Fennec Pharmaceuticals Inc. · NASDAQ:FENC
Fennec Pharmaceuticals — Technical Presentation (November 2011)
35 slides from Fennec Pharmaceuticals's technical presentation, Nov 1, 2011
Slide 1: Sodium Thiosulfate (STS) for the Prevention of Ototoxicity Induced by Platinum Chemotherapy in Pediatric Patients
Sodium Thiosulfate (STS) for the Preven6on of Ototoxicity Induced by Pla6num Chemotherapy in Pediatric Pa6ents 01 November 2011 1
Slide 2: Agenda
Pediatric Subcommi4ee of Oncology Drugs Advisory Commi4ee AGENDA Introduction Franck Rousseau, MD Pediatric Hearing Damage Kristin Knight, MS, CCC-‐A STS Preclinical and Clinical Data Edward Neuwelt, MD COG and SIOPEL Clinical Studies David Freyer, DO, MS Challenges of Otoprotection in Adults James
Slide 3: Representatives of Adherex
RepresentaAves of Adherex Lu Chen, PhD Edward Neuwelt, MD Senior Statistician, COG Professor Neurology and Neurosurgery OHSU John Delehanty. PhD Clinical, Adherex Joseph Quinn, MSPH Biostatistics, Adherex David R. Freyer, DO, MS, Chair of COG Study Franck Rousseau, MD Medical Affairs, Adherex Kristi
Slide 4: Introduction
IntroducAon • STS Orphan Drug designation March 2004 • For the prevention of platinum-‐induced ototoxicity in pediatric patients • STS only being developed for ototoxicity protection in Pediatrics • FDA Development Meeting Held March 2011 • Demonstrate STS does not reduce efUicacy of cisplatin • CO
Slide 5: Adherex Proposition
Adherex ProposiAon • A non-‐inferiority trial design for tumor protection has serious challenges • Proposal • Submit COG study as single Phase III trial to support accelerated approval • Traditional approval • SIOPEL6 • Post-‐marketing cohort safety surveillance study 5
Slide 6: Pediatric Hearing Damage
Pediatric Hearing Damage Kristin Knight, MS, CCC-‐A Assistant Professor, Director of Pediatric Audiology Oregon Health and Science University Portland, Oregon 6
Slide 7: Ototoxic Hearing Loss in Children
Ototoxic Hearing Loss in Children Baseline End of treatment (6 months) Platinum-‐induced hearing loss in a 4 year-‐old treated for neuroblastoma 7
Slide 8: Spelling Words through Simulated Hearing Loss above 2000 Hz
Spelling Words through Simulated Hearing Loss above 2000 Hz 125 250 500 1000 2000 4000 8000 1. 0 2. 10 3. z v HEARING LEVEL (dB HL) 20 p 30 h g 4. ch sh 40 j md n l oar 5. nb 50 ge u i 6. 60 70 7. 80 8. 90 100 9. 110 10. 120 Click on Speaker to Present Spelling Word. AUDIOGRAM OF FAMILIAR SOUNDS FRE
Slide 9: Ototoxicity in Children Treated with Cisplatin and/or Carboplatin
Ototoxicity in Children Treated with CisplaAn and/or CarboplaAn 61% bilateral hearing loss (ASHA criteria) at the end of treatment 41% required hearing aids that only partially restore hearing 22% of patients had dose reductions due to ototoxicity Gilmer-Knight et al., Journal of Clinical Oncology,
Slide 10: Cisplatin Ototoxicity Risk Factors
CisplaAn Ototoxicity Risk Factors Children younger than 5 years at treatment: 21 times the risk for hearing loss compared to adolescents Li et al., European Journal of Cancer, 2004, 40(16):2445-2451 10
Slide 11: Educational Impact and Quality of Life
EducaAonal Impact and Quality of Life • Even minimal hearing loss (MSHL) is damaging – High risk for being held back a grade (37% versus 3%) • Neuroblastoma survivors with hearing loss – Twice the rate of parent reported problems with reading, math, attention and need for special education – Poorer
