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Vital Signs Edition #5


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Vital Signs Edition #5

  1. 1. ONCOLOGY<br />Week of April 17th, 2011<br />By Scott Jordan, Partner --  <br />News & Events: Cancer Immunotherapy<br />News Summary<br />News & Events: Cancer Immunotherapy<br />One of the most significant milestones in cancer immunotherapy drug development occurred in 2010 with the FDA approval of Dendreon’s Provenge (sipuleucel-T) for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.<br />However, Provenge’s approval has overshadowed cancer immunotherapy’s marginal success rate. Most immunotherapeutic agents have not shown sufficient activity in early trials, and whereas some were advanced to phase III investigation, most failed in randomized comparisons. With over 333 program failures to date, many cancer vaccines lacked robust evidence of potent immunostimulation as judged by immunological monitoring (~# of new vs. circulating T Cells).<br />Contributing factors to failures in the clinic may include: <br /><ul><li>Ineffective or marginally effective agents (~quality of Dendritic cells used)
  2. 2. Low sensitivity of the detection of immune responses to uncharacterized antigens in the tumor lysates used to pulse Dendritic cells
  3. 3. An incomplete understanding of human tumor immunology (cancer cells may not be adequate targets for T cells even when a robust T cell response has been induced by the vaccine)
  4. 4. Low MHC expression or other antigen processing and presenting molecule alteration, and insensitivity to the pro-apoptotic signals from T cells would all lead to a disconnect between the results of an immune monitoring assay in peripheral blood and tumor responses
  5. 5. Patients not meeting post-surgery inclusion or exclusion criteria
  6. 6. Challenge of reliably determining disease response earlier in the data collection process
  7. 7. Lack of established surrogate markers, such as immune response making the difficulty of establishing efficacy of an adjuvant immunotherapy</li></ul>Momentum in the field may be shifting given initiatives planned and facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute, Association for Cancer Immunotherapy (C-IMT) in Europe, and International Society for Biological Therapy of Cancer in the United States supported the redefinition of biological outcome measures and clinical endpoints in cancer immunotherapy. <br />Recommendations include: <br /><ul><li>Cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes
  8. 8. Immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns.
  9. 9. Delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials.</li></ul>Clinical & Regulatory:<br />Neogenix Oncology, Inc. announced that members of its scientific staff will present laboratory studies of NEO-101, a novel monoclonal antibody in development to diagnose and treat pancreatic and colorectal cancers. The presentation is scheduled at the American Association of Cancer Research (AACR) 102(nd) Annual Meeting being held April 1-6, 2011 at the Orange County Convention Center, Orlando, FL, USA. NEO-101 (NPC-1C, or Ensituximab) is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancer and is currently in Phase I clinical trials at The Johns Hopkins University Hospital, Duke University Medical Center and North Shore University/Long Island Jewish Medical Center. NEO-101 is the first in the Neogenix pipeline of antibodies intended to target specific cancers. The NEO-101 target appears to be a variant of MUC5AC that is expressed specifically by human colon and pancreatic tumor tissues and cell lines that in testing to date, have only occasionally shown, minimal and weak cross-reactivity to certain normal GI tract tissues. The preclinical data to be presented includes in vitro mechanism of action, immuno fluorescent cell staining, in vivo anti-tumor efficacy, bio-distribution, and toxicokinetic studies.<br />Alnylam Pharmaceuticals, Inc. announced that it has completed enrollment in its ALN-VSP Phase I multi-center, multinational, open label, dose escalation clinical trial. The study's objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors with liver involvement. ALN-VSP was administered to over 40 patients at doses ranging from 0.1 to 1.5 mg/kg, with multiple patients continuing to receive therapy on the study.<br />Radient Pharmaceuticals Corporation announced preliminary results from its clinical study conducted in collaboration with a well-recognized, large third-party not-for-profit group practice and its affiliates for the validation of RPC's US FDA's cleared Onko's Sure(r) in vitro diagnostic (IVD) cancer test. The purpose of the study was to determine the effectiveness of Onko-Sure(r) (DR-70) as a useful tool in the detection of colorectal cancer in all stages of colorectal cancer (CRC), especially early stages where effective diagnosis leads to better patient prognosis. In addition, this study focused on the effectiveness of Onko-Sure(r), Carcinoembryonic Antigen (CEA) and the combination of these two tumor markers for additional clinical value. Based on preliminary results, RPC's Onko-Sure(r) IVD cancer test shows a statistical advantage over CEA in detecting CRC in the early stages of colorectal cancer. Furthermore, when Onko-Sure(r) was combined with CEA, the sensitivity of the combined test was substantially improved as opposed to using CEA alone. RPC plans to disseminate these results in a peer-reviewed journal, either independently or with other third party healthcare organizations. Additionally, RPC plans to present these results to physicians at international oncology conferences and scientific meetings.