The tale seems fitting to illustrate the evolution of drugs that target the phosphatidylinositol 3-kinase [PI3K] pathway [see Table 2 for a listing of compounds in clinical development].  Despite ample evidence that pan-PI3K inhibitors and dual PI3K/mTOR inhibitors might offer a therapeutic advantage, tailors continue to weave new compounds targeting individual components of the pathway with presumably superior properties.  But does the “mTOR” really have new clothes?

Pathway Layout

The PI3K pathway regulates cell growth, survival, proliferation, migration, and the process of angiogenesis and is frequently deregulated in cancer, which makes it one of the most attractive targets for anticancer therapy.  Big pharma’s interest in the target is evidenced in part by Sanofi-aventis’ (SNY) licensing of two early-stage PI3K inhibitor programs [XL147 and XL765] from Exelixis, Inc. (EXEL) in May 2009 that could result in development, regulatory and commercial milestone payments to the company that total over $1 billion in the aggregate [including $140 million in cash upfront], as well as royalties on sales of any products commercialized under the license.

In general, the pathway comprises the following three components starting near the cell membrane and continuing towards the nuclear machinery at the heart of cellular processes:

1.     PI3K

-       Held in check by the phosphatase PTEN, PI3K can be activated by upstream tyrosine kinase receptors

-       Four class I isoforms of PI3K [α, β, γ, δ, or alpha, beta, gamma, delta]

2.     Akt

-       Gets recruited to the proper location in the cell needed for activity [cell membrane] and is changed into the required active conformational state by phosphorylation of T308 by the action of PI3K

3.     mTOR

-       Promotes increased protein synthesis in part driven by activated Akt

-       Forms complexes called mTORC1 and mTORC2, of which mTORC2 directly increases Akt by phosphorylation on S473

Dysfunction of PI3K, Akt, and/or mTOR is associated with cancer and while cellular signaling becomes more complex on almost a daily basis, much has been discovered about the best way to effectively block the pathway in cancer cells.  Accordingly, the purpose of this article is to highlight some of the latest advances in our understanding of the PI3K pathway along with the leading companies working in this market segment.

Good, Better, and Best

Pfizer, Inc.’s (PFE) Torisel® [temsirolimus] and Novartis AG’s (NVS) Afinitor® [everolimus], both for the treatment of renal cell carcinoma, were among the first PI3K pathway inhibitors [via inhibition of mTORC1] to reach the market – Torisel in May 2007 and Afinitor in March 2009.  While inhibition of mTORC1 through rapamycin or the rapalogs [“Good”] demonstrated sufficient clinical activity for U.S. Food and Drug Administration [FDA] approval, there is clear evidence that blocking only mTORC1 activity paradoxically leads to activation of the PI3K pathway through redundant or alternative signaling mechanisms.  For example, mTORC2 can activate Akt by phosphorylation on the S473 position.  This led to the design of mTOR complex catalytic site inhibitors [“Better”] that block the activity of both mTORC1 and mTORC2.  While effective in shutting down mTOR activity, this approach still provides for partial activation of Akt on T308 by PI3K.  Therefore, simultaneous inhibition of both PI3K and mTOR kinase activity with a dual PI3K/mTOR inhibitor [“Best”] would be expected to more effectively shut down PI3K-Akt-mTOR signaling and such an agent could remain effective in situations where the activity of mTOR inhibition has been circumvented.

Isoform Selectivity: Is Less Really More?

In addition to the benefits of dual PI3K/mTOR inhibition as described in the prior section, there is also compelling biological rationale for inhibiting all four of the class one PI3K isoforms [α, β, γ, δ, or alpha, beta, gamma, delta] rather than inhibiting only a subset.  The most compelling support for pan-PI3K inhibition is the recent disclosure that the activity of any class 1A PI3K isoform [alpha, beta, or delta] can sustain cell proliferation and survival [ref 1].  Additionally, both in vitro and in vivo studies indicated that for PTEN-negative tumors inhibition of the beta isoform is needed [ref 2].  Moreover, evolving analyses of cancer tissues provides additional rationale for inhibiting the various isoforms as for example the recent finding that the gamma isoform has tumor-specific overexpression in pancreatic cancer [ref 3].

