The 51^st American Society of Hematology [ASH] Annual Meeting will take place December 5-8, 2009, at the Ernest N. Morial Convention Center in New Orleans, LA.  This is the premier event for the hematology industry, attracting more than 20,000 hematologists and other health-care professionals.

In this regard, Celgene Corporation (CELG) recently announced that data from more than 200 clinical trials involving the company’s products will be presented at the ASH annual meeting.  After reaching a 52-week low of $36.90 in April 2009, shares of Celgene have rebounded nearly 50% to close at $54.97.  As a result, investors may gravitate to other biotechnology companies specializing in the area of hematology to uncover similar investment opportunities.

Accordingly, we recently reviewed press releases from a baker’s dozen of public biotechnology companies also announcing upcoming clinical data presentations at ASH [as of November 27, 2009].  Further, to determine which topics are likely to generate significant visibility and investor interest, we tallied the number of abstracts accepted for each company, identified the product development stage(s), and consolidated the therapeutic classes into the following four general categories:

1. Kinase inhibitors
2. Biologic agents [monoclonal antibodies and small modular immunopharmaceuticals]
3. Chemotherapeutics [antimetabolites, nucleoside analogues topoisomerase inhibitors, and HDAC inhibitors]
4. Others [proteasome inhibitors and anticoagulants]

 See Table 1 below for the results from the 32 abstracts referenced in the press releases.

 Table 1. Baker’s dozen of public biotechnology companies issuing press releases regarding clinical data presentations at ASH

Note: One abstract is listed under both Keryx Biopharmaceuticals and AEterna Zentaris, as perifosine rights have been licensed to Keryx Biopharmaceuticals for North America, while AEterna Zentaris has the rest of world rights.  Two abstracts are listed under both Trubion Pharmaceuticals, Inc. and Facet Biotech Corporation, as the companies entered into a worldwide development and commercialization agreement for TRU-016.

Kinase Inhibitors

Inhibitors of intracellular kinases have the potential to be synergistic with several classes of chemotherapeutic and immunotherapeutic agents.  For example, different cancers have mutations on a few key kinases [such as PI3K], many of which lead to increased cellular growth, proliferation, angiogenesis, and survival.  In addition, many kinases have elevated expression levels or increased activity with several cancers.  Also, while antibodies may target one specific receptor, often multiple receptors are overactive in cancer cells; however, the different receptor signals may converge upon a central nodal signaling point making pharmacological intervention possible. 

Intracellular kinase inhibitors vary not only by their target [and isoform selectivity] but also by their inhibition mechanism.  For example, some small molecule inhibitors are ATP analogs, catalytic domain inhibitors, non-catalytic domain inhibitors, or target ligand inhibitors.  Some of the most studied intracellular kinases include PI3K, mTOR, AKT, SRC, JNK, and others.

One of the major drug development problems to date is that inhibition of one pathway leads to upregulation of a parallel signaling pathway.  It will be important for researchers to decipher the roles of redundant parallel pathways and feedback loops. Together, inhibition of the necessary intracellular signals needed for a cell to respond to external growth and survival factors have the potential to prevent further cancer growth. 

Due to significant interest in PI3K inhibitors, such as Keryx Biopharmaceuticals’ perifosine, we have also listed two private companies presenting Phase I clinical data at ASH.

Table 2. Kinase Inhibitor Presentations

Biologic Agents

Therapeutic applications of monoclonal antibodies [MAbs] are the most widely used form of immunotherapy for cancer at this time.  Examples of MAb mechanisms include prevention of ligand-receptor interaction, antibody dependent cellular cytotoxicity, complement mediated cytotoxicity, and immune modulation.  Most MAbs target cellular receptors that are overexpressed or specific to certain cancers.  New technology in MAbs has allowed for improved conjugations and increased penetration.

In view of significant interest in the area of MAbs, we have also included a private company presenting preclinical data demonstrating proof-of-concept at ASH with an IND planned for Q1 2010.

Table 3. Biologic Agent Presentations

Chemotherapeutics

Antimetabolites have well established anti-cancer profiles with actions on intermediary metabolism of proliferating cells.  The mechanism of action of antimetabolites is through the inhibition of nucleotide and nucleic acid synthesis.  Many of these drugs have delayed toxicity and are subject to drug resistance.  Examples of approved therapies include methotrexate, 5-FU, and more recently Allos Therapeutics’ Folotyn™ [pralatrexate injection]. 

