Hot Targets for Challenging Times - Defined...

Hot Targets for Challenging TimesThe Scientific, Clinical and Commercial Promise of Today’s Most Exciting Oncology Programs

February 17, 2011, Basking Ridge, NJ, USA

Jeffrey M. Bockman, PhD – Vice President, Defined Health

© Defined Health, 2011

The information in this report has been obtained from what are believed to be reliable sourcesand has been verified whenever possible. Nevertheless, we cannot guarantee the informationcontained herein as to accuracy or completeness. All expressions of opinion are theresponsibility of Defined Health, and though current as of the date of this report, are subject tochange.

DH Insight Briefing – February 17, 2011 Oncology - Page 2

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Introduction


Key Themes

• Introduction

• Some Lessons Learned (and Still Learning)

• New Challenges

• Addressing the Challenges: Clinical Development Paradigms

• A Skewed and Selected Look at the Pipeline

• A Few Real-World Examples

• Deal-Making & What It Might Tell Us

• PoRTM in Oncology

• Closing Thoughts



Uncovering the Key Pathways in Cancer

Cell, Vol. 100, 57–70, January 7, 2000,


Nature 455, 1061-1068 (23 October 2008)


Some Lessons Learned (and Still Learning)


The Targeted Dream, How Fulfilling, How Fulfilled?

• “Targeted” agents, specifically TKIs, appear to have an edge over “non-targeted” agents….Just not sure where MTKIs fit into this!


Nature Reviews Drug Discovery, Vol. 8, Number 1, pp. 15-6, Jan 2009



• Biologics have the apparent edge…


0%10%20%30%40%50%60%70%80%90%

100%

Phase 1-2 Phase 2-3 Phase 3-FDAReview

Review-Approval

All Candidates, 1990-06 Small, 1990-06 mAbs, 1990-06

Prob

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Adapted From- Emerging Success Rates for New Cancer Therapies, 1990-2006. Tufts Center for the Study of Drug Development October 2007

Small molecules still outnumber MAbs in development and

approvals in cancer, probably skewing

these data



• “Targeted” agents stumble, too…


AstraZeneca’s Colon Cancer Drug Recentin Fails To Meet Primary Endpoint In Phase III Study –Update(RTTNews) – Biopharmaceutical company AstraZeneca plc (AZN, AZN.L) Friday said its investigational drug Recentin, also known as Cediranib, tested as a first-line treatment of metastatic colon cancer, failed to meet the primary end point of overall survival in a second late stage study. In the second phase III trial dubbed HORIZON II, though Cediranib met the co-primary endpoint of improving progression-free survival, it did not show any improvement in overall survival. The first phase III study dubbed HORIZON III evaluated Cediranib plus chemotherapy versus bevacizumab plus chemotherapy and that trial did not meet the primary endpoint of progression-free survival.

Figitumumab Fails to Improve Survival, Increases Toxicities, in First-line Treatment of Patients with NSCLCASCO PostNovember 2010, Volume 1, Issue 6A large multicenter phase III trial has found that the addition of figitumumab, a monoclonal antibody directed at insulin-like growth factor type 1 receptor (IGF-1R), to standard first-line chemotherapy for non-small cell lung cancer (NSCLC) does not improve overall survival and increases the risk for severe toxicities-even for patients with non-adenocarcinomahistology. Figitumumab is a monoclonal antibody that targets the insulin-like growth factor-1.The trial was shut down early because of an increased number of deaths related to figitumumab therapy….Results of the study indicated that the overall survival of patients who received figitumumab in addition to chemotherapy was worse than for those who received chemotherapy alone-8.5 vs 10.3 months.

PTK787 Discontinued in CRCVatalanib (PTK787) is an oral small molecule angiogenesis inhibitor that works by selectively inhibiting the tyrosine kinase domains of vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptor-β, and c-kit. Vatalanib was being jointly developed by Novartis AG and Bayer Schering Pharma AG for certain oncology indications; however, Bayer discontinued development of the drug in 2007. Two international phase III studies in metastatic colorectal cancer were completed, and clinical trials for various other solid tumors were ongoing. Novartis was exclusively developing the agent for the treatment of ophthalmic conditions such as age-related macular degeneration (AMD). However, Novartis has discontinued development of vatalanib for metastatic colorectal cancer and other solid tumors, and for wet AMD.