<br />Amgen Inc., Millennium Pharmaceuticals, Inc. and Takeda Pharmaceutical Co. Ltd. announced top-line results from the MONET1 pivotal Phase 3 trial evaluating motesanib administered in combination with paclitaxel and carboplatin in 1,090 patients with advanced non-squamous non-small cell lung cancer. The trial did not meet its primary objective of demonstrating an improvement in overall survival (OS) (hazard ratio 0.90, 95% CI 0.78 -- 1.04, p=0.14). Overall, the adverse event profile for motesanib was consistent with that seen in previous motesanib studies in NSCLC. Notable adverse events reported included hypertension, GI events (abdominal pain, diarrhea, nausea, and vomiting), gallbladder events (cholecystitis, gallbladder enlargement), fatigue, and hematological events (neutropenia, thrombocytopenia). Serious adverse events were more frequently reported in the motesanib arm. MONET1 (MOtesanib NSCLC Efficacy and Tolerability Study) is a Phase 3, multicenter, randomized, placebo-controlled, double-blind trial that enrolled more than 1,000 men and women with NSCLC. Patients were randomized to receive either paclitaxel (200 mg/m2 IV Q3W), carboplatin (target AUC of 6 mg/mL x min IV Q3W), and motesanib (125 mg PO QD) or paclitaxel, carboplatin, and placebo. The primary endpoint of the study was OS, and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), association of placental growth factor with OS, duration of response, and safety and tolerability. Motesanib is an investigational, orally-administered small molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptors, and stem cell factor receptor.<br />Roche Holding AG announced that the second of two Phase III trials evaluating Lucentis (ranibizumab injection) in patients with diabetic macular edema (DME) met its primary endpoint. The primary endpoint of the study, known as RIDE, showed that after 24 months a significantly greater number of patients who received Lucentis, compared to those who received placebo (sham) injections, were able to read at least 15 additional letters on an eye chart than they could at the start of the study. The safety results were consistent with previous Lucentis Phase III trials and no new significant safety findings were observed. Further analyses of the data are ongoing. Topline results from the RIDE study will be presented at the EURETINA Congress in London on May 29, 2011. DME is an eye condition characterized by swelling of the retina, which can occur in patients with type 1 or type 2 diabetes and can cause blurred vision, severe vision loss and blindness.1 DME is a leading cause of blindness among the working-age population in most developed countries, 2 and there are currently no U.S. Food & Drug Administration (FDA) approved medications to treat DME. At 24 months, 33.6% of patients (42/125) who received 0.3 mg Lucentis and 45.7% of patients (58/127) who received 0.5 mg Lucentis were able to read at least 15 more letters on the eye chart than they were at baseline, compared to 12.3% of patients (16/130) who received sham injections. The difference between each Lucentis dose group and the sham injection group was statistically significant. The study was not designed to compare the Lucentis doses with each other.<br />Corporate Finance:<br />Genta Incorporated reported unaudited consolidated earnings results for the fourth quarter and year ended December 31, 2010. For the fourth quarter of 2010, the company reported a net loss of $33.9 million, or net loss per basic and diluted share of $14.46 per share, compared with a net loss of $11.7 million or $317.71 per basic and diluted share, for the fourth quarter of 2009. Net product sales were $0.065 against $0.038 for the same period a year ago. Loss before income tax benefit was $34.363 million against $14.594 million for the same period a year ago. <br />For the year ended December 31, 2010, the company reported a net loss of $167.3 million, or $246.04 per basic and diluted share, compared with a net loss of $86.3 million, or $4,200.99 per basic and diluted share, for the year ended December 31, 2009. Net cash used in operating activities for the twelve months ended December 31, 2010 was $14.3 million or approximately $1.2 million per month. Net product sales were $0.257 million against $0.218 for the same period a year ago. Loss before income tax benefit was $167.796 million against $86.301 million for the same period a year ago. <br />The company projects that average net monthly cash outflow will be approximately $1.5 million during 2011.