1 1 Investor and Analyst Day June 24, 2010 Nasdaq: LGND Exhibit 99.1 |
Ligand Pharmaceuticals, Inc. 2 2 Investor and Analyst Day John Higgins President and Chief Executive Officer June 24, 2010 - New York |
3 3 Safe Harbor Statement The following presentation contains forward-looking statements regarding Ligand’s prospects, plans and strategies, drug development programs and collaborations. Forward- looking statements include financial projections, expectations regarding research and development programs, and other statements including words such as “will,“ “should,” “could,” “plan,” etc. Actual events or results may differ from Ligand’s expectations. For example, the reverse stock split may not be completed, and the intended benefits of the reverse stock split, expense reductions and drug development programs may not be realized. In addition there can be no assurance that Ligand will achieve its guidance in 2010 and 2011. The forward-looking statements made in the presentation are subject to several risk factors, including, but not limited to, Ligand’s reliance on collaborative partners for milestone and royalty payments, regulatory hurdles facing Ligand’s product candidates, uncertainty regarding Ligand’s product development costs, the possibility that Ligand’s drug candidates might not be proved to be safe and efficacious, the commercial performance of Ligand’s approved products, and a possible failure to successfully combine the businesses of Neurogen and/or Metabasis with Ligand’s business. Additional risks may apply to forward- looking statements made in this presentation. The risk factors facing Ligand are explained in greater detail in Ligand’s, filings with the SEC, including the most recently filed annual reports on Form 10-K and quarterly reports on Form 10-Q, as well as other public filings. While forward-looking statements reflect our good faith beliefs (or those of the indicated third parties), they are not guarantees of future performance. We disclaim any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. |
4 4 Investor and Analyst Day Agenda Welcome and Company Overview John Higgins Financial Highlights John Sharp Ligand Partnered Asset Portfolio Rob McKay Promacta Nezam H. Afdhal, MD Expanding the Partnership Pipeline Syed Kazmi, PhD SARM Program Shalender Bhasin, MD Questions & Answers / Reception |
5 5 Investor Day • Ligand’s Directors own ~9% of the company • Other top holders – Wellington – Biotech Value Fund – BlackRock – UBS – Vanguard – Pennant – Chesapeake Partners – DWS Investment GmbH – RA Capital |
6 6 We Have Delivered • We have fully restructured and rebuilt Ligand • We have cut costs while building our asset base • We have met our financial guidance • We have advanced our pipeline • We have completed three valuable acquisitions |
7 7 Our Business Philosophy • Run a business that is oriented toward being a financial growth story – Our belief is we should not build a business around “biotech promises,” instead we should build a business that generates cash flow and makes investors (shareholders) money • Buy or develop a large portfolio of assets that can yield positive cash flow • Fiercely manage expenses – Unfortunately, this industry has managed to squander vast amounts of money on programs, infrastructure, and elaborate public enterprises that did not warrant the investment – No guarantee what we choose to fund will succeed, but we will be very disciplined in the process • Avoid the biotech financing loop – Avoid costly dilution – Make better long-term decisions |
8 8 Perception Reality • The rewards from discovering, developing, and commercializing a biotech drug can be enormous • True, but the vast majority of programs fail to ever reach that payoff • A biotech company should retain late-stage and/or commercial rights as the economic reward will be greater • The return is not necessarily greater, in fact it might be smaller. But for certain the risks will be greater as costs, timelines, competitiveness and pricing pressures in this industry have all gone up dramatically over the last 20 years. • Investors and the pharma industry as a whole can make money by investing in a wide array of assets and de-risking strategies • BUT if an individual biotech company is going to increase its chances to succeed, it has to do things differently than how companies were run in the early 1990s Ligand: A Business Model Built on Today’s Reality |
9 9 Why the Ligand Royalty Model is So Compelling • Integrate most functional expertise into the company • Short remaining patent life • Own products through late-stage development or commercialization Vast portfolio of royalty partnerships • 1 or 2 royalty streams Research and partnering engine Ligand Today Result • Unexciting • No growth • Fixed value company • No engine to drive new deals “Yesterday’s” Royalty Model “Yesterday’s” FIPCO Model Result • Large revenue potential • Substantial growth potential • Substantially lower costs and risk Result • High costs and risks, beholden to wall street for financing • Questionable if the ROI justifies the model |
10 10 Why the Ligand Royalty Model is So Compelling • Integrate most functional expertise into the company • Short remaining patent life • Own products through late-stage development or commercialization Vast portfolio of royalty partnerships • 1 or 2 royalty streams Research and partnering engine Ligand Today Result • Unexciting • No growth • Fixed value company • No engine to drive new deals “Yesterday’s” Royalty Model “Yesterday’s” FIPCO Model Result • Large revenue potential • Substantial growth potential • Substantially lower costs and risk Result • High costs and risks, beholden to wall street for financing • Questionable if the ROI justifies the model |
