Investor and Analyst Day April 5, 2018 Welcome and Overview Matthew Pauls President & Chief Executive Officer
2 Forward-Looking Statements
This document contains forward‐looking statements relating to the Company’s strategy, objectives, business development plans and financial position. All statements other than statements of historical facts included in this document, including, without limitation, statements regarding the Company’s future financial position, strategy, anticipated investments, costs and results, status and results of clinical trials, size of patient population, plans, outcomes of product development efforts, and objectives of management for future operations, may be deemed to be forward‐looking statements. You can identify forward-looking statements by words such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” or the negative of those terms, and similar expressions that convey uncertainty or future events or outcomes. These forward‐looking statements involve known and unknown risks, uncertainties, and other factors that may cause the Company’s actual results, performance, or achievements or industry results to be materially different from those contemplated, projected, forecasted, estimated or budgeted, whether expressed or implied, by these forward‐looking statements. Given these risks and uncertainties, investors should not place undue reliance on forward‐looking statements as a prediction of actual results. A discussion of certain of these risks may be found in the filings the Company makes with the U.S. Securities and Exchange Commission. None of these forward‐looking statements constitutes a guarantee of the future occurrence of such events or of actual results. These statements are based on data, assumptions, and estimates that the Company believes are reasonable. The forward‐looking statements contained in this document are made only as of the date hereof. Except as otherwise required by law, the Company expressly disclaims any obligation or undertaking to release publicly any updates of any forward-looking statements contained in this document to reflect any change in its actual results, assumptions, expectations or any change in events, factors, conditions, or circumstances on which any forward‐looking statement contained in this document is based.
3 Agenda
• Welcome & Overview » Matthew Pauls, President & Chief Executive Officer
• KEVEYIS » Stephen J. Moloney, MD, Vice President, Global Medical Affairs » Amit Sachdev, MD, Assistant Professor and Director at the Division of Neuromuscular Medicine, Michigan State University » Dave Bonnell, Senior Vice President, Sales and Marketing
• KEVEYIS Q&A • Macrilen » Matthew Pauls » Beverly M. K. Biller, MD, Faculty Member at Massachusetts General Hospital Neuroendocrine Unit, Professor of Medicine at Harvard Medical School » Scott Wilhoit, Senior Vice President, Global Market Access and Patient Services
• Macrilen Q&A • RECORLEV » Fred Cohen, MD, Chief Medical Officer » Richard Auchus, MD, PhD, Professor of Internal Medicine, Division of Metabolism, Endocrinology & Diabetes, University of Michigan » Matthew Pauls
• RECORLEV Q&A • Closing Remarks » Matthew Pauls
4 5 Building Therapeutically Aligned Rare Disease Franchises
Rare Rare Rare Disease Neuromuscular Endocrine Franchise #3
Adult Growth Hormone Deficiency Primary Periodic Paralysis RECORLEVTM Business (levoketoconazole) development Cushing’s Syndrome opportunities
Veldoreotide Acromegaly
5 Rare Disease Commercial and Late-Stage Portfolio
RECORLEV™ Veldoreotide (levoketoconazole) modified-release
FDA-APPROVED FDA-APPROVED PHASE 3 PRECLINICAL
The 1st and only The 1st and only An investigational Potential FDA-approved drug FDA-approved next-generation next-generation for ultra-rare oral drug for cortisol inhibitor somatostatin Primary Periodic assessing for Cushing’s analog for Paralysis* Adult Growth Syndrome Acromegaly (PPP) Hormone Deficiency (AGHD)
ACQUIRED JANUARY 2018
ORPHAN ORPHAN ORPHAN ORPHAN
*FDA-approved treatment for hyperkalemic, hypokalemic, and related variants of primary periodic paralysis
6 Medical Affairs Stephen J. Moloney, MD
7 Strongbridge Speakers & Scientific Advisors in PPP
Oregon Health and Science University University of SUNY Rochester Buffalo Michigan State University of California University of Utah University San Francisco Brigham and The Ohio Women’s Hospital University of Kansas State University Medical Center University of California Loma Linda University of Cincinnati Los Angeles University Gardener Neuroscience Institute University of Southern California UT Southwestern Medical Center
UT Health University of Miami San Antonio
8 Uncovering Periodic Paralysis: No-Cost Genetic Testing
• No-cost gene panel sequencing* for hypokalemic and hyperkalemic periodic paralysis • Panel includes comprehensive analysis of the following three most commonly associated genes: SCN4A, CACNA1S, and KCNJ2
• If medically appropriate, re-requisition to a more expansive neuromuscular panel within 90 days of original test report • Family variant testing is available to any first-degree relative of a patient newly diagnosed through the program
*Eligibility: Physician-ordered for patients 18+ years of age with episodic muscle weakness/paralysis attacks provoked by at least one of the common triggers for hyperkalemic or hypokalemic Primary Periodic Paralysis 9 The First US Patient Registry Focused on PPP
• Collaborative efforts are ongoing with physician experts and advocacy groups to create a patient-focused registry • Areas of focus: » Disease burden » Long-term outcomes of PPP » Impact of treatment interventions • Guide education and research focus in PPP
Registries that track patients over time lead to better understanding of the disease, its subtypes, and the impact of interventions.
