Alaunos Therapeutics, Inc. · NASDAQ:TCRT
Alaunos Therapeutics — ZIOPHARM Oncology — Investor Day (June 2012)
64 slides from Alaunos Therapeutics's investor day presentation, Jun 19, 2012
Slide 1: 2012 Research & Development Day
Jonathan Lewis, MD, PhD Chief Executive Officer 2012 Research & Development Day June 19, 2012
Slide 2: Forward-Looking Statements
Forward - Looking Statements This presentation contains certain forward - looking information about ZIOPHARM Oncology that is intended to be covered by the safe harbor for “forward - looking statements” provided by the Private Securities Litigation Reform Act of 1995 , as amended . Forward - looking
Slide 3: Data-Driven Oncology Portfolio
Compound Preclinical Phase 1 Phase 2 Phase 3 Palifosfamide Soft Tissue Sarcoma Small Cell Lung Cancer Other Phase 2 Study Oral DNA Therapeutics Ad - IL12 DC - IL12 Other Candidates Indibulin Breast Cancer Darinaparsin Oral Data - Driven Oncology Portfolio
Slide 4: Our Guests
Our Guests – Wael Harb, MD, Chief Community Officer of the Hoosier Oncology Group, Director of Cancer Services and Clinical Research at Indiana University Health Arnett – Ramaswamy Govindan, MD, Head of the Thoracic Oncology Program, Co - Director of Medical Oncology, and Professor of Medicine, Onco
Slide 5: Agenda
Palifosfamide Small Cell Lung Cancer Sarcoma DNA Therapeutics Rational Drug Development Program – Rational Design and Preclinical Activity – Phase 1 Bridging Study in SCLC – MATISSE: A Phase 3 Study – FDA, PFS & the Shifting Landscape in Sarcoma – The PICASSO 3 Study – AD - IL12 and DNA Therapeutics
Slide 6: Palifosfamide
Palifosfamide june 19,2012 |6
Slide 7: Biosynthesis & Metabolism
Biosynthesis & Metabolism 2 - and 3 - dechloroethylifosfamide + chloroacetaldehyde ALDH1A1 c hloroacetic acid m ainly CYP3A4/5 and CYP2B6 ifosfamide m ainly CYP3A4/5 4 - ketoifosfamide 4 - hydroxyifosfamide ADH 4 - thiofosfamide carboxyifosfamide alcoifosfamide 1,3, - oxazolidine - 2 - one aldofosfa
Slide 8: Palifosfamide mechanism: DNA crosslinking
C H 2 N H P - O H O H N - C H 2 - C H 2 5 ' - X - G - X - C - X - 3 ' 3' - X - C - X - G - X - 5' C H 2 + +++++ ++ 5 ' - X - G - C - X - X - 3 ' 3 ' - X - C - G - X - X - 5 ' 5 ' - X - G - X - X - C - 3 ' 3 ' - X - C - X - X - G - 5 ' 5 ' - X - G - X - C - 3 ' 3 ' - X - C - X - G - 5 ' Palifosfamide
Slide 9: Rational Drug Development: Extensive Early Clinical Study
Rational Drug Development: Extensive Early Clinical Study Informed Late - Stage Programs Phase 1 Dose Phase 2 Proof - of - Concept in Advanced Disease Phase 1 with Doxorubicin Phase 2 Randomized Phase 3 Randomized, Double Blind, Placebo - Controlled (prior HOG Phase 3 positive + Ifosfamide) Phase 1
Slide 10: Small Cell Lung Cancer: Rational Design and Preclinical Activity
Wael Harb, MD Small Cell Lung Cancer Rational Design and Preclinical Activity Phase 1 Bridging Study
Slide 11: A Novel DNA-Targeted Drug
Broad Application Effect in solid tumors and hematological malignancies Safety, Efficacy and Accessibility Active in ALDH hi cells, rapid on - off kinetics, less toxic and ease of administration Addressing Unmet Needs Orphan Drug status for STS in U.S. and Europe Long Commercial and Development Runw
Slide 12: Preclinical Activity & Safety
Low Toxicity No neurotoxicity or bladder toxicity Minimal Patient - to Patient Variability On/off rapid kinetics minimize interpatient variability; target cancer Broad Activity Active in multiple tumor cell lines and human cancer xenografts, including sarcoma Activity in Resistant Tumors Bypasses se
Slide 13: ALDH: Potential Impact on Cancer Stem Cells