11 11 Why the Ligand Royalty Model is So Compelling Ligand Today Vast portfolio of royalty partnerships Research and partnering engine Result • Large revenue & ER potential • Substantially lower costs and risks • Over 30 programs • Long patent lives • Some high royalties that approach a profit split • Efficient research focused on licensing at early inflection points |
12 12 Ligand’s Potential Downside Individual project set-backs Slower growth Partners drop programs Ligand’s Potential Upside Blockbuster product approved/in-development Near-term profitability Well funded/financially disciplined More royalty partnerships than any peer co Attractive fully-owned pipeline Substantial calendar of news flow Large NOLs Risk Reward The Investment Proposition: Risk vs. Reward We believe the upside reward is substantially greater than the downside risk |
13 13 Illustrative Sum of the Parts • Cash $30 million • Over $500 million in NOLs with estimated ~$100 million net present value • Avinza – up to $25 million in net present value - royalty annuity through 2017 • Promacta Currently marketed and in development for five other indications 12 years remaining patent life Tiered royalties averaging to about 9% How big will this drug be? • SERMS – approved, could launch soon • CXCR2, P-38, Dinaciclib, IL-9 – High-quality, mid-stage programs • Over 30 partnered programs – news flow and milestone potential • 10 fully owned internal programs |
14 14 Sum of the Parts Illustration Avinza • Promacta • SERMs • 30 other funded programs • Fully owned pipeline Nols Cash $180 million Current Market Capitalization “Biotech” Value How much more will this grow over the next few years? ~$25 ~$100 ~$30 $155 million |
15 15 Ligand…Why Now? • Given reduced expenses and revenue outlook, we project turning profitable on an operating basis next year • Promacta is a “now” story – New trials have initiated recently – New territories are launching for ITP – HepC P-III trials are winding down with data expected in about a year • Ligand just closed a few great acquisitions which have more than tripled our pipeline and partnered assets • Partners have announced several positive developments in past few months • Data is coming out of our internal pipeline over the next six months |
16 16 A View of the Future • 2 marketed products : Avinza and Promacta • 2 approved products pending launch: Conbriza and Fablyn • 2 products announced to have NDA filings by end of 2012: Aprela and Acadesine • 9 drug candidates could launch between 2014 and 2018 CXCR2 BACE P-38 JNK2 CDK LXR IL-9 FXR Hepatitis |
17 17 Potential Significant Revenue Expansion Over Next Several Years Illustrative Growth 2016 Promacta 2012 Avinza Promacta Conbriza Avinza Aprela Conbriza Fablyn Aprela Acadesine Fablyn CDK >$20 million royalties CXCR2 Plus license fees P-38 IL- 9 >$200 million royalties Plus license fees |
18 18 2012 2016 >$20 Mil. >$200 Mil. Potential Significant Revenue Expansion Over Next Several Years • 10 fold increase in royalties. Growth due to: – New product launches – New territories – New indications – Increasing royalty rates upon sales growth • Potential for nearly $100 million in milestones over the same period • Annual expenses over this projection period estimated to be $15 to $20 million Illustrative Royalty Revenue Growth |
Ligand Pharmaceuticals, Inc. 19 19 Financial Update Delivering Good Performance John Sharp Vice President, Finance and Chief Financial Officer |
20 20 Highlights • Operating Expenses • Overview of Net Operating Losses • Financial Guidance • Reverse Stock Split |
21 21 Operating Expense Trend $0.0 $10.0 $20.0 $30.0 $40.0 $50.0 $60.0 $70.0 $80.0 2007 2008 2009 2010 2011* G&A R&D * High end of expense guidance range • Ligand has significantly reduced expenses over the last several years • During the same period, the company closed 3 acquisitions while significantly expanding its asset base Pharmacopeia Acquisition Neurogen Acquisition Metabasis Acquisition |
22 22 Value of Net Operating Loss Carryforwards (NOL) • Ligand has accumulated substantial NOL’s through our operating history and acquisitions • NOL’s should provide significant relief on taxable income if the company turns profitable • NOL’s as of December 31, 2009 = $514 million • Due to tax code, NOL’s are limited in the quantity and the timing in which they can be used, so we do not expect to get a full offset on taxable income immediately • Estimated net present value of NOL’s = ~$100M • In near-term, the NOL tax should reduce federal tax rate from 34% down to 2% (AMT) |
23 23 Financial Guidance 2010 Guidance: • Revenue approximately $25 million Combination of royalty, contract payments and milestones • Operating expenses approximately $30 million One-third G&A, two-thirds R&D • Cash at year end projected to be greater than $30 million 2011 Guidance: • Operating expenses projected to be in range of $15 - $18 million • Projecting turning profitable on an operating basis and having positive cash flow from operations |