10 Key Publication Activities
• Current activities: » AAN posters » PK study publication » Review article – Diagnosis and Treatment of PPP (Statland et al.) • Ongoing activities: » Analysis of clinical data – Long-term efficacy, characterization and management of adverse events, quality of life exploration » Diagnosis and genetic testing review article
11 Amit Sachdev, MD
Assistant Professor of Neurology and Director of the Division of Neuromuscular Medicine, Department of Neurology and Ophthalmology, Michigan State University • Board-certified in neurology, neuromuscular medicine, and electrodiagnostic medicine • Education » MD, Michigan State University » MS, Biomedical Engineering, Wayne State University » BS, Biomedical Engineering, University of Michigan • Postdoctoral Training » Neurology training (Thomas Jefferson University) » Fellowship in neuromuscular medicine (University of Michigan) • Expertise and research interests are focused on neuromuscular medicine
The following slide presentation does not reflect the opinions of Michigan State University.
12 Clinical Experience Amit Sachdev, MD
The following slide presentation does not reflect the opinions of Michigan State University. 13 Primary Periodic Paralysis (PPP): A Rare, Complex, and Physically Disabling Condition
• A spectrum of rare and chronic neuromuscular disorders with autosomal dominant inheritance1 • Recurrent, progressive, and debilitating episodes of muscle weakness and temporary paralysis2-5 ~4K-5K • Paralytic attacks are acute episodes that can Diagnosed individuals 6 be incapacitating in the U.S.7 • Attacks may last from one hour to several days depending on the type of muscle channel involved2 • As they age, patients may experience permanent muscle weakness, further impacting their quality of life over time4
1. Greig SL. Drugs. 2016;76:501-507. 2. Charles G. J Neurol. 2013;260:2606-2613. 3. Cannon SC. Compr Physiol. 2015;5:761-790. 4. Cavel-Greant D, et al. Acta Myol. 2012;31:126-133. 5. Arya SN. Journal, Indian Academy of Clinical Medicine. 2002;3:374-382. 6. Sansone V, et al. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005045. 7. Data on file. Available from Strongbridge Biopharma plc. 14 Neuromuscular Disorders That Present With Transient Episodes: The Most Challenging to Diagnose
Epilepsy Neurologists commonly consider a range of brain- Migraine centered diagnoses when patients present with an acute Stroke attack of weakness or paralysis:
Conversion Disorder
15 Neuromuscular Disorders That Present With Transient Episodes: The Most Challenging to Diagnose
Epilepsy ALS Neuromuscular medicine encompasses the Migraine Limb Girdle neurologic system from the neck down: Stroke Myasthenia Gravis
PPP NeuromuscularConversion Disorder medicine officially became a board- certified subspecialty in 2012. Conversion Disorder
16 KEVEYIS Clinical Experience—Actual Patient Journey
Susan L (41-year-old female)—A Patient with HyperPPP
Medical History » Episodes of fluctuating weakness Family History Triggers dating back to her teens » One brother who has » Inactivity and » Predominantly shoulder and hip girdle unexplained episodes cold exposure weakness and overwhelming sense of of stiffness dating back predominantly Presenting Sign fatigue to childhood » Presents to » Attacks occurred for hours and were » Brother does not have ER unable to worse in the morning, worsened a formal diagnosis lift arms above throughout adulthood head
x 1 2 3 4
17 KEVEYIS Clinical Experience—Actual Patient Journey (cont.)
Susan L – HyperPPP Diagnosis
Differential Diagnosis Uncovering Initial Treatment » Outpatient sleep study Periodic Paralysis » Susan became disabled and had to leave ordered to rule out » No-cost gene panel test her job due to attacks, complicated by narcolepsy offered by Strongbridge anxiety/depression » Results show normal EKG Biopharma utilized » Acetazolamide and topiramate were » Susan did not test positive prescribed first, as these medications did for the 3 most common not require prior authorization genes associated with » Response inadequate after 1 month HypoPPP/HyperPPP » Made decision to switch meds
