Cancer Progress Conference Agenda: Day 1€¦ · Cancer Progress Conference Agenda: Day 1 8:15...

Cancer Progress Conference Agenda: Day 1

8:15 Opening Remarks - Jeff Bockman, PhD8:45 Keynote: Angiogenesis- George D. Yancopoulos, MD, PhD9:30 Panel- Future of cancer therapy – Where have we been, where are we going?

Neal Rosen MD Steven Averbuch MD Larry Norton MD Geert Kolvenbag MD PhDNeal Rosen, MD, Steven Averbuch, MD, Larry Norton, MD, Geert Kolvenbag MD, PhD10:30 Networking Break10:45 Panel-Novel approaches in cancer drug development and clinical trials – Are we

adapting and adopting fast enough? Jamie Freedman, MD, PhD, Richard Gaynor, MD, Eric Rowinsky, MD, Robert Iannone, MDEric Rowinsky, MD, Robert Iannone, MD

11:45 Panel- Immunotherapy for cancer – Are we there yet? The Rights and wrongs of developing next generation immunotherapies: Mary L. (Nora) Disis, MD, JeddWolchok, MD, PhD, H. Kim Lyerly MD, FACS, Jon Wigginton, MD, James Trager, PhD

12:45 Networking Luncheong2:00 Panel- Apoptosis – Why has drug development in apoptosis been stymied?

Douglas R. Green, PhD, Tak Mak, PhD, David Weng, MD, PhD, John C. Reed, MD, PhD3:00 Panel- Data, data everywhere – Generating, harvesting, and analyzing the vast fields

of cancer information: Colin Hill, Eric Schadt, PhD, Alexis Borisy, Bryan Dechairo, PhDy y4:00 Networking Break4:30 Panel- Melanoma: Tackling the intractable – But what next? Jedd Wolchok, MD,

PhD, Paul Chapman, MD, David E. Fisher, MD, PhD

Introduction to Cancer Progress

It is through science that we prove, but through intuition that we discoverintuition that we discover.- Poincare

Jeffrey M. Bockman, PhDVice PresidentVice PresidentDefined Health

23rd A l C P C f23rd Annual Cancer Progress ConferenceMarch 6th – 7th, 2012

The information in this report has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot

t th i f ti t i d h i t l t Allguarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Cancer Progress, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of the addressee and only for the purpose(s) for which the report wasthe addressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Cancer Progress, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law.This report may contain information provided by third parties such as Thomson Reuters, Wolters Kluwer, EvaluatePharma, Datamonitor, Informa Healthcare, IMS Health and others with a proprietary interest in the data provided herein. Please note that you are not permitted to redistribute any such third party information

i h f h i iwithout consent from the originator company.

Cancer Progress © 2012

3/22/2012 4

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A Holmesian Perspective on Cancer Progress

• "You will not apply my precept," he said, shaking his head. "How often have I said to you that when you have eliminated the impossible,eliminated the impossible, whatever remains, however improbable, must be the truth?"

The Sign of the Four, ch. 6 (1890)(1890)

3/22/2012 6

Some observations…Some observations…

3/22/2012 7

We’ve Come a Long Way in Ten Years…

3/22/2012 8

Cell, Vol. 100, pp. 57–70, 7 January, 2000, Cell, Vol. 144, pp. 646-674, 4 March 2011

With Cytotoxics Are Largely Genericized, Targeted Biologics and SMIs Will Drive Even More GrowthBiologics and SMIs Will Drive Even More Growth

40

WW Revenue By Major Oncology Drug Category

30

35

Alkaloids

Alkylating agents

es $

B

y j gy g g y

mAbs

20

25Anti-metabolites

Anti-neoplastic Mabs

Cytotoxic antibiotics

Anti-angiogenics (LX1)rldw

ide

Sale mAbs

Small MoleculeCytostatics

10

15Other cytostatics (LX1)