ALDH is a validated marker of cancer stem cells ALDH+ cells are generally resistant to treatment and chemotherapy ALDH+ cells are readily detectable in multiple subtypes of epithelial cancer, bone marrow derived cancer and sarcoma SCLC direct patient xenografts have an abundant population of tumor c
Slide 14: Palifosfamide + Doxorubicin Phase 1: Early Activity in STS and SCLC
IPM1002 : Phase 1 Palifosfamide + Doxorubicin – Early Activity in STS and SCLC • 13 subjects with advanced/refractory cancers, 12 evaluable – 8 STS, 2 SCLC • Study identified a clinically tolerable and effective dose combination – D oxorubicin (75 mg/m 2 ), palifosfamide - tris (150 mg/m 2 ) – C max
Slide 15: IPM1004: Phase 1b Interim Data (PaCE)
• Dose escalation palifosfamide and etoposide in selected cancers – SCLC – Other (germ cell; ovarian; uterine leiomyosarcoma; NSCLC) • 15 patients reported at interim – SCLC, 5 ( all previously treated in first - line setting; then progressing) – NSCLC, 2 – Ovarian, 2 – Germ Cell Tumor, 1 • SAEs in
Slide 16: Rapid Clinical Activity: Germ Cell Tumor
• Normalization of tumor markers: ─ Previously treated ( including ifosfamide containing regimen – developed encephalopathy) ─ β HCG reduction: 2358 to 12 mU/Ml ─ Completed 4 cycles of therapy Rapid Clinical Activity: Primary Mediastinal Nonseminomatous Germ Cell Tumor 0 500 1000 1500 2000 2500 β HC
Slide 17: Updated Phase 1b Data Bridge to MATISSE
Updated Phase 1b Data Bridge to Adaptive Phase 3 (MATISSE) Clinical Benefit Rate = 67% Range of cycles 2 – 17+ Response Assessment 1 Patients N=18 Cancer Types PR 6 Germ Cell Tumor, NSCLC, Ovarian, SCLC (2), Uterine Leiomyosarcoma SD 7 Ovarian (2), NSCLC, SCLC (2), Squamous Cell, DFSP PD 5 Adenoc ar
Slide 18: MATISSE: A Phase 3 Study in Extensive-Stage SCLC
Ramaswamy Govindan, MD MATISSE: A Phase 3 Study in Extensive - Stage Small Cell Lung Cancer
Slide 19: Small Cell Lung Cancer (SCLC)
• Significant unmet medical need in cancer with no new front - line therapies in decades – Approximately 15% of lung cancers – 30,000 - 35,000 U.S. incidence/200,000 worldwide 1 (China annual incidence alone growing to >150,000 2 ) • Platinum plus etoposide SOC front - line; concurrent w/radiation i
Slide 20: Contemporary Phase 3 Trials in First-Line ES-SCLC
Contemporary Phase 3 Trials in 1 st Line ES - SCLC: Ifosfamide – Only Positive Study Study Regimen Results Irinotecan Lara PN et al. J Clin Oncol 2009;27:2530 Cisplatin + etoposide vs cisplatin + IRINOTECAN No difference in PFS or OS Topotecan Eckardt JR et al. J Clin Oncol 2006;24:2044 TOPOTECAN +
Slide 21: Positive Phase 3 Randomized Ifosfamide Study in SCLC
Cisplatin plus etoposide with or without ifosfamide in extensive - stage small - cell lung cancer : Hoosier Oncology Group - Einhorn et. al. VIP regimen: etoposide (75 mg/m 2 ), ifosfamide (1.2 g/m 2 ), cisplatin (20 mg/m 2 ) - days 1 to 4 x four cycles. » Statistically significant difference in med
Slide 22: The MATISSE Study
The MATISSE Study: M ulticenter A daptive T rial I nvestigating S mall Cell Lung Cancer S urvival E ndpoints • A Multi - center, Open - Label, Adaptive, Randomized Study of Palifosfamide, a Novel DNA Cross - linker , in Combination with Carboplatin and Etoposide (PaCE) Chemotherapy versus Carboplati
Slide 23: MATISSE Study Design
Design Multinational, multi - center, randomized controlled, open - label, adaptive trial N Up to 548 subjects Population Males and females, age ≥18 years, with extensive - stage small cell lung cancer Primary Endpoint Overall survival (OS) Secondary Endpoints Progression - free survival (PFS) Objec
Slide 24: Adaptive Clinical Trial Design