5 6 7
18 KEVEYIS Clinical Experience—Actual Patient Journey (cont.)
Susan L – Continuing Treatment
KEVEYIS Continued Care Susan » KEVEYIS was delivered through » Susan has been on KEVEYIS since » bridge program while Panther 2017 Part of Susan’s identity is her work assisted prior authorization » Shows continued improvement at » She is well enough to consider » Susan experienced improvement current dose returning to work after taking KEVEYIS beyond prior meds quickly » Team considering increasing dose as » » Side effects were manageable attacks have not been completely Anxiety/depression symptoms eliminated have improved due to ability to work
8 9 10
19 Commercialization Dave Bonnell
20 KEVEYIS 2017 Performance Highlights & 2018 Revenue Guidance
Full-year 2018 Revenue Guidance
Full-year 2017 $16M Revenue to 2017 Q4 $19M Revenue $7M $3M
21 KEVEYIS Market Access & Reimbursement Snapshot
Payer Prior Authorization Payer Mix Broad Payer Coverage Requirements Uninsured Plans with No Approval 11% 4%
11.0% Not Required Public25.0% 33% 24% 64.0% Commercial Plans Required 65% with Approval 67% 96%
• Modest shift in mix from • Coverage includes PBMs, national • Prior authorization (PA) rates lower commercial to public and regional insurers, as well as than industry average for • Average patient age 42 years major Medicare Part D plans orphan products* • $70 monthly median out-of-pocket • PA criteria consistent with other cost since launch orphan disease categories
Source: PANTHERx *Pharmacy Benefit Management Institute 2018 Report 22 KEVEYIS Strong Demand Uptake Has Led to Increased Investments
Patient Services Advanced Sales Force & Advocacy HCP Education Analytics
• Expanded from 12- • Expanded team: • Conference • Multiple data to 24-person team: + Patient Access presence sources Managers o 21 sales • Speaker bureau • Predictive representatives + Program Operations modelling Lead • Case studies o 3 regional + Case Managers • Disease o Identify managers diagnosed • Significant • Increased focus on: awareness and Adherence/ Identify experience across education tools o Compliance Support undiagnosed multiple orphan drug launches • Genetic Testing Program
23 Q&A
24 Introduction Matthew Pauls
25 Beverly MK Biller, MD
• Professor of Medicine at Harvard Medical School (HMS) • Faculty member in the Neuroendocrine Unit at Massachusetts General Hospital (MGH) • Program Director of the Clinical Fellowship in Adult Endocrinology and Metabolism at MGH • Serves on the Council of the Endocrine Society • Membership Chair of the Growth Hormone Research Society • Publishes original research in many peer-reviewed journals • Co-authored clinical guidelines on adult GHD for the American Association of Clinical Endocrinologists
26 Adult Growth Hormone Replacement and the Need for Macrilen™ (macimorelin)
Beverly M. K. Biller, MD
Professor of Medicine Harvard Medical School Neuroendocrine Clinical Center Massachusetts General Hospital Boston, MA
27 Location of the pituitary gland where GH is made
From Harris 28 Pituitary hormones and their target glands
From Harris 29 Somatotroph (GH) axis
Brain Hypothalamus
GHRH + - SMS Anterior pituitary
bone Liver GH fat
IGF-I muscle 30 Patient case
• 43-year-old man who had surgery and radiation for a large, nonfunctioning pituitary tumor • Panhypopituitary on triple hormone replacement (thyroid, cortisol, testosterone); otherwise healthy (history of childhood seizures) • Read about GHD in a well-known publication: “Sounds just like me, especially the extra abdominal fat.” • Asked endocrinologist for testing and treatment with GH, was told: » Gold standard test (insulin tolerance test [ITT]) was too dangerous » Alternative test (growth hormone releasing hormone [GHRH]), no longer available » Another test (glucagon) “makes people sick” and lasts many hours
Therefore, no evaluation or treatment offered to this patient What journal had he read? 31 Information that patients read about GH is not always about adult pituitary GH deficiency!
USA TODAY Illicit use by athletes:
• Bodybuilding • Baseball • Olympics
32 Causes of adult GHD (FDA-approved use)
• Tumors • Infiltrative/infectious/inflammatory » Pituitary tumors » Hypophysitis » Craniopharyngioma » Sarcoidosis » Meningioma » Histiocytosis X » Rathke’s cleft cyst » TB and fungal diseases » Germinoma » Others » Others • Trauma/vascular injury • Surgery » Head trauma » Transsphenoidal » Subarachnoid hemorrhage » Craniotomy » Apoplexy • Cranial radiation (RT) » Sheehan syndrome » Brain, head/neck tumors • Childhood onset » Pituitary or whole-brain RT » Idiopathic » Organic Adapted from Cook DM Growth Horm IGF Res 1999 33 Head MRI scans – coronal slice, subjects facing viewer
Normal Pituitary Gland Large Pituitary Tumor 34 Hypopituitarism in patients with neurologic events Traumatic brain injury (TBI) & subarachnoid hemorrhage (SAH)
30%
Deficiency Secondary of specific 20% hypoadrenalism hormones Secondary hypothyroidism
10% Secondary hypogonadism Severe GHD
0% TBI SAH
Chronic trauma is a risk as well For example, retired boxers and possibly football players Aimaretti Clin Endo. 2004 61: 320 35 What happens to adults with GHD?
• Body composition altered » Fat mass increased » Lean body mass decreased » Skeletal muscle strength decreased • Cardiovascular (CV) issues » Increased risk of CV death » Lipids and other CV risk markers abnormal • Bone mineral density decreased » Increased fracture rate • Quality of life diminished
But improvement occurs with GH replacement 36 BeforeBefore GHGH Body Composition subcutaneous fat by CT
visceral fat
6 months on GH 6 months on GH creasedDecreased fat: fat: - subcutaneous - visceral
Bengtson JCEM 37 Fewer sick leave days with GH replacement
20 Mean ± SEM *P<0.05 vs baseline 15 **P<0.01 ***P<0.001 ** 10 Before GH * 5 ***
Sick leave, days days 6 / months Sick leave, ** 0 0 6 12 18 24 Time, months
Verhelst Clin Endocrinol 38 Adult GH replacement – overall summary
• Replacement improves: » body composition » muscle strength, endurance » bone mineral density » cardiovascular markers » quality of life • Well tolerated if dose titrated gradually
Yet, many patients, such as in our patient case, are not treated – why?
