On May 26, 2016 ProNAi Therapeutics, Inc. (NASDAQ: DNAI), a clinical-stage oncology company advancing novel targeted therapeutics for patients with cancer, reported it has obtained an exclusive license from Carna Biosciences, Inc., Kobe, Japan (JASDAQ: 4572), for worldwide rights to develop and commercialize AS-141, a small molecule kinase inhibitor targeting CDC7 (Press release, ProNAi Therapeutics, MAY 26, 2016, View Source [SID:1234512843]). Schedule your 30 min Free 1stOncology Demo! "Our exclusive license with Carna gives us access to a highly promising asset that was created leveraging Carna’s world-class kinase drug discovery expertise. Our team has extensive experience developing oncology drugs and will be focused on the rapid and efficient advancement of this drug candidate," said Dr. Nick Glover, President and CEO of ProNAi. "This agreement, and our focused efforts to identify additional high-quality assets to acquire, reflect our strategy of building a broad and diverse pipeline of targeted oncology drugs that will change people’s lives."
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Under the terms of the agreement, ProNAi will pay Carna Biosciences an initial upfront payment of $0.9 million and aggregate additional potential payments upon achievement of certain developmental, regulatory and commercial milestones of up to $270 million. ProNAi will also pay Carna single-digit tiered royalties on the net sales of any product successfully developed.
"ProNAi and Carna Biosciences are fully aligned in our vision of making a meaningful difference for patients with cancer," said Kohichiro Yoshino, PhD, Founder, President and CEO of Carna Biosciences. "We are confident the further development of AS-141 will be well-managed under the stewardship of the ProNAi team."
"We are very excited to work with the highly experienced team at ProNAi to progress AS-141 to the clinic," added Dr. Masaaki Sawa, Chief Scientific Officer of CarnaBio. "AS-141 has demonstrated compelling anti-tumor activity against multiple tumor types in preclinical studies and represents an opportunity for promising clinical development."
"CDC7’s role as a key regulator of both DNA replication and DNA damage response make it a compelling emerging target for the treatment of a broad range of tumor types, providing significant commercial potential for the agent," said Dr. Angie You, Chief Business & Strategy Officer and Head of Commercial for ProNAi. "While there is growing interest in targets of this class, we believe we have an opportunity with this potent and selective kinase inhibitor to be first-in-class and highly differentiated."
"Preclinical data and published literature suggest a variety of oncology indications with potential for response to CDC7 inhibitors," added Dr. Barbara Klencke, ProNAi’s Chief Development Officer. "Continued preclinical assessment of AS-141 will further inform our clinical development plans and patient selection strategies, with the objective of advancing this drug into the clinic in H2 2017.
Roche’s Gazyva/Gazyvaro showed superior progression-free survival compared to MabThera/Rituxan in people with previously untreated follicular lymphoma
On May 27, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported positive results from the pivotal phase III GALLIUM study in people with previously untreated follicular lymphoma, the most common type of indolent (slow-growing) non-Hodgkin lymphoma (iNHL) (Press release, Hoffmann-La Roche , MAY 26, 2016, View Source [SID:1234512824]). Schedule your 30 min Free 1stOncology Demo! The study compared the efficacy and safety of Gazyva/Gazyvaro (obinutuzumab) plus chemotherapy (CHOP, CVP or bendamustine) followed by Gazyva/Gazyvaro alone, head-to-head with MabThera/Rituxan (rituximab) plus chemotherapy followed by MabThera/Rituxan alone. Results from a pre-planned interim analysis showed that Gazyva/Gazyvaro-based treatment significantly reduced the risk of disease worsening or death (progression-free survival; PFS, as assessed by investigator) compared to MabThera/Rituxan-based treatment. Adverse events with either Gazyva/Gazyvaro or MabThera/Rituxan were consistent with what was seen in previous clinical trials when each was combined with various chemotherapies. Data from the GALLIUM study will be presented at an upcoming medical meeting and submitted to health authorities for approval consideration.
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"People with follicular lymphoma continue to need better initial treatment options because their disease is incurable and becomes more difficult to treat with each relapse," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "GALLIUM is the second study in which Gazyva/Gazyvaro showed superior progression-free survival compared to MabThera/Rituxan, when each was combined with chemotherapy."
In the first head-to-head comparison of Gazyva/Gazyvaro and MabThera/Rituxan, the CLL11 study in people with previously untreated chronic lymphocytic leukaemia and comorbidities, Gazyva/Gazyvaro plus chlorambucil significantly extended PFS compared to treatment with MabThera/Rituxan plus chlorambucil (median PFS 26.7 months vs. 14.9 months, respectively; HR=0.42; 95% CI, 0.33-0.54; p<0.0001).1 The most common side effects of Gazyva/Gazyvaro plus chlorambucil were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhoea.