Adaptive Clinical Trial Design: • Prospectively planned opportunity to modify the study by adjusting specified aspects of the study design and/or hypotheses • Adjustments based on analysis of real time data (usually interim data) from subjects in the study • Analyses of accumulating study data perfo
Slide 25: MATISSE Adaptive Trial Design
MATISSE Adaptive Trial Design Single pre - planned evaluation by the IDMC • Optimize chances of success • Stop trial for efficacy/futility • Complete trial as planned or resize study 125 Events Continue trial with decreased sample size Complete trial as planned Continue trial with increased event si
Slide 26: Palifosfamide: Rational Development in High Unmet Medical Need
• Rationale: – Ifosfamide has been only front - line therapy to show survival benefit added to SOC… but with excessive toxicity , never adopted – High mutant variability in SCLC necessitates a treatment with broad DNA, multi - genomic, cancer stem cell activity – Palifosfamide added to SOC demonstra
Slide 27: Sarcoma: FDA, PFS & the Shifting Landscape
Mark Thornton, MD, PhD Sarcoma FDA, PFS & the Shifting Landscape
Slide 28: The Changing Landscape of PFS as a Primary Endpoint
• A PFS primary endpoint in Phase 3 registration trials has undergone pendulum swings over time, and is now in favor: – In 2011, four products were approved based on PFS as primary trial endpoint – In 2012, pazopanib (Votrient ® ) became the 5 th precedent, and the first for STS • Rajeshwari Sridhar
Slide 29: Criteria for Full Approval Based on PFS
• Criteria for PFS (Sridhara, May 18, 2012): – Rare cancer – Large magnitude of benefit (“months not weeks”) – High quality data – No negative impact/trend on OS – Favorable risk/benefit • Note that setting (1 st line, 2 nd line) is not a factor in applying the policy. Rare is rare. – However, for a
Slide 30: Impact of Rare Disease Advocates on PDUFA
• PDUFA reauthorization cycle coincides with intensive reform lobbying by advocacy community – PDUFA will mandate FDA: • Listen to patient input regarding acceptable risk/benefit • Show evidence of flexibility in rare disease settings • Enhance use of accelerated approval beyond HIV/oncology • Relev
Slide 31: Relevance to Regulatory Strategy for Palifosfamide in STS
• Current policy is clear by both precedent, as well as by recent public comments from senior FDA officials • Pazopanib full approval for STS confirms sound strategy of PFS as primary endpoint for palifosfamide to attain FDA approval as lead indication in front - line STS • PFS is appropriate primar
Slide 32: The PICASSO Study
Robert Maki, MD, PhD The PICASSO 3 Study
Slide 33: Soft Tissue Sarcoma
Soft Tissue Sarcoma $ in Millions • Currently over 100,000 people diagnosed with STS worldwide; estimated metastatic front - line of 23,000 people for U.S. and Europe* – Estimated 9,000 treated for front - line metastatic disease in U.S., target indication – Estimated 14,000 being treated in Europe
Slide 34: IPM2001: Palifosfamide Monotherapy Effect on Tumor Mass
IPM2001: Phase 1/2 (Palifosfamide Monotherapy) Effect on Tumor Mass Presented at the Liddy Schriver Sarcoma Initiative, 2009 Refractory L iposarcoma Baseline 12 Weeks 13.9 x 11.2 cm 9.0 x 7.0 cm
Slide 35: PICASSO: A Phase 2 Randomized Study
PICASSO: A Phase 2 Randomized Study Selected Best of ASCO (2010) Patients with unresectable/ metastatic Soft Tissue Sarcomas Arm B: Doxorubicin (75 mg/m 2 ) • Age (≥65 or <65) • Histologic subtype (leiomyosarcoma, synovial sarcoma or other) E very 3 weeks x 6 cycles U pon completion of 6 cycles Pali
Slide 36: Randomized Phase 2 Data (PICASSO)
Arm A : Pali+Dox Arm B : Dox PFS: median 7.8 mos. 4.4 mos. PFS: hazard ratio 0.43 OS: hazard ratio ( with crossover ) 0.78 2 - yr survival ( with crossover ) ** 40% 30% Safety • Similarity between arms • No encephalopathy, hemorrhagic cystitis, Fanconi's Syndrome Grade 3+ events • Neutropenia and el