39 GH replacement therapy in adults Barriers to Treatment
Lack of awareness about efficacy Concern about Daily injections neoplasia Diagnosis perceived as difficult to make Insurance Dosing and issues/cost monitoring not Unusual standardized prescribing system Why not just measure GH? 40 Pulsatile patterns of GH secretion in a normal adult and a patient with GHD
25 Sleep
20
15 GH (µg/L)
10
5
0 0900 2100 0900 Clocktime Random GH levels overlap with normals: not useful in diagnosis
From Harris, courtesy of Ho 41 GH stimulation tests
Pharmacologic agents which provoke release of GH into the blood. Samples of GH measured several times over 2-4 hours after agent given
Insulin-Tolerance Test L-dopa Arginine Clonidine Pyridostigmine GHRH
GHRH + - SMS
Pancreas
Glucagon GH Ghrelin/mimetics (macimorelin) 42 Diagnosis of GHD in adults
What tests were used after GH was approved in the US to make the diagnosis of GHD?
50 11 different stimulation 40 tests were used! % 30 20
10
0 Arg Ldopa ITT Arg-LD ITT-GHRH Arg-GHRH Glucagon <1%
Hartman JCEM 2002 43 Diagnosis of adult GHD
• ITT is the gold standard, but not used often » Intentionally lower glucose with intravenous insulin (contraindications) » May cause palpitations, sweating, anxiety, poor mentation » Risks: seizures, unconscious/coma, death if not rescued » Requires frequent glucose checks, physician must be available » Resources (MD, code cart, IV glucose) required are rate-limiting • Arg-GHRH is a good alternative, but GHRH not available • Glucagon is preferred over ITT, but has major drawbacks: » Given as an intramuscular injection » May cause nausea, vomiting, headache » Takes 3-4 hours to perform Until now, no safe and easy test » Risk of low blood sugar later available to diagnose adult GHD 44 Oral macimorelin FDA-approved for adult GHD diagnosis December 2017
• Easier than other stimulation tests » Administered as a drink » Only 4 blood samples (vs 6-9) » Only 90 minutes long (vs 2-4 hours) » Well-tolerated; no tests stopped for side effects • Accurate for diagnosis of adult GHD • Highly reproducible
45 Macimorelin phase 3 study design
• Compared directly against ITT • Multicenter, international trial • 4 subject groups: high, medium, low risk of GHD, normals
Pivotal Phase 3 Study Extension Study – EU Only Open-label, randomized, 2-way crossover N = 34 subjects
157 ITT macimorelin macimorelin Patients macimorelin ITT macimorelin
46 Macimorelin phase 3 study aims
• Positive/Negative Agreement » Positive agreement: Proportion of ITTs positive for GHD (low GH response) also positive by macimorelin » Negative agreement: Proportion of ITTs negative for GHD (normal GH response) also negative by macimorelin • Proportion of tests evaluable on 1st try (vs needing retesting) • Reproducibility » Is the result the same on different days? » Subset of patients were tested twice with macimorelin
47 Macimorelin test accurately diagnoses AGHD vs ITT
Insulin Tolerance Insulin Tolerance Test (ITT) Test (ITT) Percent Agreement All Subjects (GH cutoff 5.1 Total Subject (GH cutoff 5.1 ng/mL) Total macimorelinPercent Agreement and ITT ng/mL) Tests Tests (allM acrilentests combined)and ITT* • Agreement between Positive Negative macimorelin and the ITT overall shown Positive Positive 55 4 59 Agreement* • Negative agreement (both macimorelin 74% (GH cutoff tests confirm normal growth 2.8 ng/mL) Negative hormone levels) 94% Negative 19 62 81 Agreement* 94% • Positive agreement (both tests confirm GHD) higher (89%) for Overall high-risk patients and lower Total Tests 74 66 140 Agreement 84% among lower-risk patients
• Negative Agreement: 93.94% (CI: 85.20%, 98.32%): Met predefined performancecriterion (ie, excluded negative agreement with ITT of less than 75% with 95% confidence) • Positive Agreement:74.32% (CI: 62.84%, 83.78%): Did not meet predefinedperformance criterion (ie, could not exclude positive agreement with ITT of less than 70% with 95% confidence) *Co-primary efficacy endpoints; a positive test is one that fails to reach the respective test’s GH cutoff
Data on File. Trevos, PA: Strongbridge Biopharma; 2018. 48 Compared to ITT, macimorelin is highly evaluable
ITT not evaluable at first test 17% Macimorelin not evaluable at first test 1%
Macrilen evaluable at ITT evaluable at Macimorelinfirst testevaluable 99% first test 83% at first test 99%
• Only one “non-evaluable” macimorelin 1st test vs 17% of ITTs
49 Macimorelin was highly reproducible
3%
97% of tests in agreement
• Subset of patients were tested twice with macimorelin • 97% of tests provided the same result on 1st and 2nd test • Highly reproducible vs ITT (reported at 58%-90%) 50 Patient case outcome
• 43-year-old man who asked for testing and treatment for GHD
• Undetectable GH levels on diagnostic tests (profoundly deficient)
• Started commercial daily GH Improvement in: body composition bone mineral density energy
51 Conclusions
Adult GHD is caused by pituitary and neurologic disorders
Diagnostic testing is the gateway to GH replacement
Access to a safe, simple, accurate test is needed
Macimorelin is an important advance in diagnosis
