VarSeq 2.3.0: New TSO-500 and Genomic Signature Support in VSClinical AMP
Aggarwal Biomarker Presentation Lyon France 2011
1. 2012
Session: Open Innovation in Oncology (chairpersons:
Emerging Role of Biomarkers for Success of F. BERGER / TBC)
Targeted Cancer Therapies
• Innovative Cancer Biomarkers: Links Between
Key Note Presentation at BIOVISION EU Populations and Patients
Pierre HAINAUT, International Agency for Research on
Cancer
• Emerging Role of Biomarkers for Success of Targeted
Cancer Therapies
Saurabh AGGARWAL, Novel Health Strategies, LLC,
Bethesda, USA
• Envisioning the Future of Early Anticancer Drug
Development
www.NovelHealthStrategies.com Johann DE BONO, Institute of Cancer Research, Royal
Marsden Hospital, UK
Contents Types of Biomarkers
• Types of biomarkers Type of Biomarkers Description
• Clinical trial design strategies Predictive biomarkers Any measurement associated with response to or lack of
response to a particular therapy.
• Past, present and future of biomarkers
PK/PD biomarkers PK and PD biomarker data analysis for determination of
• New emerging biomarkers: Case studies biologically active dose
– T315I Safety/Toxicity Measurement and monitoring of biomarkers to minimize
– ALK toxicity of cancer drugs
– Hedgehog Prognostic biomarkers Provide information on the natural course of disease after
– BRAF standard treatments
– BRCA Intermediate end‐point Markers that reflect treatment benefit at an earlier time
• Implications for discovery and development of targeted point than would be required to attain the primary
objective of the study
cancer therapies
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Factors to Consider for Biomarker and Drug Co‐development Clinical Trial Designs for Biomarker Validation
Clinical Design Strategy Description
• Characterization and selection of biomarker Enrichment Design Enrichment studies may be preferred when the biomarker
– Specificity is well understood; supporting data suggest little benefit of
– Sensitivity the drug in biomarker‐ negative populations or suggest
substantial drug toxicity or resistance in biomarker‐positive
• Standardize assay methods patients
• Clinical trial design that allows evaluation of predictive All‐Comers Designs Accrual of patients is prospective, the biomarker
evaluation may be conducted either prospectively or
responsiveness retrospectively
• Ability to incorporate emerging data and advanced Adaptive biomarker Midtrial modifications are allowed, based on new interim
technology enrichment information either from inside or outside the trial.
Requires specification of Type I and Type II errors
Past, Present and Future of Biomarkers
ALK Combination biomarkers
ER BCR‐ABL Hedge Hog Molecular arrays
Her‐2 C‐Kit T315I Biomarkers for monitoring
PSA KRAS BRAF Biomarkers for maintenance Case Study 1: T315I
BRCA therapy
1990 2000 2010 2020
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Emerging Biomarker Case Study 1: T315I Discovery of Ponatinib
• BCR‐ABL targeted agents such as Gleevec have shown • Rationally designed inhibitor
remarkable efficacy in CML patients, but still many patients of BCR‐ABL
relapse due to T315I mutation • Active against T315I mutant
• Limited benefit of 2nd generation TKIs used as 3rd line – Unique approach to
accommodating gatekeeper
therapy
residue
– Failure‐free survival 20 months
• Potent activity against an
• No available therapy for T315I
array of BCR‐ABL variants
– Median survival in CP 22 months
• Also targets other
• There is a need for new agents that can target this mutation
therapeutically relevant
and provide another treatment option for advanced CML
kinases:
patients
• – Inhibits FLT3, FGFR, VEGFR
and PDGFR, and c‐KIT
Ponatinib Phase I Clinical Trial Patient Characteristics Ponatinib Phase I Clinical Trial Results
Chronic Phase CML
Advanced Phase CML
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Emerging Biomarker Case Study 2: ALK
• Activating mutations or translocations of the anaplastic
lymphoma kinase gene (ALK) have been identified in several
types of cancer
Case Study 2: ALK • In non–small cell lung cancer, EML4‐ALK is an aberrant fusion
gene that encodes a cytoplasmic chimeric protein with
constitutive kinase activity
• EML4‐ ALK is uncommon, occurring in 2 to 7% of all non–
small‐cell lung cancers
• Preclinical studies have shown that selective ALK inhibition
specifically reduces the proliferation of cells carrying genetic
alterations in ALK
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Discovery of Crizotinib Crizotinib Clinical Trial Patient Characteristics
• Crizotinib (PF‐02341066, Pfizer) is an oral ATP‐ competitive
selective inhibitor of the ALK and MET tyrosine kinases
• Inhibits tyrosine phosphorylation of activated ALK at nanomolar
concentrations.
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Crizotinib Clinical Trial Results Crizotinib Clinical Trial Results
Shows a Kaplan–Meier curve of estimated progression‐free
survival, with the lighter curves above and below the Kaplan–
Meier curve representing 95% Hall–Wellner confidence limits.
