Well Does Current Therapy Maintain Calcium Homeostasis?
Mitchell et al, JCEM, 2012 Assessed control of serum Ca (7 years) by plotting % of time each patient was in target range (Ca 7.5-9.5 mg/dl) – GREEN (yellow – low Ca, orange – high Ca) Erratic control – not uncommon à depended on etiology of HP: postsurg (84%), autoimmune (65%), constitutive Casr mut
Slide 71: 688 Danish Patients vs. Controls
HR 1 2 3 4 5 3.67 (CI: 2.41-5.59) 4.82 (CI: 2-11.6) 4.95 (CI: 2.88-8.5) 3.82 (CI: 2.15-6.79) No increased risk for arrhythmia, CVD, death Unterbjerg et al, JBMR, 2013 Renal complications Renal stones Renal insufficiency Hospitalization - seizures 688 Danish Patients (vs. Controls)
Slide 72: Other Complications – Danish Cohort
Fractures, spinal stenosisNO increase CancerNO increase Neuropsychiatric disease – bipolar affective disorder, depression2.0 fold (CI1.14-3.46) Infections1.4 fold (CI:1.2-1.67) Unterbjerg et al, JBMR, 2014 * Other Complications – Danish Cohort
Slide 73: Current Standard of Care Therapies
Fall short of achieving adequate day to day control of serum calcium Fail to control the hypercalciuria and resulting renal complications of the disease and/or may contribute to them Impose an unwelcome “pill burden” Current “Standard of Care” Therapies
Slide 74: Human Parathyroid Hormone – Approved 1/2015
His Glu Ser Gly 1 10 20 30 Ser Val Ile Gln Leu Met Asn Leu Lys His Leu Asn Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe - COOH H2N Gly Teriparatide (the active portion of the 84 a.a. molecule Intact PTH (1-84) Human Parathyroid Hormone – Approved 1/2015
Slide 75: Biochemical Outcomes
Placebo injections – A PTH(1-84) injections – B Open symbols - serum Closed symbols - urine Shaded: optimal ranges Biochemical Outcomes Patients treated with rhPTH(1-84) had stable serum Ca, but urinary Ca excretion was not improved
Slide 76: Conclusions
Hypoparathyroidism – substantial impact on quality of life, huge toll on patient and family to manage the disease End-organ complications Cataracts, kidney stones, renal and brain calcifications, chronic kidney disease (can progress to dialysis) Behavioral and psychiatric Conventional therapy – regi
Slide 77: TransCon PTH: Once-daily for Hypoparathyroidism
TransCon PTH: Once-daily for Hypoparathyroidism David B. Karpf, M.D. VP, Clinical Development
Slide 78: Hypoparathyroidism – Not Only About Serum Calcium
Hypoparathyroidism – Not Only About Serum Calcium Hypoparathyroidism affects 77,000 patients in the U.S.1 Patients suffer numerous comorbidities: Hypocalcemia and hypercalcemia Hypercalciuria (stones, nephrocalcinosis) Psychiatric disorders, depression Reduced QOL Until recently, hypoparathyroidism
Slide 79: Physiology of PTH
Physiology of PTH Adapted from Shoback NEJM 2008, 359: 391-403 PTH text box for doses copy goes here Decreased calcium reabsorpion increased PO43- reabsorption No increased calcium reabsorption, Mildly decreased PO43- reabsorption
Slide 80: Natpara Does Not Control Urinary Calcium
ULN for U. Ca Natpara Does Not Control Urinary Calcium1 1 FDA presentation Natpara Advisory Committee September 12, 2014
Slide 81: Sustained Release of PTH is More Physiological
Sustained Release of PTH is More Physiological1 1 FDA presentation Natpara Advisory Committee September 12, 2014
Slide 82: Intermittent PTH Caused Decrease in Cortical BMD
Intermittent PTH Caused Decrease in Cortical BMD Six years of therapy with Natpara was associated with a progressive decrease in cortical BMD1 Continuous exposure to PTH(1-34) restores bone turnover to normal levels while avoiding the overstimulation of daily or twice daily injections2 TransCon PTH