Should lead to more patients being offered treatment
52 Commercialization Scott Wilhoit
53 A Significant Market Opportunity for Macrilen™ (macimorelin) in the Immediate and Medium Term
TBI’s 40-60k 33% increase 2.5M per year*** Annual in AGHD (on-label: no Tests* testing** further clinical studies needed)
Immediate Term
• Annual assessments of adult patients Near Term with a pituitary tumor/pituitary Medium Term surgery, radiation, chemo, as well as • Expected increase in testing for patients transitioning into adulthood AGHD because of Macrilen • *Physicians indicated Macrilen would • All patients with moderate to severe TBI require • Increased testing expected due to be the majority of 1st-line AGHD evaluation of pituitary function. In addition, the profile of Macrilen assessments symptomatic patients with mild TBI and impaired quality of life are at risk for hypopituitarism**** • Does not include potential 40K pediatric *Oppenheimer 2011—manufacturer-sponsored research; Navigant, 2009—manufacturer-sponsored research; Symphony, 2017— manufacturer-sponsored research; TVG Research—manufacturer-sponsored research, 2017; Lumelian, 2017—manufacturer- population, which requires clinical studies sponsored research. **Results of quantitative (n=40 endocrinologists) and qualitative (n=5) market research conducted by a 3rd party sponsored by Strongbridge (2017). ***https://www.cdc.gov/traumaticbraininjury/severe.html. ****AACE/ACE Disease State Clinical Review: A Neuroendocrine Approach to Patients with Traumatic Brain Injury. 54 Both Physicians and Payers have a Positive Opinion of Macrilen
Summary Feedback - Prescribers Summary Feedback - Payers
Somewhat/extremely likely to use • Macrilen likely to be incorporated into medical policy 83% Macrilen (based on draft profile) to help protect payers from paying for costly HGH treatments Expected increase of testing for AGHD 33% • If Macrilen is supported by the Endocrinology/KOL because of Macrilen community it would help to support Macrilen inclusion in updated GH testing policies Physicians indicated Macrilen would be >50% the majority of 1st line AGHD assessments • Payers suggest that Macrilen may end up on the medical benefit and would be accessible to physicians through a buy and bill model or through >40% Macrilen share of AGHD assessments specialty pharmacy distribution “It would allow me to start testing in my “It is well differentiated and could change the office” - Endocrinologist practice for GH testing” – Commercial Payer
Results of quantitative (n=40 endocrinologists) and qualitative (n=5) market research conducted Results of qualitative (n=10 payers) market research by a third party sponsored by Strongbridge conducted by by Strongbridge
55 Macrilen Go-To-Market Strategy
TARGETING FIELD FORCE COVERAGE & ACCESS
• Educate commercial & • Neuroendocrine • Sales force of ~15 government payers pituitary center • Field reimbursement • Flexible & scalable endocrinologists personnel ~5 distribution model • High-volume • Cover >=80% of the • Provider & patient endocrinologist testers target audience reimbursement support
AWARENESS
• Conference presence • Patient advocacy • Peer-to-peer partnerships programming • TBI-Pituitary disease • Demonstration kits awareness campaign
56 Macrilen Launch Preparations Are Underway to Support a Strong Start
AACE 2018 Product Theater
P&R/Value Development
Design, Development & Implement Services & Distribution Model
KOL/Pituitary Center Outreach LAUNCH Q1 Q2
“Coming Soon” Campaign
Branded Campaign/Website
Field Force Recruiting/Hiring Training & Deployment
ENDO 2018 Product Stakeholder Theater & Advisory Board Advisory Boards
57 Q&A
58 Cushing’sCushing’s Syndrome Syndrome and and RECORLEV™RECORLEV (levoketoconazole) (levoketoconazole) FredFred Cohen, Cohen, MD MD Chief Medical Officer, Strongbridge Biopharma
59 Cushing’s Syndrome Is a Rare Disorder
Underlying cause is chronic exposure to excess serum cortisol due to any of several etiologies
Pituitary adenoma Exogenous Medications (eg, glucocorticoids) (Cushing’s disease) (75-80%) ( / : 4:1) Cushing’s syndrome ACTH-dependent Ectopic ACTH (80-85%) and CRH tumors (15-20%) ( / : 1:1) Endogenous Hyperplasia ACTH-independent (rare) (15-20%) Pituitary and adrenal carcinomas (~90%)
Abbreviation: ACTH, adrenocorticotropic hormone. Source: Sharma TS, et al. Clin Epidemiol. 2015;7:281–293. 60 Health and Economic Burden of Cushing’s Syndrome
Compared to those without Cushing’s Cushing’s Syndrome Impact to disease, young patients with Cushing’s Health System disease have:1* CD CD-free 95% 2-5x higher incidence rates of comorbidities (eg, cardiovascular, endocrine, musculoskeletal, and mental 61% 63% health conditions) 50% 7x higher medical costs 20% 4x higher pharmacy costs 11%
Inpatient ED visits Outpatient visits admissions
*According to a retrospective analysis of claims from a large US commercial health plan (885 selected Cushing’s disease cases and 2,655 matched controls without Cushing’s disease) from 2007 to 2011. 1. Burton T, et al. Pituitary. 2016;19:167–174.