Emerging Biomarker Case Study 3: Hedgehog
• Hedgehog is a key regulator of cell growth and differentiation
during development, controls epithelial and mesenchymal
interactions in many tissues during embryogenesis
• Extracellular hedgehog protein binds to patched homologue
Case Study 3: HedgeHog 1(PTCH1), a 12‐transmembrane receptor, and prevents
PTCH1‐mediated inhibition of signaling by smoothened
homologue (SMO), a 7‐transmembrane protein
• Basal‐cell carcinoma is associated with mutations in
components of the hedgehog signaling pathway
• Mutations cause constitutive hedgehog pathway signaling,
which in basal‐cell carcinomas can mediate unrestrained
proliferation of basal cells of the skin
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Discovery of GDC‐0449 GDC‐0449 Clinical Study Patient Characteristics
• The novel SMO inhibitor GDC‐0449 was discovered by high‐
throughput screening of a library of small‐molecule compounds and
subsequent optimization through medicinal chemistry
• GDC‐0449 is a selective hedgehog pathway inhibitor with greater
potency and more favorable pharmaceutical properties than
cyclopamine
GDC‐0449 Clinical Study Patient Characteristics
Case Study 4: BRAF
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Emerging Biomarker Case Study 4: BRAF Discovery of PLX4032
• 40 to 60% of melanomas, and 7 to 8% of all cancers, carry an • PLX4032 (also known as RG7204
activating mutation in the gene encoding the serine– or RO5185426), an oral drug
threonine protein kinase B‐RAF (BRAF) with high affinity for the
• BRAF mutations are also found in 40 to 70% of papillary or mutated BRAF
anaplastic thyroid cancers and in a small percentage of several • Although almost 90% of BRAF
other types of tumor mutations constitute V600E
• BRAF mutation constitutively activates BRAF and downstream mutations which are targeted by
signal transduction in the MAP kinase pathway PLX4032, there is mounting
evidence that other V600
mutations also might be
susceptible to selective
inhibition
PLX4032 Clinical Trial Patient Characteristics PLX4032 Clinical Trial Study Results
• Patients who had
melanomas with the V600E
mutation in BRAF were
overrepresented because of
the selective activity of
PLX4032 against such
tumors in preclinical testing
• For the extension cohort,
eligibility was restricted to
patients with melanomas
harboring a V600E BRAF
mutation
PLX4032 induced complete or partial tumor regression in 81% of patients who
had melanoma with the V600E BRAF mutation.
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Emerging Biomarker Case Study 5: BRCA
• A germ‐line mutation in one BRCA1 or BRCA2 allele is
associated with a high risk of the development of a number of
cancers, including breast, ovarian, and prostate cancer
Case Study 5: BRCA • Cells carrying heterozygous loss‐of‐function BRCA mutations
can lose the remaining wild‐type allele, resulting in deficient
homologous‐recombination DNA repair, which causes genetic
aberrations that drive carcinogenesis
• This tumor‐ specific defect can be exploited by using PARP
inhibitors to induce selective tumor cytotoxicity, sparing
normal cells
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Implications for Discovery and Development of
Olaparib Clinical Trial Results
Targeted Cancer Therapies
• Biomarker strategy is becoming critical to demonstrate
success of targeted cancer therapies
• Biomarker validation remains one of the major challenges for
success of targeted cancer therapies
• Future clinical trial designs need to integrate biomarker
Objective antitumor activity was reported only in mutation carriers, all evaluation either prospectively or retrospectively
of whom had ovarian, breast, or prostate cancer and had received
multiple treatment regimens
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Developing Oncology HEOR, Marketing, Pricing, Market
References Access and Reimbursement Strategy
• Envisioning the future of early anticancer drug development, Nature Review Drug
Discovery 2010
• Inhibition of Mutated, Activated BRAF in Metastatic Melanoma, NEJM, 2010
• Inhibition of Poly(ADP‐Ribose) Polymerase in Tumors from BRCA Mutation Carriers,
NEJM, 2009 Join Novel Health's Team for Discussion on Key Trends and Emerging Topics for Oncology Products
• Crizotinib — Latest Champion in the Cancer Wars?, NEJM 2010 Oncology is the highest selling indication for pharmaceutical and biotech products. It is projected that global sales of cancer drugs
could reach $75‐$100 billion by 2016‐2020. Currently more than 40% of on‐going clinical trials are for cancer indications. There are
• A Phase 1 Trial of Oral Ponatinib (AP24534) in Patients with Refractory Chronic several factors that play a role in clinical and market success of new emerging cancer drugs. Join us for a live discussion on July 10,
2012 on the following topics:
Myelogenous Leukemia (CML) and Other Hematologic Malignancies, ASH 2010 What is the global outlook for cancer drugs for 2013‐2020?
