Jefferies Global Healthcare Conference, June 2015 · Opportunity to create cutting -edge products...
Transcript of Jefferies Global Healthcare Conference, June 2015 · Opportunity to create cutting -edge products...
Jefferies Global Healthcare
Conference, June 2015
Robert Kirkman, MD, President and CEO Julie Eastland, CFO
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Forward-looking Statements This presentation contains forward-looking statements, including statements concerning anticipated research, preclinical and clinical development activities, the potential benefits of proprietary technologies and product candidates, the potential of securing partnerships for development of protocell technology in new fields, potential market size and anticipated clinical milestone dates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements. These risks and uncertainties include, among others, the possibility that preclinical and clinical trials of product candidates (including those using the protocell technology) will not be successful, or be completed, or confirm earlier results, risks associated with obtaining additional financing or funding from third parties, risks related to obtaining and protecting intellectual property rights, risks related to the timing and costs of preclinical development and clinical trials and the receipt of regulatory approvals and the other risk factors set forth in the company’s filings with the Securities and Exchange Commission and Canadian securities regulators, including the company’s Quarterly Reports on Form 10-Q and its Annual Report on Form 10-K for fiscal year 2014. The company undertakes no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof.
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Oncothyreon – Leading Oncology Product Candidates and Cutting-Edge Technology
ONT-380 – Potential best-in-class small molecule HER2 Inhibitor Positive data at ASCO 2015
Clinical activity in advanced stage patients Well-tolerated with no grade 3 diarrhea Responses in central nervous system metastases
Development plan in 3rd line MBC and potentially CNS metastases
Protocell technology places Oncothyreon at forefront of nanoparticle biosciences
Protocells offer potential best-in-class delivery technology for large molecules, from enzymes to nucleic acids Opportunity to create cutting-edge products in oncology, immunotherapy, gene therapy and protein replacement
Additional product opportunities ONT-10 – Phase 1b trial in combination with varlilumab Chk1 inhibitor – Collaboration with Sentinel Oncology Immunotherapy – Antibody discovery collaboration with Adimab
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Oncothyreon Oncology Product Pipeline
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DISCOVERY PRE- CLINICAL PHASE 1 PHASE 2 PHASE 3
Clinical Programs
Breast Ovarian
ONT-10 (Immunotherapy)
HER2+ Breast
ONT-380 (Small Molecule)
Licensed from Sentinel Oncology Licensed from Array BioPharma
Research Programs
Chk1 Inhibitor (Small Molecule)
Oncology
Immunotherapy (Antibody)
Oncology Rare Diseases
Protocells
Research Collaboration with Adimab LLC
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Overview of HER2+ Breast Cancer
HER2: Member of the HER/EGFR receptor tyrosine kinase family Overexpressed in ~ 15-20% of all breast cancers Associated with increased mortality in early stage disease, decreased time to relapse, and increased incidence of metastases
HER2 targeted therapy in (neo)adjuvant and metastatic settings has led to marked and ongoing improvements in ORR, PFS and survival
Marketed agents include Herceptin®, Perjeta®, Kadcyla®, Tykerb® Modest single agent activity, best activity with combinations
Increased incidence of CNS metastases Up to 50% of patients with HER2+ metastatic breast cancer develop CNS metastases CNS was site of first recurrence in 13-14% of patients in CLEOPATRA trial in first line treatment of HER2+ metastatic breast cancer
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ONT-380: The TKI of Choice for Use in HER2+ Breast Cancer
Exceptional potency and selectivity profile Single digit nanomolar potency for HER2 with 500-fold selectivity vs. EGFR Drug selectivity results in reduced incidence and severity of diarrhea/rash compared with lapatinib and neratinib
Potential for improved CNS activity ONT-380 shows superior activity compared with lapatinib and neratinib in CNS tumor models
Improved tolerability positions ONT-380 as the preferred drug to combine with other HER2-targeted agents or chemotherapy
Superior CNS activity and drug tolerability supports evaluation of ONT-380 in treating this key unmet medical need
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HER2+ Breast Cancer Treatment Paradigm - Where Does ONT-380 Fit?