Slide 12: STS Preclinical and Clinical Studies Supporting Otoprotection and Lack of Tumor Protection
STS Preclinical and Clinical Studies Suppor6ng Otoprotec6on and Lack of Tumor Protec6on Edward A Neuwelt, MD Director Blood Brain Barrier Program Professor Neurology and Neurosurgery Oregon Health and Science University Portland, Oregon 12
Slide 13: Sodium Thiosulfate
Sodium Thiosulfate Properties • Na2S2O3 • Water soluble • Thiol compound • Reducing agent • Excreted by kidney • Biological T1/2 18 min • Antidote for cyanide Relevant Effects • Covalent thiol-binding of electrophilic platinum • Scavenging of reactive oxygen species • May concentrate in cochlear end
Slide 14: STS Protection Against Cisplatin Cochlear Toxicity in the Guinea Pig
STS ProtecAon Against CisplaAn Cochlear Toxicity in the Guinea Pig STS given 2 hours after cisplatin protected against cochlear damage Muldoon LL et al. Clin Cancer Res 2000;6:309-315 14
Slide 15: STS Protects Against Cisplatin Ototoxicity in the Rat
STS Protects Against CisplaAn Ototoxicity in the Rat Change from baseline hearing threshold. Effect of STS (8 g/m2 IV) 4 hrs*, 8 hrs*, or 12 hrs after administration of cisplatin (6 mg/kg IA) *Statistically signiUicant Dickey DT et al. J Pharmacol Exp Therapeut 2005;314:1052-1058 15
Slide 16: Time-Dependent Tumor Protection of STS in Cisplatin-Treated Cells
Time-‐Dependent Tumor ProtecAon of STS in CisplaAn-‐Treated Cells DAOY medulloblastoma cells were treated with STS from 0 to 8 hrs after treatment with cisplatin. Data were normalized to maximum chemoprotection with STS STS did not protect tumor cells if given >4 h after cisplatin Dickey DT et al.
Slide 17: Time-Dependent Tumor Protection of STS after Cisplatin in Nude Mice
Time-‐Dependent Tumor ProtecAon of STS aPer AdministraAon of CisplaAn in Nude Mice Nude mice with subcutaneous neuroblastoma cells. STS was administered with cisplatin and 6 hr after cisplatin Harned TM et al. Clin Cancer Res 2008;14:533-540 17
Slide 18: Preclinical and early clinical data set the stage for COG and SIOPEL6
• These preclinical and early clinical data set the stage for the COG and SIOPEL6 studies 18
Slide 19: COG and SIOPEL Clinical Studies
COG and SIOPEL Clinical Studies David R. Freyer, DO, MS Chair of the ACCL0431 Study Director, LIFE Cancer Survivorship & Transition Program, Children's Center for Cancer & Blood Diseases, Children's Hospital Los Angeles, California Keck School of Medicine, University of Southern California 19
Slide 20: ACCL0431: Randomized Study of STS for Prevention of Cisplatin-induced Hearing Loss
ACCL0431: Randomized Study of Sodium Thiosulfate (STS) for Preven6on of Cispla6n-‐induced Hearing Loss Presenta(on to Pediatric ODAC November 1, 2011 David R. Freyer, DO, MS Study Chair Children’s Hospital Los Angeles Children’s Center for Cancer and Blood Diseases CHILDREN’S ONCOLOGY GROUP
Slide 21: Specific Aims
Specific Aims Primary Evaluate efficacy of STS for prevention of hearing loss in children receiving cisplatin chemotherapy Secondary Compare change in mean hearing thresholds Compare incidences of other Grade 3 and 4 toxicities (renal and hematological toxicity) Monitor EFS and OS in two
Slide 22: Methods
Methods Key Eligibility Criteria Diagnosis: any malignancy treated with cisplatin (most common: NBL, HBL, MBL, OGS, GCT) Planned cumulative cisplatin dose ≥ 200 mg/m2 Normal audiometry Randomization: STS vs. no STS (Control) STS administered IV over 15 min six hours post-CDDP CHILDREN’S