About the GALLIUM study
GALLIUM (NCT01332968) is a global Phase III open-label, multi-centre, randomised two-arm study examining the efficacy and safety of Gazyva/Gazyvaro plus chemotherapy, as compared to MabThera/Rituxan plus chemotherapy, followed by Gazyva/Gazyvaro or MabThera/Rituxan alone for up to two years. Chemotherapies used were CHOP, CVP or bendamustine as selected by each participating study site. GALLIUM included 1401 patients with previously untreated indolent non-Hodgkin lymphoma (iNHL), of which 1202 patients had follicular lymphoma. The primary endpoint of the study was investigator-assessed PFS in patients with follicular lymphoma, with secondary endpoints including PFS assessed by independent review committee (IRC), PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response, CR), overall survival (OS), disease-free survival (DFS) and safety. The GALLIUM study is being conducted in cooperation with the German Low Grade Lymphoma Study Group (GLSG; Germany), the East German Study Group Hematology and Oncology (OSHO; Germany) and the National Cancer Research Institute (NCRI; United Kingdom).
About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system. Gazyva/Gazyvaro is currently approved in more than 70 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia. The approval was based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil. Furthermore, Gazyva was recently approved by the U.S. Food and Drug Administration in combination with bendamustine followed by Gazyva alone for people with follicular lymphoma who did not respond to a MabThera/Rituxan-containing regimen, or whose follicular lymphoma returned after such treatment. The approval was based on the GADOLIN study, showing a significant improvement in progression-free survival with Gazyva/Gazyvaro-based therapy compared to bendamustine alone. Those results have also been submitted to other health authorities around the world for approval consideration and resulted in the recent positive opinion by the EU Committee for Medicinal Products for Human Use for Gazyvaro in combination with bendamustine chemotherapy followed by Gazyvaro maintenance as a new treatment for people with follicular lymphoma who did not respond to, or who progressed during or up to six months after treatment with MabThera or a MabThera-containing regimen. Gazyva is marketed as Gazyvaro in the EU and Switzerland.
Gazyva/Gazyvaro continues to be studied in a large clinical programme, including the phase III GOYA study, comparing Gazyva/Gazyvaro plus CHOP chemotherapy head-to-head with MabThera/Rituxan plus CHOP chemotherapy in first line diffuse large B-cell lymphoma (DLBCL). Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are planned or underway across a range of blood cancers.
About follicular lymphoma
Follicular lymphoma is the most common indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), accounting for about one in five cases of NHL2 It is considered incurable and relapse is common. It is estimated that more than 75,000 people are diagnosed with follicular lymphoma each year worldwide.3
$1.8 Million Fast-Track NIH SBIR Grant for Manocept™ Immunotherapeutics Evaluation in Kaposi’s Sarcoma Awarded to Navidea
On May 26, 2016 Navidea Biopharmaceuticals, Inc. (NYSE MKT: NAVB) reported the receipt of an initial notice of award for a Fast- track Small Business Innovation Research (SBIR) grant providing for up to $1.8 million from the National Institutes of Health’s (NIH) National Cancer Institute (NCI) to fund evaluation of an investigational Manocept-based immunotargeted treatment for Kaposi’s Sarcoma (KS) (Press release, Navidea Biopharmaceuticals, MAY 26, 2016, View Source;p=RssLanding&cat=news&id=2172821 [SID:1234512817]).
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The novel Manocept construct is designed to specifically deliver doxorubicin, a chemotoxin, which can kill KS tumor cells and their tumor-associated macrophages (TAMs) potentially altering the course of cancer. KS is a serious and potentially life threatening illness in persons infected with the human immunodeficiency virus (HIV) and the third leading cause of death in this population worldwide. The prognosis for patients with KS is poor with high probabilities for mortality and greatly diminished quality of life. The development activities of the Manocept immunotherapeutic platform will be conducted by Navidea and its subsidiary, Macrophage Therapeutics.
The funds for this Fast-track grant (National Cancer Institute of the National Institutes of Health under Award Number R44CA206788) will be released in three parts, which together have the potential to provide up to $1.8 million in resources over 2.5 years with the goal of completing an investigational new drug (IND) submission for a Manocept construct (MT1000 class of compounds) consisting of tilmanocept linked to doxorubicin for the treatment of KS. The first part of the grant will provide $232,000 to support analyses including in vitro and cell culture studies and will be followed by Part 2 and 3 animal testing studies. If successful, the information from these studies will be combined with other information in an IND application that will be submitted to the U.S. Food and Drug Administration (FDA) requesting permission to begin testing the compound selected in human KS patients.
