1 Small Molecule Platform Improving Radiation Treatment SphingoGene, Inc. Delaware C-CorporationJames S Norris PhDBoard President and Interim CEOIntroductionsDarren: and we are sphingogene, and we are here to tell you about an exciting new strategy for improving radiation therapy for prostate cancer patietns.
2 ObjectiveTo obtain funding or partnerships in order to complete preclinical development of SPG105 for IND filing
3 Sphingolipids/Ceramides A family of lipids involved in cell signalingCell differentiationProliferationProgrammed cell death – apoptosis
4 Sphingolipids are mediators of cell death in response to cancer therapies Dysregulation of ceramide accumulation is a common mechanism of resistance to therapies
6 Current Sphigolipid Drugs – Still Early Fingolimod (Gilenya, Novartis)First oral drug for Multiple Sclerosis$1.2B sales in 2012, up 147% from 2011iSONEP (Lpath)Phase 2 clinical development for wet AMD (macular degeneration)$500M partnerships with PfizerOthers - in preclinical development
7 SPG105 is a small molecular drug that inhibits acid ceramidase
8 Rational for Our Drugs Mechanism of Action: CancerCellDeathCeramideAcidCeramidasePrevents ceramide accumulationAllows escape from cell deathSphingogene has developed a drug that does exactly that: sensitizes prostate cancer to radiation. When you irradiate a tumor, which is represented by this illustration, it stresses the cancer cells causing an increase in a molecule called ceramide. When ceramide accumulates, it causes cancer cell death, which is the goal of radiation therapy. At sphingogene, our scientists have discovered that when prostate cancer is irradiated, ceramide accumulation is prevented by an increase in an enzyme called acid ceramidase. Ultimately we have discovered that this causes cancer cells to escape cell death, limiting the effectiveness of radiation therapy. To combat this effect, Sphingogene has developed a drug called SPG105 that specifically inhibits acid ceramdiase, which restores ceramide accumulation, restoring the effectiveness of radiation therapy.Radiation Therapy
9 How our drugs work: SPG105 Cancer Cell Ceramide Death Acid Ceramidase Inhibits Acid CeramidaseAnd Potentiates Radiation Induced Cancer KillingAcidCeramidasePrevents ceramide accumulationAllows escape from cell deathSphingogene has developed a drug that does exactly that: sensitizes prostate cancer to radiation. When you irradiate a tumor, which is represented by this illustration, it stresses the cancer cells causing an increase in a molecule called ceramide. When ceramide accumulates, it causes cancer cell death, which is the goal of radiation therapy. At sphingogene, our scientists have discovered that when prostate cancer is irradiated, ceramide accumulation is prevented by an increase in an enzyme called acid ceramidase. Ultimately we have discovered that this causes cancer cells to escape cell death, limiting the effectiveness of radiation therapy. To combat this effect, Sphingogene has developed a drug called SPG105 that specifically inhibits acid ceramdiase, which restores ceramide accumulation, restoring the effectiveness of radiation therapy.Radiation Therapy
10 Background on SphingoGene Founded in 2006 by scientist-entrepreneurs at the Medical University of South Carolina (MUSC)Obtained exclusive worldwide rights to the intellectual property from MUSC
11 Why Start with Prostate Cancer? “My granddad died of prostate cancer. I have dedicated my thesis work which has led to our lead clinical compound to him.”Joseph ChengMUSC MD/PhD candidateSphingoGene Researcher“Hurry up! The Baby Boom generation is getting prostate cancer!”Ken BurgerAuthor of “Baptized in Sweet Tea”Prostate Cancer Patient, Charleston, S.C.