<br />Nippon Kayaku Co. Ltd. reported consolidated earnings results for the nine months ended February 28, 2011. For the period, the company reported increasing net profit 2.7% to JPY 7.4 billion. Revenue was up 6.9% to JPY 111 billion. Operating profit increased 35.7% to JPY 15.9 billion and ordinary profit rose 29% to JPY 15 billion. Earnings per share rose from JPY 39.8 to JPY 40.9 per share.<br />The company provided earnings guidance for the year ending May 31, 2011. The company maintained net profit forecast of JPY 11.5 billion and full-year revenue forecast is unchanged at JPY 151 billion.<br />AVI Biopharma, Inc. has filed a Follow-on Equity Offering.<br />Helix Biopharma Corp. (TSX: HBP) announced a private placement of 1,652,719 units at a price of $2.39 per unit for gross proceeds of $3,949,999 on March 28, 2011. Each unit consists of one common share and one common share purchase warrant. Each warrant entitles the holder to purchase one common share of the company at a price of $3.35 for up to five years after the closing date of the private placement. Net proceeds after expenses are $3,900,000. Jack Kay, a Director of the company and his wife acquired 209,205 units and a related party, Kay Family Charitable Foundation of which Kay is a trustee acquired an additional 209,205 units. As a result, Kay’s holdings in the company including his wife and the Foundation is 1.32% of the common shares currently outstanding and if warrants to purchase up to 418,410 common shares and stock options to purchase up to 205,000 common shares are exercised, then the stake will increase to 2.24% in the company.<br />Advanced Life Sciences Holdings, Inc., 1 : 30, Stock Split or Significant Stock Dividend, Mar-29-2011<br />Legal & Litigation:<br />The U.S. Court of Appeals for the Federal Circuit will hear arguments on April 4, 2011 in a landmark case centering on whether human genes should be patentable. The court battle started in 2009, when the Assn. for Molecular Pathology and others sued Myriad Genetics Inc. challenging the validity of Myriad's patents on two genes linked to breast and ovarian cancer. Myriad's sole rights to the genes and its diagnostic analysis leaves women unable to confirm their test results elsewhere, and other women cannot afford Myriad's $3,000 test.<br />Mergers & Acquisitions:<br />Rumors are going around that Torrent Pharmaceuticals Ltd. may sell stake to AstraZeneca PLC. A sourceclose to the matter said, “Torrent and AstraZeneca are in talks to work jointly in the area of clinical trials, co-marketing and developing new molecules.” The news report mentioned that as part of the deal, which is likely to be struck sometime in 2011, AstraZeneca will outsource molecules of its patented drugs to be sold in developed countries. According to the sources, most of these would be in the chronic therapeutic segments such as cardio, diabetology, oncology and psychiatry. They added that a deal is likely to add INR 5 billion to Torrent Pharma's top line. According to the report, the company has denied any stake sale. Spokesperson for Torrent stated, “The ongoing market rumors about a possible stake sale by Torrent Pharmaceuticals to AstraZeneca are absolutely baseless and untrue and the management denies the same. There is no move on the part of the promoters of Torrent Pharma or its management to sell any stake in the company to any players, national or global.”<br />Cephalon Inc (Nasdaq: CEPH) made an offer to acquire remaining 72.48% stake in ChemGenex Pharmaceuticals Limited (ASX: CXS) from Merck Sante, GBS Venture Partners Ltd and other shareholders for approximately AUD 140 million in cash on March 29, 2011. Cephalon will make an offer of AUD 0.7 for each ChemGenex Pharmaceuticals share, cum dividends and other rights and an offer of AUD 0.02 for each ASX-listed ChemGenex option. Cephalon intends to fund the transaction consideration from its available cash on hand. Cephalon Inc holds a prebid stake of 27.52% in ChemGenex.The offer for shares is subject to Cephalon CXS having a relevant interest in at least 90% of ChemGenex shares, no material adverse change, during the condition period, no member of the ChemGenex group should conduct its business otherwise than in the ordinary course, no change of control event should be triggered, no approval issued by a regulatory authority to or otherwise held by any member of the ChemGenex group is or is able to be revoked, withdrawn, terminated or varied, approval of US Hart-Scott-Rodino Antitrust Improvements Act, no prescribed occurrences. <br />The deal is also subject to no member of the ChemGenex Group acquiring any one or more entities, businesses or assets the price, or aggregate price, of which exceeds AUD 1 million, disposing any one or more entities, businesses or assets the price, or aggregate price, of which exceeds AUD1 million, entering into any agreement involving a commitment greater than AUD 1 million or the term of which cannot be terminated within 6 months, incurring any indebtedness or issues any debt securities, entering into any joint venture, shareholders, partnership or strategic alliance agreement, certain other conditions and the option offer having become or having been declared free of all conditions. The offer for ChemGenex listed options is subject to the same conditions which are for the offer for shares except that before and at the end of the offer period, Cephalon CXS should have a relevant interest in at least 90% of ChemGenex options and the share offer having become or having been declared free of all conditions. Subject to obtaining advice on the applicable U.S. law requirements, Cephalon will consider extending the share offer to holders of ChemGenex American Depository Receipts (ADRs) if compliance with those requirements is not unduly onerous or impracticable.