Slide 83: Designed Specifically for Hypoparathyroidism
Designed Specifically for Hypoparathyroidism Predictable release of parent drug in the body PTH(1-34) PTH(1-34) TransCon carrier TransCon linker Inactive Prodrug Designed TransCon PTH as a sustained-release prodrug, providing free PTH in the physiological range over 24 hours Achieves once-daily dosi
Slide 84: TransCon PTH Designed to Mimic PTH Infusion
TransCon PTH Designed to Mimic PTH Infusion Physiological Effect in Hypoparathyroidism Oral Calcium and Vitamin D Natpara Once Daily1, 2 PTH Infusion Increase serum calcium Reduce pill burden N/A Normalize urinary calcium excretion X X Reduce clinical hypercalcemia X X Reduce clinical hypocalcemia X
Slide 85: Infusion-like Profile Confirmed in Primates
Total PTH [ng/mL] Continuous PTH exposure to the renal tubule ensures the renal calcium-conserving and phosphaturic effects PK profile of TransCon PTH in 3 Cynomolgus monkeys (5 µg/kg) supports infusion-like profile following daily administration Hours 0 4 8 12 16 20 24 28 32 36 40 44 48 0 10 20 30
Slide 86: Designed to Provide Physiological PTH
TransCon PTH is designed to maintain serum PTH levels in the physiological range, mimicking physiological exposure 1 Simulation based on 100 µg QD Natpara and 70 µg QD TransCon PTH; Simulation of 3 repeat doses of Natpara and TransCon PTH at steady state Physiological Range 10-65 pg PTH(1-84)/mL Nat
Slide 87: Dose-dependent Increase of Serum Calcium
TransCon PTH in 6 healthy Cynomolgus primates leads to sustained elevation of serum calcium lasting more than 24 hours with low individual variability Dose-dependent Increase of Serum Calcium Ca2+ [mmol/L] TransCon PTH designed to simultaneously provide tight calcemic and phosphatemic control withou
Slide 88: Normalizes Calcium in Hypoparathyroidism Model
TransCon PTH (5µg/kg) compared to PTH(1-84) (70µg/kg) following SC injections in a hypoparathyroidism model (TPTx rats, n=9/group) TransCon PTH normalizes serum calcium in a relevant disease model of hypoparathyroidism Sham surgery TPTx + TransCon PTH 5µg/kg TPTx + Vehicle TPTx + PTH(1-84) 70µg/kg v
Slide 89: TransCon PTH: Highlights
TransCon PTH: Highlights Preclinical data demonstrated daily injections of TransCon PTH provides desired target profile of physiological PTH replacement Development risk lowered as TransCon PTH based on parent drug (teriparatide) with clinical proof of principle and proven TransCon technology Planni
Slide 90: Achondroplasia
Achondroplasia Cathleen L. Raggio MD Orthopedic Director K.O. and A.C. Greenberg Center for Skeletal Dysplasias -Hospital for Special Surgery
Slide 91: Achondroplasia
Achondroplasia What is it? What causes people to become patients?
Slide 92: Achondroplasia
Achondroplasia Most common form of non-lethal skeletal dysplasia 1 case per 25,000 births Autosomal dominant inheritance pattern Single gene, AD trait (4p16.3) (gene coding for fibroblast growth factor receptor 3) Advanced paternal age Intelligence is normal Abnormal endochondral bone formation is p
Slide 93: Slide 93
Slide 94: Molecular Pathogenetic Breakdown
Molecular Pathogenetic Breakdown FGFR3 chromosomal locus 4p16.3 Autosomal Dominant Over 80% of affected individuals are born to average stature parents-random new mutation >99 % of individuals with Achondroplasia have one of two mutations in FGFR3 resulting in Gly380Arg: 98% G>A point mutation at nu
Slide 95: Endochondral Ossification
Endochondral Ossification classes.aces.uiuc.edu/AnSci312/ Bone/Bonelect.htm www.