61 RECORLEV™ (levoketoconazole) Clinical Development Phase 3 Studies in Cushing’s Syndrome Phase 3 Cushing’s Syndrome Clinical Program
DOSE TITRATION: MAINTENANCE: EXTENDED EVALUATION: 2 to 21 weeks 6 months 6 months
Titrate in 150 mg increments up Maintain UFC normalization Primary endpoint UFC to max 600 mg 2x daily until UFC with fixed therapeutic dose level measured normalization is achieved
Up to 19 weeks Open-label extension SONICS-completers enter at Randomized Withdrawal RANDOMIZED WITHDRAWAL: LEVOKETOCONAZOLE- (Active) NAÏVE-ONLY DOSE RESTORATION PHASE TITRATION: 14 to 19 weeks RANDOMIZED WITHDRAWAL: (Placebo)
OPTICS is not intended as pivotal. 63 Single Arm, Open-Label Phase 3
2 – 21 weeks 6 months 6 months
Extended Dosing Maintenance Evaluation
Increase dose in 150mg increments up to max of Maintain UFC normalization without Primary 600mg 2x daily endpoint until UFC normalization need for dose increase
Secondary 94 Patients Enrolled endpoints
Strongbridge Management Is Behind Data Firewall to All Efficacy & Disposition Information clinicaltrials.gov NCT01838551. 64 Primary and Secondary Objectives
• Primary objective: » Evaluate clinical responder rate, defined as proportion of subjects with normal UFC after 6 months of treatment in the Maintenance Phase without dose increase, and to evaluate the range of effective doses o Sensitivity analysis will include the UFC normalization rate regardless of dose increase
• Secondary objectives are to evaluate: » Proportion of subjects with clinical response after each month » Proportion of subjects with partial response (50% reduction of UFC) » Changes from baseline and shifts from normality in UFC » Changes from baseline in salivary and serum cortisol » Effects on Cushing’s-specific clinical signs and symptoms » Effects on quality of life and depression » Changes in biomarkers of CS comorbidities (diabetes, hypertension, hypercholesterolemia, and obesity) » Safety and tolerability
65 Sample Size & Power
• SONICS sample size of 90 subjects yields 90% power, based on excluding a 20% or lower UFC response with 95% confidence • We estimate that at least 25% of subjects achieving the primary endpoint would likely result in statistical significance at the 5% level • We believe ~25% UFC response would be important if other improvements in signs, symptoms, or comorbidities of Cushing’s syndrome are seen
66 Efficacy Endpoints at 6 Months
RECORLEV™ Korlym Signifor Measure (levoketoconazole) (mifepristone) (pasireotide) Schedule Efficacy Efficacy Late-Night Salivary and Monthly Increases during treatment LNSC: 7-12% decrease Serum Cortisol BMI / Abdominal Girth Monthly / baseline & Body weight loss 6.6% in DM cohort; BMI reduced at months 6 by 1.6 Months 1,4,6 BMI / girth NA kg/m2 / waist by 2.6 cm HbA1c and Fasting Glucose Monthly HbA1c –1.14% among DM patients Significant increases in both oGTT (“Prediabetics” only) Baseline, Months 4&6 Not assessed Worsens Appearance, Signs & Symptoms Monthly Not assessed Majority same or improved Blood Pressure Monthly No change in DBP or SBP SBP decrease 7-13 mmHg; DBP decrease 3-8 mmHg
Lipids (Cholesterol / Monthly Total and HDL-C decrease; <5% decrease in total and LDL-C; Triglycerides) no change in LDL-C or TGs <8% increase in triglycerides C-Reactive Protein Monthly Not assessed; no change in Not available E-selectin, adiponectin, TAT CushingQOL Baseline, Months 4 & 6 No change Improved by 9-10 points (41 @ BL) Depression (BDI-II) Baseline, Months 4 & 6 No change Improved by 5 points (18 @ BL)
Korlym and Signifor pivotal study data at 6 months time points.
