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Small Molecule Platform Improving Radiation Treatment

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Presentation on theme: "Small Molecule Platform Improving Radiation Treatment"— Presentation transcript:

1 Small Molecule Platform Improving Radiation Treatment
SphingoGene, Inc. Delaware C-Corporation James S Norris PhD Board President and Interim CEO Introductions Darren: 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 Objective To 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 signaling Cell differentiation Proliferation Programmed 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

5 Sphingolipids as Therapeutics
Alleviate resistance to Chemotherapy Radiation Therapy Synergistic killing with targeted therapies (combination therapy) TKIs – imatinib, dasatinib, nilotinib, sorafenib, sunitinib HDAC inhibitors – vorinostat mAbs – Rituximab, milatuzumab

6 Current Sphigolipid Drugs – Still Early
Fingolimod (Gilenya, Novartis) First oral drug for Multiple Sclerosis $1.2B sales in 2012, up 147% from 2011 iSONEP (Lpath) Phase 2 clinical development for wet AMD (macular degeneration) $500M partnerships with Pfizer Others - in preclinical development

7 SPG105 is a small molecular drug that inhibits acid ceramidase

8 Rational for Our Drugs Mechanism of Action:
Cancer Cell Death Ceramide Acid Ceramidase Prevents ceramide accumulation Allows escape from cell death Sphingogene 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 Ceramidase And Potentiates Radiation Induced Cancer Killing Acid Ceramidase Prevents ceramide accumulation Allows escape from cell death Sphingogene 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 Cheng MUSC MD/PhD candidate SphingoGene Researcher “Hurry up! The Baby Boom generation is getting prostate cancer!” Ken Burger Author 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 gland Most common cancer in men Risk increases with age In 2012: 241,740 men will be diagnosed 25,170 will die from the disease

14 How Our Platform Works Ceramide levels increase during radiation therapy; leads to cancer cell death Acid ceramidase (AC) and Sphingosine Kinase (SK) activity increase during radiation therapy in cancer cells AC reduces ceramide levels, SK forms S1P, both permitting cancer cell survival Our compounds inhibit AC or SK or mimic ceramide making radiation or other therapies more effective at inducing cancer cell death

15 Progress and Leads Clinical efficacy established in animal models of cancer at nM concentrations Dose Escalation: No toxicity observed at effective doses and 20 X higher doses Lead Small Molecule Candidates (of 40): Drug Target Stage of Development SPG 105 AC Inhibitor Clinical lead; efficacy established in rodent tumor xenograft models and cell culture models of prostate and breast cancers SPG 103 Ceramide-like Drug Efficacy established in rodent tumor xenograft pancreatic cancer models and cell lines SPG 104 SK1 Inhibitor Clinical Efficacy in vitro and in vivo pending

16 In Vivo Efficacy SG105 (clinical lead) Significantly Reduces Tumor Size; in vivo mouse Xenograft Prostate Tumor Model Control (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 Efficacy SPG105 Significantly Reduces Mortality; in vivo mouse Xenograft Prostate Tumor Model Percent Survival

18 Xenograph toxicity studies
I don’t have the figures. Would you please insert?

19 PK/PD studies

20 Toxicity Study There is No Significant Toxicity Observed in Blood Chemical Test in Animal after Multiple Injections (150mg/kg ip every other day x5) Un-treated Cremophore LCL521 Mode Means SD ALB(g/DL) 3.38 0.40 3.50 0.12 3.23 0.25 WBC(10/L) 5.54 1.46 7.30 2.50 7.29 ALP(U/L) 98.25 7.76 89.50 10.38 88.50 13.08 LYM (10/L) 4.57 1.07 5.36 0.19 5.50 1.81 ALT(U/L) 97.00 32.59 92.50 85.02 81.75 57.38 MON (10/L) 0.20 0.18 0.30 0.27 0.26 0.24 AMY(U/L) 42.26 955.75 37.53 946.25 40.36 GRA (10/L) 0.77 0.52 1.64 2.25 1.56 1.37 TBIL(mg/DL) 0.28 0.05 0.00 LY % 83.30 7.91 78.80 20.63 77.90 10.83 BUN(mg/DL) 23.50 2.52 20.25 2.87 17.50 2.38 MO % 3.28 2.09 3.55 2.02 3.35 2.14 CA++(mg/DL) 10.85 0.29 10.45 10.70 GR % 13.45 8.00 17.68 18.70 18.80 10.03 PHOS(mg/DL) 6.95 1.02 7.35 7.90 0.93 RBC (12/L) 12.30 0.37 12.00 0.67 11.98 CRE (mg/DL) HGB (g/DL) 14.78 14.10 0.61 14.35 GLU (mg/DL) 140.75 20.04 134.50 17.75 127.50 21.44 HCT % 51.69 50.49 2.70 51.12 2.07 NA+ (MMO/L 155.75 1.26 154.25 0.96 156.25 2.99 MCV ( fl ) 42.00 42.75 K+ (MMO/L) 6.05 0.81 6.63 7.85 MCH (pg) 11.78 0.21 TP (g/DL) 5.88 5.63 0.22 5.78 MCHC (g/DL) 28.55 0.47 27.95 0.44 28.05 1.40 GLOB (g/DL) 0.45 2.13 0.13 2.55 0.06 RDWc % 15.95 0.56 16.20 0.42 17.00 0.63 n=4 PLT (10/L) 386.75 251.67 562.00 76.68 630.25 47.41 PCT % 0.17 0.36 0.41 0.03 MPV ( fl ) 6.35 6.45 6.48 PDWc % 28.80 0.35 28.63 0.71 29.75 0.68