<br />The Directors of ChemGenex Pharmaceuticals have recommended the transaction in the absence of a superior offer. David Petrie and Michael Gregory of Merrill Lynch acted as the financial advisor and Johnson Winter & Slattery acted as the legal advisor to Cephalon. Canaccord Genuity acted as the financial advisor and McCullough Robertson acted as the legal advisor to ChemGenex. Rebecca Wilson of Buchan Consulting acted as the public relations advisor to ChemGenex.<br />News & Events:<br />Source Precision Medicine, Inc. announced that 16 molecular diagnostic development programs will be offered for sale on April 29, 2011. These molecular diagnostic programs are blood-based, not tissue-based. Eight programs cover the following cancers: prostate, lung, breast, cervical, ovarian, colon, bladder and melanoma. In addition, two programs cover infectious diseases: sepsis and hepatitis C infection; three programs cover autoimmune diseases: rheumatoid arthritis, multiple sclerosis, lupus, osteoarthritis and ocular and one covers transplant rejection.<br />Strategy & Strategic Alliances:<br />Ono Pharma has signed an exclusive licensing agreement with OncoTherapy Science Inc. to develop, manufacture and commercialise the latter's therapeutic peptide vaccine, the Japanese pharma announced yesterday. Under the terms of agreement, the indication for the therapeutic vaccine covers all types of cancers including hepatocellular carcinoma in the geographical areas of Japan, South Korea, and Taiwan. Ono Pharma will also hold an option to widen territory based on development status. In return, it will make an upfront payment, development and commercial milestone payments and sales royalties to the biotech. No financial figure has been disclosed.<br />Calypso Medical Technologies, Inc. announced the installation of a Calypso System at The Harley Street Clinic. With its GPS for the Body technology, the Calypso System use miniature implanted Beacon transponders to provide precise, continuous information on the location of the tumor during external beam radiation therapy.<br />Alnylam Pharmaceuticals, Inc. announced that it has earned a $10 million technology transfer payment from Takeda Pharmaceutical Company Limited as part of the strategic alliance the companies formed in May 2008. This payment is related to the achievement of certain pre-defined objectives in the transfer of Alnylam's platform technology, including documents, materials, and know-how, to Takeda for the development of RNAi therapeutics. Alnylam had previously received $140 million in upfront and technology transfer payments from Takeda. Alnylam is also eligible to receive significant milestones and royalties related to the Takeda's successful advancement of RNAi therapeutic products, and has retained certain product opt-in rights in the U.S. market. The Alnylam-Takeda alliance, which is valued at potentially over $1 billion, represents the industry's broadest RNAi therapeutics partnership. The agreement provides Takeda with broad, worldwide, non-exclusive access to and enablement with Alnylam's RNAi therapeutics platform technology and intellectual property in the fields of oncology and metabolic disease, with the right to expand the number of therapeutic fields in the future. In addition, it includes a collaboration and cross-license of delivery technologies between the two companies, and a drug discovery collaboration on certain RNAi targets. Alnylam also has the right to opt-in and co-develop and co-commercialize Takeda RNAi therapeutic programs in the U.S. market on a 50-50 basis; the opt-in right can be exercised up until the start of Phase III clinical trials.<br />Pacific Edge Limited and Healthscope Ltd. have signed an agreement to market Pacific Edge's (PE) novel diagnostic test for the detection of bladder cancer, Cxbladder® across the Tasman. Under the terms of the agreement, Healthscope Pathology will market and offer laboratory services to urologists and general practitioners (GP) for the detection of bladder cancer using Cxbladder® in Australia. Pacific Edge will provide services to New Zealand urologists and GPs through its subsidiary Pacific Edge Diagnostics NZ Ltd, with its diagnostic laboratory based in Dunedin. Pacific Edge will retain the rights to the rest of the world for the marketing of Cxbladder®. The terms of the license agreement are confidential.