24 24 Reverse Split • Over Ligand's history, company raised money through a series of highly dilutive financings • Company initiated restructuring about three years ago but never addressed its bloated share base • Now is an appropriate time given the progress of the company and our outlook for the business • A lower share count and higher stock price provides numerous benefits including improving trading dynamics, lower costs and increased per share reported amounts • The middle of the reverse split range would yield a share count of approximately 16 million shares versus 118 million shared currently outstanding |
25 25 Illustrative Income Statement Assuming Reverse Split ($ in millions) Pre-split Post-split Revenue 40.0 $ 40.0 $ Expenses 20.0 20.0 EBIT 20.0 20.0 Interest & other 1.0 1.0 Taxes (0.4) (0.4) Net income 20.6 $ 20.6 $ EPS 0.18 $ 1.31 $ Shares outstanding 117.6 15.7 * * assumes midpoint of split range;1-for-7.5 |
Ligand Pharmaceuticals, Inc. 26 Ligand Partnered Asset Portfolio Value Through Shots on Goal Rob McKay Associate Director, Business Development |
27 Ligand’s Partnered Asset Portfolio Ligand has a very large portfolio of partnered programs which are the core of Ligand's financial growth model |
28 Ligand’s Partnered Asset Portfolio The Ligand partnered portfolio consists of 33 fully funded programs that have the potential to generate over $500M in milestones and royalties on future sales |
29 Ligand’s Partnered Asset Portfolio Significant potential for new product launches and expanded indications the next several years * * |
30 Ligand’s Partnered Asset Portfolio Over half of the partnered portfolio is in mid-late stage clinical trials |
31 Ligand’s Partnered Asset Portfolio Significant news flow over the next 18 months • Aprela NDA Filing • Promacta-Japan ITP Approval • Promacta HepC PIII Data • SARM PI Data •BACE PII Initiation • IL-9 PII Completion • Conbriza EU Launch • Oral EPO Clinical Candidate • Glucagon Clinical Candidate • TR-beta Clinical Candidate • Dinaciclib PII Completions • Acadesine PIII Data • GCGR PI Initiation • Promacta PII Oncology Data • Roche HepC PII Initiation |
32 Quality Partnerships and Portfolio Value • Ligand's promising long-term growth is firmly based on finding partners who can deliver our assets into the hands of patients • Ligand’s ideal partners have the following qualities: – The expertise to bring each unique asset through development into the marketplace – A need for our product in their portfolio – The resources to make it all happen Long-term Ligand shareholder value is highly based on the quality of our partnerships |
33 Examples of Value Through Quality Partnerships Assessing the value of Ligand’s partnered portfolio by examining two premier partnerships |
34 The Merck-Ligand Collaboration • A pipeline of innovative products in established or emerging Merck franchises • The potential for milestone and royalty revenue in the near and long-term • Regular news flow from a variety of programs Phase III CABG Phase II COPD Phase II Oncology Phase I Alzheimer’s Pre-clinical Multiple assets under the control of one of the world’s leading pharmaceutical companies has the potential to produce enormous value for Ligand shareholders *Acadesine was licensed to Merck by PeriCor 5 Programs BACE Dinaciclib SCH 527123 Acadesine* |
35 • What does SCH 527123 do? Antagonist of chemokine receptor 2, blocking the activation of neutrophils. Reduces airway damage and mucous build up seen in diseases like COPD • What stage of development is SCH 527123 at? Phase II study for COPD. Expected to be completed in 3Q12 • Why is SCH 527123 interesting? 12M COPD patients in US with no effective long-term treatment Part of the respiratory franchise for Merck Novel NME with strong patent protection SCH 527123 (CXCR2 Antagonist) SCH 527123 is a potential first-in-class, blockbuster medication for pulmonary obstruction diseases like COPD Airway Obstruction in COPD (thinkcopddifferently.com-2010) |
36 • What does Dinaciclib do? Inhibitor of cyclin dependent kinase (CDK) Inhibiting CDK should block cell-cycle progression and promote apoptosis • What stage of development is Dinaciclib at? Multiple Phase II studies for cancer. The studies will complete in late 2010 through 2012 • Why is Dinaciclib interesting? Merck is making a large commitment to becoming a player in the oncology field Novel kinase inhibitors are the next wave of therapeutics in the oncology space Novel NME with strong patent protection Dinaciclib (CDK Inhibitor) Dinaciclib is a pro-apoptotic cyclin dependent kinase inhibitor with potential anti-neoplastic activity CDK Control of the Cell Cycle (sandwalk.blogspot.com-2009) |
37 • What does a BACE Inhibitor do? BACE inhibitors block the activity beta-secretase (BACE) Inhibiting beta-secretase should lower the amount of beta- amyloid protein produced in the brain, limiting the plaque formation that is thought to be a cause of Alzheimer’s disease • What stage of development is BACE Program at? Merck has a BACE molecule in Phase I • 58% reduction in beta-amyloid protein seen in single dose PI study Ligand anticipates a late 2010 Phase II initiation • Why are BACE inhibitors interesting? 5-6M patients in the US with little therapeutic options • Estimated at more than 15M world-wide Completely novel mechanism of action Novel NME with strong patent protection BACE Inhibitor Program The Merck BACE inhibitor program is developing a novel, first-in-class therapeutic for Alzheimer’s disease by targeting beta-secretase BACE Cleavage of beta-amyloid Protein (sigmaaldrich.com-2008) |