Current development plan focused on metastatic disease First line – Herceptin, Perjeta, docetaxel Second line – Kadcyla Third line – no preferred regimen: Opportunity for ONT-380 Prevention or treatment of CNS metastases: Opportunity for ONT-380
Potential additional opportunities Neoadjuvant Adjuvant Earlier metastatic treatment line
Neoadjuvant Surgery+/- radiation Adjuvant Metastatic
first line Metastatic
second line
Metastatic third line
or greater
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Major Market Potential for 3rd Line Metastatic and Metastatic CNS HER2+ Breast Cancer
Third line metastatic disease 2014 GlobalDataa estimate for Stage IV, third line patients is 13,425 GlobalData estimate of Tykerb’s average annual US cost ~$60,000 Assuming 10% premium to Tykerb and comparable major market pricing Estimated addressable market for Stage IV 3rd line is ~$890M
HER2+ CNS Metastatic Disease 2014 GlobalData estimate for Stage IV patients is 67,127 Estimated Stage IV patients with brain metsb - 25% or 16,782 Similar pricing assumptions Estimated addressable market for CNS mets is ~$1.1B
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Major markets are US, JP, GM, UK, FR, IT, SP
b Clayton AJ, Danson S, Jolly S, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004;91:639-643.
a HER2 Positive Breast Cancer - Global Forecast 2013-2023, September 2014
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ASCO 2015 Data Presentations
ONT-380 in the Treatment of HER2+ Breast Cancer Central Nervous System (CNS) Metastases (Mets) Cristiano Ferrarioa, Stephen Welchb, Jorge Chavesc, Luke Walkerd, Ian Krope, Erika Hamiltonf,g, Virginia Borgesh, Stacy Moulderi
aSegal Cancer Centre -Jewish General Hospital, Montreal, Quebec; bLondon Regional Cancer Program, London Health Sciences Centre, London, Ontario; cNorthwest Medical Specialties, Tacoma, WA; d Oncothyreon Inc., Seattle, WA; eDana-Farber Cancer Institute, Boston, MA fSarah Cannon Research Institute, Nashville, TN; gTennessee Oncology, Nashville, TN hUniversity of Colorado Cancer Center, Aurora, CO; iMD Anderson Cancer Center, Houston, TX;
A Phase 1b Study of ONT-380, an Oral HER2-Specific Inhibitor, in Combination with Capecitabine (C) and Trastuzumab (T) in 3rd line+ Treatment of HER2+ Metastatic Breast Cancer (MBC) Erika Hamiltona,b, Denise A. Yardleya,b, Gabriel Hortobagyic, Luke Walkerd, Virginia F. Borgese, Jorge Chavesf, Alison Conling, Stacy Moulderc aSarah Cannon Research Institute, Nashville, TN; bTennessee Oncology, Nashville, TN; cMD Anderson Cancer Center, Houston, TX; dOncothyreon Inc., Seattle, WA; eUniversity of Colorado Cancer Center, Aurora, CO, fNorthwest Medical Specialities, Tacoma, WA, gProvidence Cancer Center, Portland, OR
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Overview of ONT-380 + Capecitabine (C) + Trastuzumab (T) Phase 1b Trial
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Parallel 3+3 dose escalation of ONT-380 in combination with either C alone or T alone, followed by evaluation in combination with both C and T Selected Study Objectives
Evaluate safety of ONT-380 in combination with C and T Explore anti-tumor activity based on assessment of response by RECIST 1.1
Patient Population HER2+ breast cancer with progression after prior therapy with trastuzumab and T-DM1 for metastatic disease CNS disease -- Untreated asymptomatic metastases or progressive metastases after prior whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) allowed
Treatments 21 day cycle ONT-380 300 mg PO BID (no food restrictions) Capecitabine 1000 mg/m2 BID Days 1-14 Trastuzumab 8 mg/kg IV Cycle 1 Day 1, then 6 mg/kg q 21 days starting Cycle 2 Prophylactic anti-diarrheal medication not required
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Patient Characteristics
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ONT-380 + C
(n = 7) T
(n = 13) C + T
