Buyout Buzz at ASH Hematology Confab

Scientific and medical advances weren’t the only topic of discussion at the 51st American Society of Hematology [ASH] Annual Meeting that began over the weekend in New Orleans, LA, as merger and acquisition activity took center stage.

Early this morning, Celgene Corporation (CELG) announced the acquisition of privately-held Gloucester Pharmaceuticals for $340 million in cash plus another $300 million in future U.S. and international regulatory milestone payments.  Gloucester’s Istodax® (romidepsin) was approved in November 2009, by the U.S. Food and Drug Administration [FDA] for the treatment of cutaneous T-cell lymphoma [CTCL] and is being developed for other hematological malignancies, including peripheral T-cell lymphoma [PTCL].

While many potential acquirers may have been sitting on the sidelines watching the market valuations of cash-poor companies continue to decline throughout the year, those depressed share prices may not last much longer.  Improving capital markets for small-cap life sciences companies, evidenced in part by this month’s $48 million follow-on financing by ZIOPHARM Oncology, Inc. (ZIOP), could accelerate merger and acquisition activity in the sector as larger companies race to fill anticipated patent expirations and gaps in their product pipelines.  Indeed, a favorable climate for merger and acquisition activity was one of the main tenets of our positive perspectives for biotechnology in 2009.

Following Celgene’s acquisition of Gloucester, we revisited the baker’s dozen of public biotechnology companies announcing upcoming clinical data presentations at ASH [as of November 27, 2009] from our recent article and identified three small-cap [eg, market capitalization less than $1 billion] biotechnology companies with unpartnered, late-stage [eg, marketed or entering pivotal trials] hematological malignancy programs:

  • Allos Therapeutics, Inc. (ALTH): The company is commercializing Folotyn™ (pralatrexate injection), an antimetabolite approved for the treatment of patients with relapsed or refractory PTCL.  While Allos has retained exclusive worldwide rights to Folotyn, which became available in the United States in October 2009, potential competition from Istodax by Celgene/Gloucester may be a concern as a supplemental NDA for PTCL is expected by year-end 2010.  Further, the company was the subject of an article in the December 4, 2009, New York Times questioning its pricing for Folotyn.
  • Seattle Genetics, Inc. (SGEN): In February 2009, the company initiated a pivotal trial of its brentuximab vedotin product candidate in patients with relapsed or refractory Hodgkin lymphoma under a Special Protocol Assessment with the FDA.  Seattle Genetics expects to submit both a New Drug Application [NDA] with the FDA under the accelerated approval regulations and a Marketing Authorization Application with the European Medicines Agency for conditional marketing authorization in the first half of 2011.  The company has retained exclusive worldwide rights to brentuximab vedotin.
  • Cyclacel Pharmaceuticals, Inc. (CYCC): At the ASH meeting, Cyclacel reported promising 1-year survival data from a Phase 2 randomized trial of its oral sapacitabine capsules in elderly patients with acute myeloid leukemia [AML] and separately interim response data in myelodysplastic syndromes [MDS].  The company is planning to start a pivotal trial with sapacitabine in 2010 and has retained exclusive worldwide rights with the exception of Japan where Daiichi-Sankyo has a right of first refusal to market the drug under terms to be negotiated.

Biotech Baker’s Dozen to Watch at Hematology Meeting

The 51st 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

Name Nasdaq Ticker Symbol # of Abstracts Accepted Development Stage(s) Therapeutic Class(es)
Allos Therapeutics, Inc. ALTH ****** Marketed Chemotherapeutics
Onyx Pharmaceuticals, Inc. ONXX ***** Phase IIb, Phase I Kinase inhibitors, Others
Facet Biotech Corporation FACT **** Phase I Biologic agents
Seattle Genetics, Inc. SGEN **** Pivotal trial, Phase Ib Biologic agents
ImmunoGen, Inc. IMGN *** Phase I Biologic agents
Gentium S.p.A. GENT ** Phase II/III Others
Cyclacel Pharmaceuticals, Inc. CYCC ** Phase II Chemotherapeutics
Sunesis Pharmaceuticals, Inc. SNSS ** Phase Ib, Phase II Chemotherapeutics
Trubion Pharmaceuticals, Inc. TRBN ** Phase I Biologic agents
Pharmacyclics, Inc. PCYC ** Phase I Kinase inhibitors, Chemotherapeutics
Keryx Biopharmaceuticals, Inc. KERX * Phase I/II Kinase inhibitors
Aeterna Zentaris, Inc. AEZS * Phase I/II Kinase inhibitors
ARIAD Pharmaceuticals, Inc. ARIA * Phase I Kinase inhibitors