38 Merck Collaboration Summary The Merck collection of assets has the potential to produce one of the next blockbuster drugs in the Ligand asset portfolio Phase III CABG Phase II COPD Phase II Oncology Phase I Alzheimer’s Pre-clinical The opportunity is for any one (or several) of these assets to become the next Promacta for Ligand 5 Programs BACE Dinaciclib SCH 527123 Acadesine* |
39 The GSK-Ligand Collaboration • Increasing royalty revenue over time from expanded indications • Regular news flow of filings and approvals • Regular news flow from a variety of programs • 2nd Generation TPO Receptor Agonist licensed to GSK as a follow-on molecule to Promacta Approved ITP Phase III HepC Phase II Oncology Phase II Thrombo Phase I Other Indications GSK and Ligand have a long-standing collaboration to develop thrombopoietin receptor agonists for treatment of thrombocytopenia Promacta GSK 2285921* Promacta Promacta Promacta |
40 • What does Promacta do? Promacta is a once daily oral medicine that activates the thrombopoietin (TPO) receptor Activation of the TPO receptor causes an increase in the production of platelets • What is Promacta approved for? Promacta is approved for ITP in multiple countries • What are the next indications for Promacta? Promacta is in Phase III for HepC-related thrombocytopenia and we project it to launch in 2012 Promacta is in Phase II for thrombocytopenia related to various cancer types Promacta Facts Promacta is a first-in-class therapy for raising platelet levels in patients experiencing thrombocytopenia |
41 • GSK is currently running two potentially large Phase III studies in HepC patients Study 1 (PEGASYS/Ribavirin) Study 2 (PEGINTRON/Ribavirin) • Both studies are randomized, double blind, placebo controlled in 750 patients currently on peginterferon/ribavirin • Primary outcome is Sustained Virologic Response (SVR) 6 months after treatment • Data is expected from both in 3Q11 • Phase II data showed 65% of patients on 75mg daily of Promacta finished viral therapy course, compared to 6% on placebo. • 10% of all HepC patients cannot finish viral therapy due to thrombocytopenia, resulting in a sub-optimal therapeutic response Promacta and HepC-Related Thrombocytopenia The ongoing Phase III studies for HepC-related thrombocytopenia are the basis for a large expansion of the Promacta value |
42 • The platelet segment is the next frontier in the multi-billion dollar hematology market • Promacta and its backup compound will build a long-term platelet franchise for GSK/Ligand • GSK is expending large amounts of resources and money to expand Promacta markets and indications Two 750 patient studies for HepC-related thrombocytopenia • Data expected in 2H11 Currently in multiple PI and PII studies for cancer-related thrombocytopenia Filings and approvals in new countries • ITP approval in Japan expected in 2H10 Promacta: Reasons for Excitement Ligand shareholders have many reasons to be very excited about Promacta |
43 What Promacta Means to Ligand Independent Analyst Projected Sales for Promacta* Potential royalty revenues from Promacta are the basis for transformative growth at Ligand 0 200 400 600 800 1000 1200 1400 2012 2013 2014 2015 2016 Year Yearly Revenue Projections for Ligand from Promacta Sales** *Projected sales figures are the average projections from 6 independent analyst groups, including Bank of America-Merrill Lynch, Credit Suisse, JP Morgan, Morgan Stanley, Nomura, and UBS **There can be no assurance these results will be achieved. Projections derived from analyst revenue estimates. |
Ligand Pharmaceuticals, Inc. 44 Promacta and its Role in Treating HepC-Related Thrombocytopenia Nezam Afdhal, M.D. Gastroenterology Chief of Hepatology, Beth Israel Deaconess Medical Center |
The Role for Eltrombopag in the Treatment of HepC-Related Thrombocytopenia N. Afdhal M.D Beth Israel Deaconess Liver Center Harvard Medical School |
Agenda Eltrombopag Background Conclusions from the ELEVATE Study Eltrombopag PII HepC Study Results The ENABLE 1 and ENABLE 2 PIII Studies |
The Unmet Medical Need for Thrombocytopenia Thrombocytopenia is a major factor in patients being unable to achieve a desired clinical outcome in dozens of diseases Currently estimated to be nearly two million patients annually in the US who need to be treated for thrombocytopenia Current non-drug techniques used to increase platelets (i.e. platelet transfusion, splenectomy) are costly, risky, and inconvenient. The need for a more convenient and effective method for combating thrombocytopenia is clear |
Liver Disease–Associated Thrombocytopenia Platelet counts may be as low as 20,000–40,000/µL Prevalence of thrombocytopenia increases with severity of liver disease Degree of thrombocytopenia correlated with severity of liver disease Thrombocytopenia predictive of reduced 5-year survival Thrombocytopenia may develop or worsen with interferon-based therapy Degree of Liver Damage Thrombocytopenia Prevalence Normal liver 2.3% Fatty liver 5.1% Chronic hepatitis 20.3% Advanced liver disease 31.8% |
Eltrombopag Thrombopoietin receptor agonist Oral, once-daily tablet Induces megakaryocyte proliferation and differentiation Increases platelet counts in patients with HCV 1 1. McHutchison J, et al.N Engl J Med. 2007;357:2227–2236. |
Cytoplasm STAT RAS/RAF MAPKK p42/44 SOS SOS GRB2 SHC Cell membrane Eltrombopag – Mechanism of Action thrombopoietin receptor inactive receptor active receptor Signal Transduction eltrombopag Increased platelet production |
Eltrombopag Clinical Studies Conclusions from the ELEVATE Study |