(n = 12) Age, median (range) 54 (38-70) 49 (35-67) 48 (36-67) ECOG 0/1 (n) 3/4 5/8 8/4 Hormone receptor positive (n) 5 10 8 Prior non-hormonal systemic treatments for metastatic disease, median (range)
3 (2-7) 4 (2-9) 3 (2-6)
Trastuzumab (n) 7 13 12
Pertuzumab (n) 4 6 7
T-DM1 (n) 7 12 12 Lapatinib (n) 3 12 4
History of CNS metastases (n) 2 11 6 Prior treatment for CNS
metastases (n) 2 11 4
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Safety Overview
Majority of AEs Grade 1 or 2 in severity; no Grade 3 diarrhea
Most common AEs overall (in ≥5 pts) Diarrhea, nausea, constipation, fatigue, palmar-plantar erythrodysesthesia syndrome (PPE), vomiting, headache, dyspepsia, dizziness, hot flush, and arthralgia
11 SAEs overall 10 SAEs considered unrelated to study drugs 1 SAE in pt treated with ONT-380 300 mg BID + C + T considered related to both ONT-380 and capecitabine
Reversible Gr 4 edema at site of pre-existing untreated asymptomatic thalamic metastasis; considered possible treatment effect Considered a DLT; no other DLTs on study
No significant changes in left ventricular ejection fraction
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Anti-tumor Activity
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ONT-380 + C
(n =7 ) T
(n =13 ) C + T
(n = 12) Best overall response (RECIST 1.1) Evaluable patients, n 7 11 9 CR 0 1 1 cPR 5 3 4 SD or non-CR non-PD 2 5 2a PD 0 2 2 Too early to evaluate 0 2 3
a. Includes pt with unconfirmed PR without follow-up scan
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Change in Measurable Disease: ONT-380 + C + T
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T,P,K T,L,K T,L,P,K T,P,K T,P,K T, K T,L,P,K T,K T,L,P,K
-100%
-80%
-60%
-40%
-20%
0%
20%
40%
60%
Max
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Cha
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in S
um o
f Lon
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Dia
mte
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(%)
ONT-380 + Capecitabine +Trastuzumab
Prior treatment history T = trastuzumab L = lapatinib P = pertuzumab K = T-DM1
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ONT-380 in the Treatment of HER2+ Breast Cancer CNS Mets - 1
Patients with response-evaluable CNS metastases were selected for inclusion in this case series from the following ongoing phase 1b studies:
ONT-380-004: Phase 1b, open-label study of ONT-380 + T-DM1 (ado-trastuzumab emtansine)
Population: Patients with HER2+ breast cancer with progression after prior therapy with both trastuzumab and a taxane
ONT-380-005: Phase 1b, open-label study of ONT-380 +/- capecitabine (C) and +/- trastuzumab (T)
Population: Patients with HER2+ breast cancer with progression after prior therapy with both trastuzumab and T-DM1
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ONT - 380 300 mg PO BID
T - DM 1 3 . 6 mg / kg IV q 21 days
Capecitabine 1000 mg / m 2 PO BID
Cycle Days 1 - 14
Trastuzumab 8 mg / kg IV C 1 D 1 ;
6 mg / kg IV q 21 days
Capecitabine +
Trastuzumab
In combination with :
ONT - 380 Study 005 ONT - 380 Study 004
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ONT-380 in the Treatment of HER2+ Breast Cancer CNS Mets - 2
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CNS metastases were considered response-evaluable if they met either of the following criteria:
Untreated, asymptomatic lesions in patients who had never received radiotherapy or surgery to the CNS Progressive or new lesions in patients who had received previous radiotherapy and/or surgery to the CNS
Groups analyzed separately based on data suggesting lower CNS response rates to systemic tx in previously radiated pts Previously radiated lesions that did not have obvious progression were not considered response evaluable
CT scans and brain MRI at baseline and once every 6 weeks through cycle 6, then once every 9 weeks. Overall response assessment and treatment decisions per RECIST 1.1