Slide 96: Clinical Features
Clinical Features Short stature Rhizomelic shortening of the arms and folds on limbs Limitation of elbow extension Trident configuration of the hand Genu Varum Exaggerated lumbar lordosis Spinal stenosis ***FORAMEN MAGNUM*** Large head with frontal bossing Most have hydrocephalus-usually communicati
Slide 97: Radiographic findings
Radiographic findings Metaphyseal dysplasia Narrowing of the interpediculate distance of the spine Notch-like sacroiliac groove Genu varum and ankle varum with relative overgrowth of fibula
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Slide 99: Achondroplasia - The person becomes a patient
Achondroplasia - The person becomes a patient Age birth-2 : Foramen Magnum Stenosis; Thoracolumbar Kyphosis; Hypotonia Age 2-4: ENT-tonsils/adenoids; OM Age 4-8: Social skills/Schooling – adjusting to “average” Age 8: Bowing /Instability of Knees; Limb Lengthening Teens and beyond: Spinal Stenosis
Slide 100: Achondroplasia Orthopedic Concerns
Spinal stenosis Foramen Magnum Cervical Lumbar Thoracolumbar kyphosis Varus deformities of the knees Achondroplasia Orthopedic Concerns
Slide 101: Achondroplasia
Achondroplasia Diminished size of the foramen magnum May result in a variety of neurologic problems (i.e., cervicomedullary compression, apnea, death) Delayed milestones; handedness; snoring; too floppy
Slide 102: Slide 102
Slide 103: The Foramen Magnum Stenosis
The Foramen Magnum Stenosis Work-up: MRI; Cervical spine X-rays – flexion/ extension Sleep Studies Surgical Decompressions-50%
Slide 104: Achondroplasia - Kyphosis
Achondroplasia - Kyphosis Thoraco-Lumbar Kyphosis is present before walking age but generally improves with ambulation
Slide 105: Achondroplasia - Kyphosis
Achondroplasia - Kyphosis Resolves in 90% of cases: observe prior to ambulation If no resolution after ambulation Brace Candidates for surgery persistent apical wedging kyphosis > 40 degrees after age 5
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Slide 107: Achondroplasia – Kyphosis - Adult
Achondroplasia – Kyphosis -Adult Thoracolumbar Kyphosis up to 35% incidence Kyphosis may be associated with apical wedging at T12 or L1
Slide 108: Kyphosis - Adults
Kyphosis - Adults What happens? Loss of bladder/ bowel control Spasticity Loss of walking ability Pain
Slide 109: Achondroplasia - Stenosis
Achondroplasia - Stenosis Lumbar Stenosis usually occur in late adolescence through early adult-hood posterior decompression without fusion Cervical Stenosis usually occur in early to middle adult years Decompression 80-90% of our patients require one or both
Slide 110: Achondroplasia - Spine
Achondroplasia - Spine Spinal stenosis >50% Thickened laminae Thickened facets Short, thickened pedicles Interpedicular narrowing
Slide 111: Achondroplasia - Stenosis
Achondroplasia - Stenosis Short, thickened pedicles Interpedicular narrowing
Slide 112: Cervical Stenosis
Cervical Stenosis What happens? Loss of hand use Spasticity Difficulty walking Bowel/bladder changes Paralysis
Slide 113: SAG T2 FS
SAG T2 FS Fo: 220 mm Slice: 3m BY: 122. 07031 25 Series: 4 Image no: 9 Image 9 of 18
Slide 114: Lumbar Stenosis
Lumbar Stenosis What happens? Decreased ability to walk Pain Numbness
Slide 115: hs GD
C: 1297.0, W: 2594.0 hs GD Series: 3 Image no: 8 Image 8 of 16
Slide 116: Achondroplasia - Genu Varum
Achondroplasia - Genu Varum Genu Varum (second major concern) affects at least 50% Etiology more rapid growth of fibula postulated intramembranous growth Osteoarthritis is rare
Slide 117: Achondroplasia - Genu Varum