Eltrombopag in Chronic Liver Disease Patients with Thrombocytopenia Undergoing an Elective Invasive Procedure: Results from ELEVATE, a Randomised Clinical Trial N. Afdhal, E. Giannini, G.N. Tayyab, A. Mohsin, 4 J-W. Lee, 5 A. Andriulli, 6 L. Jeffers, 7 J. McHutchison, 8 F. Campbell, 9 N. Blackman, 10 D. Hyde, 9 A. Brainsky, 11 D. Theodore 12 1. Division of Gastroenterology/Liver Center, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2. Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; 3. Department of Medicine, Gastroenterology and Hepatology, Post Graduate Medical Institute, and Lahore General Hospital, Lahore, Pakistan; 4. Department of Gastroenterology, Services Hospital Lahore, Services Institute of Medical Sciences, Lahore, Pakistan; 5. Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, Korea; 6. Department of Internal Medicine, Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, San Giovanni Rotondo, Italy; 7. Center for Liver Diseases, University of Miami, Miller School of Medicine, Miami, FL, USA; 8. Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA; 9. Clinical Development, GlaxoSmithKline, Stockley Park, Uxbridge, UK; 10. Biometrics and Epidemiology, GlaxoSmithKline, Collegeville, PA, USA; 11. Clinical Development, GlaxoSmithKline, Collegeville, PA, USA; 12. Clinical Development, GlaxoSmithKline, Research Triangle Park, NC, USA 1 2 3 |
Median Platelet Count from ELEVATE 147 144 145 141 139 134 132 131 50 49 128 125 116 125 120 117 125 127 Placebo Eltrombopag n = n = Number with available data: Eltrombopag Placebo 0 20 40 60 80 100 120 140 160 180 200 220 Screening Day 1 Day 8 Day 15 Day 16–19 7 DFU 14 DFU 21 DFU 30 DFU Median (interquartile range) Treatment Period Procedure |
Primary Endpoint: Avoiding Platelet Transfusions with Elective Invasive Procedure Difference 53% (95% CI: 43, 62) p < 0.0001 0 10 20 30 40 50 60 80 100 Placebo (N = 147) Eltrombopag (N = 145) 70 90 72% 19% n = 28 n = 104 |
Selected Adverse Events Placebo (N = 145) Eltrombopag (N = 143) n (%) n (%) Bleeding 25 (17) 19 (13) Thrombotic event 2 (1) 6 (4) Ocular (focus on cataracts / visual acuity decrease) 6 (4) 6 (4) Malignancies* 1 (<1) 1 (<1) * Basal cell carcinoma (Grade 2) reported for one patient receiving placebo and B cell lymphoma (Grade 4) reported for one patient receiving eltrombopag; neither was considered to be related to treatment by the investigator. |
Summary of Thrombotic Events Thrombotic event Temporal relationship to last dose Temporal relationship to procedure Platelet count at event (Gi/L) Procedure PV / SMV thrombosis +1 –6 days 417 Brain tumour resection PV thrombosis +5 +4 days 288 Oesophageal variceal ligation SMV thrombosis +8 +7 days 235 Dental extraction SMV / mesenteric thrombosis +9 +7 days 289 HCC ablation SPV thrombosis +14 +13 days 241 TACE PV thrombosis +38 +34 days 33 Oesophageal variceal ligation Acute MI +20 +19 days 83 Colon resection Non-occlusive PV and mesenteric thrombosis +128 +128 days Unknown Oesophagoduo- denoscopy PV, portal vein; SMV, superior mesenteric vein; SPV, spleno-portal vein; MI, myocardial infarction Eltrombopag Placebo |
Thrombotic Events and Platelet Count Platelet count >200,000/µ L YES NO 47 patients (16%) 241 patients (84%) YES = 5 (10.6%) NO = 42 (89.4%) YES = 3 (1.2%) NO = 238 (98.8%) TEs |
Conclusions Eltrombopag 75 mg for 14 days – Reduced the need for platelet transfusions in CLD patients with thrombocytopenia undergoing elective invasive procedures – Increased platelets during treatment period and up to 2 weeks following treatment – Similar incidence of adverse events and serious adverse events – More thrombotic events in the eltrombopag group |
Eltrombopag Clinical Studies HepC Studies |
Eltrombopag PII HepC Study Design 4 wk 12 wk PEG-IFN + ribavirin + eltrombopag Pre-antiviral Eltrombopag 4 wk 4 wk 4 wk 12 wk + Eltrombopag 12 wk same here 12 wk same here INITIATE antiviral Rx if platelets >70–100 K/µL 30 mg 50 mg 75 mg PART 1 PART 2 4 wk 4 wk 4 wk 4 wk Follow-up |
Primary Efficacy Endpoint Platelet count 100,000/uL at Week 4 PLACEBO 30 mg 50 mg 75 mg 0.0007 0.0003 < 0.0001 0% 74% 75% 95% 0% 20% 40% 60% 80% 100% McHutchison, NEJM 2007 |
Subjects Initiating PEG-IFN Therapy at Week 4 PLACEBO 30 mg 50 mg 75 mg 22% 74% 71% 91% 0% 20% 40% 60% 80% 100% |
Subjects Completing 12 Weeks of PEG-IFN Therapy PLACEBO 30 mg 50 mg 75 mg 6% 53% 36% 65% 0% 20% 40% 60% 80% 100% |
HCV Phase II Study Median Platelet Count 0 50 100 150 200 250 0 14 28 42 56 70 84 98 112 Study Day Placebo 30 mg 50 mg 75 mg INITIATION MAINTENANCE McHutchison, AASLD 2006 |
Adverse Events – Pre-Antiviral Phase Treatment Group, n (%) PBO N=18 30mg N=14 50mg N=19 75mg N=23 Any AE 10 (56) 11 (79) 10 (53) 13 (57) Headache 3 (17) 5 (36) 3 (16) 4 (17) Dry mouth 1 (6) 2 (14) 2 (11) 2 (9) Pruritus 0 0 0 2 (9) Nausea 0 1 (7) 2 (11) 1 (4) Fatigue 0 0 2 (11) 1 (4) Upper abdominal pain 0 2 (14) 2 (11) 0 Insomnia 0 0 2 (11) 0 Arthralgia 0 2 (14) 1 (5) 0 No thromboembolic or elevated LFT events of concern |
Conclusions Eltrombopag increased platelet counts in subjects in all dose groups A significant number of subjects achieved the primary endpoint (Week 4) in all dose groups compared to placebo Eltrombopag enabled 45/56 subjects to initiate IFN therapy – 31 subjects completed 12 weeks of IFN therapy Preliminary PK findings in general indicate exposure increases with dose with wide variability No safety signals of concern in this initial short term study Safety and efficacy data supports further investigation of eltrombopag in this patient population |