CNS response defined as ≥30% decrease in sum of the longest diameter (SLD) of CNS target lesions (target lesions must be ≥1 cm) CNS progression defined as ≥20% increase from nadir and ≥5 mm absolute increase in the SLD of all target lesions, or unequivocal progression in non-target lesions
Definition of Response-Evaluable CNS Metastases
CNS Assessment
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ONT-380 in the Treatment of HER2+ Breast Cancer CNS Mets - 3
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ONT-380 + T-DM1 C T C+T Total
Patients enrolled (n) 36 7 13 12 68
No history of CNS metastases (n) 14 5 2 6 27
Stable treated CNS metastases (n) (not evaluable for CNS response) 10 1 6 2 19
Response-evaluable for CNS metastases (n) 12 1 5 4 22
Untreated asymptomatic 6 0 0 2 8
Progression after prior CNS treatment (n) 6 1 5 2 14
Patients: 22 out of 68 patients had response-evaluable CNS metastases
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Anti-tumor Activity
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Untreated, Asymptomatic CNS Mets n=8
Progressive/ New CNS Mets after Tx n=14
Best Response CNS Only Overall CNS Only Overall
CR 1 0 0 0
PR 2 2 2 4
SD 3 4a 6 5b
PD 0 2 0 0
Not evaluable 2c 0 1d 0
Too early 0 0 5 5
a. Includes one pt with unconfirmed PR who went off study for AE of PPE b. Includes 1 pt with non-CR non-PD (i.e. has non-target lesions only) c. 2 pts with systemic PD but without follow up CNS scan on study d. 1 pt with increasing lesion taken off study for surgical resection; pathology revealed no viable tumor cells
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Anti-tumor Activity
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Change in Measurable CNS Lesions
T,P,L T
T,L,P T,L,P T,L,P T T,L,P
-100%
-80%
-60%
-40%
-20%
0%
20%
40%
Best
Res
pons
e in
Max
imum
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iam
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) In
CN
S M
etas
tase
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Prior Local Therapy
+ Capecitabine + Trastuzumab
+ Capecitabine
+ Trastuzumab
+ T-DM1
T T,P T,P T,P T
-100%
-80%
-60%
-40%
-20%
0%
20%
40%
Best
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) in
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S M
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s
Untreated/Asymptomatic
3 pts not shown: 1 non-target lesions only, 2 without f/u CNS scans at time of systemic PD
7 pts not shown: 5 active patients who have not yet had first f/u MRI, 1 pt with non-target lesions only, 1 pt taken for surgical resection of increasing target lesion with no viable tumor found
+ T-DM1
Anti-tumor Activity
Patient History Previously treated with trastuzumab, paclitaxel and pertuzumab for 11 months Found to have new asymptomatic CNS metastases at the time of study screening No history of prior CNS radiation therapy
Case Study: Untreated/Asymptomatic CNS Metastases
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Treatment: ONT-380 + T-DM1 MRI:
Post 6 cycles: Complete resolution of target and non-target lesions in CNS (Images selected to demonstrate longest axis of lesions)
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Anti-Tumor Activity
Patient History: Whole brain radiotherapy 21 months prior to study entry Progression of 4 of 5 known lesions while on lapatinib + cabazitaxel for 4 mos, just prior to study enrollment
Treatment: ONT-380 + Trastuzumab + Capecitabine
MRI:
Post 6 cycles: -60% reduction in CNS lesions (Images selected to demonstrate longest axis of lesions)
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Screening Post-cycle 6:
Case Study: Progressive CNS Lesion after Local Therapy
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Summary and Conclusions from ASCO 2015
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ONT-380 300 mg BID in combination with each of T-DM1, trastuzumab, capecitabine, or trastuzumab + capecitabine has been well tolerated in patients with HER2+ breast cancer
Majority of AEs were Grade 1 or 2 in severity, with no Grade 3 diarrhea