The role of PI3K in a wide range of normal biologic processes raised potential toxicity concerns about pan-PI3K inhibitors and dual PI3K/mTOR inhibitors, which led to the development of isoform-selective inhibitors.  However, clinical data presented at the 2010 American Society of Clinical Oncology [ASCO] annual meeting demonstrated relatively consistent toxicity profiles among pan-PI3K, dual PI3K/mTOR, and isoform-selective PI3K inhibitors, with no discernable safety advantage among the class [see Table 1 below].  The most common side effects reported with these inhibitors included diarrhea, nausea, vomiting, and fatigue [ref 8].  Liver damage, as evidenced by elevated aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, were reported only with orally administered pan-PI3K, dual PI3K/mTOR, and PI3K delta isoform-specific inhibitors and were dose limiting in some cases.  Interestingly, insulin resistance [hyperinsulinaemia or hyperglycaemia] was originally predicted to be one of the most likely toxicities resulting from on-target effects of PI3K inhibitors, but has not been widely observed in clinical trials to date.

Table 1. Adverse Event Profiles as Reported at 2010 ASCO Annual Meeting

+ = Adverse event listed among the top five most frequent Grade 1 or 2 in the trial

++ = Dose limiting toxicities

* = For GDC-0941, results are from GDC4254g study; for PX-866, AST/ALT toxicity is only in the continuous daily dosing arm

n/r = Grade 1 and 2 data has not been reported

Helping explain the lack of variation between pan-PI3K, dual PI3K/mTOR, and isoform-selective PI3K inhibitor toxicity profiles is the translation of data from in vitro potency to in vivo settings.  For example, while Calistoga Pharmaceuticals’ (private) CAL-101 product candidate demonstrates relative selectivity for the PI3K delta isoform using traditional two-dimensional [2D] monolayers of cancer cells, the significant blood levels seen clinically suggest that all isoforms may be inhibited at least part of the time.  In addition, in a PTEN-null PC3 xenograft model Roche Holding AG’s (RHHBY.PK) PI3K inhibitor GDC-0941 at 75mg/kg daily [ref 4] showed similar inhibition of about 80% of tumor growth as Semafore Pharmaceuticals’ (private) dual PI3K/mTOR inhibitor SF1126 at 20mg/kg three times per week [ref 5] even though SF1126 is reported to be at least 10-times less potent on all PI3K isoforms.  Two recent publications help further support the dramatic differences between 2D and 3D cell cultures and perhaps shed some light on how potency translates, or fails to translate, into in vivo models [refs 6,7].

Future Directions

Prodrugs

One of the most widely studied PI3K inhibitors, LY294002 possesses a unique mechanism of drug action through dual inhibition of all Class 1 PI3K isoforms and mTOR, inhibition of additional cancer kinases such as PIM1, DNA-PK, and PLK1, and the molecule’s ability to induce apoptosis and oxidative stress through other mechanisms.  However, the strong hydrophobicity of LY294002 drastically limits its use in natural form.  In addition, there is the aforementioned concern for toxicity through the non-specific, indiscriminate inhibition of the PI3K pathway in normal cells.  Therefore, Semafore Pharmaceuticals sought to improve the use of LY294002 by enhancing its solubility, selectivity and in vivo delivery by preparing a functional prodrug that selectively accumulates in tumor areas to maximize efficacy and minimize toxicity.  The resulting new chemical entity, SF1126, has been tested in more than 50 patients in Phase 1 trials.

Disease Settings and Biomarkers

In general, the standard paradigm for early drug development is to test compounds in a broad range of cancers to identify those in which the compounds work, which then forms the basis for future clinical development and regulatory strategy.  Such has been the case with development of PI3K inhibitors.

Across the nine mixed solid tumor Phase 1 studies reported at ASCO 2010, 114 out of 469 patients [24%] showed stable disease, prolonged in some cases, as the best response [ref 8].  Only 5 partial responses out of 469 patients [1%] of unknown duration were reported from the group in total.  Of these 3 were in breast cancer patients, one was in non-small cell lung carcinoma [NSCLC], and one was in a patient with lung cancer/Cowden disease.   On this basis, there is no clear direction for development of PI3K inhibitors in the solid tumor setting.