Achondroplasia - Genu Varum Two treatments proximal Tib-Fib osteotomy proximal or distal fibular epiphysiodesis Bracing is NOT effective INDICATION for SURGERY- PAIN and THRUST /Instability
Slide 118: Achondroplasia - Limb Lengthening
Achondroplasia - Limb Lengthening Controversial within the LP community Generally begun around age 7 Requires committed patient and family Lower limbs bilateral at same time Upper limb required Surgeries occur over a period of years External fixation or IM magnetic rods
Slide 119: Limb Lengthening
119 Limb Lengthening
Slide 120: Management
Management Narrowing of the foramen magnum. X-rays: C-spine with flexion/extension views MRI Surgical decompression Thoracolumbar kyphosis Supportive strollers, carrying devices, etc. Bracing if necessary, some patients come to surgery Genu varum (bowed knees)/instability-surgery Lumbar lordosis Spi
Slide 121: Treatments
Treatments The goal would be to keep the person from becoming a patient – eliminate the surgeries The goal would be to allow the person freedom and ease in their activities of daily living – hygiene , elevators , stores .
Slide 122: Thank You
THANK YOU
Slide 123: TransCon CNP: Once-Weekly CNP for Achondroplasia
TransCon CNP: Once-Weekly CNP for Achondroplasia Jonathan Leff, M.D. Chief Medical Officer
Slide 124: 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 125: Achondroplasia Signaling Defect is Well Understood and CNP Corrects It
1Adapted from Current Opin Pediatrics 2010; 22:516-523 D1 D2 D3 Heparin-binding Ligand-binding Extracellular Intracellular JM Kinase FRS2 Tyr GRB RAS RAF MEK ERK p38 PKG Plasma Membrane TM FGFR3 NPR-B cGMP GTP CNP FGF STAT FGFR3 Signaling Pathway1 FGFR3 normally negatively regulates chondrocyte grow
Slide 126: Achondroplasia Signaling Defect is Well Understood and CNP Corrects It
MEK ERK p38 Achondroplasia Signaling Defect is Well Understood and CNP Corrects It FGFR3 normally negatively regulates chondrocyte growth, and hence bone growth Achondroplasia results from a mutation which constitutively activates the FGFR3 receptor CNP inhibits FGFR3 pathway promoting proliferation
Slide 127: CNP Reverses Achondroplasia Phenotype in Animal Models
CNP Reverses Achondroplasia Phenotype in Animal Models Current Opin Pediatrics 2010; 22:516-523
Slide 128: FGFR3 Activity and CNP Levels Balance Growth Regulation
FGFR3 Activity and CNP Levels Balance Growth Regulation Normal bone growth depends on balanced pathways FGFR3 Activity CNP Levels FGFR3 Activity CNP Levels FGFR3 Activity CNP Levels Tall Stature Short Stature
Slide 129: No FDA-Approved Drug Therapy
No FDA-Approved Drug Therapy 1 Biomarin R&D Day, April 2016 Therapeutic Goal: Optimize CNP efficacy with a well tolerated and convenient dosage form Growth hormone therapy minimally effective and does not correct underlying pathology Vosoritide in clinic for achondroplasia; reported promising height
Slide 130: TransCon Technology Offers Potential Solution
TransCon Technology Offers Potential Solution Predictable release of parent drug in the body CNP TransCon carrier TransCon linker Inactive Prodrug Creation of TransCon Prodrug CNP Longer CNP half-life Maintain small enough size to allow penetration into growth plates Effective shielding of CNP from
Slide 131: TransCon CNP Weekly Profile Confirmed in Primates
TransCon CNP Weekly Profile Confirmed in Primates PK of TransCon CNP in Cynomolgus monkeys (n=3) Data from ongoing and completed preclinical studies supports weekly dosing in patients with achondroplasia
Slide 132: TransCon CNP Provides Prolonged Half-life