Hormone therapies

Platinum compounds

Other anti-cancer

Wor

MultitargetedTKIs

0

5

Ot e a t ca ce

Unclassified oncology sales

1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 2016EvaluatePharma

2011 Drug Approvals Show Continued Rise of Niche & Stratified Cancer IndicationsStratified Cancer Indications

• Preponderance of orphan products, which accounted for 11 out of 30 approvals, and reflects a shift towards “niche busters” — predominantly made up of cancer products (7 out of 11), in

fl h d b l f d ff b lpart reflecting the increased ability to stratify cancer patients into different subpopulations.– Pfizer’s crizotinib for the treatment of anaplastic lymphoma kinase-positive non-small-cell lung cancer and Roche’s

vemurafenib for the treatment of BRAF-V600 mutation-positive metastatic melanoma. In both cases, therapeutic–diagnostic co-development enabled short clinical trial paths and rapid approvals.

Cancer Drugs in US Development

• 85 out of 192 Phase III (US) have orphan ( ) pdesignation: 44%

•158 of 492 Phase II (US): 32%• 135 out of 768 Phase I or I/II (US): 18%

FDA drug approvals since 1993. New molecular entities (NME) and biologics license applications (BLA) approved by the Center for Drug Evaluation Source: Nature Reviews Drug Discovery 11, 91-94 (February 2012)

Source: Adis R&D Insight, Defined Health

3/22/2012 10

and Research (CDER) since 1993, the first full year during which the US Food and Drug Administration worked under a Prescription Drug User Fee Act (PDUFA) agreement.

Oncology Deals Slowed, But So Did Most Other TAs

Source: In Vivo , May 2011

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As in the Past, Some of the More Interesting and Largest Deals Over the Last Two Years Were Discovery D l A d N l Pl fDeals Around Novel Platforms

4 of top 10 deals of past two years: Boehringer Ingelheim’s deal with MacroGenics ($2.2B total value) around their DART bispecific antibodies , Kyowa Hakko Kirin’s deal with Dicerna ($1.4B) on RNAi, Roche’s deal with

Aileron around their stapled peptides ($1.1B) and the Amgen-Micromet deal (pre-acquisition) ($1B).

Average Licensing Deal Financials: Cancer Market, 2010-2011

Licensing Deals by Stage of Development at Signing: Cancer Market, 2010-2011

p p p ($ ) g (p q ) ($ )

Source: Deloitte Recap, www.recap.comAverages: Deal size $377.7 mil, Upfront $22.21 mil, Total milestones $299.11 mil. Additional payments available but not shown – R&D, equity,

Source: Deloitte Recap, www.recap.com . Includes pharma, biotech & university deals with or without financial details. Numbers in percentages

3/22/2012 12

p y q yadjusted milestones, loans, royalties. Includes pharma, biotech & university deals with financial details.

Large Molecule Deals Edged Out Small Molecule Ones, And While Antibodies Lead the Way, Other Approaches A G i i S T iAre Gaining Some Traction

Licensing Deals by Technology: C M k 2010 2011

Over the past two years, of the top 20 deals with

publically announced d l i (t t l d llCancer Market, 2010-2011 deal sizes (total dollars

from $467M to $2.2B), 11 of these deals involved

biologics, including primarily antibodies but

also fusion proteins, RNAi, recombinant

viruses with immune payloads and cell-based

therapiestherapies.

Source: Deloitte Recap, www.recap.comIncludes pharma, biotech & university deals with or without financial detailsNumbers in percentages

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Phase I to Market Transition Rates for Cancer Shows Heme as a Better Place to Place BetsHeme as a Better Place to Place Bets

Defined Health believes that the higher success rates in

heme malignancies reflect in part the inherent differences in the underlying biology of

these cancers versus the highly heterogeneous solid tumors.

In addition broad settingsIn addition, broad settings such as lymphoma actually

include a diversity of indications each with their

own unique treatment l i h d i (algorithm and regimens (NHL, HL, CLL, T-cell lymphomas

[PTCL and CTCL], etc.) as well as situations where the same drug has multiple approvals

Source: Deloitte Recap, www.recap.comData current as of January 31, 2012, see following slide for detailsDeloitte Recap DEVELOPMENT optimizer™

g p pp(e.g., Rituxan for aggressive and indolent non-Hodgkin’s lymphomas such as follicular

and DLBCL, respectively).

