Oncology: Pharmacogenetics is Not Just for...

Oncology:

Pharmacogenetics is Not Just for Targeted Therapies –

Making Intelligent Space for Chemotherapy in the 21st Century

Insight Briefing Oct 6, 2005

DH Insight Briefing – October 2005 Oncology - © Defined Health, 2005

Oncology:

Pharmacogenetics is Not Just for Targeted Therapies –

Making Intelligent Space for Chemotherapy in the 21st Century

Jeffrey M. Bockman, PhD

Vice President, Defined Health


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 guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change.

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History Lesson

Commercialization of penicillin


Definitions

• What is cytotoxic and what targeted?

– When does a multi-targeted agent become a chemo agent?

– When does multi-targeted go from broad spectrum to non-specific?

– What of targeted cytotoxics (tubulin, topo II)?

– Is it historical? What happens when old or new chemo agents have their very specific targets discovered?

– Is it cell killing versus cytostatic? What of Rituxan, then?

– Is the definition in safety?


Cytotoxics – Losing Out to “Targeted” Agents?

Defined Health analysis from Adis R&D Insight

IN DEVELOPMENT, SOMEWHAT…

CytostaticsCytotoxic

ImmuneOther

From Aghazadeh, Arnold, and Beever, In Vivo, Jan 2005, pg. 59. Other includes chemosensitizers, cell therapies,etc.

30% 38% 28%41%

0%

20%

40%

60%

80%

100%

Colorectal Lung Prostate Breast

CytotoxicsCytostaticsImmuneOthers

Phase II/III Oncology Pipeline by Global Mechanism

Clinical Stage Oncology Pipeline for Major Tumor Markets by Global Mechanism


Cytotoxics – Losing Out to “Targeted” Agents?

EvaluatePharma – Sum CAGR 2004-2009

AND CONSENSUS ANALYST GROWTH RATES…CERTAINLY

Growth of targeted therapies driven by continued penetration into current markets, expansion into new segments (e.g., front-line breast for Avastinand Herceptin), and approval of new agents.

Conventional cytotoxic agents growth is driven by increasing incidence/prevalence, some expansion into new segments (e.g., adjuvant in CRC II/III)


Future of Anticancer Therapy

Conventional Chemotherapy

Conventional Chemotherapy

TargetedTherapy

TargetedTherapy

Cancer Early Advanced

MolecularDiagnostics Molecular

Diagnostics

2005 2010

Cancer Early AdvancedAdvancedConventionalChemotherapy

TargetedTherapy

CombinationAdvancedCombination

ConventionalChemotherapy

TargetedTherapy

Targeted Therapy A

Targeted Therapy B

2 TargetedAgents


Future of Anticancer TherapyTargeted Therapies Will Continue to Need to be Used Most Commonly in Combination with Cytotoxics


• Data on targeted plus cytotoxics having better outcomes than targeted or cytotoxics alone


Anti-CancerMOA’s –

Major Buckets

Anti-metabolites

Signal Tranduction- Master Switches

Immunological Targets

Other InterestingMechanisms

Epigenetic Agents

Hormone Therapy Transcriptional

Regulation

Microtubule / Cytoskeletal

Inhibitors

Cell Cycling

DNA Targeting Agents

Cell and Gene Therapies

Other signal transduction

pathwaysPro-Apoptotic Mechanisms

Angiogenesis, cellular

Trafficking, Tumor Invasion

Growth Factor Receptors

Essential MOA Buckets

IDdb, Adis R&D InsightCell surface

targeting


Major Pharma Has a Diversified Approach

• Profiles show pipelines of key players by broadly grouped MOAs:

Key MOA “buckets” of drug development among biopharma – CLINICAL STAGE

Chemotherapy/cytotoxics

Angiogenesis/tumor invasion/metastases

Cell cycle

Hormone

Immune approaches (e.g., vaccines)

Intracellular signaling/growth factors

Epigenetic targets

Apoptosis

Targeted cell surface (e.g., antibodies with cytotoxic payloads)


Major Pharma Has a Diversified Approach

But most everyone of the major players are staying with cytotoxic chemotherapies in their pipelines.


Framing the Problem

• Despite some significant advances with novel “targeted” agents, we still, by and large, have most cancer patients dying.