Slide 37: Phase 3 Structure (PICASSO 3)
Phase 3 Structure ( PICASSO 3) N : Approximately 424 patients; front - line metastatic STS Regimen: Palifosfamide + doxorubicin vs doxorubicin + placebo Primary Endpoint: PFS for accelerated approval; OS for full approval Powered for PFS & OS PFS Power: 85% power to detect 0.60 HR, 3 month median Δ
Slide 38: PICASSO 3 Study Schema
PICASSO 3 Study Schema R A N D O M I Z E 1:1 Palifosfamide 150 mg/m 2 d1,2,3 + Doxorubicin 75 mg/m 2 d1 q 21 d x 6 cycles Histology (LMS, SS, other) A ge (<65 vs >=65) Placebo d1,2,3 + Doxorubicin 75 mg/m 2 d1 • Frontline metastatic STS (central review of histology) • Neo/adjuvant Gemzar ® and Taxot
Slide 39: Palifosfamide for Front-Line Soft Tissue Sarcoma
• High unmet medical need with no new approved treatments in over 30 years in the front - line setting • April 2012 FDA full approval of Votrient ® validate PFS endpoint • Objective of palifosfamide in combination with doxorubicin as standard of care for front - line metastatic STS • PICASSO 3 resul
Slide 40: DNA Therapeutics
DNA Therapeutics June 19, 2012
Slide 41: DNA Therapeutics
• A revolutionary technology for the precise, controlled delivery of therapeutic proteins in vivo • Lead therapeutic / early validation of the platform – IL - 12 is a prime target for a controlled release approach – IL - 12 is an increasingly compelling target to big pharma • “Next - wave” of therap
Slide 42: Ad-IL12 and DNA Therapeutics
Hagop Youssoufian, MD AD - IL12 and DNA Therapeutics
Slide 43: DNA Therapeutics: Capabilities
Leverage the power of DNA technology to build novel therapeutic products • Precision: control over biologic drug distribution (local/systemic) • Controlled: in vivo control of dosing through first in - human biological on/off switch (RheoSwitch Therapeutic System ® ) • Adaptable: multiple therapeuti
Slide 44: Using Natural Cell Biology to Produce Proteins
Using Natural Cell Biology to Produce Proteins Controlled mRNA Oral ligand activates DNA, protein production begins Therapeutic proteins Target Cell Precision Translation Adaptable
Slide 45: IL-12 DNA
• IL12 – A renewed interest in an well characterized, naturally occurring cytokine – Activity alone and in combination • Indications of interest – Melanoma – Breast cancer – Head and neck cancer IL - 12 DNA
Slide 46: IL12: Foundation for Immunotherapy
IL12: Foundation for Immunotherapy • Preserve anti - tumor potency • Deliver safely IL12 Remodel Tumor Environment Antiangiogenic Enhance Tumor Immunity
Slide 47: Two Clinical Stage Product Candidates
Two Clinical Stage Product Candidates • DC - IL12 Phase 1b in metastatic melanoma – Safety profile predictable – 2 PRs, 2 SDs, biomarker effects • Ad - IL12 Phase 1b in metastatic melanoma – S afe to date – Preliminary activity – Significant data expected 2H 2012 P ost - treatment Pre - treatment CT
Slide 48: Phase 1/2 of Ad-IL12 + AL in Melanoma
Next Phase of Development: • Remains a significant unmet need in metastatic melanoma despite evolving landscape • Phase 2 to begin at confirmation of biologically effective dose • Phase 2 modifications to include additional patient - selection criteria to maximize signal detection • Planned to be co
Slide 49: Additional Directions: Breast Cancer
Additional Clinical and Preclinical Directions: Breast Cancer • Significant unmet medical need • Potential for multiple approaches to treatment: - Ad - IL12 monotherapy - Ad - IL12 in combination with palifosfamide (novel - novel strategy) • Study design under evaluation
Slide 50: Additional Directions: Head and Neck Cancer