Nucleoside analogues are similar in mechanism to alkylating agents.  Many nucleoside analogues kill cells by binding to DNA and forming strand breaks leading to an inhibition of DNA synthesis and function.  Nucleoside analogues are associated with nephrotoxicity but have shown to be synergistic with other therapies such as vinblastine.  Examples of approved nucleoside analogues include cisplatin and carboplatin.   In terms of development candidates, Cyclacel recently reported topline survival data from a Phase II study of its oral nucleoside analog, sapacitabine, in elderly patients aged 70 or older with either newly diagnosed acute myeloid leukemia [AML] or AML in first relapse.  The study was a three-arm, randomized trial evaluating three dosing schedules of sapacitabine.  The primary endpoint of one-year survival was approximately 30% in two out of the three schedules tested and further details of the study will be presented at ASH.

Histone deacetylase enzymes [HDACs] are a group of proteins that deacetylate lysine residues on core histones resulting in chromatin condensation and gene repression.  In addition, HDACs have been shown to inhibit transcription factors and interact with other proteins including p53 and c-myc.  There are three classes of HDACs each with unique domains and cellular expression profiles [and cancer expression profiles].  Thus, HDACs have a diverse and complex role in cellular activity.  HDAC inhibitors have shown to induce apoptosis, while it is not clear if HDAC specific or pan-HDAC inhibitors, such as Pharmacyclics’ PCI-24781, will have the best clinical outcome.   An example of an FDA approved HDAC inhibitor is Merck & Co.’s (MRK) Zolinza® [vorinostat].

Table 3. Chemotherapeutic Presentations

Others

In 2003, Velcade® [bortezomib] by Millennium Pharmaceuticals, Inc., a wholly-owned subsidiary of Takeda Pharmaceutical Company Limited, became the first proteasome inhibitor to be approved for use in the U.S.  Bortezomib disrupts normal protein homeostasis by targeting the proteasome, the final enzyme in the proteolysis cycle that is critical for normal protein turnover and homeostasis.  Proteasome inhibitors are linked with decreased NF-kappaB [NFkB] activity, which has been shown to be a central transcription factor involved with this disease.  In addition to NFkB, proteasome inhibition has other antitumor activity such as p53 stabilization.  Because the proteasome has been validated as a target for myeloma, other drugs, such as Onyx Pharmaceuticals’ carfilzomib, are in development with novel features such as decreased toxicity and increased potency.

In August 2009, Gentium S.p.A. announced top-line results from a Phase III trial designed to evaluate the safety and efficacy of 25 mg/kg/day of defibrotide, a deoxyribonucleic acid derivative derived from cow lung or porcine mucosa, for the treatment of severe veno-occlusive disease in hematopoietic stem cell transplant patients.  The results did not reach the protocol-specified levels of significance for the primary and secondary endpoints at 100 days.  The Company plans to present full results from the trial at ASH.

Table 4. Other Presentations

Summary

Stocks to watch at ASH by conference/presentation date:

Saturday, December 5, 2009: IMGN, FACT, CYCC, SNSS, TRBN, KERX, AEZS, ALTH

Sunday, December 6, 2009: IMGN, PCYC, SGEN

Monday, December 7, 2009: FACT, IMGN, ARIA*, TRBN, SNSS, GENT, PCYC, ONXX*, ALTH, SGEN

Tuesday, December 8, 2009: ALTH

* Company has announced plans to host an investor teleconference in connection with the ASH presentation(s)

Tags: AEterna Zentaris, AEZS, Allos Therapeutics, ALTH, American Society of Hematology, ARIA, ARIAD Pharmaceuticals, Calistoga Pharmaceuticals, CELG, Celgene, chemotherapeutics, CYCC, Cyclacel Pharmaceuticals, Facet Biotech, FACT, GENT, Gentium SPA, HDAC inhibitors, IMGN, ImmunoGen, KaloBios Pharmaceuticals, kerx, Keryx Biopharmaceuticals, kinase inhibitors, monoclonal antibodies, nucleoside analogues, ONXX, Onyx Pharmaceuticals, PCYC, Pharmacyclics, pi3k, proteasome inhibitors, sapacitabine, Seattle Genetics, Semafore Pharmaceuticals, SGEN, small modular immunopharmaceuticals, SNSS, Sunesis Pharmaceuticals, TRBN, Trubion Pharmaceuticals

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