Encouraging signs of activity in both systemic and CNS metastases in a heavily pretreated population for all combinations evaluated
Clinical benefit and response seen in patients previously treated with trastuzumab, pertuzumab, T-DM1, or lapatinib
Decrease in size of target CNS lesions (up to 100%) seen in patients with and without prior history of CNS local therapy, with CNS tumor control of >6 months in some patients
Based on observed clinical benefit and responses seen, a Phase 2 study to further evaluate the activity of ONT-380 in combination with capecitabine and trastuzumab in patients with advanced HER2+ breast cancer with progression after pertuzumab and T-DM1 is planned
Further study of CNS activity of ONT-380 is warranted
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Protocells: A Nanoconstruct to Address Intractable Therapeutic Challenges
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The Protocell Advantage
Attributes Historical Challenges of Nanoconstructs Protocell Solution
Stability and Loading
Poor stability leads to cargo leakage and off-target
toxicities
Nano-silica core stabilizes drug product allowing outer, lipid layer to be functionalized for ideal in vivo behavior while carrying 1000x
the cargo of liposomes
Targeting
Despite surface targeting ligands, previous constructs rely primarily on Enhanced Permeability and Retention
(EPR) characteristics
Fluid lipid bilayer with targeting ligands enables multivalent and cooperative binding to target cells, leading to a 100x improvement over
similarly-targeted liposomes
Safety and Immunogenicity
Increasing target ligand density for greater target
specificity leads to greater immunogenicity
Targeting is achieved with a minimal number of ligands, thereby reducing unintended
interactions and reducing immune profile
Therapeutic Applicability
Payloads limited in terms of chemical/molecular classes
Protocells deliver diverse cargos including small molecules, all nucleic acids (DNA, siRNA,
mRNA), and peptides/proteins
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Protocell Platform – Planned 2015 POC Studies
Oncology – Improved risk/benefit Cargo: Cytotoxics, targeted small molecules and protein toxins with limited therapeutic windows Targeting: Tumor-associated antigens Goal: Show improved efficacy and superior therapeutic index; enable development of targeted toxins as superior alternative to ADC’s
Rare genetic diseases – gene replacement or modulation Cargos: Proteins/enzymes, mRNA, DNA Targeting
Liver for lysosomal storage diseases Tissue-specific receptors (non-liver targets)
Goal: Deliver protein replacement therapeutics in vivo for lysosomal and other genetic diseases
CAR T-cells – potential of in-vivo CAR T-cell transfection Cargo: Chimeric antigen receptor mRNA/DNA Targeting: T-cell specific receptors Goal: Show in vivo transfection of T-cells with reporters and CARs; initiate animal tumor models in 2H 2015
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Expected Milestones – 2015
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Expected Milestone Date
√
Q4 15
√
Protocell preclinical data
Protocell partnership Q4 15
ONT-10 varlilumab combination trial data Q4 15
ONT-380 Phase 1b T-DM1 data Q4 15
ONT-380 Phase 1b update at ASCO
ONT-380 Phase 2 trial initiation in MBC Q4 15
Q2 15 √
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Oncothyreon – The Investment Opportunity
ONT-380 – potential best-in-class small molecule HER2 inhibitor Clinical activity in advanced stage patients; no grade 3 diarrhea Exclusive license to develop and commercialize Phase 2 trial in third line metastatic breast cancer planned Additional data and CNS plan Q4 2015
Expanding product discovery capabilities Protocells in oncology and rare diseases
Additional preclinical data expected H2 2015 Business development opportunities
Chk1 inhibitor Immunotherapy antibody discovery collaboration with Adimab
Well funded Cash and investments -- $77.5 million at March 31, 2015