12 U.S. Cancer Stats – Prostate Cancer Most Prevalent Source: Cancer Facts and Figures 2012
13 Prostate Cancer Most common cancer in men Risk increases with age Forms in male prostate glandMost common cancer in menRisk increases with ageIn 2012:241,740 men will be diagnosed25,170 will die from the disease
14 How Our Platform WorksCeramide levels increase during radiation therapy; leads to cancer cell deathAcid ceramidase (AC) and Sphingosine Kinase (SK) activity increase during radiation therapy in cancer cellsAC reduces ceramide levels, SK forms S1P, both permitting cancer cell survivalOur compounds inhibit AC or SK or mimic ceramide making radiation or other therapies more effective at inducing cancer cell death
15 Progress and LeadsClinical efficacy established in animal models of cancer at nM concentrationsDose Escalation: No toxicity observed at effective doses and 20 X higher dosesLead Small Molecule Candidates (of 40):DrugTargetStage of DevelopmentSPG 105AC InhibitorClinical lead; efficacy established in rodent tumor xenograft models and cell culture models of prostate and breast cancersSPG 103Ceramide-like DrugEfficacy established in rodent tumor xenograft pancreatic cancer models and cell linesSPG 104SK1 InhibitorClinical Efficacy in vitro and in vivo pending
16 In Vivo EfficacySG105 (clinical lead) Significantly Reduces Tumor Size; in vivo mouse Xenograft Prostate Tumor ModelControl (n=6)Radiation (Rad) Only (n=10)Vehicle Only (n=8)Vehicle + Rad (n=10)SPG105 Only (n=10)SPG105 + Rad (n=10)(% of initial volume)Log 2 Tumor Size
17 In Vivo EfficacySPG105 Significantly Reduces Mortality; in vivo mouse Xenograft Prostate Tumor ModelPercent Survival
18 Xenograph toxicity studies I don’t have the figures. Would you please insert?
20 Toxicity StudyThere is No Significant Toxicity Observed in Blood Chemical Test in Animal after Multiple Injections (150mg/kg ip every other day x5)Un-treatedCremophoreLCL521ModeMeansSDALB(g/DL)3.380.403.500.123.230.25WBC(10/L)5.541.467.302.507.29ALP(U/L)98.257.7689.5010.3888.5013.08LYM (10/L)4.571.075.360.195.501.81ALT(U/L)97.0032.5992.5085.0281.7557.38MON (10/L)0.200.180.300.270.260.24AMY(U/L)42.26955.7537.53946.2540.36GRA (10/L)0.770.521.642.251.561.37TBIL(mg/DL)0.280.050.00LY %83.307.9178.8020.6377.9010.83BUN(mg/DL)23.502.5220.252.8717.502.38MO %3.282.093.552.023.352.14CA++(mg/DL)10.850.2910.4510.70GR %13.458.0017.6818.7018.8010.03PHOS(mg/DL)6.951.027.357.900.93RBC (12/L)12.300.3712.000.6711.98CRE (mg/DL)HGB (g/DL)14.7814.100.6114.35GLU (mg/DL)140.7520.04134.5017.75127.5021.44HCT %51.6950.492.7051.122.07NA+ (MMO/L155.751.26154.250.96156.252.99MCV ( fl )42.0042.75K+ (MMO/L)6.050.816.637.85MCH (pg)11.780.21TP (g/DL)5.885.630.225.78MCHC (g/DL)28.550.4727.950.4428.051.40GLOB (g/DL)0.4188.8.131.520.06RDWc %15.950.5616.200.4217.000.63n=4PLT (10/L)386.75251.67562.0076.68630.2547.41PCT %0.170.360.410.03MPV ( fl )6.356.456.48PDWc %28.800.3528.630.7129.750.68
22 Our Value PropositionEnhances Radiotherapy leading to more effective cancer treatmentFewer side effectsAchieve same clinical benefit with reduced radiationBetter quality of lifeGreater preservation of sexual functionReduce incidence of relapse = Reduced overall treatment costs and reduced death rateSmall Molecules = Easy manufacturing and delivery
23 More effective radiotherapy of prostate cancer means: Same clinical benefit with reduced radiationFewer side effectsGreater preservation of sexual function and continence issuesReduced incidence of relapseTargets mechanism of radioresistanceReduced death ratesAnd, enhanced radiotherapy is a very worthwhile goal. As I’ve previously mentioned, radiation can be curative for prostate cancer patients, however radiation has significant side effects including urinary and bowel incontinence, as well as sexual dysfunction, which are huge quality of life issues for this population of patients. In addition, a substantial percentage of patients do eventually relapse, so by targeting the specific mechanism of radioresistence we hope to reduce these rates of relapse and ultimately increase the number of prostate cancer patients whose disease is cured by radiation therapy.