In contrast, significant responses in hematological cancers have been reported with PI3K inhibitors.  For example, Calistoga Pharmaceuticals’ delta selective PI3K inhibitor CAL-101 demonstrated overall response rates of 57%, 67%, and 30% in indolent non-Hodgkin’s lymphoma [NHL], mantle cell lymphoma [MCL], and chronic lymphocytic leukemia [CLL], respectively.  However, in acute myeloid leukemia [AML], multiple myeloma [MM] and diffuse large B-cell lymphoma [DLBCL] there were no responses and no stable disease.  Accordingly, several pan-PI3K inhibitors and dual PI3K-mTOR inhibitors are advancing clinical development in the responsive B-cell malignancies both alone and in combination with potentially synergistic agents.  Updated clinical data from various PI3K inhibitor programs is expected at the upcoming American Society of Hematology [ASH] annual meeting held December 4-7, 2010, in Orlando, FL.

Instead of testing compounds in mixed patient populations, another strategy is to use the most compelling preclinical data to guide genotype-directed trials.   For example, preclinical work suggests that cancers with PIK3CA mutations might be most sensitive [ref 9] and cancers with KRAS mutations might be difficult to treat with single agent PI3K inhibitors [refs 10,11].

Dual Pathway Inhibition – Better than Best?

Beyond the aforementioned PI3K pathway redundancies highlighting the potential benefits of dual PI3K/mTOR inhibition, recent data demonstrate crosstalk between the mitogen-activated protein kinase [MAPK] pathway and PI3K pathway.  This can serve as a back-up pathway to survival, particularly in the case of mutations in the MAPK pathway such as KRAS mutations [ref 10].

This discovery has led to the unusual step of evaluating clinical combinations of unapproved PI3K and MAPK inhibitors.  For example, Novartis’ PI3K inhibitor BKM120 is being combined with GlaxoSmithKline plc’s (GSK) MEK inhibitor GSK1120212 in a Phase 1 study focused on tumors with RAS/RAF mutations and triple negative breast cancer [ref 12].  In addition, Merck & Company, Inc.’s (MRK) allosteric Akt inhibitor MK-2206 is being combined with AstraZeneca plc’s (AZN) MEK inhibitor AZD6244 [ref 13] and Roche Holding AG has a trial combining their PI3K inhibitor GDC-0941 and MEK inhibitor GDC-09773 [ref 14].

Developing one investigational drug is challenging enough, but developing two investigational compounds simultaneously can be daunting.   Complexities can arise from trying to match different administration schedules and differing pharmacokinetics [PK], distribution, and metabolism profiles between the combined agents.  A single molecule that simultaneously inhibits both PI3K and MAPK would therefore be preferable and the following three companies are currently pursuing this single-molecule, dual pathway inhibition strategy with their respective preclinical product candidates:

1.     AEterna Zentaris, Inc. (AEZS): preclinical molecule [AEZ132] that inhibits PI3K and Erk

2.     Progenics Pharmaceuticals, Inc. (PGNX): preclinical molecule [PGNX-01/02] that inhibits mTOR/PI3K and MNK [downstream of Erk]

3.     Semafore Pharmaceuticals: preclinical molecule [SF2626] that inhibits PI3K and MEK

Conclusion

Our understanding of the PI3K pathway has advanced significantly since the FDA approved the first mTORC1 inhibitors for the treatment of renal cell carcinoma in 2007/2009.  Promising results have been demonstrated in the area of hematological malignancies with next-generation PI3K inhibitors and new insights into the pathway biology has led to the development of new molecules and combination approaches that will allow us to realize the ultimate potential of this pathway as a therapeutic target for a variety of diseases.

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Table 2: Select PI3K Pathway Inhibitors in Clinical Development

REFERENCES:

1. Lazaros C. Foukasa, Inma M. Berenjenoa, Alexander Grayb, Asim Khwajac, and Bart Vanhaesebroeck  “Activity of any class IA PI3K isoform can sustain cell proliferation and survival”, Proceedings of the National Academy of Sciences, June 22, 2010; vol. 107, No. 25, 111381-11386.
2. Kyle A. Edgar, Jeffrey J. Wallin, Megan Berry, Leslie B. Lee, Wei Wei Prior, Deepak Sampath, Lori S. Friedman, and Marcia Belvin, “Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors”, Cancer Research, February 1, 2010; vol.70, No. 3, 1164-1171.
3. Charlotte E. Edling, Federico Selvaggi, Richard Buus, Tania Maffucci, Pierluigi Di Sebastiano, Helmut Friess, Paolo Innocenti, Hemant M. Kocher, and Marco Falasca, “Key Role of Phosphoinositide 3-Kinase Class IB in Pancreatic Cancer”, Clinical Cancer Research, published OnlineFirst on September 28, 2010 as 10.1158/1078-0432.CCR-10-1210.
4. See Figure 5 of Reference 2.
5. Joseph R. Garlich, Pradip De, Nandini Dey, Jing Dong Su, Xiaodong Peng, Antoinette Miller, Ravoori Murali, Yiling Lu, Gordon B. Mills, Vikas Kundra, H-K. Shu, Qiong Peng, and Donald L. Durden, “A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity”, Cancer Research, January 1, 2008; vol. 68, No. 1, 206-215.
6. Ville Harma, Johannes Virtanen, Rami Makela, Antti Happonen, John-Patrick Mpindi, Matias Knuuttila, Pekka Kohonen, Jyrki Lotjonen, Olli Kallioniemi, Matthaias Nees, “A Comprehensive Panel of Three-Dimensional Models for Studies of Prostate Cancer Growth, Invasion and Drug Responses”, PLoS ONE May 2010, vol. 5, e10431
7. Maria Laura Polo, Maria Victoria Arnoni, Marina Riggio, Victoria Wargon, Claudia Lanari, Virginia Novaro, “Responsiveness to PI3K and MEK Inhibitors in Breast Cancer.  Use of a 3D Culture System to study Pathways Related to Hormone Independence in Mice”, PLoS ONE May 2010, vol. 5, e10786.
8. Joseph Garlich, Candace Shelton, Wenqing Qi, Xiaobing Liu, Laurence Cooke, Daruka Mahadevan,”Update on the Novel Prodrug Dual nTOR-PI3K Inhibitor SF1126″, Poster presented at: Next-Gen Kinase Inhibitors Oncology and Beyond, June 21-23, Cambridge, MA.  Poster available at: http://www.semaforepharma.com/publications.html.
9. Shingo Dan, Mutsumi Okamura, Mariko Seki, Kanami Yamazaki, Hironobu Sugita, Michiyo Okui, Yumiko Mukai, Hiroyuki Nishimura, Reimi Asaka, Kimie Nomura, Yuichi Ishikawa, and Takao Yamon, “Correlating Phosphatidylinositol 3-Kinase Inhibitor Efficacy with Signaling Pathway Status: In silico and Biological Evlauations”, Cancer Research, June 15, 2010; vol. 70, No. 12, 4982-4993.
10. Martin L. Sosa, Stefanie Fischera, Roland Ullrich, Martin Peifer, Johannes M. Heuckmann, Mirjam Koker, Stefanie Heynck, Isabel Stuckrath, Jonathan Weiss, Florian Fischer, Kathrin Michel, Aviva Goel, Lucia Regales, Katerina A. Politi, Samanthi Perera, Matthaus Getlik, Lukas C. Heukamp, Sascha Ansen, Thomas Zander, Rameen Beroukhim, Hamid Kashkar, Kevan M. Shokat, William R. Sellers, Daniel Rauh, Christine Orr, Klaus P. Hoeflich, Lori Friedman, Kwok-Kin Wong, William Pao, and Roman K. Thomasa, “Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer” Proceedings of the National Academy of Sciences, October 27,2009; Vol.106, No. 43, 18351-18356.
11. Nathan T. Ihle, Robert Lemos, Jr., Peter Wipf, Adly Yacoub, Clint Mitchell, Doris Siwak, Gordon B. Mills, Paul Dent, D. Lynn Kirkpatrick, and Garth Powis, “Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras is a Dominant Predictor for Resistance, Cancer Research, January 1, 2009; Vol. 69, No. 1, 142-150.
12. Source:  www.clinicaltrials .gov website. Clinical Trials.gov identifier number NCT01155453, started April 2010.
13. Source:  www.clinicaltrials .gov website. Clinical Trials.gov identifier number NCT01021748, started November 2009.
14. Source:  www.clinicaltrials .gov website. Clinical Trials.gov identifier number NCT00996892, started November 2009.

While a comprehensive preview of AACR is beyond the scope of this article, we note that two companies working in the area of cyclin-dependent kinase [CDK] inhibition made headlines in the months leading up to AACR.  Further evidence of interest in the area is demonstrated by the fact that the 2001 Nobel Prize in Physiology or Medicine was awarded for the discovery of CDKs and cyclins and the complete description of cyclin and cyclin-dependent kinase mechanisms. 