New Challenges


It’s Getting Rough Out There


GAITHERSBURG, Md. – July, 2010 - An advisory panel has voted 12 to 1 to recommend that the FDA remove the advanced breast cancer indication from bevacizumab (Avastin), after two large clinical trials failed to demonstrate a clinically meaningful benefit of the drug, which carries serious side effects.

The Oncologic Drugs Advisory Committee voted that bevacizumab, when added to standard chemotherapy, does not extend progression-free survival long enough to be clinically meaningful in HER2-negative, metastatic breast cancer.

Source: Evaluate Pharma, WSJ, MedPage Today


Trouble in Paradise?


Medpage Today, Feb 8, 2011; N Engl J Med 2004; 351:501-505


Pricing and Performance


ONCOLOGY BUSINESS REVIEW • WWW.ONCBIZ.COM • MARCH 2010; REUTERS, Feb 16, 2011


Addressing the Challenges:Clinical Development Paradigms


The Development Paradigm - Problematic


Nature Reviews Drug Discovery 9, 253-254 (April 2010)

William N. Hait, M.D., Ph.D., is Senior Vice President and Worldwide Head at Ortho Biotech Oncology Research and Development, 920 Route 202, Raritan, New Jersey 08869, USA.


Biomarkers – Still Getting There


N Engl J Med 2010; 363:1760-1762October 28, 2010; N Engl J Med 2010;363:1693-703; N Engl J Med 2010;363:1734-9

The EML4 (echinoderm microtubule-associated protein-like 4)–ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non–small-cell lung cancers.


Biomarkers – Still Getting There


N Engl J Med 2011;364:205-14

Seekingalpha.com, January 30, 2011; Bloomberg Businessweek,, Jan 28, 2011


The Development Paradigm – Phase I StudiesLooking Earlier for Insight


Nature Reviews Cancer 10, 514-523 (10 June 2010)


The Development Paradigm – Phase I StudiesLooking Earlier for Insight


Nature Reviews Cancer 10, 514-523 (10 June 2010)

Nature. 2010 Sep 30;467(7315):543-9


Seminal Randomized Discontinuation Trial


Role of Sunitinib and Sorafenib in the Treatment of Metastatic Renal Cell Carcinoma, Medscape, April 2008; Activity of Tivozanib (AV-951) in Patients With Renal Cell Carcinoma (RCC): Subgroup Analysis From a Phase 2 Randomized Discontinuation Trial (RDT), ASCO 2010


Adaptive Design Gets Super-Sized

• I-SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium.

• The overall trial design for I-SPY 2 features two arms of a standard neoadjuvant chemotherapy regimen, starting with weekly paclitaxel (plus trastuzumab (Herceptin) for HER2+ patients) followed by doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan). In the other arms, five new drugs are tested simultaneously, each being added to standard therapy. On the basis of statistical models, each drug will be tested in a minimum of 20 patients and a maximum of 120 patients.


Clin Pharmacol Ther. 2009 Jul;86(1):97-100. Epub 2009 May 13


Adaptive Design Gets Super-Sized

• BATTLE I: patients with chemo-refractory metastatic were stratified according to the presence of the (highest ranked) biomarker identified in a core needle biopsy: EGFR, KRAS, BRAF, or cyclin D. Primary endpoint was 8-week disease control (DC). Based on tumor biomarker analysis, patients were adaptively randomized under a Bayesian model into four treatment: erlotinib, sorafenib, vandetanib, or erlotinib + bexarotene. The primary 8-week DC endpoint was shown to predict overall survival (median overall survival: 9 months).


Scott M. Lippman, M.D.. The Future of NSCLC

The phase II clinical trial found evidence that each of the four drugs targets specific molecular signatures better than the other three. The drugs used in the trial were erlotinib (Tarceva®), sorafenib (Nexavar®), vandetanib (Zactima®) and erlotinib with bexarotene (Targretin®). Each drug is designed to target specific molecular pathways; currently, none has a validated biomarker to guide its use.BATTLE's end point was disease control at eight weeks, which recent research has found is a good indicator of overall survival. The study found, for example, that 61 percent of patients with a KRAS mutation in their tumors who took sorafenib had disease control at eight weeks, compared with 32 percent for the other three drugs. Erlotinib did best against EGFR mutations, vandetanib for high VEGFR-2 expression and the erlotinib-bexarotene fared best with Cyclin D1 defects or amplified numbers of the EGFR gene. These exploratory analyses raise interesting areas of future research.Overall, 46 percent of patients on the trial had disease control at 8 weeks, compared with a historical experience of around 30 percent for late-stage lung cancer patients. Median overall survival was nine months, and 38 percent of patients survived to one year. Toxicities from the four drugs were minimal, with only 6.5 percent of patients experiencing a significant side effect. (M. D. Anderson News Release 04/15/10)