"We believe that given the data to date from the Manocept platform, these studies along with a host of other human tumor model studies ongoing and planned for animal testing will provide a powerful gateway to a new class of anti-TAM immunotherapies directed at solid tumors. A drug that selectively kills cells that are highly expressing CD206 is expected to have an overwhelming, immediate, conspicuous and easily measured effect on KS tumors," said Frederick Cope, Ph.D., M.S., F.A.C.N., C.N.S., Senior Vice President and Chief Scientific Officer of Navidea. "This grant will bring us to submission of an IND and the first time human evaluation for a Manocept immunotherapeutic. We anticipate if trials are successful, we can bring an effective and life-sparing new therapy to KS patients who are in desperate need for such a new treatment."
"The Manocept platform may offer a unique approach to the treatment of Kaposi’s sarcoma (KS) and is, we believe, a translational portal to the therapy of a number of other solid tumors in which macrophages and tumor-associated macrophages play a key role in tumorigenesis and metastasis," said Michael Goldberg, M.D. Chairman of the Board of Navidea, "We believe that KS serves as model for a development strategy that can be expanded to other macrophage-dependent solid tumors as well as a model for therapeutics targeting viruses that incubate in macrophages. We are encouraged that our therapeutic program has been recognized by the NIH so soon after we began our therapeutic development effort. We plan on submitting additional grant requests as soon as we obtain results from the multiple ongoing studies in various cancer models, which should read out shortly."
About the MT1001 Study Efforts in KS
These IND-enabling studies will be conducted in three parts. Part 1 studies require in vitro and cell culture experiments related to safety and efficacy of an intravenous injection of MT100. In Part 2 and 3, nine preclinical animal studies will build on the Part 1 results and will further refine safety and efficacy variables including dosing and drug administration regimens and evaluating the feasibility of the MT 1000-class of molecules, as a novel treatment for KS. Following these studies, Navidea expects to submit an IND application to the FDA seeking permission to begin Phase 1/2 clinical evaluation of MT1001 in KS patients.
About KS
Kaposi sarcoma (KS) is a serious and potentially life threatening illness in persons infected with the HIV, the causative agent of acquired immunodeficiency syndrome (AIDS). Tumor associated macrophages (TAMs) constitute an important tumor component for most types of cancer (including KS) that contributes to tumor growth and protection from immune responses. Navidea, through its subsidiary Macrophage Therapeutics, is developing a receptor targeted drug construct that may be able to effectively treat KS and could contribute to effective immunotherapy for a wide variety of cancers.
About the Manocept CD206-targeting platform
Navidea Biopharmaceuticals is developing Manocept, a new pharmaceutical platform technology, targeting cells that express the macrophage mannose receptor (CD206). A wide variety of immune-targeting applications for this platform technology are envisioned. Macrophages play important roles in many disease states and are an emerging target in many disorders. This flexible and versatile platform acts as an engine for purpose-built molecules that may enhance diagnostic accuracy, clinical decision-making, targeted treatments and ultimately patient care. As an immunodiagnostic tool, the Manocept technology can utilize a breadth of imaging modalities, including SPECT, PET, intra-operative and/or optical-fluorescence detection. By linking a therapeutic agent on the Manocept molecular backbone, there is the potential to develop novel, targeted immunotherapies specifically designed to selectively deliver an agent that can kill or alter disease-associated macrophages. MT1000 class of compounds , consisting of a Manocept construct linked to doxorubicin, is the first in a series of drug delivery constructs that will utilize Navidea’s Manocept CD206 targeted drug delivery platform. Navidea’s FDA-approved immunodiagnostic agent, Lymphoseek (technetium 99m tilmanocept) injection, is representative of the platform’s ability to successfully exploit this mechanism and offer the potential for development of new CD206-targeted immunodiagnostic agents and immunotherapeutics. The development activities of the Manocept immunotherapeutic platform will be conducted by Navidea‘s subsidiary, Macrophage Therapeutics.
About Lymphoseek
Lymphoseek (technetium Tc 99m tilmanocept) injection is the first and only FDA-approved receptor-targeted lymphatic mapping agent. It is a novel, receptor-targeted, small-molecule radiopharmaceutical used in the evaluation of lymphatic basins that may have cancer involvement in patients. Lymphoseek is designed for the precise identification of lymph nodes that drain from a primary tumor, which have the highest probability of harboring cancer. Lymphoseek is approved by the U.S. Food and Drug Administration (FDA) for use in solid tumor cancers where lymphatic mapping is a component of surgical management and for guiding sentinel lymph node biopsy in patients with clinically node negative breast cancer, melanoma or squamous cell carcinoma of the oral cavity. Lymphoseek has also received European approval in imaging and intraoperative detection of sentinel lymph nodes in patients with melanoma, breast cancer or localized squamous cell carcinoma of the oral cavity.