By selectively interrupting the cell cycle regulation in cancer cells, inhibition of CDKs represents a promising strategy for cancer therapy.  Accordingly, with more than 50 abstracts related to CDK inhibition scheduled for presentation at this year’s AACR annual meeting, we provide an overview of the target and highlight some of the companies and programs being discussed.

CDK overview

Each time a cell divides it undergoes a series of events collectively known as the cell cycle.  Controlled and regulated cellular division is a normal part of cell physiology. 

Cancer is characterized by uncontrolled cellular division and growth, which can be caused by mutations in DNA resulting in the overexpression of cancer-promoting oncogenes or repression of tumor suppressor genes.  There are many examples of oncogenes and tumor suppressor genes but some of the more common ones include signaling proteins [PI3K], receptors [HER2], and DNA damage and repair regulating proteins that control cell cycle check-points such as p53 and BRCA. 

CDKs are a group of signaling kinases that play a direct role in the regulation and progression of the cell cycle.  CDK activity is dependent on the availability of their regulatory subunits called cyclins, which CDKs phosphorylate in order to stop cell cycle progression in cancerous cells.  Production and destruction of cyclins are tightly regulated in coordination with cell cycle progression.  Targeting CDK/cyclin macromolecular complexes is an attractive strategy for the design of novel anticancer drugs. 

There are over a dozen known CDK/cyclin complexes.  The most extensively studied subtypes are CDK2/cyclin E, CDK2/cyclin A, CDK7/cyclin H, and CDK9/cyclin T which are key components of the p53 pathway and CDK4 and CDK6 interacting with cyclin D1, which are key components of the retinoblastoma or Rb pathway.

Many tumor mutations interfere or deregulate the tight control of cyclin-CDK interactions leading to overactive CDKs, resulting in continuous cellular proliferation or unscheduled re-entry into the cell cycle.  In addition, deregulated CDK activity can result in genomic and chromosome instability, a feature observed in many advanced or aggressive tumors.

Early Failures

First generation, pan-CDK inhibitors have not demonstrated improved clinical outcomes.  Reasons for early failures include non-specific drug targets or suboptimal dosing and scheduling.    Also, pan-CDK inhibitors may not have an acceptable pharmacological window due to high toxic side effects or limited efficacy. 

For example, CDK7, CDK8, and CDK9 play a role in DNA transcription.  While it may be advantageous to target these CDK/cyclins as part of a multikinase drug profile, strong inhibition may result in the broad disruption of transcription, which is not desirable. 

This may have been the case with BMS-387032 [subsequently known as SNS-032], a small molecule cell-cycle modulator that targets CDKs 1, 2, 4, 7, and 9.  The compound demonstrated significant safety risks in Phase I studies conducted by Bristol-Myers Squibb (BMY), including increases in certain phases of the cardiac cycle, known as the QT interval. 

In 2005, Sunesis Pharmaceuticals, Inc. (SNSS) acquired rights to BMS-387032 for an up-front payment of $8 million in Sunesis’ stock, future milestone payments totaling $78 million, and royalties on net sales.  However, in December 2008, Sunesis notified Bristol-Myers that the company was terminating the license agreement for SNS-032 after no responses demonstrating efficacy were observed in a Phase I trial.

Next generation CDK inhibitors target select CDK sub-types and have shown improved potency along with other drug-like properties.  The various CDK sub-types are active at different points within the cell cycle and discrete cancers are dependent on specific CDK sub-types.  Therefore, each CDK inhibitor sub-type may be relevant to different tumors or genetic mutations. 

For example, CDK4 is frequently deregulated in glioblastoma and CDK2 activity is commonly altered in colon cancer.  Recently published evidence implicates certain cyclins and in particular cyclin E, the partner of CDK2, as a mediator of acquired resistance in several cancers, such as lung and breast cancer.  Some of these next-generation programs are highlighted below [also refer to Table 1]:

Pfizer, Inc. (PFE)

In late March 2010, Pfizer made headlines with a preclinical study published in the journal Cancer Research.  Results from the study demonstrated that PD-0332991, a drug being developed by Pfizer, could arrest the growth of glioblastoma multiforme [GBM] in animals.  PD-0332991 is an oral agent that inhibits certain CDKs, mainly CDK4 and CDK6.  Six abstracts related to PD-0332991 are scheduled for presentation at AACR.  Pfizer is managing and funding all clinical development of PD-0332991, which the company licensed from Onyx Pharmaceuticals, Inc. (ONXX).  PD-0332991 is the subject of various clinical trials in multiple myeloma, NHL, mantle-cell lymphoma, glioblastoma and breast cancer. 