Getting (Better) at Combinations


Nat Rev Drug Discov. 2010 Nov;9(11):843-56; AstraZeneca press release, June 1, 2009


A Skewed and Selected Look at the Pipeline


Pipeline Snapshot - Phase I Through II (WW)


Adis R&D Insight, Feb 2011










A Very Selective & Non-Systematic View

• “Incremental” Twists

• Just Plain Interesting (Including Quirky or Out-of-the-Box)

• Paradigm Shifters

• A Few Real-World Examples



“Incremental” Twists


Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) launched for mBC after failure of combination chemotherapy or relapse within six months of adjuvant chemotherapy

Phase III NSCLC, melanoma, ovarian, prostate and pancreatic cancers; Phase II stomach, bladder, H&N

June 2010February 2005

Defined Health; EvaluatePharma; Abraxis web site

http://replay.waybackmachine.org/20050519082843/http://www.abraxisoncology.com/index.html�


“Incremental” Twists

• Poster 423 - Phase 1 dose escalation, safety and pharmacokinetic study of CRLX101, a novel nanopharmaceutical containing camptothecin, in advanced solid tumor cancer patients

• Background: IT-101 (CRLX101) is a novel polymeric nanoparticlecomprised of biocompatible cyclodextrin-polyethylene glycol co-polymer conjugated to camptothecin (CPT). CPT is a potent, broad-spectrum antitumor agent that inhibits type I DNA topoisomerase. The polymeric nanoparticle formulation of the drug conjugate is specifically designed to (a) enhance delivery of active CPT to tumor tissue, (b) augment efficacy by prolonging therapeutic drug exposure to cancer cells, and (c) minimize toxicity by maintaining low systemic free drug level in circulation. IT-101 has demonstrated all three of these properties in pre-clinical animal model studies. A Phase 1 dose escalation study of IT-101 was conducted to assess safety, to characterize pharmacokinetics (PK), and to establish the maximum tolerated dose (MTD) in patients with advanced solid tumors.

• Material and Methods: Patients with advanced solid tumors received IT&hyphen;101 on a weekly x3 or an every-other-week schedule in a 28&hyphen;day cycle. IT-101 was administered by intravenous infusion over 90 minutes. Serial plasma samples were analyzed for IT-101 and unbound CPT. Biological activity measurements were taken after every two cycles of therapy by CAT scan.

• Results: Twenty-four (24) patients received IT-101 at 5 dose levels and on the 2 dosing schedules, ranging from 6 mg/m2 to 18 mg/m2 of CPT per dose. The every-other-week schedule was well-tolerated and an MTD was defined. The weekly ×3 schedule was found to have a less acceptable safety profile. Stable disease for greater than six (6) cycles of therapy was observed in four (4) patients, including two (2) with advanced non-small cell lung cancer (NSCLC). Safety and PK data will be presented along with a clinical data review from both dosing schedules.

• Conclusion: IT-101 is found to have a favorable safety and PK profile in humans, confirming the intended properties of its nanoparticle formulation design. Observations of prolonged stable disease in multiple patients with advanced solid tumors demonstrate biological activity and support further clinical development.


22nd EORTC-NCI-AACR Symposium on “Molecular Targets and Cancer Therapeutics,” October 2010, Berlin, Germany; Boston.com, Nov 15, 2010

Because Lilly knows cytotoxics, because it helps (potentially) balance out the risk of novel agents in Lilly’s pipeline, other?

http://www.ceruleanrx.com/index.html�


“Incremental Twists”


Nektar presentation, JPMorgan, Jan 2011


Just Plain Interesting (Quirky or Out-of-the-Box)


Oncolytics presentation, 13th Annual Bio-CEO Investor Conference, Feb 2011

http://www.oncolyticsbiotech.com/index.html�


Just Plain Interesting (Quirky or Out-of-the-Box)


Senesco presentation, Bio CEO, Feb 14 2011


Just Plain Interesting (Quirky or Out-of-the-Box)• The number of papers describing bacterial anticancer

therapies has grown exponentially (dashed black line) since the mid-1990s.