Tumor Type Treatment: First Line Response

Treatment: Second

LineResponse

Breast Cancer Combination Chemotherapy

ORR = 58%MS = 23 months (1)

Trastuzumab + Chemotherapy


Colorectal Cancer FOLFOX ORR = 45%MS = 19.5 months (3) FOLFOX + bevacizumab ORR =

MS = 12.5 months (4)

Prostate Cancer Androgen Deprivation ORR =80%MS = 36 months (5)

Combination Chemotherapy


Non-Small Cell Lung Cancer

Combination Chemotherapy

ORR = 41% MS = 10 months (7) Tarceva ORR = 9%

MS = ~7 months (8)

Pancreatic CancerGemcitabine ORR = 24%

MS = 6 months (9)

Sutent or Nexavan(neither is yet approved)


An oncology example:

One Intergroup study of nearly 1000 patients with Stage III colorectal cancer (CRC)

• 45% surgery alone, alive and disease-free after 5 years• 65% surgery plus chemo (5-FU) alive and disease-free after 5 years

Conclusion: Using the 5 year endpoint, approx. 55% patients didn’t need adjuvant chemo and 35% died even with it.

Responders vs. Non-Responders

Framing the Problem


Framing the Problem

THE NEW ENGLAND JOURNAL OF MEDICINE | VOLUME 352 | FEBRUARY 3 2005 | 476-487


Targeted Therapies Need Further Targeting: Parsing the Market

Herceptin - Gleevec - Avastin


Targeted Therapies Need Further Targeting:Parsing the Market

Herceptin - Gleevec - AvastinIn 75 percent of patients, leukemia cells can no longer be detected after treatment with Gleevec. Within four years of follow-up, 16 percent of patients have developed resistance. Together, some 41% either don’t respond well or later fail on therapy.


Targeted Therapies Need Further Targeting:Parsing the Market

Herceptin - Gleevec - Avastin

http://content.nejm.org/content/vol350/issue23/images/large/05f2.jpeg


Targeted Safety & Tolerability: Not Perfect

• Rituxan

Company websites



• HerceptinHerceptin Safety Profile

Herceptin therapy does involve risks. Serious side effects have occurred in patients treated with Herceptin in metastaticbreast cancer. Herceptin administration can result in the development of ventricular dysfunction and cardiac failure.

Severe hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary events have been infrequently reported. Rarely, these were fatal.

In clinical trials, approximately 40 percent of patients experienced symptoms such as chills and fever during the first infusion. These and other symptoms, including nausea, vomiting, and pain, occurred infrequently with subsequent infusions. In clinical trials, the incidence of moderate to severe neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those receiving chemotherapy alone. There was an increased incidence of anemia leukopenia, diarrhea, and infection when Herceptinwas used in combination with chemotherapy.



• AvastinAvastin Safety ProfileThe addition of Avastin to chemotherapy is generally well tolerated. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were infrequent, and included gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia. The most common adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria.


Why Do Anticancer Treatments Fail?

Reasons for failure in drug development. a | 198 NCEs in clinical development by large UK companies, 1964–1985. b | 121 NCEs, excluding the anti-infectives from diagram a. (Source: Centre for Medicines Research; redrawn from Ref. 13).

Nature Reviews Drug Discovery 2, 665-668 (2003);

Is cancer different from other categories?



Is cancer different from other categories? Yes, it seems so.



BioCentury Vol 13 No 31 - For the week of July 11, 2005


Why Do Anticancer Treatments Fail?• Risk of novel targets, of course

• Commercial risk?

IN VIVO, Jan. 2005

Analysis was done using Adis R&D Insight and IDdbto identify all drugs in Phase II (278) or Phase III (140) clinical developmentbetween July 1997 and July 2004 for the following 14 pharmaceutical and five biotechnology companies (Pfizer Inc., Wyeth, Merck& Co. Inc., Novartis AG, Roche, sanofi−aventisSA, Johnson & Johnson, GlaxoSmithKline PLC, Bristol−Myers Squibb Co., Eli Lilly & Co., Bayer AG, Abbott Laboratories Inc., Schering−PloughCorp., AstraZeneca PLC, Biogen Idec Inc., AmgenInc., Chiron Corp., Genentech Inc., and Genzyme Corp.).