Cyclacel Pharmaceuticals, Inc. (CYCC)

Cyclacel Pharmaceuticals, which is developing a clinical stage CDK inhibitor candidate, also made headlines earlier this year.  The company’s oral compound seliciclib [CYC202 or R-roscovitine], inhibits CDK2/E, CDK2/A, CDK7/H, and to a lesser degree CDK9/T.  Seliciclib is currently in Phase IIb clinical trials for non-small cell lung cancer [NSCLC] and nasopharyngeal cancer.

Shares of Cyclacel Pharmaceuticals jumped from $1 to more than $4 in January 2010 when independent investigators published data in the peer-reviewed journal Clinical Cancer Research showing that both seliciclib and a second-generation CDK inhibitor from Cyclacel reversed resistance to lung cancer cells with K-Ras or N-Ras mutations.  Cancers with Ras-activating mutations are thought to be among the most difficult to treat and are not responsive to modern targeted drug therapy, such as EGFR inhibitors.  The data also showed that lung cancer cells are addicted to cyclin E/CDK2.  Cyclacel expects to report top line results from its APPRAISE NSCLC Phase IIb trial with seliciclib later this year. 

A different investigator group also recently published data in the peer-reviewed journal Clinical Cancer Research demonstrating that seliciclib reversed resistance to the aromatase inhibitor Femara® [letrozole].  Seliciclib killed hormone receptor-positive breast cancer cells that had become insensitive to the effects of letrozole because of over expression of low molecular weight Cyclin E. 

At AACR, Cyclacel is introducing a second-generation CDK product candidate, which is currently in investigational new drug [IND]-directed development.  The undisclosed molecule is a second generation oral CDK inhibitor with increased potency.  Three abstracts related to both seliciclib and the second-generation compound are scheduled for presentation at AACR.

Sanofi-Aventis SA (SNY)

Sanofi-Aventis is developing its lead CDK inhibitor, flavopiridol [HMR-1275, alvocidib] for the treatment of both solid and hematologic malignancies.  Flavopiridol is a pan–CDK inhibitor that blocks CDK9, -2, -4, and -6 at nanomolar concentrations.  Published data from flavopiridol clinical trials suggest that its main toxicities are induction of neutropenia and secretory diarrhea.  Phase II studies of flavopiridol as a single agent have been completed in metastatic melanoma, endometrial adenocarcinoma, and multiple myeloma demonstrating limited efficacy as a monotherapy.  However, flavopiridol has shown promise as a combination therapy, with the best responses observed in CLL patients in combination with fludarabine and cyclophosphamide.  Four abstracts related to flavopiridol are scheduled for presentation at AACR.

Merck & Co., Inc. (MRK)

Merck is developing its lead CDK inhibitor, SCH 727965 [dinaciclib], for multiple indications including solid tumors, NHL, multiple myeloma, ACL, and ALL.  SCH 727965 is an intravenously-delivered CDK1, CDK2, CDK5, and CDK9 inhibitor.  The drug is administered by a 2-hour IV infusion once every 21 days.  Merck is currently recruiting patients for a Phase II study evaluating SCH 727965 to determine the activity of SCH 727965 in patients with breast cancer and in patients with lung cancer compared to standard treatment, capecitabine and erlotinib respectively.  One abstract regarding the activity of SCH 727965 in cell lines for childhood cancers is scheduled for presentation at AACR.

Bayer (BAY.DE)

Bayer will introduce its CDK inhibitor, BAY 1000394, in an abstract scheduled for presentation at AACR.  BAY 1000394 is a nanomolar pan-CDK inhibitor targeting CDK1/Cyclin B, CDK2/Cyclin E, CDK4/Cyclin D1, and CDK9/Cyclin T1.  The maximum tolerated dose for BAY 1000394 was found to be 2.0 mg/kg on QD schedule and 2.5 mg/kg on a BID intermittent schedule.  BAY 1000394 is being tested in a broad range of histological tumor subtypes.