The transport properties of bacterial therapies produce preferable drug concentration profiles. The concentration of bacterially produced molecules (blue lines on graphs) is greatest in distal tumor regions. The concentration of chemotherapeutic molecules is greatest in systemic blood and drops as it is cleared by the liver or kidneys. Based on these profiles, bacterially produced molecules will be more cytotoxic (shown by dashed lines on the graph) in the distal regions of tumors and less systemically toxic.

Nature Reviews Cancer 10, 785-794 (14 October 2010); Cell Cycle, Dec 2010; Anaeropharma web site

Leading Anti-cancer Drug Candidate; APS001The company’s leading anti-cancer drug candidate, APS001 is recombinant anaerobic bacteria Bifidobacterium modified to express the cytosine deaminase (CD) gene, which results in overexpression of the CD enzyme. Bifidobacteria are a major component of normal human intestinal flora; they can be detected in a wide variety of mammalian species. When APS001 is administered intravenously to tumor-bearing mice, the bacteria localize and grow specifically in the tumors, but not in normal tissues. When flucytosine (5-FC, a fluorinated analog of cytosine that is licensed for use as an anti-fungal agent in the US) is administered in the presence of APS001, the CD enzyme converts the cytosine residue of 5-FC to uracil, producing Fluorouracil (5-FU). Eisai Co., Ltd. and Shinshu University venture company Anaeropharma Science, Inc. announced on September 29, 2010, that they have concluded an option agreement concerning APS001.


Paradigm Shifters

• Immunotherapy

• Stem Cells

• MicroRNA/siRNA

• Metabolism



Immunotherapy


Source: Defined Health


Paradigm Shifters - Immunotherapy


Corporate presentation, JPMorgan, Jan 2011

http://www.immatics.com/index.php�




The serum marker CA125 is known to originate from the transmembrane protein, MUC16; however, the biological importance of MUC16 is not known. In vivo data suggest that MUC16 drives a more aggressive phenotype in ovarian cancer, including increased growth, invasion and dissemination. MUC16 transfection of ovarian cancer cells is also associated with the upregulation of specific signaling kinases, including EGFR, Erk, Src and Akt.

This trial aims to evaluate if the repeated vaccination with Abagovomab creates an immune response which is able to maintain remission and disease-free survival. Patients who achieve the remission after chemotherapy are screened for study participation and if they met the criteria for inclusion they were started with a single subcutaneous injection every 2 weeks (for the first 4 doses - induction phase) and then every 4 weeks (maintenance phase).

Source: Menarini web site; Ann Oncol (2006) 17 (10):1568-1577; Defined Health;




• In numerous preclinical models, when Imprime PGG is administered in combination with anti-cancer monoclonal antibodies, there is a significant enhancement in cancer cell killing. This synergistic effect does not result from enhancing the known killing mechanisms of ADCC and CDC. Instead, this synergistic effect relies on the therapeutic antibody’s ability to target the cancer cells and activate complement on the surface of the tumor cells.

Source: 35th European Society for Medical Oncology Congress, Oct 2010; Defined Health;

Yeast-derived soluble β-1,3/1,6 glucans have been shown to enhance antitumor activity of tumor-specific MAbs in numerous mouse syngeneic and xenograft models


Paradigm Shifters – Cancer Stem Cells


Mabs Vol1 ( 1), p. 12-25;, 2009; Expert Opinion Therapeutic Targets (2007), Vol. 11 (7), pp. 915-927




Corporate Presentation, January 10, 2010; Company web site Fact Sheet



• Human glioblastoma contains tumorigenic stem-like neural precursors (Ignatova, Kukekov et al. 2002; Singh, Clarke et al. 2003; Galli, Binda et al. 2004 ; Singh, Clarke et al. 2004; Singh, Hawkins et al. 2004). A minor population of cancer stem-like cells may represent the source of tumor cell expansion, recurrence and metastasis, thus determining the biological behavior of tumors including proliferation, progression, and subsequently response to therapy. In human brain tumors, this cancer stem cell population expresses CD133, which to date has been the gold standard tumor stem cell marker used (Singh, Hawkins et al. 2004). However, considering the conflicting literature on CD133 as a marker to identify GICs (Bao, Wu et al. 2006; Beier, Hau et al. 2007; Pfenninger, Roschupkina et al. 2007; Clement, Dutoit et al. 2009), Clément et al. elaborate a new method discriminating the CSC with their morphological and intrinsic properties.