Small molecule cytotoxics would fall here


Cancer as a Robust System

Feedback loops for hypoxia responses of tumour cells. Hypoxia occurs because of a rapid increase in tumour mass that outpaces angiogenesis. Hypoxia induces hypoxia-inducible-factor 1 (HIF1), which upregulates various genes, including those that encode vascular–endothelial growth factor (VEGF)116–118, CXCR4 (REF. 119), MET120, matrix metalloproteinase 2 (MMP2), and the urokinasetypeplasminogen-activator receptor (uPAR). At the same time, progression through the cell cycle is inhibited by HIF1-dependent and -independent mechanisms. VEGF upregulation promotes angiogenesis, so that hypoxia of tumour cells can be resolved by vascularization. Simultaneously, chemokine receptors such as CXCR4 and MET are upregulated, so that tumour cells can respond to chemokines in the environment. MMP2 and uPAR are upregulated, leading to degradation of the extracellular matrix (ECM), so that tumour cells can migrate away from the hypoxic region and metastasize120,121. When hypoxia is resolved in this way, cell-cycle arrest is released and further proliferation is initiated. Multiple feedback loops ensure robust responses of tumour cells to hypoxia. In response to nutrient deprivation, tumour cells can also switch metabolic pathways from an oxygen-dependent tricarboxylic acid (TCA) cycle to glycolysis — both of which result in ATP production122. Mechanisms that maintain tissue integrity despite changes in oxygenation are hijacked by tumours to ensure tumour progression and survival. Correcting this hijacked mechanism has been proposed as a means of anticancer therapy48,123–126, and this might be effective if potential heterogeneous feedback can be fully controlled. HGF, hepatocyte growth factor; SDF1α, stromal-derived factor 1α.

NATURE REVIEWS | CANCER VOLUME 4 | MARCH 2004 | 227

“Complex,multilayered and multidirectional interaction loops occur between tumourcells and the stroma and extracellular matrix, immune cells, the vasculature andother tumour cells.”


Therapeutic Index

OBD, optimal biologic dose; MTD, maximum tolerated dose (Rowinsky, 2000)

“The bottleneck to the development of safe and effective anticancer drugs does not lie in an inability to identify chemicals that will kill cancer cells. In fact, thousands of compounds have been identified over the past 50 years that will accomplish this feat. Instead, the bottleneck lies in our inability to identify chemicals that will kill cancer cells at concentrations that do not harm patients. Most of the chemotherapeutic agents used today have remarkably low THERAPEUTIC INDICES and narrow THERAPEUTIC WINDOWS.”

NATURE REVIEWS | CANCER VOLUME 5 | SEPTEMBER 2005 | 689


Synthetic Lethality – What to Combine

Models of oncogene addiction. a | Many oncogenes paradoxically induce pro-mitogenicsignals as well as antimitogenic (or pro-apoptotic) signals. Growth stimulation results from oncogeneactivation presumably because the former is dominant to the latter. However, acute inactivation of the oncogene might cause growth cessation or death if the anti-mitogenic/pro-apoptotic signals decay more slowly than the mitogenic signals (for example, because of differences in mRNA and protein halflife). b | Oncogene dependency due to gene–gene interactions. Cancer cells accumulate mutations (arrows) over time that cumulatively lead to a transformed phenotype. Selection favoursacquisition of mutations that are neutral or beneficial (adaptive) in the context of the mutations that preceded them. However, some of these changes might be deleterious (red arrow) were it not for the changes that preceded them. If true, correcting early genetic changes (yellow arrow) will unmask these deleterious effects. In this model, cancer cells behave like a molecular ‘house of cards’. c | Activation (indicated by bold arrow) of an oncogenic pathway diminishes selection pressure to maintain collateral signalling pathways. Silencing of these collateral pathways over time, because of genetic or epigenetic changes, leads to oncogene dependency.

NATURE REVIEWS | CANCER VOLUME 5 | SEPTEMBER 2005 | 689

“TARGET-DRIVEN” THERAPEUTIC INDEX VS.

“CONTEXT-DRIVEN” THERAPEUTIC INDEX


When to Combine?Models for repopulation. In an untreated tumour, cells that have migrated further away from blood vessels, as a result of proliferation, will become depleted of oxygen and other nutrients. These peripheral cells will tend to die spontaneously. Radiotherapy (because of selective effects against well-oxygenated cells) and chemotherapy (because of higher drug concentration and selective effects against proliferating cells) are more toxic to cells that are close to blood vessels in tumours. As a result, the migration of cells away from vessels and the rate of spontaneous cell death are reduced. Repopulation occurs from the more distal cells, which tend to be spared by treatment. RT, radiotherapy; CT, chemotherapy.