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Partnered Versus Un-Partnered Programs & Probability of Successof Success

As Deloitte notes, at least three factors could be

reflected in the data includingreflected in the data, including 1) Molecules that successfully undergo due diligence in the partnering process may be

inherently higher “quality” and thus more likely to succeed; 2)

Partnered molecules may benefit from the partner’s

increased resources and/or expertise as applied toexpertise as applied to

development decisions; or 3) Un-partnered drugs may

terminate more often due to funding or prioritization issues

h h d

Source: Deloitte Recap, www.recap.comData current as of January 31, 2012, see following slide for detailsDeloitte Recap DEVELOPMENT optimizer™

than their partnered counterparts.

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Early 2012 Deal: Will the Genentech and Constellation Deal Be a Landmark Collaboration?Deal Be a Landmark Collaboration?• The deal may be viewed as a right in Genentech’s “sweet spot of targeted therapies

and underlying biology” according to Kevin Sin, Director, Genentech Partnering, with whom Defined Health discussed this deal.

• This collaboration has some similarities to the original Roche Genentech deal, with Genentech now accessing through Constellation its domain expertise in chromatin biology, discovery tools, and the ability to look holistically at the nodes and crosstalk within epigenetics and not focusing on only one particular target.crosstalk within epigenetics and not focusing on only one particular target.

Genentech & Constellation

Under terms of the deal, Genentech committed funding of $95 million, including an upfront t d h f di th C t ll ti ill b li ibl f d l tpayment and research funding over three years. Constellation will be eligible for development

and commercialization milestone payments as well as up to double-digit royalties on commercial sales of products taken to market by Genentech.Constellation will retain exclusive development and commercialization rights to selected programs, the companies said in the press release, and Genentech would have to pay Constellation if those products are brought to market.The partnership does not cover Constellation’s other programs, the Boston Business Journal reported. Those include an inhibitor of the BET chromatin reader and EZH2 chromatin writer proteins

S S i i i J 1 2012 fi d H l h S i C J 23 2012

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Source: San Francisco Business Times, Jan 17, 2012; Defined Health Source: BioCentury, Jan 23, 2012

Top 20 Phase III Oncology Drugs by Sales Potential: Mostly Next Generation Approaches to Well-Validated T B I i l N l I h iTargets, But Increasingly Novel Immunotherapies

drug name Originator Licensee Lead Indication

Sales (M)

pert mab Genentech Ch ai 990 6


Sales (M)

Axitinib Pfizer Inc SFJ Renal cancer 363 7pertuzumab Genentech Chugai 990.6

MDV-3100 University of California

Astellas, Medivation

Prostate cancer 903.7

BAY-88-8223 Algeta ASA, Bayer AG

Bone metastases 532.9

Axitinib Pfizer Inc PharmaRenal cancer 363.7

necitumumab ImClone BMS NSCLC 347.8

regorafenib Bayer AGColorectal cancer 297.6

pasireotide Novartis 471.0

aflibercept Regeneron Bayer, Sanofi

Colorectal cancer 434.8

Kirin

brivanibalaninate BMS Liver cancer 282.2

ridaforolimus ARIAD Merck & Co

Sarcoma 242.5

astuprotimut-r GSKMelanoma/

235 9tivozanib Kirin

Brewery Co 403.0

carfilzomib Yale University Ono

Multiple myeloma 388.5

trastuzumabemtansine Genentech Chugai,

RocheBreast cancer 387.4

astuprotimut r GSK NSCLC 235.9

obinutuzumab GlycartBiotech

B cell lymphoma 224.4

velimogenealiplasmid Vical Inc AnGes MG

Malignant melanoma 222.0

emtansine Roche cancer

Reolysin Oncolytics Biotech Inc

Head and neck cancer 385.8

pomalidomide EntreMedMultiple myeloma 378.5

bosutinib Wyeth Research

CML 202.7

emepepimut-S OncothyreonEMD, Merck KGaA, Ono

Non-small cell lung cancer 202.4

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*THOMSON REUTERS CORTELLIS™ FOR COMPETITIVE INTELLIGENCE

KGaA, Ono

Top 20 Phase III Oncology Drugs by Sales Potential*


Sales (M)

pertuzumab Genentech Chugai 990.6


Sales (M)