• Saurabh Aggarwal, Targeted Cancer Therapies, Nature Review Drug Discovery 2010 How is oncology market different from other pharmaceutical and biotech products?
What are the key factors for clinical and market success of cancer drugs?
• Saurabh Aggarwal, What’s fueling the biotech engine‐2010, Nature Biotechnology How to develop HEOR evidence generation strategy for oncology products?
How to develop pricing and reimbursement strategy for new cancer drugs?
What lessons can be learned from launch price and reimbursement trends for all approved cancer drugs (US, EU and Asia)?
What is the role of HEOR, QoL and CEA evidence for market access of cancer drugs?
What is the role of HTAs, comparative effectiveness and CEA for oncology products?
What are some of new reimbursement models that are emerging for cancer drugs in the US, EU, LatAm and Asian markets?
How to develop robust budget impact models (Excel, iPad and Android) and CEA for cancer drugs?
Lessons learned from pricing and reimbursement case studies for CRC, RCC and CML
Note: Due to proprietary data analyses in this webinar this presentation can be requested only for in‐person live replay
http://www.novelhealthstrategies.com/oncology.htm
Targeted Cancer Therapies: Nature Reviews Drug
Novel Heath’s Expertise Areas
Discovery
Oncology has become one of the major anticancer therapies reached $10.4 billion — with the FOLFOX4 (oxaliplatin (Eloxatin;
focus areas for pharmaceutical and an almost twofold increase since 2005 (FIG. Sanofi–Aventis) plus leucovorin plus EXPERTISE AREAS RECENT HEOR PROJECTS RECENT MARKET
biotechnology companies. In 2009, ~16,000 1a) 5‐fluorouracil) chemotherapy regimen2.
of the ~40,000 Phase I, II and III trials listed — and their sales share increased from 46% The success of combining one targeted US & Global Market Access Strategy HEOR Evidence Development Strategy for Novel ACCESS PROJECTS
on ClinicalTrials.gov were related to cancer in 2005 to 56% in 2009. drug with chemotherapy has led to the First in Class Product (Multiple Projects)
(~40%). This large interest stems from the Antibodies are the market leaders hypothesis that efficacy could be enhanced HEOR Evidence Generation Strategy
existence of high unmet need for improved Currently, there are 22 FDA‐approved by adding two or more targeted agents3, Economic Modeling for Blockbuster Product 40 Country Pricing and Reimbursement
treatments of multiple types of cancer and targeted cancer therapies, 9 of which are especially to combat the resistance Economic Modeling (Multiple Projects) Strategy
the monoclonal antibodies (mAbs), 12 of which mechanisms used by cancer cells. Although
substantial market success of targeted cancer are small‐molecule drugs and one of which such combinations have shown promising US & Global Pricing Strategy GVD for Blockbuster Product (Multiple Projects) 2020 P&R Vision for Oncology Market
therapies launched in the past decade. is a fusion protein (see Supplementary efficacy in preclinical models, the results (Assessment Aided in Acquisition of Cancer
US oncology market growth information S1 (table)). Among these drugs, in clinical trials so far have not been Global Value Dossier Development HTA & Guidelines Review and Strategic Biotech for $2.5B)
Although the overall growth in four mAbs — bevacizumab (Avastin; Roche), encouraging in general. For example, Implications
pharmaceutical sales in the United States rituximab (Rituxan/MabThera; Biogen Idec/ the CAIRO2 trial showed that addition of Payer Segmentation Analysis P&R Assessment for Ten Fixed Dose
— the largest pharmaceutical market — has Roche), trastuzumab (Herceptin; Roche) and cetuximab to capecitabine (Xeloda; Roche), HEOR & Payer Publication Strategy for Blockbuster Combinations
been slowing in recent years (to ~2–5% in cetuximab (Erbitux; Eli Lilly/Bristol‐Myers oxaliplatin and bevacizumab resulted Medical Device Reimbursement Strategy Product
2008–2009; REF. 1), the oncology market Squibb) — and one small‐molecule drug — in significantly shorter progression‐free 15 Country Reimbursement Strategy for
continues to grow at double‐digit rates. imatinib (Gleevec; Novartis) — constitute survival and inferior quality of life for Rare Disease Products Novel Medical Device Product
In 2009, the US sales of oncology drugs 86% of the 2009 US sales (FIG. 1b). In 2009, first‐line treatment of patients with US & Global Market Access Strategy for Ultra
(excluding hormonal therapies and vaccines) the small‐molecule drugs constituted 23% metastatic colorectal cancer4. Nevertheless, Value Assessment for M&A or Licensing Orphan Product
(~$2.4 billion) of the total US sales of targeted with further optimization of dose regimens NPV/DCF Valuation for Neurology Product
therapies, with ~50% of those sales being and greater understanding of biomarker
derived from imatinib. data, it is possible that some patient
subpopulations could benefit from such
combinations.
http://www.novelhealthstrategies.com/Targeted_Cancer_Therapies.pdf
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