Tragara Pharmaceuticals (private)

Tragara Pharmaceuticals is developing TG02 [also known as SB1317], an oral multi-kinase inhibitor that targets CDK 1, 2, 7 and 9, as well as two other kinases – JAK2 and FLT3.  TG02, which was licensed from S*BIO Pte Ltd in January 2009, is being prepared for IND filing in Q2 2010 with plans to proceed in hematology and solid tumors.  Tragara recently received a $1 million grant form the Multiple Myeloma Research Foundation [MMRF] to fund the early-stage drug development TG02 in treating multiple myeloma.  One abstract regarding the activity of TG02 in leukemia cell lines is scheduled for presentation at AACR.

Conclusion

 CDKs play a pivotal role in a cell’s entry into division; de-regulated CDK activity is a well-documented player in tumor progression and represents an attractive therapeutic anti-cancer option.   However, first generation CDK inhibitors have not demonstrated improved clinical outcomes.  Next generation CDK inhibitors, such as those being discussed at AACR, are CDK sub-type specific and have shown improved potency along with other drug like properties.  In addition, next generation CDKs are demonstrating their importance in several difficult to treat cancers, such as those dependent on Ras-activating mutations.

Table 1: Abstracts for CDK Inhibitors at AACR

* MD Becker Partners reporting live from the JP Morgan Healthcare Conference

This week, nearly 6,500 registrants gathered in San Francisco, California for the JP Morgan Healthcare Conference to hear 25-minute presentations from 338 life science companies.  For industry executives and investors, the annual event serves as a good barometer for the rest of the year.

We roamed the familiar halls of the Westin St. Francis Hotel to assess the mood among participants and also monitored online media commentaries throughout the event.  In general, there was a flurry of activity, the plane flights and networking receptions were crowded as usual, and several industry observers “Tweeted” a sense of optimism for 2010.  However, we sought to construct a less subjective assessment by analyzing year-over-year statistics from the conference.

Accordingly, we extensively reviewed company press releases issued during the JP Morgan Healthcare Conference in both 2009 and 2010, with a particular focus on identifying the number of merger & acquisitions, licensing & partnering transactions, and financing deals announced each year during the four day event.

Merger and Acquisitions

In contrast to the absence of any significant M&A deals announced during the JP Morgan Healthcare Conference in 2010, several large M&A transactions with an aggregate value of $702 million were disclosed during the first two days of the event in 2009 [January 12-15, 2009].  The largest deal went to Cephalon, Inc. (CEPH), which announced an agreement providing the company with an option to purchase all outstanding capital stock of Ception Therapeutics, Inc., a privately held biopharmaceutical company.  Under the terms of the option agreement, Cephalon paid Ception $100 million upfront for the option.  If Cephalon exercises its option, the company will purchase all of the outstanding capital stock of Ception for $250 million along with additional payments related to clinical and regulatory milestones.  Other transactions announced that year included:

• Medtronic, Inc.’s (MDT) acquisition of privately held Ablation Frontiers, Inc. for an initial payment of $225 million plus potential additional payments contingent upon achievement of certain clinical milestones
• The Medicines Company’s (MDCO) merger agreement with Targanta Therapeutics Corporation for $42 million in cash and additional regulatory and commercial milestone payments
• NuVasive, Inc.’s (NUVA) option to acquire Progentix Orthobiology BV, a Netherlands based company focused on developing novel orthobiologics, consisting of an upfront investment of $15 million along with the obligation to purchase the remaining equity of Progentix for $45 million upon accomplishment of certain development milestones [with additional potential payments of up to $25 million upon the achievement of additional milestones and based upon NuVasive's sales success]

Licensing and Partnering

Kicking off the JP Morgan Healthcare Conference in 2010, privately held KaloBios Pharmaceuticals, Inc. announced a $290 million agreement with Sanofi Pasteur, the vaccines division of the sanofi-aventis Group (SNY), for the development and commercialization of KB001, an investigational new biologic for the treatment or prevention of Pseudomonas aeruginosa [Pa] infections.  KaloBios, which is developing first-in-class human antibody therapeutics that offer advantages over other methods of human antibody creation in terms of immunogenicity, potency, and manufacturing yields, will receive an upfront payment of $35 million, plus development, regulatory and commercial milestones for a potential further $255 million, as well as royalties on eventual product sales.