67 Newly Published Data: LFT Abnormalities with Ketoconazole (KTZ)
Castinetti study (2018)1 Naïve to KTZ* KTZ Continuation† • Based on observational prospective French cohort study (compassionate use program) 32% 23% at least 1 ALT at least 1 ALT » 108 treated (47 KTZ-naïve and 61 KTZ elevation elevation continuation) » ~10% of screened population excluded due to liver disease and abnormal liver 19% 23% function tests <5X ULN <5X ULN • Not a clinical study: did not include protocol, site monitoring, CRFs, etc. 13% 0% ≥5x ULN ≥5x ULN
• Methodological limitations hamper accurate estimation of liver injury risk with KTZ • We believe that a properly designed and monitored clinical trial of KTZ would yield higher rates of LFT abnormalities than observed thus far
Abbreviations: ALT, alanine aminotransferase; CRF, case report forms; ULN, upper limits of normal. *No KTZ use in prior 4 weeks; ALT n=31. †Previously using KTZ>6 mos.; ALT n=35. Source: 1. Young et al. Eur J Endocrinol. 2018 Feb 22. pii: EJE-17-0886. doi: 10.1530/EJE-17-0886. [Epub ahead of print] 68 Second Phase 3 Trial and Open-Label Extension
Double-blind, randomized, DESIGN Open-label Extension placebo-controlled, Phase 3 study
~35 patients with endogenous CS, approximately Patients with endogenous CS who have PATIENTS one-half of whom will have participated completed SONICS or LOGICS (by invite-only) in SONICS
• Double-blind, randomized withdrawal phase: • Open-label levoketoconazole at therapeutic TREATMENT levoketoconazole† or placebo (8 to 9.5 weeks) dose for up to 3 years & DURATION • Double-blind restoration phase: • Routine visits every 3 months levoketoconazole† + placebo (8 to 9.5 weeks)
PRIMARY Loss of therapeutic response (24-hour UFC) to Assess long-term safety and efficacy durability OBJECTIVE levoketoconazole of levoketoconazole
OPTICS is not intended as pivotal. Abbreviations: CS, Cushing’s syndrome; UFC, urinary free cortisol. *Dose titration and maintenance phase to therapeutic dose for levoketoconazole-naïve patients (14 to 19 weeks) †Up to 1200 mg daily. Source: LOGICS Trial. ClinicalTrials.gov. 69 Recent and Anticipated RECORLEV™ (levoketoconazole) Milestones
2017 2018 2019
1H 1H 2H 1H
Topline efficacy & safety Topline Full Initiate efficacy (Q1) enrollment enrollment & safety (Q2) (Q1) Long- term data (Mid-year) (Q1)
70 Richard Auchus, MD, PhD Professor of Pharmacology and Professor of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan • Board-certified in endocrinology, diabetes, and metabolism • Education » MD and PhD, Pharmacology, Washington University, St. Louis, MO » SB, Chemistry, Massachusetts Institute of Technology, Cambridge, MA • Postdoctoral Training » Postdoctoral training in pediatric endocrinology, UCSF, CA » Endocrinology, Wilford Hall USAF Medical Center, Lackland, AFB, TX » Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA • Expertise and research interests are focused on steroid biosynthesis, enzymology, protein engineering, and endocrine tumors • PI for SONICS and sub-PI for LOGICS • Strongbridge Endocrine SAB member 71 Cushing’s Syndrome Clinical Experience Richard Auchus, MD, PhD
72 Potential Utility of RECORLEV™ (levoketoconazole) in Cushing’s Syndrome
• Levoketoconazole is the pure 2S,4R enantiomer of ketoconazole
• Levoketoconazole is the active half of ketoconazole responsible for cortisol synthesis inhibition in vivo CYP1CYP11A11A1 CYP1CYP17A17A1 CYP11B1
2R,4S2R,4S-ketoconazole-ketoconazoleenantiomerenantiomer 25,08025,080 596595.7 1,365 10-26x Ketoconazole,Ketoconazole, racemateracemate 2,267 57.7758 139138.6 1.6-2.7x Levoketoconazole* 1,447 28 52
50% inhibitory concentration, nmol/L; lower number indicates greater inhibition potency
• RECORLEV has received orphan designation in the US and EU for treatment of endogenous Cushing’s syndrome
Source: Auchus RJ, U. of Michigan, data on file. *The active ingredient in RECORLEV. 73 Potential for Lower Liver Toxicity vs 2R,4S-ketoconazole Enantiomer
Plasma Concentration Over Time 12 times less potent 10,000 inhibitor of CYP7A, the 2S,4R-ketoconazole 2R,4S-ketoconazole
rate-limiting enzyme for 8,000 bile acid synthesis SD (ng/mL)SD ± ~3 times greater plasma 6,000 concentration* implies less liver extraction of 4,000 levoketoconazole 2,000 Plasma concentration 0 0 4 8 12 16 20 24 Time (hours) *Day 5 data from 24 healthy patients dosed with 400mg KTZ Days 1-4 plus 80mg atorvastatin on Day 5. Source: Rotstein DM, Kertesz DJ, Keith A. M. Walker, and David C. Swinney. Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992;35(15):2818–2825. 74 Features of Cushing’s Syndrome
Manifestation % Obesity or Weight Gain 95% Facial Plethora 90% Rounded Face 90% Decreased Libido 90% Thin Skin 85% Menstrual Irregularity 80% Hypertension 75% Hirsutism 75% Depression/Emotional Lability 70% Easy Bruising 65% Glucose Intolerance 60% Proximal Weakness 60%
Biller B. In Atlas of Clinical Endocrinology 2000.