Additional Clinical and Preclinical Directions: Head and Neck Cancer + Erbitux ® • Head and neck cancer ─ Significant unmet medical need ─ Ad - IL12 in combination with Erbitux ® ─ May lead to a pivotal study ─ Various paths forward
Slide 51: Conclusions
Conclusions • IL12 - based intratumoral therapy has yielded initial proof - of - concept and appears to be well tolerated • Melanoma to be pursued as lead indication - Protocol discussions with FDA to establish and maintain alignment and clarity toward an approval path • Head - and - neck and breast
Slide 52: Cancer Biology in the 21st Century: Translation in the Clinic
Larry Norton, MD Cancer Biology in the 21 st Century: Translation in the Clinic
Slide 53: Tycho Brahe and Johannes Kepler
Tycho Brahe 1546 - 1601 Johannes Kepler 1571 - 1630
Slide 54: Ki67 Not Greater than in Non-Metastatic Lines
But Ki67 (Mitotic Fraction) is Not Greater than in Non - Metastatic Lines 0 100 200 300 400 500 600 700 800 0 10 20 30 40 50 4175 (n=9) 1834 (n=10) 1833 (n=5) Parental (n=5) Tumor volume (mm 3 ) Days post - injection Growth in Mammary Fat Pad Minn , Gupta et al., Nature 2005 4175 1833
Slide 55: The Self-Seeding Model of Epithelial Cancer
The Self - Seeding Model of Epithelial Cancer Norton, Massagué: Nature Med 2006
Slide 56: Self-Seeding Explains Gompertzian Growth
0.00000001 0.000001 0.0001 0.01 1 100 0 20 40 60 80 100 dN t / dt = k* N t a /c N t b /c Arbitrary (Arithmetic) Time Scale Cubic Centimeters Self - Seeding Explains Gompertzian Growth Bigger Tumor = Lower Surface to Volume Ratio = Slower Growth at Surface Smaller Tumor = Greater Surface to Volume
Slide 57: Palifosfamide I.V. vs. MX-1 Breast Cancer Xenograft
Figure 1 Palifosfamide I.V. vs. MX-1 Breast Cancer Xenograft AN, /dt = k*N2/— Ni P/¢ Peak Day — 180mg/kg 16 — 120mg/kg 16 38 — 80mg/kg 14 Norton-Simon Parameter = — 53mg/kg 12 5 ° is 2 5 10 1s 20 25 1400 4 + Control Data Pd — Curve Fit 1200 £ 4 Data @ 180 mg/kg 3 — Curve Fit g 800 ™ Data @ 120 mg/kg
Slide 58: In Conclusion…
Jonathan Lewis, MD, PhD In Conclusion…
Slide 59: Data-Driven Oncology Portfolio
Compound Preclinical Phase 1 Phase 2 Phase 3 Palifosfamide Soft Tissue Sarcoma Small Cell Lung Cancer Other Phase 2 Study Oral DNA Therapeutics Ad - IL12 DC - IL12 Other Candidates Indibulin Breast Cancer Darinaparsin Oral Data - Driven Oncology Portfolio
Slide 60: Two Pivotal Programs Representing Significant, Global Market Potential
Two Pivotal Programs Representing Significant, Global Market Potential Blended EU/US Price Per Patient STS Patients Treated $ 30,000 $ 40,000 $ 50,000 Soft Tissue Sarcoma 9,000 $ 270 $ 360 $ 450 10,000 $ 300 $ 400 $ 500 11,000 $ 330 $ 440 $ 550 Small Cell Lung Cancer 14,000 $ 420 $ 560 $ 700 16,000
Slide 61: Anticipated Key Clinical Milestones 2012
IL - 12 DNA Program Phase 1 Data 2012 Phase 2 Melanoma 2H 2012 New DNA Candidates • Preclinical Data 2012 Palifosfamide and DNA Therapeutics: 2012 Anticipated Key Clinical Milestones Palifosfamide DNA Therapeutics PICASSO 3 STS Pivotal PFS Data 2H 2012 MATISSE SCLC Phase 3 Initiation 2Q 2012
Slide 62: Balance Sheet Support Through Key Milestones
• Primary shares outstanding: approximately 79.5MM • Cash: approximately $ 128MM @ 3/31/12 Balance Sheet Support Through Key Milestones
Slide 63: ZIOPHARM Highlights
An intelligent portfolio of therapeutics addressing unmet medical needs in cancer • Palifosfamide – Wholly - owned asset – Near - term, Phase 3 study results in STS – Phase 3 for SCLC now enrolling – Potential in multiple solid and hematological tumors – >$1 Bn total market potential in two indicati
Slide 64: Better Cancer Medicine Questions
Better Cancer Medicine Questions