Company Présentation, Clément et. al.: 2010. Nature Methods


Paradigm Shifters – MicroRNA

• MicroRNAs are involved in multiple biological processes that are dysregulated in tumor cells and are being increasingly viewed as major contributors to the pathogenesis of cancer. Since they have either oncogenic or tumor suppressive functions, they can serve as anticancer therapeutic targets or as therapeutic modalities (akin to antisense or siRNA).

• A significant body of experimental data indicate that specific microRNA inhibition or replacement can successfully modify the proliferative and/or invasive properties of tumor cells.


Expert Opin. Ther. Targets (2011) 15(3) 275


Paradigm Shifters – MicroRNA

• The effectiveness of in vivo miR inhibition in cancer models has already been shown, but studies to date showed only changes in tumor size when cells were transfected with anti-miR ex vivo and then injected to produce the tumor model.


Cancer Research, June 2010; Pancreas, Oct 2009; Cancer Research, Oct 2010, 15;70(20):8077-87

http://www.regulusrx.com/index.php�


Paradigm Shifters – siRNA

• Validated target, unvalidated approach, unvalidated delivery approach…


The growth of the resulting tumors was monitored for nearly 2 weeks post-injection via bioluminescence imaging (Fig. 7A). At all time points examined, median tumor signal was lower for cells treated with siR2B+5 than for all other treatment groups. This reduced tumor growth rate is consistent with RT-CES growth data obtained for additional cells thatreceived these treatments (Fig. 7B).

Calando web site; Clin Cancer Res 2007;13:2207-2215

Calando Pharmaceuticals’ siRNA-containing nanoparticles are targeted to cancer cells through transferrin (pink) and consist of a water-soluble polymer (gold) and a stabilizer (black).

http://www.calandopharma.com/�


Paradigm Shifters - Metabolism


Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core cellular metabolism and provide support for the three basic needs of dividing cells: rapid ATP generation to maintain energy status; increased biosynthesis of macromolecules; and tightened maintenance of appropriate cellular redox status.The best characterized metabolic phenotype observed in tumor cells is the Warburg effect, which is a shift from ATP generation through oxidative phosphorylation to ATP generation through glycolysis, even under normal oxygen concentrations. This effect is regulated by the PI3K, hypoxia-inducible factor (HIF), p53, MYC and AMP-activated protein kinase (AMPK)–liver kinase B1 (LKB1) pathways.Metabolic adaptation in tumors extends beyond the Warburg effect. It is becoming clear that alterations to metabolism balance the need of the cell for energy with its equally important need for macromolecular building blocks and maintenance of redox balance. To this end, a key molecule produced as a result of altered cancer metabolism is reduced nicotinamide adenine dinucleotide phosphate (NADPH), which functions as a cofactor and provides reducing power in many enzymatic reactions that are crucial for acromolecular biosynthesis. Nature Reviews Cancer 11, 85-95 (February 2011)




Nature Biotechnol.ogy 2010 Sep;28(9):888-91



• Cornerstone’s lead drug candidate from its AEMD platform (Altered Energy Metabolism Directed), CPI-613, is a first-in-class, small molecule drug (thioctan) targeting pyruvate dehydrogenase (“PDH”) complex (“PDC”). PDC functions as a catalyst which funnels the pyruvate from the glycolytic cycle to the TCA cycle. Selective in-vitro cancer cell activities:

– Localization in cancer cell mitochondria

– Key bioenergeticenzyme inactivation

– Selective and substantial induction of oxidative stress

– Inhibition of mitochondrial energy production

– Disruption of mitochondrial membrane potential

– Induction of multiple cell death pathways

– Compelling preclinical efficacy profile

• CPI-613 is currently being evaluated in three clinical trials:

– (i) a Phase I/II clinical study in cancer patients designed to determine its maximum tolerated dose, and evaluate its safety and efficacy,

– (ii) a Phase I/II trial evaluating CPI-613 in first-line treatment for pancreatic cancer in combination with Gemcitabine and

– (iii) a Phase I study evaluating CPI-613 in hematologic malignancies, including acute myelogenous leukemia (AML.)