75 Key Issues in the Medical Management of Cushing’s Syndrome
• Medication should address: » Glucocorticoid manifestations – Diabetes, osteoporosis, muscle weakness, cognitive dysfunction • Mineralocorticoid manifestations » Hypertension, potassium loss • Androgen manifestations (important to women) » Excess hair growth, oily skin, acne • Considerations for medication choice: » Patient type » Efficacy and reliability » Onset of action » Ease of monitoring » Stability of response » Safety and tolerability
76 Cushing’s Syndrome Patient Case 1
• 55-year-old woman • Confusion, blood clots, seizure • Exam: weakness, bruising, fat pads • High urine and blood cortisol, ACTH • Low potassium, high BP • Difficult surgery, adherent tumor • Cortisol improved, not normal • Discharged to rehabilitation unit
Found Dead 1 Week Later
77 Cushing’s Syndrome Patient Case 2
• 37-year-old woman • Weight gain, no menses, hirsutism, bruising, weakness • Poor sleep, memory problems, new hypertension • Exam: weakness, skin thinning, fat pads, bruises • Urine, saliva, and serum cortisol high; ACTH high • Potassium low, glucose mildly elevated • MRI: normal • Petrosal sinus sampling: pituitary source • Surgery: no tumor found, high cortisol persists
What to do next?
78 Cushing’s Syndrome Patient Case 2
• Repeat surgery? » Unlikely successful, risk hypopituitarism • Radiotherapy? » Will take years and cause hypopituitarism » Will need medical therapy in interim • Adrenalectomy? » Risk of tumor growth, adrenal crisis • Wait and reimage? » Risk bone loss, diabetes, morbidities • Medical therapy? But which one?
79 Cushing’s Syndrome Medical Management Options in the US
Name FDA Indication Advantages Disadvantages Signifor® Adults with Cushing’s disease for FDA approved CD only, inadequate cortisol control common (pasireotide) whom pituitary surgery is not an Acts directly on tumor Frequent hyperglycemia option or has not been curative ~90% have some UFC response 2-3 daily self-injections Frequent diarrhea, malabsorption, gallstones Korlym® Control hyperglycemia secondary to Oral, 1-2x Daily Limited indication (mifepristone) hypercortisolism in adults with Reliable, sustained effects to Cannot use UFC, cortisol to monitor endogenous Cushing’s syndrome reduce elevated glucose Does not treat hypertension or hypokalemia and diabetes or IGT after failed Fairly rapid onset Abortifacient, endometrial hypertrophy surgery / not candidates for surgery Drug interactions, nausea, fatigue, headache Ketoconazole Not FDA approved Oral Many potential DDIs Rapid onset, reliable effect Potential for liver toxicity requires monitoring Lowers cortisol and testosterone GI upset (nausea) common, gynecomastia in men Metyrapone Not FDA approved Oral Dosing is 2-4 times daily Rapid onset of action Uncommonly normalizes UFC Long experience Acne, hirsutism in women, nausea common Generally well tolerated Single supplier (via Europe) Cabergoline Not FDA approved Oral, 2-3 doses weekly Useful only in CD Acts directly on tumor Typical complete response in ~10% Lowers cortisol “Escape” in up to 1/3 of responding patients Generally well tolerated Hypotension, transient asthenia
80 Outcome of Case 2
• Tried cabergoline » No response • Wrote script for mifepristone » Insurance denied; not diabetic • Tried pasireotide » Modest response, but experienced hyperglycemia, disliked BID injections • Patient declined radiotherapy • Performed bilateral adrenalectomy » Chronic hydrocortisone and fludrocortisone therapy » Medical alert identification, carries emergency hydrocortisone » Never “back to normal”
81 Ideal Drug Profile for Case 2-Like Patient
• Reliable efficacy • Oral, convenient dosing regimen • Good safety profile for long-term therapy • Improve, not worsen, glucose • Lowers cortisol, easily monitored • Lowers blood pressure, normal potassium • Lowers testosterone, restores menses • Clinically meaningful improvement » Patient-reported outcomes
82 RECORLEV™ (levoketoconazole) Commercial Opportunity Matthew Pauls
83 Potential Commercial Opportunity for RECORLEV™ (levoketoconazole)
Patient Population • No FDA-approved product with broad Estimated US diagnosed prevalence Cushing’s syndrome indication ~25,000 • If approved, position RECORLEV as first-line,
Active disease: Remission first-choice therapy addressable (often relapse) ~7,000 ~18,000 • Currently approved therapies priced at ~$200K-500K/patient/year Active disease: Active disease: Rx-treated Not Rx-treated ~5,000 ~2,000 • RECORLEV time to peak sales is potentially Initial earlier due to Macrilen strong strategic fit target
Controlled Not-controlled ~3,000 ~2,000
84 RECORLEV™ (levoketoconazole) Q&A
85 Closing Remarks
Matthew Pauls
86 2018 Milestones
1H 2H
CORPORATE Q1 Q2 & Q3 Earnings Earnings
Quarterly Sales Quarterly Sales KEVEYIS Quarterly Sales Updates UpdatesUpdates
Commercial Quarterly Sales MACRILEN Launch Updates (mid-2018)
RECORLEV Initiate enrollment—Q1 Topline data—Mid-Year
87