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

Company Symbol Abstract #: Title Date/Time (Central)
Keryx Biopharmaceuticals, Inc. KERX 1869: Perifosine in Combination with Bortezomib and Dexamethasone Extends Progression-Free Survival and Overall Survival in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Bortezomib: Updated Phase I/II Trial Results Saturday, December 5, 2009, 5:30pm to 7:30pm
Aeterna Zentaris, Inc. AEZS
Calistoga Pharmaceuticals, Inc. Private 286: CAL-101, An Oral p110δ Selective Phosphatidylinositol-3-Kinase (PI3K) Inhibitor for the Treatment of B Cell Malignancies Inhibits PI3K Signaling, Cellular Viability and Protective Signals of the Microenvironment Monday, December 7, 2009, at 7:45am
Onyx Pharmaceuticals, Inc. ONXX 588: Phase I Study of the Novel Oral JAK-2 Inhibitor SB1518 in Patients with Relapsed Lymphoma: Evidence of Clinical and Biological Activity Monday, December 7, 2009, 4:00pm to 4:15pm
ARIAD Pharmaceuticals, Inc. ARIA 643: A Phase 1 Trial of Oral AP24534 in Patients with Refractory Chronic Myeloid Leukemia and Other Hematologic Malignancies: First Results of Safety and Clinical Activity against T315I and Resistant Mutations Monday, December 7, 2009, at 4:30pm
Pharmacyclics, Inc. PCYC 3713: A Phase I Dose Escalation Study of the Btk Inhibitor PCI-32765 in Relapsed and Refractory B Cell Non-Hodgkin Lymphoma and Use of a Novel Fluorescent Probe Pharmacodynamic Assay Monday, December 7, 2009, 6:00pm to 8:00pm
Semafore Pharmaceuticals Private 3879: Preliminary Results of a Phase I Study of the Pan-PI3 Kinase Inhibitor SF1126 in Patients with Relapsed and Refractory Myeloma Monday, December 7, 2009, 6:00pm to 8:00pm
Calistoga Pharmaceuticals, Inc. Private 922: Evidence of Clinical Activity in a Phase 1 Study of CAL-101, An Oral P110δ Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase, in Patients with Relapsed or Refractory B-Cell Malignancies Tuesday,
December 8, 2009, at 8:15am

 

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

Company Symbol Abstract #: Title Date/Time (Central)
ImmunoGen, Inc. IMGN 1862: Phase I Study of BT062 Given as Repeated Single Dose Once Every 3 Weeks in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma Saturday, December 5, 2009, 5:30pm to 7:30pm
Facet Biotech Corporation FACT 1744: Glycovariant CD37 Small Modular Immuno-Pharmaceutical (TruADhanCe™ SMIP) Promotes Enhanced Natural Killer Cell Mediated Cytotoxicity against Primary Chronic Lymphocytic Leukemia Cells Saturday, December 5, 2009, 5:30pm to 7:30pm
Trubion Pharmaceuticals, Inc. TRBN
KaloBios Pharmaceuticals, Inc. Private 1728: A Recombinant Human Antibody to EphA3 with Pro-Apoptotic and Enhanced ADCC Activity Shows Selective Cytotoxicity against Myeloid Leukemia Cells and CD123-Positive Leukemic Stem Cells Saturday, December 5, 2009, 5:30pm to 7:30pm
ImmunoGen, Inc. IMGN 2883: Phase I Study of IMGN901, Used as Monotherapy, in Patients with Heavily Pre-Treated CD56-Positive Multiple Myeloma – A Preliminary Safety and Efficacy Analysis Sunday, December 6, 2009, 6:00pm to 8:00pm
Seattle Genetics, Inc. SGEN 2731: The Antibody-Drug Conjugate Brentuximab Vedotin (SGN-35) Induced Multiple Objective Responses in Patients with Relapsed or Refractory CD30-Positive Lymphomas in a Phase 1 Weekly Sunday, December 6, 2009, 6:00pm to 8:00pm
Seattle Genetics, Inc. SGEN 2721: CD40 Pathway Activation Status Predicts Response to CD40 Targeted Therapy in Diffuse Large b-Cell Lymphoma Sunday, December 6, 2009, 6:00pm to 8:00pm
Seattle Genetics, Inc. SGEN 2870: Dacetuzumab (SGN-40), Lenalidomide, and Weekly Dexamethasone in Relapsed or Refractory Multiple Myeloma:  Multiple Responses Observed in a Phase 1b Study Sunday, December 6, 2009, 6:00pm to 8:00pm
Facet Biotech Corporation FACT 432: A Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results Monday, December 7, 2009, at 11:45am
ImmunoGen, Inc. IMGN 585: Phase I Multi-Dose Escalation Study of the Anti-CD19 Maytansinoid Immunoconjugate SAR3419 Administered by Intravenous (IV) Infusion Every 3 Weeks to Patients with Relapsed/ Refractory B-Cell Non-Hodgkin’s Lymphoma (NHL) Monday, December 7, 2009, at 3:15pm
Seattle Genetics, Inc. SGEN 586: A Phase 1b Clinical Trial of Dacetuzumab in Combination with Rituximab and Gemcitabine:  Multiple Responses Observed in Patients with Relapsed Diffuse Large B-Cell Lymphoma Monday, December 7, 2009, at 3:30pm
Facet Biotech Corporation FACT 3876: A Phase 1/2 Study of Elotuzumab in Combination with Bortezomib in Patients with Multiple Myeloma with One to Three Prior Therapies: Interim Results Monday, December 7, 2009, 6:00pm to 8:00pm
Facet Biotech Corporation FACT A Phase 1 Trial of TRU-016, An Anti-CD37 Small Modular Immunopharmaceutical (SMIP™) Protein in Relapsed and Refractory CLL: Early Promising Clinical Activity Monday, December 7, 2009, 6:00pm to 8:00pm
Trubion Pharmaceuticals, Inc. TRBN