Axitinib Pfizer Inc SFJ Pharma

Renal cancer 363.7








brivanib

Pertuzumab plus Herceptin (trastuzumab) plus docetaxel used as first-line treatment for HER2-positive metastatic breast cancer

significantly prolonged PFS with no increase in cardiac toxic effects (>90% of patients were HER2 3+), showing that the two

ti HER2 l l tib di ith l t MOApasireotide Novartis 471.0



tivozanib Kirin Brewery Co 403.0



Sarcoma 242.5

astuprotimut-r SmithKline Beecham plc

Melanoma/NSCLC 235.9

anti-HER2 monoclonal antibodies with complementary MOAs have valuable combination clinical activity in preventing the

ligand-dependent formation of HER2 dimers. Interesting next generation biologic approaches around engineering the Fc

region could enhance the interactions for patients with the low-Brewery Co




Roche Breast cancer 387.4





binding alleles. In addition, agents like MacroGenics’ MGAH22 , which is in Phase I, could expand the potential beyond HER2 3+ patients in mBC and in other cancers where HER2 expression is

low. (Breast Cancer Research 2011, 13:R123)





CML 202.7



3/22/2012 18




Sales (M)



Sales (M)

Axitinib Pfizer Inc SFJ Pharma Renal cancer 363.7It has been a long road for Regeneron’s VEGF-Trap (aflibercept/Zaltrap) in cancer,








brivanib

although it is having a very strong showing in AMD since its launch (as Eylea). From the early days of being developed with Aventis as a direct biologic competitor to Avastin, it

has faced numerous challenges, but despite the disappointing results in NSCLC and pancreatic cancer, the data from the VELOUR trial in CRC has demonstrated the potential value of adding aflibercept to FOLFIRI in metastatic colorectal cancer patients previously






ridaforolimus ARIAD Merck & Co Sarcoma 242.5



value of adding aflibercept to FOLFIRI in metastatic colorectal cancer patients previously treated with oxaliplatin-based regimens, including those progressing on Avastin, with benefits in OS and PFS that are statistically significant and clinically meaningful. The

clinical development activity around next generation anti-angiogenesis approaches, both large and small molecules, has been intense. Results with MTKIs have been mixed ,

d di th t t S t ti h i l d th t tiBrewery Co









depending on the tumor type. Some next generation approaches include those targeting the splice variants and processing of VEGF transcripts. For example, PTC Therapeutics’ PTC299 is an oral small molecule VEGF inhibitor that acts upstream of current VEGF-targeted therapies by targeting the untranslated region (UTR)-mediated processes regulating translation and thereby inhibiting VEGF protein expression, as well as





CML 202.7

emepepimut-S Oncothyreon

EMD, Merck KGaA, Ono


modulating other angiogenic cytokines such as IL-6 and PlGF. PTC299 is hypothesized to inhibit tumor VEGF production while sparing physiological VEGF production, and inhibits

the production of all angiogenic VEGF-A splice variants (San Antonio Breast Cancer Symposium 2011, P2-16-08).

3/22/2012 19




Sales (M)



Sales (M)


Renal cancer 363.7

Viral-based therapies (whether truly gene therapies or not) have been pursued for many years, with the early generation products dogged by many of the same issues that faced early generation immunotherapies:

suboptimal first gen products, problematic trial design, and an evolving standard of care with monoclonals








brivanib

subop a s ge p oduc s, p ob e a c a des g , a d a e o g s a da d o ca e o oc o a sand M/TKIs that has complicated the relevance of outcomes. Oncolytic viruses have been designed to

specifically exploit some of the same altered/defective pathways that promote/drive tumor growth, whether tumor-specific mutations in antiviral defense programs, signaling pathways or transcriptional programs that

are constitutively activated or by restriction of virus to cancer cells by binding/entry via unique or over-d ll f ti I dditi f th t ti h d li ipasireotide Novartis 471.0