<br />Champions Biotechnology, Inc. has signed an agreement with Cephalon Inc., under which Champions will conduct low passage Tumorgraft(TM) studies on two proprietary chemical compounds, CEP-32496, an inhibitor of mutant B-Raf, and CEP-37440, a selective dual ALK-FAK inhibitor, provided by Cephalon to determine the activity or response in potential clinical indications. The results of these studies will be used to inform the future clinical development path of these compounds. Under the terms of the agreement, Cephalon will pay Champions an initiation fee of $1.39 million by April 15, 2011, and will also pay Champions various amounts totaling $27 million upon achieving certain milestones. In addition, Cephalon will pay Champions royalties on any commercialized products developed under the agreement.<br />Biomoda Inc. announced the signing of a Memorandum of Understanding with the University of Texas Health Science Center at San Antonio to collaborate on research to optimize the CyPath(R) diagnostic assay for lung cancer.<br />Morphotek, Inc. entered into a collaboration and license agreement with Biocare Medical, LLC.Under the agreement, the parties will collaborate to develop and commercialize an immunohistochemical (IHC) diagnostic kit utilizing Morphotek's proprietary monoclonal antibody to specifically detect human folate receptor alpha (FRA) with Biocare's intelliPATH Automated Stainer. The agreement provides Biocare with a non-exclusive license to develop, manufacture and commercialize an IHC kit for detection of FRA on formalin-fixed paraffin-embedded (FFPE) tumor tissues. FRA is a cell surface protein that is over-expressed in a variety of cancers including non-small cell lung adenocarcinoma and ovarian carcinoma. Studies have found its expression variable among different cancer types. In light of this variability, a diagnostic assay that can identify patients with FRA-positive cancers may enable better diagnosis and treatment of patients affected with FRA-expressing cancers. FRA is the target of Morphotek's therapeutic candidate, farletuzumab, which is currently being tested in several clinical trials against different types of cancers.<br />deCODE Biostructures, Inc. and ChemDiv, Inc. have announced the formation of a strategic drug discovery and development alliance which will provide biotech and pharmaceutical companies with fully integrated structure based small molecule discovery services, from gene to clinic. This collaboration enhances both companies' portfolios of offerings to their customers and creates synergistic effects by delivering high quality services and best value to the industry. Partnership with ChemDiv will provide an access to broad bioscreening and assay development platforms, CMC, formulation and API capabilities, pharmacology and translational research focused on oncology, CNS, CV/metabolics, inflammation and anti-infective and rare disease therapeutic areas. The collaboration announced establishes a strategic preferred partner co-marketing relationship which allows ChemDiv's clients to access Emerald's structural biology expertise in solving challenging protein targets. Emerald's clients can now benefit from the range of ChemDiv's discovery and development services. The companies will utilize their distinctive translational and fully integrated drug discovery and development platform to support collaborative efforts.<br />Ariad Pharmaceuticals Inc. and MolecularMD Corp. announced an exclusive collaboration agreement in which MolecularMD will develop and commercialize a companion diagnostic test to identify the T315I mutation of the BCR-ABL gene in patients with chronic myeloid leukemia and Philadelphia positive acute lymphoblastic leukemia. ARIAD is advancing its investigational, pan-BCR-ABL inhibitor, ponatinib, in the pivotal PACE trial of patients with resistant or intolerant CML and Ph+ ALL, or those with the T315I mutation. MolecularMD has performed BCR-ABL mutation testing with its standardized and validated sequencing test in patients enrolled in ARIAD's earlier Phase 1 trial of ponatinib and now is conducting similar testing prior to patient treatment in the PACE trial. As part of this collaboration agreement, MolecularMD will further optimize its currently available sequencing test and will file a Premarket Approval Application with the U.S. Food and Drug Administration to support commercialization of the diagnostic test. The companies expect MolecularMD to submit the PMA at approximately the same time as ARIAD files its New Drug Application for ponatinib in 2012. MolecularMD will also seek a CE Mark for a companion diagnostic test kit in Europe. Once approved, MolecularMD will have responsibility for commercializing the T315I diagnostic test. Under terms of the collaboration agreement, ARIAD will reimburse MolecularMD for predefined expenses for the development of the T315I diagnostic test. ARIAD will also pay MolecularMD milestones for achievement of key development and regulatory activities. The MolecularMD companion diagnostic test is being developed to identify CML and Ph+ ALL patients who have the T315I mutation. A companion diagnostic test is not necessary to support the broader potential use of ponatinib in patients who are resistant or intolerant to the current second-generation BCR-ABL inhibitors, as being studied in the PACE trial. Many mutations in addition to T315I account for resistance to currently marketed BCR-ABL inhibitors.<br />