2 parallel global Phase III studies Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE peginterferon alfa-2a (PEGASYS) plus ribavirin – ENABLE 1 peginterferon alfa-2b (PEG-Intron) plus ribavirin – ENABLE 2 ENABLE 1 & 2 |
open label eltrombopag Eltrombopag + PEG-IFN/Rib Pre-Antiviral Phase Open-label eltrombopag (2 – 9 weeks) Antiviral Phase Randomised (up to 48 weeks) Placebo + PEG-IFN/Rib platelets >90,000/uL (E1) or 100,000/uL (E2) 25mg>50mg>75mg>100mg • 2:1 randomisation eltrombopag:placebo • Dose titration of eltrombopag allowed throughout • Primary endpoint = proportion of patients achieving SVR (6M off –Tx) • N=750 dosed/675 randomised study • 3 regions, 26 countries, >250 centres SVR SVR 6 months off-Tx Randomised Withdrawal Design |
ENABLE 1 & 2 Study Design Screening 45 Days Platelets <75K/µL 25mg Pre-Antiviral Treatment Phase Open-label eltrombopag dosed for up to 9wks until platelet count increases to enable initiation of antiviral therapy. Part 1 (2-9 Wks) Open-Label 2 Weeks Platelets 90K/µL* Platelets 90K/µL* Platelets 90K/µL* *Platelets <90K/µL *Platelets <90K/µL *Platelets <90K/µL WD START 50mg 1-2 Weeks 75mg 1-2 Weeks 100mg 1-3 Weeks *Platelets <90K/µL Platelets 90K/µL* *90K/µL (ENABLE 1) 100K/µL (ENABLE 2) 2:1 Randomisation (Eltrombopag:Placebo) Eltrombopag plus Antiviral Therapy Antiviral Treatment Phase Randomised either to maintain dose of eltrombopag from Part 1 or to matched placebo. Part 2 ( 48 Wks) Double-Blind Placebo plus Antiviral Therapy or a 24 Week FU Ocular/SVR a Post-last dose of investigational product. |
SVR rate defined as percentage of subjects with non-detectable HCV-RNA at 24 weeks post-completion of the planned treatment period Platelet count 90-100,000/ L in Part 1 Dose modifications Safety and tolerability Platelet counts PK RVR, EVR and ETR Health-related quality of life Endpoints |
Eltrombopag is an effective platelet stimulator in CLD Eltrombopag can reduce need for platelet transfusion in CLD patients but final dose and safety concerns must be addressed ENABLE studies will confirm role of eltrombopag in HCV therapy in 2011 Eltrombopag Summary |
Ligand Pharmaceuticals, Inc. 72 Ligand Business Development Expanding the Partnership Pipeline Syed Kazmi, Ph.D. Vice President, Business Development and Strategic Planning |
73 • Conduct only early-stage research Do what we are good at • Very successful track record of discovery and IND generation – Over 40 clinical candidates, 22 INDs, 5 drugs approved and 3 on the market Proven and productive technology platform • Strong research capabilities for discovering more selective drugs • Select high quality discovery programs Unmet medical needs Large, non-primary care markets Likely branded premium pricing Tissue selective approach to reduce side effects • Partner at appropriate value inflection point from pre-IND to clinical proof of concept Likely partners - big pharma Generate revenue streams from upfronts, milestones and royalties The Business Model at Ligand |
74 Ligand Unpartnered Assets SARM TRß Agonist Glucagon H3 EPO Androgen Receptor Modulator Thyroid Receptor-beta Agonist Glucagon Receptor Antagonist Histamine H3 Receptor Antagonist Oral EPO Receptor Agonist Muscle Wasting Dyslipidemia Diabetes Cognitive Disorders Anemia Phase Ib Pre-Clinical Pre-Clinical Pre-Clinical Pre-Clinical Program Disease Status |
75 Ligand Unpartnered Assets SARM TRß Agonist Glucagon H3 EPO Androgen Receptor Modulator Thyroid Receptor-beta Agonist Glucagon Receptor Antagonist Histamine H3 Receptor Antagonist Oral EPO Receptor Agonist Muscle Wasting Dyslipidemia Diabetes Cognitive Disorders Anemia Phase Ib Pre-Clinical Pre-Clinical Pre-Clinical Pre-Clinical Program Disease Status |
76 • Metabasis acquisition brings a robust IP portfolio and industry-leading experience in liver-targeted drug delivery using proprietary HepDirect Technology • Ligand brings deep experience in nuclear hormone receptor chemistry and pharmacology for discovering novel liver-targeted TR agonists for hyperlipidemia The Ligand TR-beta Program The combination of Ligand and Metabasis creates a synergistic drug discovery platform for discovering liver-specific TR agonists |
77 • Target validation: TR activation in liver affects the expression of several genes, leading to reductions in LDL, triglycerides,Lp(a), and ApoB TRß is the major isoform expressed in liver for tissue-specific effects • TR activation in extra-hepatic tissues result in dose-limiting side effects, including arrhythmia, muscle, bone and thyroid hormones • Product Profile: Oral drug lowering lipids without suppressing thyroid axis or invoking cardiovascular liabilities Combination with statins in patients not reaching LDL goal on current maximal therapies • Avoid mechanism-based safety concerns: Alterations in thyroid axis – decrease in T4 and increased TSH levels Potential for adverse cardiovascular events Thyroid Receptor Overview |
78 Dyslipidemia – Unmet Medical Need Low Cardio Risk Med Cardio Risk High Cardio Risk Statin Intolerant 26M US Dyslipidemic Patients Largely Meeting LDL Goals on Existing Therapies 20% 15% Approximately 9M Patients in need of Add-On Therapies Add-on treatments for patients still not reaching LDL goals on current maximal therapy is a multi-billion dollar market TR-b Target Pop. |