Sarcoma 242.5



expressed cell surface antigens. In addition, more of the next generation approaches are delivering immunotherapy payloads, such as OncovexGM-CSF, from BioVex , which was acquired in 2011 by Amgen for up to $1B and became the first significant partnering validation in the space. While adenovirus-based systems

have been most studied, along with pox and herpes, the Reovirus system offers the advantage of replication being limited to RAS activating mutations or activating mutations of upstream signals (EGFR, PDGFR) found in

Brewery Co









many high unmet need cancers (pancreatic, SCCHN, GBM, CRC, lung), which could be exploited through patient stratification approaches such as Reolysin’s in KRAS mutant NSCLC and CRC.





CML 202.7



3/22/2012 20




Sales (M)



Sales (M)


Renal cancer 363.7








brivanib

More MTKIs targeting angiogenesis and/or proliferation targets, from

Aveo/Astellas, Pfizer, Bayer, and BMS. Will these any of these become











Sarcoma 242.5

astuprotimut-r GSKMelanoma/NSCLC 235.9

blockbusters to rival the monoclonals, especially outside of

heme malignancies like CML?





Brewery Co













CML 202.7



3/22/2012 21


Top 20 Phase III Oncology Drugs by Sales Potential


Sales (M)



Sales (M)


Renal cancer 363.7








brivanib

Has the age of immunotherapy at last arrived? The approval of Provenge and Yervoy

has invigorated the field, but has probably pasireotide Novartis 471.0






Sarcoma 242.5


xxx

xxx

g , p ynot de-risked across the diverse range of

approaches. Just represented in this list are three different platforms, 2 antigen-based

and one co-stimulatory-based: GSK’s recombinant MAGE A3 antigen MerckBrewery Co









recombinant MAGE A3 antigen; Merck Serono’s 25-mer peptide fragment of MUC-1

antigen; and Vical’s plasmid-based system encoding HLA-B7 and ß2 microglobulin for

enhancing antigen presentation. Reolysin Oncolytics

Biotech IncHead and neck cancer 385.8



CML 202.7



DATA SOURCE THOMSON REUTERS CORTELLIS™ FOR COMPETITIVE INTELLIGENCE DEFINED HEALTH

3/22/2012 22

DATA SOURCE: THOMSON REUTERS CORTELLIS™ FOR COMPETITIVE INTELLIGENCE; DEFINED HEALTH





Sales (M)


Renal cancer 363.7

Follow-on biologics, specifically monoclonals, has limited precedence in cancer, other than the Erbitux-

Vectibix and Rituxan Arzerra examples Anti CD20

Follow-on biologics, specifically monoclonals, has limited precedence in cancer, other than the Erbitux-

Vectibix and Rituxan Arzerra examples Anti CD20MDV-3100 University of

CaliforniaAstellas, Medivation






brivanib

Vectibix and Rituxan-Arzerra examples. Anti-CD20, along with anti-EGFR and HER2, have represented a

sizeable portion of next generation approaches, typically utilizing modification of glycosylation or protein engineering. Given the impending paten

Vectibix and Rituxan-Arzerra examples. Anti-CD20, along with anti-EGFR and HER2, have represented a

sizeable portion of next generation approaches, typically utilizing modification of glycosylation or protein engineering. Given the impending paten







Sarcoma 242.5


expiration of Rituxan and anticipated biosimilars (at least in certain geographies), it will be a fascinating case study in action to see how Roche’s own follow-

on plays out. Similarly, necitumumab is a fully human IgG1 mAb directed against EGFR Preclinical

expiration of Rituxan and anticipated biosimilars (at least in certain geographies), it will be a fascinating case study in action to see how Roche’s own follow-

on plays out. Similarly, necitumumab is a fully human IgG1 mAb directed against EGFR PreclinicalBrewery Co









human IgG1 mAb directed against EGFR. Preclinical studies indicated that the antitumor activity is either

comparable with or superior to that of ImClone'schimeric anti-EGFR mAb cetuximab.