Slide 23: ACCL0431 Study Schema
ACCL0431 Study Schema Cisplatin per STS 6 hrs STS Arm treatment post cisplatin protocol Cisplatin- Standard audiometry at baseline based Randomize and < 8 days before each protocol cisplatin course Cisplatin per treatment protocol Control Arm Audiometry at 4 weeks and Complete 12 months post-treatme
Slide 24: Current Status—Diagnoses
Current Status—Diagnoses Control STS Total Germ cell tumor 13 13 26 Neuroblastoma 10 14 24 Medulloblastoma 11 10 21 Osteosarcoma 13 11 24 Hepatoblastoma 3 2 5 Other 1 4 5 Not yet reported 1 1 2 Total 52 55 107 CHILDREN’S ONCOLOGY GROUP 24
Slide 25: Interim Activities (Mar-Sept, 2011)
Interim Ac6vi6es (Mar-‐Sept, 2011) Planned Interim Analyses Tumor Response Screen Best responses summarized for each tumor type by study regimen (STS vs. Control) Futility Analysis on Otoprotection Centrally-reviewed audiometry results by study regimen Both reviewed by COG DSMC on 8/10/
Slide 26: Study Plans
Study Plans Current enrollment 107 of planned 135 patients Current enrollment > 1 per week Completion of accrual anticipated mid-2012 Data available for analysis mid-2013 CHILDREN’S ONCOLOGY GROUP 26
Slide 27: SIOPEL 6: Multi-Centre Open Label Phase III Trial of Sodium Thiosulphate
SIOPEL 6: MulA-‐Centre Open Label Phase III Trial of the Efficacy of Sodium Thiosulphate • Led by Penelope Brock, MD • Additional supportive data • Hepatoblastoma only • Cisplatin only • Randomized study of STS vs. No STS • International setting • Current enrollment: 46 of planned 102 27
Slide 28: Challenges in Otoprotection in Adults
Challenges in Otoprotec6on in Adults James A. Talcott, MD, SM Director, Center for Health Care Quality and Outcomes Research Continuum Cancer Centers of New York New York, NY 28
Slide 29: Clinical Differences in Adult and Pediatric Cancers
Clinical Differences in Adult and Pediatric Cancers • In adult cancers lower response rates to platinum-‐containing regimens • Complex regimens reduce and obscure the contribution of platinum – Combination chemotherapy regimens, chemoradiotherapy • Cisplatin response “signal” hard to detect in adult
Slide 30: Practical Dilemmas
PracAcal Dilemmas • Low response rates and multiple agent treatments require very large studies • High response rates necessary to establish clinically meaningful non-‐inferiority differences • High response occurs only in rare tumors, such as testis and placental choriocarcinoma 30
Slide 31: Ethical Dilemmas
Ethical Dilemmas • High response rates increase the difUiculty of non-‐inferiority trials – Clinical “stakes” high for curative treatments (e.g., testis, head & neck) – Damage to hearing much less serious for adults, even young adults, than for children • DifUicult to consent patients to study that
Slide 32: Adult Paradox
Adult Paradox • The greater the assumed chemoprotective risk, the greater the hurdle to approving an non-‐inferiority trial • The lesser the assumed chemoprotective risk, the weaker the rationale for an non-‐ inferiority trial 32
Slide 33: Way Forward
Way Forward Franck Rousseau, MD Medical Affairs Adherex 33
Slide 34: Adherex Proposition
Adherex ProposiAon • Proposal • Submit COG study as single Phase III trial to support accelerated approval • Data to support traditional approval • SIOPEL6 • Post-‐marketing cohort safety surveillance study 34
Slide 35: Merci
Merci 35
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