NATURE REVIEWS | CANCER VOLUME 5 | JULY 2005 | 516

Model curves that illustrate the potential effects of repopulation on the total number of cells present in a tumour at different times during chemotherapy, relative to the start of treatment. It is assumed that 70% of tumour cells are killed after each administration of chemotherapy, which is given at 3-week intervals. a | Assumes a constant rate or repopulation of surviving tumour cells between treatments, characterised by a doubling time of either 10 days or 2 months. b | Assumes accelerating repopulation of surviving tumour cells between successive courses of chemotherapy, characterised by the indicated doubling times. c | Assumes a delay in onset of repopulation after each cycle of chemotherapy, followed by accelerating repopulation of surviving tumour cells with the indicated doubling times. Note that accelerated repopulation can lead to the remission and regrowth of tumours during chemotherapy, as is commonly observed in clinical practice, without anychange in the intrinsic chemo-sensitivity of the tumourcells. TD, cell doubling time.


When to Combine? When to Dose?• “A reappraisal of the best ways of administering chemotherapy is underway. Instead

of only using short bursts of toxic MTD chemotherapy interspersed with long breaks to allow recovery from the harmful side effects, there is now a shift in thinking towards the view that more compressed or accelerated schedules of drug administration using much smaller individual doses than the MTD would be more effective — not only in terms of reducing certain toxicities, but perhaps even improving antitumour effects as well… The most recent refinement of this concept is called ‘metronomic’ chemotherapy, which refers to the frequent, even daily, administration of chemotherapeutics at doses significantly below the MTD, with no prolonged drug-free breaks.”

Different therapeutic regimens. Metronomic chemotherapy regimens differ from the standard maximum tolerated dose (MTD) chemotherapy regimens that have been common practice in medical oncology for decades. a | In standard chemotherapy, a drug is typically given in a single bolus injection or infusion at the MTD, interspersed by a long break —for example, 3 weeks — before the next course of this therapy is administered. Doses that exceed the MTD (‘high-dose’ chemotherapy) must be accompanied by an autologous bone-marrow stem-cell transplant and supportive-care growth-factor drugs to prevent lethal bone-marrow failure. In b and c, examples of metronomic chemotherapy regimens are shown where, for example, the chemotherapy drug is administered more frequently, such as weekly (b) or daily (c), with no prolonged drug-free interruptions.

NATURE REVIEWS | CANCER VOLUME 4 | JUNE 2004 | 423


Combinations - Merck

Peter Kim, PSA, Sept 2005


Combinations - CombinatoRx

• “For example, one anticancer coupling includes an antipsychotic(chlorpromazine) and an antiparasitic(pentamidine). "When he saw it, a world-leading oncologist said, 'Who the heck would have put these together?'" Borisyrecalls.”

• CRx-026 contains two active pharmaceutical ingredients which, when combined, synergistically blocks cancer cell division by inhibiting two critical elements of the cancer cell’s mechanism for dividing. One component of CRx-026, chlorpromazine, inhibits hsEg5/KSP, a mitotic kinesin essential for centrosome separation. The other component, pentamidine, is reported to inhibit PRL phosphatases, which play an important role in regulating mitotic progression and proper chromosome separation.

Bio-IT World Oct 4, 2005

NATURE REVIEWS / DRUG DISCOVERY / VOLUME 4 / JANUARY 2005


Combinations - Celator

CombiPlexSM/TM Technology

• The Role of Drug Ratios in Combination Chemotherapy to Treat Cancer

Research efforts led by Celator have shown that individual chemotherapeutic agents can interact synergistically, additively or antagonistically when combined at certain ratios. Thus, the ability to identify the ratio of drugs that will produce a synergistic benefit – and a technology able to control that ratio systemically – could have a profound impact on the overall efficacy of combination chemotherapy agents used to treat millions of cancer patients each year.

Company websites


Combinations - Celator

CombiPlexSM/TM Technology

• The Role of Drug Ratios in Combination Chemotherapy to Treat Cancer

Research efforts led by Celator have shown that individual chemotherapeutic agents can interact synergistically, additively or antagonistically when combined at certain ratios. Thus, the ability to identify the ratio of drugs that will produce a synergistic benefit – and a technology able to control that ratio systemically – could have a profound impact on the overall efficacy of combination chemotherapy agents used to treat millions of cancer patients each year.