21 Toxicity Study

22 Our Value Proposition Enhances Radiotherapy leading to more effective cancer treatment Fewer side effects Achieve same clinical benefit with reduced radiation Better quality of life Greater preservation of sexual function Reduce incidence of relapse = Reduced overall treatment costs and reduced death rate Small Molecules = Easy manufacturing and delivery

23 More effective radiotherapy of prostate cancer means:
Same clinical benefit with reduced radiation Fewer side effects Greater preservation of sexual function and continence issues Reduced incidence of relapse Targets mechanism of radioresistance Reduced death rates And, 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 therapy Market penetration expected similar to other cancer therapeutics No increase in cases, no relapses $8000 per treatment per patient (drug cost) Estimated worldwide market projected in billions

26 Other Markets Platform 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: 1,600,000 Breast: 1,380,000 Pancreatic: ,000 Oral cavity: ,900 Brain: ,913 Total: 3,701,813 cases/year Estimated worldwide market projected in billions

27 China’s Cancer Crisis – Lung Cancer Prevalent
3.5M new cases/yr; 2.5M death/yr Source: The National Cancer Registry under the Ministry of Health

28 Radiation Therapy for Other Cancers – Candidates for SPG105
Lung Gy in fractions Breast Gy in fractions Pancreas Gy in fractions Melanoma 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. Chemotherapy TKI targeted therapies HDACI therapies mAb therapies

32 Patent Position SphingoGene has filed broad patents around targets and various classes of compounds which can affect their targets Lead Compounds: Worldwide Patent pending for SPG105 (clinical lead); US 2011/ A1 Issued patent for SPG103; US8,093,393 B2 Patent 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 radiotherapy Primary Endpoint: Safety/Tolerability Phase IIa: Prostate Cancer Patients undergoing primary radiotherapy Second Endpoint: Efficacy/biochemical relapse Overall Timeline to Exit:

34 Company Funding to Date
NIH/NCI (University) Program Project Grant: $1.6million NIH Small Business Technology Transfer (STTR) Grant: $432,000 ARRA stimulus package: $180,000 South Carolina Research Authority (SCRA) start-up funds and SBIR match: $125,000 Total: $2.34 Million of Non-dilutive funding

35 Need $2M to Complete the Following:
GMP synthesis Formulation Toxicity testing (rats, non-human privates

36 Anticipated Funding Phase I/II Small Business Innovative Research (SBIR) Grant (CA ): $2,115,479 Phase I STTR (CA ): $346,792 Up to $200,000 (SCRA) Total: $2.6 Million of Non-dilutive Funding

37 Anticipated Financial Needs
Projected cost for each milestone GMP Synthesis (SBIR) $149,400 Formulation $79,100 Toxicity Testing (rats, non human primates) $1,618,649 Phase I Trial (Hollings Cancer Center) $1,100,000 Phase II Trial (Hollings Cancer Center) $3,640,000 So 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 CEO Professor, Department of Microbiology & Immunology Medical University of South Carolina (MUSC) David Haselwood, Board Member & Business Advisor Experienced life science VC, entrepreneur & operator Burrill & Co, Roche, Proventys, Pharmasset, Primera Yusuf Hannun, MD, Director of the Stony Brook University Cancer Center Joel Kenney Professor of Medicine, and the Vice Dean for Cancer Medicine World famous expert in sphingolipid biochemistry

39 Advisors: Allen Conger, MBA University of Chicago
Experienced investment banker Andrew 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 president Sphingogene’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 metabolism Xiang Liu, MD, PhD, Key scientist and expert on acid ceramidase in cancer Alicja Bielawska, Ph.D., Key chemist Zdzislaw M. Szulc, PhD key chemist

41 Clinical Advisors Thomas Keane, MD, Chairman of Urology, Medical University of SC Michael Lilly, MD, Professor Department of Medicine, Hem-Onc, Medical University of SC David Marshall, MD, Associate Professor, Radiation Oncology, Medical University of SC Carolyn Britten, MD, Associate Professor, Department of Medicine, Hem-Onc, Medical University of SC

42 Press 1165/seeking-a-cure-musc-biotech-spinoff-wages-its-own-small-war- on-cancer 1010/improved-prognosis-tech-transfer-at-musc


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