Cornerstone, non-confidential presentation


A Few Real-World Examples


Targeting Smac for Apoptosis

• One hallmark of cancer cells is their relative resistance to undergo apoptosis, or programmed cell death. Strategies targeting key apoptosis regulators with the goal of overcoming resistance to apoptosis have significant therapeutic potential for the development of new classes of anticancer drugs.

• Historical focus has been on the first described target, bcl2.

• Smac is a pro-apoptotic protein which, by binding to the inhibitor of apoptosis proteins (IAPs), antagonizes their cellular anti-apoptotic function. It interacts with IAPs through its four N-terminal amino acid residues (AVPI). Small molecules that mimic this four residue sequence are being studied as the basis of a new therapeutic strategy for the treatment of human cancers and other diseases.

Diagram from Nature Clinical Practice Oncology

SMAC worthy of further exploration


Smac - TL32711 – Tetralogic

• Tetralogic is developing a novel Smac mimetic that has recently completed dosing of the first cohort in a Phase I study. There are very few Smac mimetics that have

reached the Phase I milestone.• Tetralogic is a small company established in 2004

and privately financed.• This is a small molecule program (i.v.) originating

from Y. Shi’s and G. Mclendon’s study of the intrinsic apoptotic pathway proteins at Princeton University.

• IAPs (Inhibitors of apoptosis proteins) bind to and reduce the activity of caspases (see figure right). Smac (secondary mitochondrial activator of caspases) interacts with caspases relieving IAP inhibition and thus lowering the threshold for apoptosis induction.

Molecular mechanism of Smac mimetics (a) The N-terminal tetrapeptide motif of Smac (orange) bound to a surface groove of the third baculoviral IAP repeat domain of XIAP (green). The N-terminal IAP-binding tetrapeptide motif (orange in a) of Smac competes with a similar motif in caspase-9 for binding to the same conserved surface groove on XIAP-BIR3, thus removing XIAP-mediated inhibition of caspase-9.

Source: Defined Health; Trends in Biochemical Sciences, Volume 29, Issue 9, September 2004, Pages 486-494


Smac - TL32711 – Tetralogic

• No data is available from the multiple ascending does study, though the first patient cohort has been finished.

• TL32711 inhibits the survival of multiple cancer cell lines in vitro.

• In pre-clinical experiments, TL32711 blocks binding of several IAPs to caspase, including, XIAP, cIAP1, cIAP2, and ML, IAP.

• Data were presented at the November 2009 AACR/EORTC conference demonstrating that TL32711 suppresses growth of breast cancer xenografts in an orthotopic model (figure right). This appears to be an exceptionally potent agent in this model.

• The compound did not cross the blood brain barrier and was well tolerated up to 10mg/kg.

• The half-life appears to be sub-optimal as it was injected 3 times a day for 5 days. However, the persistence of the drug in tumor tissue was longer than in normal compartments.

Defined Health; November 2009, AACR/EORTC


Targeting PIM Kinase for Multiple Effects

• The Pim kinase family of serine/ threonine kinases is composed of three isoforms, Pim-1, Pim-2 and Pim-3, which have an important role in tumor progression.

• Pim kinases suppress apoptosis and regulate cell-cycle progression and have been suggested to function synergistically with c-myc as well as serving a putative oncogenic function.

• Elevated levels of Pim kinases have been reported in solid tumors such as prostate cancer and pancreatic cancer.

• Early studies demonstrated over-expression of PIM1 in a significant fraction (30%) of human myeloid and lymphoid leukemia (including 51 primary patients samples and 19 leukemia cell lines) in absence of any apparent gene rearrangements or amplifications.

SGI-1776, a Novel Pim Kinase Inhibitor, for the Treatment of Cancer, Sven de Vos, International Symposium on Targeted Anticancer Therapies 2010


PIM - SGI-1776– SuperGen

• SGI-1776, is a orally administered, small molecule that effectively blocks Pim kinases thereby inducing apoptosis in malignant cells. In addition, Pim-1 kinase has been linked with chemo resistance in prostate cancer cells.

• A Phase I clinical trial to evaluate the safety, tolerability and pharmacokinetic profile of SGI-1776 is currently underway. The first in human clinical trial program will enroll patients with solid tumors with specific emphasis on hormone refractory prostate cancer and refractory non-Hodgkin's lymphomas which have been reported to over-express the Pim kinase family of proteins at a high frequency.