CPX-1 (Irinotecan-HCI: Floxuridine) is in clinical trials as a treatment for colorectal cancer. CPX-351 (Cytarabine-Daunorubicin) is in development as a treatment for acute myeloid leukemia, or AML. Platinum-based combinations are in preclinical evaluation as therapy options for a range of head and neck cancers and lung cancers.


Pharmacogenetics - Today

NATURE REVIEWS | CANCER VOLUME 1 | NOVEMBER 2001 | 99


Pharmacogenetics – Today

Patients with low hepatic DPD activity cannot efficiently metabolize 5-FU (which is used totreat colon and breast cancer) and its accumulation causes toxicity. b | Polymorphisms inthymidylate synthase (TS) affect 5-FU efficacy. In tumour tissue, the active metabolite of 5-FU,5-fluorodeoxyuridine monophosphate (5-FdUMP), inhibits TS. The presence of triple tandemrepeats of 28 base pairs in the enhancer region of the TS gene is associated with higher TSactivity and lower probability of response to 5-FU when compared with patients that have onlytwo tandem repeats.


TOX

EFFICACY

Colorectal Cancer


Pharmacogenetics - Today


Thiopurine methyltransferase polymorphisms that affect mercaptopurine therapy. a | The leukaemia drug mercaptopurine (MP) is converted by the enzyme hypoxanthine phosphoribosyl transferase (HPRT) to its active metabolites, thioguanine nucleotides (TGNs). TGNs are incorporated into DNA and result in antileukaemic effects, but also in myelosuppression.The enzyme thiopurinemethyltransferase (TPMT) competes for the MP substrate, catabolizing it to methylmercaptopurine (MeMP), an inactive metabolite.b | The population frequency distribution of TPMT activity displays a trimodal pattern. The three modes of TPMT activity (indicated here in erythrocytes) correspond to 0.3% of the population being homozygous (mut/mut) for mutations in TPMT, 10% being heterozygous (wt/mut) for mutations in TPMT, and 90% being wild-type (wt/wt) TPMT. c | TPMT genotype is related to phenotype. Mut/muthomozygotes have very little TPMT activity, and therefore accumulate excess amounts of intracellular TGNs, leading to myelosuppression and an increased risk of secondary cancers. Wt/wt homozygotes express high levels of this enzyme and produce lowlevels of active TGNs, which decreases the risk of myelosuppression, but might also increase the risk of relapse of the leukaemia. Heterozygotes (wt/mut) have intermediate TGN levels.

Acute Lymphoblastic Leukemia

TOX

EFFICACY


Pharmacogenetics - Tomorrow

• Examples:

– CRC

– Breast cancer

Pharmacogenomics (2005) 6, 603-614



• Examples:

– CRC

– Breast cancer

The Pharmacogenomics Journal (2004) 4, 143–153



• Examples:

– CRC

– Breast cancer

NATURE CLINICAL PRACTICE ONCOLOGY NOVEMBER 2004 VOL 1 NO 1



• A strong call for the pharmaceutical industry to invest money in predicting responses to cancer drugs.

Beyond Fast Track for Drug ApprovalsThomas G. Roberts, Jr., M.D., and Bruce A. Chabner, M.D.The New England Journal of Medicine 351, pp 501-505, July 29, 2004

• But wait, not so fast, and with all due respect…


Chemo Is Dead – Long Live Chemo

• SG Cowan 2000 analyst report on Sanofi-Synthelabo, Eloxatinforecast: $150M US in 2005

• Sales in 2004 were $897M and sales estimated to be $1.2B in 2005.

EvaluatePharma

Eloxatin

• The point is not that they miscalled—everyone does that—but that they failed to appreciate how a next generation agent, if differentiated, could gain clinical and commercial traction.


Chemo Pipeline

• Next Generation Cytotoxics

• Novel Cytotoxics

Adis R&D Insight; IDdb

Microtubule-Targeting Agents, Phase I and up


Chemo Pipeline



Cell Cycle Targeting Agents, preclinical

Adis R&D Insight; IDdb


Chemo Pipeline




Chemo’s Future

• “THIS REPORT OF MY DEATH WAS AN EXAGGGERATION”

Mark Twain, May 1897


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