TransCon CNP is designed to provide exposure for a full week with a low Cmax TransCon CNP Provides Prolonged Half-life Vosoritide TransCon Released CNP ng/ml Modeling of CNP released1 from a single dose of TransCon CNP (red) and 7 daily injections of vosoritide (blue)2 1 Ascendis Pharma; data on fil
Slide 133: No CV Safety Signals Observed for TransCon CNP
No hypotension or increased heart rate observed in telemetrized cynomolgus monkeys (n=4/group) receiving TransCon CNP BP changes in this study comparable to previous vosoritide study2 No CV Safety Signals Observed for TransCon CNP1 1 “Vosoritide” refers to a synthesized molecule with the same amino
Slide 134: Continuous Infusion More Effective Than Daily
Right Tibia Length (mm, ±SEM) Mouse Growth Study Right Tibia Length 50 nmol/kg/day (n=9/group) Same amount of CNP given as continuous infusion in mice is more efficacious than daily SC injection over 35 days Same effect demonstrated for Ascendis‘ CNP peptide Vosoritide Infusion Vehicle Vosoritide SC
Slide 135: Juvenile Cynomolgus Growth Study Ongoing
Comparing weekly TransCon CNP to a higher cumulative daily dose of vosoritide 6-month data expected in 1Q 2017 Juvenile Cynomolgus Monkeys Bone length assessed over 6 months Other endpoints/ markers of CNP bioactivity: bone turnover markers, urinary cGMP TransCon CNP Weekly Dosing Vehicle Vosoritide
Slide 136: Juvenile Cynomolgus Growth Study – Interim Data
Change From Baseline (mm+SEM) Control TransCon CNP 40µg/kg Weekly Vosoritide 20µg/kg Daily Control TransCon CNP 40µg/kg Weekly Vosoritide 20µg/kg Daily TransCon CNP dose ~one third of vosoritide on a weekly basis Both TransCon CNP and vosoritide demonstrated a trend of bone growth over control-treat
Slide 137: TransCon CNP: Highlights
TransCon CNP: Highlights TransCon CNP leverages Ascendis’ technology platform to develop a potential best in class product Once-weekly administration with continuous exposure to CNP Improved tolerability expected due to low Cmax Prolonged half-life extension and efficacy trend observed in Cynomolgus
Slide 138: ascendis LA
ascendis LA pharma
Slide 139: Building a Leading Rare Disease Company
Building a Leading Rare Disease Company Leverage the validated TransCon technology to create best-in-class products Advance the company’s pipeline of three rare disease endocrinology product candidates: Phase 3 ongoing for TransCon Growth Hormone File INDs for TransCon PTH and TransCon CNP in 2017 O
Slide 140: ascendis LA
ascendis LA
Slide 141: Speaker Biographies
Speaker Biographies Ascendis Pharma R&D Update
Slide 142: Barbara Lippe, M.D.
Ascendis Pharma R&D Update Barbara Lippe, M.D. is a retired Professor of Pediatrics and Interim Executive Chair of the Department of Pediatrics at the UCLA School of Medicine, Division of Endocrinology. Dr. Lippe trained at the UCSF School of Medicine, completed her pediatric internship and residenc
Slide 143: Cathleen L. Raggio, M.D.
Ascendis Pharma R&D Update Cathleen L. Raggio, M.D. specializes in general pediatric orthopedics, scoliosis and in the treatment of osteogenesis imperfecta and skeletal dysplasia and is the Co-Director of the Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias at Hospital for Special Sur
Slide 144: Dolores Shoback, M.D.
Ascendis Pharma R&D Update Dolores Shoback, M.D. is Professor of Medicine at UCSF and Staff Endocrinologist at the Veterans Affairs Medical Center. She has been an active clinician, researcher and teacher at UCSF since she joined the faculty in 1985. Dr. Shoback is a graduate of the University of Pe