• SGI-1776 appears to be the only PIM kinase specific inhibitor that is currently being studied in clinic. Cylene Pharmaceuticals has a preclinical PIM kinase program. Based on Patent information several other companies appear to be actively pursuing this target including Vertex Pharmaceuticals, Inc., Exelixis, Inc., Abbott Laboratories, Boehringer Ingelheim International GMBH, MUSC Foundation for Research Development, Novartis Vaccines and Diagnostics, Inc. and Oncorex, Inc.

Defined Health; Adis R&D Insight


• Cytotoxicity and proliferation assays show that SGI-1776 is cytotoxic with IC50values in the nanomolar range in AML cells.

• SGI-1776 has cytotoxic activity in primary patient leukemia cells or NHL cells.

• Xenograft models with leukemic cell lines show that SGI-1776 has potent tumor inhibition activity with complete regression of established tumors observed in two AML xenograft models.

• Animal toxicology studies showed that SGI-1776 has a favorable toxicity profile.

• A first-in-human study in currently ongoing in subjects with hormone and docetaxel refractory prostate cancer or relapsed/refractory non-Hodgkin’s lymphomas. A Phase 1/2 study in subjects with leukemia is planned.

PIM - SGI-1776– SuperGen

AML Model

Defined Health; SGI-1776, a Novel Pim Kinase Inhibitor, for the Treatment of Cancer, Sven de Vos, International Symposium on Targeted Anticancer Therapies 2010; Business Wire, Nov 10, 2010


HSP90 - AT13387 – Astex

• Novel, fragment-derived, non-ansamycin, HSP90 inhibitor.

• Extended pharmacodynamics, long tumor half life, intermittent dosing.

• Astex sponsored Phase II in GIST, with potential registration path as single agent and/or combination with standard of care. Various Phase II studies via CRADA with NCI including: single agent trial with AT13387 given on a twice weekly consecutive day schedule and as monotherapy in TKI refractory non small cell lung carcinoma; multiple combination trials including with Herceptin in Her-2 over-expressing breast cancer, Velcade in multiple myeloma and Ara-C in FLT3-driven AML.

Defined Health; Astex non-confidential package, April 2010

http://www.astex-therapeutics.com/home.php�


HSP90 - AT13387 – Astex

• Preclinical data on AT13387 show it as one of the leading differentiated HSP90 inhibitors. AT13387 can be dosed less frequently In xenograft models and achieve equivalent or better efficacy. Preclinical data on GIST supports the scientific rationale for a single agent development path in TKI-resistant patients.

• PD models have been developed based on murine studies that allow correlation of responses to drug activity in patient samples from a Phase I study (Poster 596, 22nd EORTC-NCI-AACR -“Molecular targets and Cancer Therapeutics” - Berlin, Germany, 16 - 19 November 2010).

Defined Health; Astex non-confidential package, April 2010

http://www.astex-therapeutics.com/home.php�


Deal-Making & What It Might Tell Us


Cash on the Barrel – Top Upfronts


• A mixed bag: platform/technology deals, two-plus product deals, antisense, vaccines, monoclonals…

• 11/20 were Phase II or higher at time of deal; 14/20 were clinical stage

Top 20 Upfront Payments, Past Three Years

Late-Breaking Deal, January 24, 2011

Defined Health; EvaluatePharma


Stars in Their Eyes – Top Bioworld Value


• Still a mixed bag…

• But, only 5/20 Phase II or higher; only 11/20 clinical stage

Top 20 Deal Value, Past Three Years

Defined Health; EvaluatePharma


Cancer Vaccine: Amgen-BioVex

• OncoVEXGM-CSF is a gene deleted (ICP34.5-/ICP47-) oncolytic HSV-1 that encodes human GM-CSF. OncoVEXGM-CSF causes direct oncolytic tumor cell destruction and immune activation by releasing tumor antigens and GM-CSF effects that may co-operate with CRT to increase loco-regional control in SCCHN

• The addition of OncoVEXGM-CSF to radical CRT shows promise for the first line treatment of locally advanced stage III/IV SCCHN. Treatment with OncoVEXGM-CSF

was easily added to a standard chemoradiation regimen along with each cycle of cisplatin, without significant additional toxicity being observed. Radiological responses, and particularly pathological responses, were impressive, with 94% of patients demonstrated to be tumor free at surgery. Rates of locoregional control at up to 40 months of follow up remains at 100% with no patient experiencing a locoregional relapse so far. Rates of metastatic relapse were also low (17%; all patients), particularly at virus doses > 107 pfu/ml (7.7%). Disease specific survival at > 107 pfu/ml is 82.4% at 19-40 months follow up. Overall, the data strongly suggests a benefit of OncoVEXGM-CSF therapy in achieving long term disease control when combined with CRT in patients with SCCHN. As a result, planning for a Phase 3 study is underway.