79 MB07811 - First generation liver-targeted prodrug • Phase Ib study completed in 56 subjects Clinical proof of concept with dose-dependent decrease in LDL (15- 41%), Apo B, TGs, and Lp(a) Modest dose-related side effects including thyroid axis suppression in a small cohort of subjects 2 nd generation Liver-selective compounds (e.g. MB10866) • Improved preclinical safety and efficacy profiles in validated animal models • Lead optimization studies ongoing to further improve liver selectivity Thyroid Receptor Program Status |
80 • Robust Partnering Package Extensive clinical package with first generation drug candidate to help drive SARs 2 generation lead candidates representing novel chemistry platforms Strong IP for a well validated target Potential for first-in-class NME in a growing area of unmet medical need • Partnering Landscape Established clinical proof of concept with MB07811 (Metabasis) and Eprotirome (Karo Bio) Well-defined regulatory path to approval High unmet medical need beyond generic statins • Differentiation from Competition HepDirect Technology Nuclear receptor expertise TR Partnering Opportunity nd |
81 • LGD-4033, a Selective Androgen Receptor Modulator (SARM), for the treatment of muscle wasting disorders • LGD-4033 has desirable tissue-selective properties A potent, full agonist on bone with anabolic and anti- resorptive effects A potent, full agonist on skeletal muscle with anabolic effects A low potency, weak agonist on prostate and sebaceous glands with high selectivity resulting in minimal drive on these tissues SARM Overview LGD-4033 retains the beneficial properties of natural androgens, while mitigating the toxic actions and side effects of steroidal androgens |
82 • Phase I Single Ascending Dose study completed late 2009 LGD-4033 is safe and well tolerated at single doses up to 22mg Suitable for once-daily dosing No SAEs or dose-related clinical significant adverse events reported • Phase I Multiple Ascending Dose study ongoing LGD-4033 doses of 0.1 - 3mg once daily for 2-3 weeks Objectives include safety, tolerability, and measurement of muscle protein biomarkers, lean body mass, and strength (stair climb) • 90-day toxicology studies ongoing, allowing for seamless transition into Phase II patient populations SARM Program Status |
83 The pipeline snapshot below is based upon the developmental agents listed for treatment of cachexia (various disease states) and sarcopenia. Competitive Pipeline – Relevant to LGD-4033 Development Muscle Wasting Disease Development in the US Preclinical Preclinical Phase II Phase I Phase III Ostarine (GTx-024) LGD-3303 SARM Ghrelin receptor Others Data Source: Thomson-Pharma.com, LGD-4033 GLPG-0492 Anamorelin (RC-1291) VT-122 imidapril |
84 • Robust Partnering Package • New NME with clinical POC data for a well validated target • A large library of novel SARM back-up candidates • Blockbuster drug potential in a high unmet medical need area • Partnership Landscape Multiple commercial markets allow for both large and orphan indications • Muscle Wasting Disorders (cachexia, sarcopenia, frailty) • Rehabilitation • Muscular dystrophy • Osteoporosis (in men and women) • Differentiation from Competition Higher potency Oral dosing Enhanced tissue Selectivity LGD-4033 Partnering Opportunity |
Ligand Pharmaceuticals, Inc. 85 Selective Androgen Receptor Modulator LGD-4033 Shalendar Bhasin, M.D. Professor of Medicine, Boston University School of Medicine Chief, Section of Endocrinology, Diabetes, and Nutrition Director, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Anabolic Therapies Principal Investigator, LGD-4033 Phase Ib Clinical Trial |
86 Shalender Bhasin, MD Professor of Medicine, Boston University School of Medicine Chief, Section of Endocrinology, Diabetes, and Nutrition Director, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies Boston Medical Center The Unment Medical Need for a SARM Therapeutic The Unment Medical Need for a SARM Therapeutic |
Aged Population as a Share of Total U.S. Population Continues to Grow |
88 Age-Related Decline in Lean Mass and Muscle Strength (BLSA; Roy et al 2002) Age (years) Leg and Arm Lean Mass (kg) Quadriceps and Biceps Strength (N) Age (years) |
89 Aging baby boomers: 65+ will grow from 35 million in 2000 to over 70 million in 2030. Recent rate of disability —40% (ACS, 2004). The oldest old: the fastest growing segment Grow from 3.0 to 6.2 million in the next decade Social Security Disability Program and the Supplemental Security Program pay $62.5 billion yearly to 7.5 million disabled persons; this amount will grow several-fold. Growth in Disability Among Older Adults: The Staggering Economic Cost |
90 The Unmet Medical Need – Frailty & Sarcopenia • Age-related loss of muscle mass, strength and functionality • Estimated 10 million Americans over the age of 65 suffer from sarcopenia • Currently no FDA-approved treatment options available |
91 Rationale for Function Promoting Anabolic Therapies Androgen Therapy Alterations in Gene Expression Stem Cell Commitment Increased Muscle Mass Increased Muscle Strength and Performance Improved Physical Function Decreased Physical Dependence, Improved Health Perceptions and Health-Related Outcomes |
92 -2 -1 0 1 2 3 4 5 6 7 8 9 10 Young Men (18-34) Older Men (60-75) T Dose (mg) 25 50 125 300 600 Change in FFM (kg) T Dose Effect P <0.0001 Age Effect P = 0.22 Change in T X age P = 0.46 Bhasin et al, JCEM 2005 Testosterone Dose Response in Young and Older Men: Testosterone Dose Response in Young and Older Men: Change in Fat Free Mass Change in Fat Free Mass |