24 Market opportunity United States: 241,740 cases/year Worldwide: ,500 cases/year@50% of patients will receive IR therapy % of these patients will relapse. In a couple of studies 50% of patients relapsed and 51% of them had local disease (not metastatic) making local control relevant to survival. Our preclinical indication is that SPG105/IR therapy will reduce relapse and improve survival.
25 Financial Assumptions and Forecast Based on annual estimated US prostate cancer cases treated with radiation therapyMarket penetration expected similar to other cancer therapeuticsNo increase in cases, no relapses$8000 per treatment per patient (drug cost)Estimated worldwide market projected in billions
26 Other MarketsPlatform applicable to the majority of solid tumors and any cancer for which patients receive radiation therapy, including internal radiotherapy (brachytherapy).Approximate Incidence of other cancer markets (cases/year):Lung: 1,600,000Breast: 1,380,000Pancreatic: ,000Oral cavity: ,900Brain: ,913Total: 3,701,813 cases/yearEstimated worldwide market projected in billions
27 China’s Cancer Crisis – Lung Cancer Prevalent 3.5M new cases/yr; 2.5M death/yrSource: The National Cancer Registry under the Ministry of Health
28 Radiation Therapy for Other Cancers – Candidates for SPG105 Lung Gy in fractionsBreast Gy in fractionsPancreas Gy in fractionsMelanoma Gy in 6-30 fractions (big variability)Head and Neck Gy in fractions.Potential: If clinical trials successfully model the preclinical data then SPG105 has the potential to become a standard of care blockbuster drug in the radiation treatment industry.
29 Competing Radiosensitizer Drugs The first annual workshop for preclinical and clinical development of radiosensitizers took place at the NCI in August 2012 (JNCI, pages 1-8, 2012 advanced access).Summary:There are ongoing trials many of which are focused on biomarker indicators to improve patient selection.A partial use of drugs being studied include standard chemotherapeutic drugs such as Gemcitabine, 5-Fu, Cisplatin while others are kinase inhibitors such as; Erlotinib, Bevacizumab as examples.Other categories of drugs include ER inhibitor Tamoxifen and Her-2 inhibitors like Trastuzumab.Two potential drugs that inhibit aspects of the ceramide-S1P rheostat with an unknown value in the radiation therapy domain include Fingolimod and ASONEP. Both of these drugs act downstream of SPG105.A recent preclinical publication demonstrated rapamycin might be useful as a radiosensitizer.
30 SPG105 Specificity – “Cleaner” Than Fingolimod SPG105 is clean, unlike Gilenya which has multiple effects (“dirty drug”):It inhibits Acid Ceramidase by specifically targeting acidic compartments (lysosomes) and functioning in lysosomes to inhibit lysosomal enzyme. Investigations have not found actions anywhere else.