 

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

Company Symbol Abstract #: Title Date/Time (Central)
Cyclacel Pharmaceuticals, Inc. CYCC 1061: A Randomized Phase 2 Study of Sapacitabine, An Oral Nucleoside Analogue, in Elderly Patients with AML Previously Untreated or in First Relapse Saturday, December 5, 2009, 5:30pm to 7:30pm
Cyclacel Pharmaceuticals, Inc. CYCC 1758: A Randomized Phase 2 Study of Sapacitabine, An Oral Nucleoside Analogue, in Older Patients with Myelodysplastic Syndromes (MDS) Refractory to Hypomethylating Agents Saturday, December 5, 2009, 5:30pm to 7:30pm
Sunesis Pharmaceuticals, Inc. SNSS 1037: A Phase 2 Dose Regimen Optimization Study of Three Schedules of Voreloxin as Single AgentTherapy for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia Saturday, December 5, 2009, 5:30pm to 7:30pm
Allos Therapeutics, Inc. ALTH 1678: Pralatrexate Induces Responses in Patients with Highly Refractory Peripheral T-Cell Lymphoma (PTCL) Saturday, December 5, 2009, 5:30pm to 7:30pm
Allos Therapeutics, Inc. ALTH 1675: Safety and Management of Pralatrexate Treatment in Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) Saturday, December 5, 2009, 5:30pm to 7:30pm
Allos Therapeutics, Inc. ALTH 1681: Correlation between Baseline Methylmalonic Acid Status and Mucositis Severity in the PROPEL Saturday, December 5, 2009, 5:30pm to 7:30pm
Allos Therapeutics, Inc. ALTH 1674: Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies: Phase 1 Results Saturday, December 5, 2009, 5:30pm to 7:30pm
Pharmacyclics, Inc. PCYC 2726: Phase I Analysis of the Safety and Pharmacodynamics of the Novel Broad Spectrum Histone Deacetylase Inhibitor (HDACi) PCI-24781 in Relapsed and Refractory Lymphoma Sunday, December 6, 2009, 6:00pm to 8:00pm
Sunesis Pharmaceuticals, Inc. SNSS 635: Phase 1b/2 Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Combination Voreloxin and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia Patients Monday, December 7, 2009, at 5:30pm
Allos Therapeutics, Inc. ALTH 3420: Stem Cell Transplant (SCT) and Pralatrexate Therapy: Outcome of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma Who Received SCT Prior to or Following Pralatrexate Therapy Monday, December 7, 2009, 6:00pm to 8:00pm
Allos Therapeutics, Inc. ALTH 919: Pralatrexate is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial Tuesday, December 8, 2009, 7:30am

 

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

Company Symbol Abstract #: Title Date/Time (Central)
Onyx Pharmaceuticals, Inc. ONXX 302: Updated Results of Bortezomib-Naive Patients in PX-171-004, an Ongoing, Open-Label, Phase II Trial of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM) Monday, December 7, 2009, 7:15am to 7:30am
Onyx Pharmaceuticals, Inc. ONXX 303: PX-171-004, an Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM); Updated Results from the Bortezomib-Treated Cohort Monday, December 7, 2009, 7:30am to 7:45am
Onyx Pharmaceuticals, Inc. ONXX 304: Phase Ib Multicenter Dose Escalation Study of Carfilzomib Plus Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and Refractory Multiple Myeloma (MM) Monday, December 7, 2009, 7:45am to 8:00am
Onyx Pharmaceuticals, Inc. ONXX 430: Carfilzomib (CFZ), a Novel Proteasome Inhibitor for Relapsed or Refractory Multiple Myeloma is Associated with Minimal Peripheral Neuropathic Effects Monday, December 7, 2009, 11:15am to 11:30am
Gentium S.p.A. GENT 653: Defibrotide (DF) for the Prevention of Hepatic Veno-Occlusive Disease (VOD) in Pediatric Stem Cell Transplantation: Results of a Prospective Phase II/III Randomized, Multicenter Study Monday, December 7, 2009, at 5:30pm
Gentium S.p.A. GENT 654: Defibrotide (DF) in the Treatment of Severe Hepatic Veno-Occlusive Disease (VOD) with Multi-Organ Failure (MOF) Following Stem Cell Transplantation (SCT): Results of a Phase 3 Study Utilizing a Historical Control Monday, December 7, 2009, at 5:45pm

 

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)