While other licensing and partnering transactions were announced during the JP Morgan Healthcare Conference in 2010, they were substantially smaller or specific financial terms were not disclosed.  These include:

• Proteus Biomedical Inc. announced an exclusive worldwide license and collaboration agreement with Novartis AG (NVS) to develop and commercialize pharmaceutical products that incorporate Proteus’ novel sensor-based technologies in the field of organ transplantation along with certain option rights in cardiovascular and oncology product applications.  Under the terms of the agreement, Novartis will make upfront cash and equity investments in Proteus totaling $24 million and Proteus will also receive royalties on worldwide net sales of any Novartis products incorporating its sensor-based technology.
• Trillium Therapeutics, Inc., a biopharmaceutical company developing innovative immune-based biologics, announced that it has entered into a definitive license agreement with Biogen Idec, Inc. (BIIB), granting the latter exclusive worldwide rights to one of Trillium’s development programs.  Under the terms of the agreement, Trillium will receive an upfront payment and is eligible to receive milestone payments based on achievements of specified clinical, regulatory and commercial accomplishments.  Trillium will also receive royalties on global product sales.  Biogen Idec will be solely responsible for clinical development, regulatory approvals, manufacturing and commercialization.
• MedGenesis Therapeutix Inc., a biopharmaceutical company developing and commercializing innovative treatments for patients with serious central nervous system [CNS] diseases, announced an agreement with Amgen, Inc. (AMGN) that provides MedGenesis with an exclusive, worldwide license for glial cell line-derived neurotrophic factor [GDNF] protein in CNS and non-CNS indications.  As part of the license agreement, Amgen now holds a small equity stake in MedGenesis.  In parallel, Biovail Corporation (BVF) and MedGenesis concluded an agreement to collaborate on the development of GDNF in Parkinson’s disease and potentially other CNS indications.  GDNF is a naturally-occurring growth factor capable of protecting and promoting the survival of dopamine producing nerve cells.
• AstraZeneca Plc (AZN) and CrystalGenomics announced a research collaboration to discover and develop a novel anti-infective for use as a potential antibacterial agent.  Under the terms of this agreement, Korea-based CrystalGenomics will receive research funding from AstraZeneca for two years.  CrystalGenomics will also be eligible to receive future milestones and royalty payments associated with development and commercialisation of a drug candidate.
• AnaptysBio, Inc., a privately-held therapeutic antibody platform and product company, announced it has signed an agreement with Roche (RHHBY) for the development of novel antibody therapeutics.  Under the terms of the agreement, AnaptysBio will be responsible for generating novel antibodies using its proprietary somatic hypermutation platform and Roche will receive a worldwide license to develop and commercialize antibodies optimized by AnaptysBio.  In addition to a signing fee paid by Roche, AnaptysBio will be eligible to receive milestone payments and royalties upon product sales.

The six transactions announced during the JP Morgan Healthcare Conference in 2010 with reported financial terms totaling $314 million pale in comparison to the ten deals reported at the meeting during 2009 worth more than $2.4 billion in aggregate value.  These included a $1.1 billion deal between ZymoGenetics, Inc. (ZGEN) and Bristol-Myers Squibb Company (BMY), a $500 million deal between Peptimmune, Inc. and Novartis AG, a $396 million deal between Micromet, Inc. (MITI) and Bayer AG (BAYZF.PK), and a $200 million deal between FORMA Therapeutics the Novartis Option Fund to develop inhibitors for an undisclosed protein-protein interaction target in the field of oncology, among others.

Financing

The quantity and aggregate dollar value of public and private financing transactions announced during the JP Morgan Healthcare Conference were essentially flat in 2010 compared with the prior year as reflected in the table below.

Outlook

At the start of 2009, we provided a positive outlook for biotechnology, citing the sector’s defensive characteristics, favorable technical aspects, and improving fundamentals, such as the number of new product approvals, products in clinical trials and the brisk pace of industry consolidation and licensing transactions.  The latter was quickly reinforced by M&A transactions with an aggregate value of $702 million and licensing & partnering deals worth more than $2.4 billion in aggregate value announced January 12-15, 2009, during the JP Morgan Healthcare Conference. 

While we believe that a positive outlook for 2010 is once again warranted, and the first two weeks of the year don’t necessary indicate a trend, hopefully the paucity of M&A activity coupled with the decline in both the quantity and value of licensing & partnering transactions announced during the JP Morgan Healthcare Conference in 2010 is simply the pause that refreshes and the action improves throughout the year.