Alternative approaches include th two epitope,

human IgG1 mAb directed against EGFR. Preclinical studies indicated that the antitumor activity is either

comparable with or superior to that of ImClone'schimeric anti-EGFR mAb cetuximab.

Alternative approaches include the two epitope,





CML 202.7



double mAb mix against EGF from Symphogen. Animal data show better efficacy than Erbitux, activity in Erbitux partial responders, and

possible activity in non-responders.

double mAb mix against EGF from Symphogen. Animal data show better efficacy than Erbitux, activity in Erbitux partial responders, and

possible activity in non-responders.

3/22/2012 23


Some speculation…Some speculation…

3/22/2012 24

The Pressure Is On, But Can Targeted Agents Allied to Stratified Patient Segments Allay the Risk?Stratified Patient Segments Allay the Risk?• Reliance on oncology just when payers are applying more scrutiny to cancer drugs – it is no

longer sacrosanct.• Payers are starting to experiment with “clinical pathways” rather than prior authorization.

3/22/2012 25

Source: In Vivo , May 2011, “What New Cancer Pathway Programs Mean for the Drug Industry”

Stratifying Ad Infinitum: The Old Worry of the Oncology Marketing Head Was Fragmentation of the MarketMarketing Head Was Fragmentation of the Market…

Source: http://costprojections.

Source: Nature, 455: 1069-1075, 2008; Cancer Res 68: 6913-6921, 2008

p p jcancer.gov/

…And 10-15 Xalkori’s to equal the…And 10 15 Xalkori s to equal the 2015 NSCLC Market

3/22/2012 26

Source: EvaluatePharma, Feb 28, 2012

And It Takes Many Niche-busters to Equal an Avastin

3/22/2012 27

Data Is No Longer Limiting…But Does Data = The Answer?But Does Data The Answer?

S 4 4 Lif i / h O f d h l i S i i 22 b 2012

3/22/2012 28

Source: 454 Lifesciences/Roche, Oxford Nanopore Technologies, New Scientist, 22 February 2012

How To Treat Metastases – Secondary Prevention & Maintenance Therapy (Preventing Recurrence)?Maintenance Therapy (Preventing Recurrence)?

Late Dissemination Model

Early/Parallel Dissemination Model

Nature Reviews Cancer 12, 133-143 (February 2012)

Cancers 2011, 3, 298-318

3/22/2012 29

Nature Reviews Cancer 9, 302-312 (April 2009)

When Will We Move Beyond Treatment to Prevention?

3/22/2012 30

Nature Reviews Drug Discovery 8, 213-225 (March 2009)

Thinking Mechanistically, Holistically & DynamicallyNature Reviews Cancer 6, 924-935 (December 2006)Cancer as an evolutionary and ecological processLauren M.F. Merlo, John W. Pepper, Brian J. Reid3 & Carlo C. Maley

Nature Reviews Cancer 11, 375-382 (May 2011)An analogy between the evolution of drug resistance in bacterial communities and malignant tissuesG ill L b t L i E té S l St OhGuillaume Lambert, Luis Estévez-Salmeron, Steve Oh, David Liao, Beverly M. Emerson Thea D. Tlsty & Robert H. Austin

3/22/2012 31

How Do We Balance Data, Deduction & Inspiration?

• In the great Argentinean writer Jorge Luis Borges’ short story "Funes the Memorious" ("Funes el memorioso” La Nación in June 1942) Borgesmemorioso , La Nación in June 1942), Borges describes his character, Ireneo Funes, whose memory is following a fall becomes so prodigious that he remembers everything, “not only every leaf of every tree of every wood but also every one ofof every tree of every wood, but also every one of the times he had perceived or imagined it.”

• “He was…almost incapable of ideas of a general, Platonic sort. Not only was it difficult for him to

h d th t th i b l d bcomprehend that the generic symbol dog embraces so many unlike individuals of diverse size and form; it bothered him that the dog at three fourteen (seen from the side) should have the same name

th d t th fift ( f th f t) ”as the dog at three fifteen (seen from the front).”

3/22/2012 32

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