ASCO 2010, Harrington et al; Amgen press release; BioVex web site


Cancer Stem Cells: Bayer-OncoMed

• The Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Secreted Wnt ligands bind to Frizzled receptors and activate cascades important in development. Inappropriate regulation and activation of these cascades is associated with several pathological disorders including cancer (notably in 90% of colorectal cancer), retinopathy, and bone and cartilage disease such as arthritis. In addition, recent research suggests that Wnt signaling is also essential in stem cell self-renewal. The expression of Wnt proteins in the bone marrow suggests that they may influence hematopoietic stem cells (HSCs) as well. Wnt signaling has been shown to increase the expression of HoxB4 and Notch-1 genes, both of which are implicated in the specification and/or self-renewal of HSCs.


Expert Opin. Biol. Ther. (2010) 10(9):1315-1329; OncoMed press release

http://www.bayer.com/�


Cancer Metabolism: Celgene-Agios


Agios web site; BioWorld, April 16, 2010


Cancer Epigenetics: GSK-Epizyme, Abbott-EpiTherapeutics


Xeconomy.com Jan 10, 2011; Abbott /EpiTherapeutics press release


Real Late Breaker!


FierceBiotech, Feb 17, 2011; AVEO web site

http://aveopharma.com/�


PoRTM in Oncology


Vatalanib/PTK787

• During the first quarter of 2007, Novartis and Schering AG (now Bayer Schering Pharma AG) completed two global phase III clinical trials (CONFIRM 1 and CONFIRM 2 trials) of vatalanib in patients with metastatic colorectal cancer in combination with first- and second-line chemotherapy. Treatment with vatalanib did not achieve the overall survival primary endpoint in either study, confirming previously reported interim results on progression-free survival. However, both CONFIRM 1 and 2 independently confirmed that vatalanib had a positive impact on progression-free survival in poor prognosis patients with high serum LDH. Vatalanib has been removed from near term regulatory submissions for this indication and development has been discontinued.

The CONFIRM 1 trial (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line) studied the potential progression-free and overall survival benefit of once daily oral treatment with vatalanib in combination with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX4) compared with FOLFOX4 + placebo in chemotherapy naive patients. Interim results presented in March 2005 showed positive drug effects in advanced colorectal cancer. However, a central review assessment of the primary endpoint of progression-free survival showed a 12% reduction in risk that did not achieve statistical significance. By comparison, a pre-planned analysis of the same endpoint, as assessed by investigators, demonstrated a significant 17% reduction in risk of disease progression 4 5.

The CONFIRM 2 trial (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in Second-line) investigated the survival benefit of the same regimen as in CONFIRM 1 among patients with metastatic colorectal cancer who had progressed after irinotecan-based first-line chemotherapy. Results showed that overall survival duration was similar between FOLFOX4 plus vatalanib and FOLFOX4 alone. However, FOLFOX4 + vatalanib was associated with a better progression-free survival duration than FOLFOX4 alone in patients overall, and especially in those with high baseline lactate dehydrogenase (LDH) levels (5.6 vs 3.8 months; p<0.001) 6 7 8.


Adis R&D insight

http://bi.adisinsight.com/RDI/809046771','286293339�








Tivozanib/AV-951


Defined Health SWOT (Sept 2009)

Defined Health; Activity of Tivozanib (AV-951) in Patients With Renal Cell Carcinoma (RCC): Subgroup Analysis From a Phase 2 Randomized Discontinuation Trial (RDT), ASCO 2010


Closing Thoughts


The Future of Cancer Management


Scott M. Lippman, M.D., “The Future of NSCLC”


BIO-Europe Spring 2011March 14–16, 2011 •

Milan, Italy

BioPharm America 2011 September 14-16, 2011 •

Boston, MA

71 © Defined Health, 2010

See us at these upcoming EBD conferences:

http://www.definedhealth.com/�

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