93 The Need for a SARM Therapeutic 80 years of empiric, clinical, epidemiological, and clinical trials data provide 80 years of empiric, clinical, epidemiological, and clinical trials data provide unequivocal evidence that androgens increase skeletal muscle mass and unequivocal evidence that androgens increase skeletal muscle mass and strength. strength. Testosterone is not the answer Testosterone is not the answer – Concern about potential adverse effects on prostate – Many older men have microscopic foci of prostate cancer. Testosterone might make these subclinical foci grow. – Inherent bias towards detection of greater number of prostate events in Testosterone-treated men We need a SARM SARMs are non-steroidal and rogens that act preferentially on skeletal muscle while sparing tissues associated with side effects, like the prostate |
94 Potential Indications for SARMS are Broader than Frailty Elderly • Osteoporosis • Anemia • Sexual dysfunction • Men with prostate cancer who are deemed cured after radical prostatectomy • Muscle wasting • Cancer cachexia • COPD • Chronic Kidney Disease Potential Indications for SARMS are Broader than Frailty |
95 • Selective Androgen Receptor Modulator (SARM) that has the following properties – Anabolic in muscle and bone – Restores libido/sexual function (CNS-active) – Minimal or no drive on prostate in men – Minimal or no virilization in women – No adverse cardiovascular or hepatic effects at therapeutic doses – Non-steroidal – cannot be converted to estrogen SARM Therapeutic Target Profile |
96 Clinical Trial of Ostarine: Increased Total Lean Mass and Decreased Total Fat Mass J Dalton. Data presented at 2007 Endo Meeting, Toronto. We Need More Potent SARMs with Greater Tissue Selectivity Total Lean Mass (all subjects) -500 0 500 1000 1500 2000 2500 3000 Placebo 0.1 mg 0.3 mg 1 mg 3 mg Dose # p<0.001 compared to placebo, p<0.0001 compared to baseline * p=0.055 compared to placebo, p=0.020 compared to baseline # * Total Fat Mass (all subjects) -500 0 500 1000 1500 Placebo 0.1 mg 0.3 mg 1 mg 3 mg Dose # p=0.049 compared to placebo # |
97 • Ligand is developing LGD-4033, a Selective Androgen Receptor Modulator (SARM), for the treatment of muscle wasting disorders • LGD-4033 has desirable tissue-selective properties – A potent, full agonist on bone with anabolic and anti-resorptive effects – A potent, full agonist on skeletal muscle with anabolic effects – A low potency agonist on prostate with high selectivity resulting in minimal drive on the prostate – A weak, low potency agonist on sebaceous glands resulting in minimal drive on these tissues LGD-4033 Overview LGD-4033 retains the beneficial properties of natural androgens, while mitigating the toxic actions and side effects of steroidal androgens |
98 Tissue selectivity of LGD-4033 for skeletal muscle vs. prostate LGD-4033 0 50 100 150 200 Prostate Muscle >500x Dose (mg/kg/day, po) Ostarine 0 50 100 150 200 >390x Comparison of LGD-4033 and Ostarine in the rat model for male hypogonadism |
99 LGD-4033 Increases Muscle Mass Throughout the Body * * * Effect of LGD-4033 on the weight of skeletal muscle in female rats treated once daily with 3 mg/kg LGD-4033 for 4 weeks |
100 LGD-4033: Similar Potency on Muscle and Bone Indicates Potential for Treating Osteoporosis Dose (mg/kg/day, po) -4 -2 0 2 4 6 8 10 Lumbar Spine DEXA Analysis in Female Rats Skeletal Muscle Weight in Male Rats Dose (mg/kg p.o.) 0 20 40 60 80 100 120 |
101 Study Objective Key Observations SAD — 001 Single dose safety and tolerability / Pharmacokinetics 0.1-22 mg Well tolerated at all doses; Dose proportional AUC; T 1/2 : ~26-38 hrs No SAE’s reported MAD — 002 Multiple dose safety and tolerability / Pharmacokinetics Study ongoing LGD-4033 Phase I Development - Overview |
102 • Drug exposure was high and dose-proportional after a single oral dose suggesting that a low dose will give sufficient systemic exposure to be therapeutically effective • Elimination half-life (t 1/2 31 hours) consistent with once- a-day oral dosing • No serious adverse events occurred • A total of 5 mild-to-moderate AEs were considered drug- related by the investigator – No AE was dose-related – No more than one drug-related AE was observed in any MedRA category Summary of Single Ascending Dose Study (L4033-01) |
103 L4033-02 Multiple Ascending Dose Study 3 mg Dose Cohort 4 (N=8) * 1 mg Dose Cohort 3 (N=20) 0.3 mg Dose Cohort 2 (N=20) 0.1 mg Dose Cohort 1 (N=8) Biomarkers: DEXA for Lean Body Mass, 1-RM for strength, FSR for muscle protein synthesis Healthy Males: 21-50 years Doses: 0.1, 0.3, 1 & 3 mg Treatment Duration: 21 days Objective: Evaluation of Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) Design: Single-center, randomized, double-blind, placebo- controlled, sequential escalation, once-daily for 3 weeks |
104 Regulatory Pathway for SARM Drugs • Demonstrating improvements in: – Physical function – Health outcomes, such as quality of life, reduction in falls • FDA feedback on required primary end points for Phase IIb as disclosed by GTx – Total lean body mass – Performance measure (e.g.Stair climb) – Weight is not an acceptable end point NIA-Academic Task Force is establishing a regulatory pathway - Held in US and Europe |
105 Conclusion • Growth in the aged population presents an enormous unmet need for function promoting therapies • Testosterone demonstrates the benefits of androgens in the frail elderly, but adverse effects limit its use • SARMs may produce equal or better functional improvements with more a favorable safety profile • LGD-4033 demonstrates a promising profile of high potency and selectivity in a SARM |
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