31 Therapeutic Potentials Beyond Radiation Sensitizer SPG105 can be used in resistance of different therapies that involve ceramide pathway.ChemotherapyTKI targeted therapiesHDACI therapiesmAb therapies
32 Patent PositionSphingoGene has filed broad patents around targets and various classes of compounds which can affect their targetsLead Compounds:Worldwide Patent pending for SPG105 (clinical lead); US 2011/ A1Issued patent for SPG103; US8,093,393 B2Patent pending for SPG104; US 2012/ A1
33 Regulatory Path and Timelines Investigational New Drug Application (IND) Filing in US:Phase I: Prostate Cancer Patients undergoing primary radiotherapyPrimary Endpoint: Safety/TolerabilityPhase IIa: Prostate Cancer Patients undergoing primary radiotherapySecond Endpoint: Efficacy/biochemical relapseOverall Timeline to Exit:
34 Company Funding to Date NIH/NCI (University) Program Project Grant: $1.6millionNIH Small Business Technology Transfer (STTR) Grant: $432,000ARRA stimulus package: $180,000South Carolina Research Authority (SCRA) start-up funds and SBIR match: $125,000Total: $2.34 Million of Non-dilutive funding
35 Need $2M to Complete the Following: GMP synthesisFormulationToxicity testing (rats, non-human privates
36 Anticipated FundingPhase I/II Small Business Innovative Research (SBIR) Grant (CA ): $2,115,479Phase I STTR (CA ): $346,792Up to $200,000 (SCRA)Total: $2.6 Million of Non-dilutive Funding
37 Anticipated Financial Needs Projected cost for each milestoneGMP Synthesis (SBIR)$149,400Formulation$79,100Toxicity Testing (rats, non human primates)$1,618,649Phase I Trial (Hollings Cancer Center)$1,100,000Phase II Trial (Hollings Cancer Center)$3,640,000So as you can see, the conservative and potential markets for sphingogene are huge, but in order to get to that point, we need investors to carry us through our third milestone Phase Iia clinical trial, after which we believe Sphingogene will be a huge market asset. This investment may seem large, but remember how large our potential markets are: prostate cancer is exceedingly common and is likely to increase with an aging population, and we believe we will ultimately be able to market this drug to many different cancers. Pharmaceutical companies pay on the order of one billion dollars for compounds with far more limited applicaitions, so there is really unbelievable potential return on this investment. EMPHASIZE MILESTONE 3
38 Management Team & Advisors James Norris, PhD, Chairman of the board and Interim CEOProfessor, Department of Microbiology & ImmunologyMedical University of South Carolina (MUSC)David Haselwood, Board Member & Business AdvisorExperienced life science VC, entrepreneur & operatorBurrill & Co, Roche, Proventys, Pharmasset, PrimeraYusuf Hannun, MD, Director of the Stony Brook University Cancer CenterJoel Kenney Professor of Medicine, and the Vice Dean for Cancer MedicineWorld famous expert in sphingolipid biochemistry
39 Advisors: Allen Conger, MBA University of Chicago Experienced investment bankerAndrew Barkan, BBA in management /finance Georgia State University Asset Management & Investment Banking background. Work in asset management with Wells Fargo, as vice president, Oppenheimer & Company as director, and Morgan Stanley as senior vice presidentSphingogene’s management and advisors consist of the following. Dr. James Norris is a career research scientist, founding member of Sphingogene and acting CEO.Dr Yusuf Hannun is the director of the Stony Brook Cancer Center and is a research scientist who is considered one of the fathers of sphingolipid biomedical research and is a founding member of Sphingogene.Mr. David Haselwood is the head of business and corporate development of Gradalis, Inc and has an extensive background in investment and operation within the healthcare industry.Mr. Allen Conger is an experienced, successful investment banker and is our acting CFO.
40 Scientific Advisors and Collaborators Besim Ogretmen, Ph.D., Key expert on sphingolipid metabolismXiang Liu, MD, PhD, Key scientist and expert on acid ceramidase in cancerAlicja Bielawska, Ph.D., Key chemistZdzislaw M. Szulc, PhD key chemist
41 Clinical AdvisorsThomas Keane, MD, Chairman of Urology, Medical University of SCMichael Lilly, MD, Professor Department of Medicine, Hem-Onc, Medical University of SCDavid Marshall, MD, Associate Professor, Radiation Oncology, Medical University of SCCarolyn Britten, MD, Associate Professor, Department of Medicine, Hem-Onc, Medical University of SC