Accurate diagnostic evaluation of cancer is critical, as results guide therapy decisions and determine patient prognosis and risk of recurrence. Overall in the U.S., solid tumor cancers may represent up to 1.2 million cases per year. The sentinel node label in the U.S. and Europe may address approximately 600,000 new cases of breast cancer, 160,000 new cases of melanoma and 100,000 new cases of head and neck/oral cancer diagnosed annually.
Lymphoseek Indication and Important Safety Information
Lymphoseek is a radioactive diagnostic agent indicated with or without scintigraphic imaging for:
Lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in patients with solid tumors for which this procedure is a component of intraoperative management.
Guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma.
Important Safety Information
In clinical trials with Lymphoseek, no serious hypersensitivity reactions were reported, however Lymphoseek may pose a risk of such reactions due to its chemical similarity to dextran. Serious hypersensitivity reactions have been associated with dextran and modified forms of dextran (such as iron dextran drugs).
Prior to the administration of Lymphoseek, patients should be asked about previous hypersensitivity reactions to drugs, in particular dextran and modified forms of dextran. Resuscitation equipment and trained personnel should be available at the time of Lymphoseek administration, and patients observed for signs or symptoms of hypersensitivity following injection.
Any radiation-emitting product may increase the risk for cancer. Adhere to dose recommendations and ensure safe handling to minimize the risk for excessive radiation exposure to patients or health care workers.
In clinical trials, no patients experienced serious adverse reactions and the most common adverse reactions were injection site irritation and/or pain (<1%).
FULL LYMPHOSEEK PRESCRIBING INFORMATION CAN BE FOUND AT: WWW.LYMPHOSEEK.COM
AVEO Announces Dosing of First Patient in the Pivotal Phase 3 TIVO-3 Study of Tivozanib in Renal Cell Carcinoma
On May 26, 2016 AVEO Oncology (NASDAQ:AVEO) reported that the first patient has been dosed in the Company’s pivotal TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC) (Press release, AVEO, MAY 26, 2016, View Source [SID:1234512802]). Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). Schedule your 30 min Free 1stOncology Demo! The Phase 3 trial is expected to enroll approximately 322 patients with recurrent or metastatic RCC who have failed at least two prior regimens, including VEGFR-TKI therapy (other than sorafenib). Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients will be randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is progression free survival. Secondary endpoints include overall survival, overall response rate, and safety and tolerability. Top line readout of the study is currently projected for the first quarter of 2018.
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The TIVO-3 trial, together with the previously completed TIVO-1 trial of tivozanib in the first line treatment of RCC, is designed to support a first and third line indication for tivozanib in the U.S. Marketing authorization applications seeking approval of tivozanib as a treatment for first line renal cell cancer are currently pending in Europe and Russia based on applications submitted by AVEO’s partners EUSA Pharma and Pharmstandard in those respective territories.
"While significant advances have been made in the treatment of renal cancer, there remains a need for effective yet more tolerable treatments, both for single agent and combination use," said Brian Rini, M.D., Professor of Medicine at the Cleveland Clinic Lerner College of Medicine. "In past studies, tivozanib has demonstrated a unique tolerability profile among VEGF targeted therapies, owing to its high selectivity for the VEGF pathway, that have resulted in fewer dose interruptions or reductions. I am pleased to see tivozanib return to the clinic, with the goal of better understanding its single agent potential through TIVO-3, and I look forward to realizing its potential for combination use with checkpoint inhibitors in future studies."
"Launch of the pivotal TIVO-3 trial marks a vital step forward for our North American development and registration strategy for tivozanib, and is a defining moment in the turnaround story unfolding at AVEO," said Michael Bailey, president and chief executive officer of AVEO. "In less than 18 months, we have meaningfully progressed our defined clinical development and regulatory paths forward for tivozanib in the US and Europe, executed multiple partnerships to advance and de-risk our pipeline while retaining substantial North American rights to our three oncology therapeutic assets, and strengthening our balance sheet. We look forward to diligently executing on this study, and to a number of potential value creating milestones, including those that could arise from tivozanib approval decisions, in the quarters ahead."
About Tivozanib
Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.
8-K – Current report
On May 25, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that it urged its stockholders to reject Sanofi’s attempt to replace the company’s entire Board of Directors with hand-picked nominees through a proposed consent solicitation, which Medivation believes is a tactic for Sanofi to facilitate its substantially inadequate and opportunistically-timed proposal to acquire Medivation (Filing, 8-K, Medivation, MAY 25, 2016, View Source [SID:1234512818]). Medivation expects to promptly file consent revocation materials with the U.S. Securities and Exchange Commission.
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On April 29, 2016, the Medivation Board unanimously rejected Sanofi’s unsolicited, non-binding proposal to purchase Medivation for $52.50 per share in cash because it substantially undervalues the company, its leading oncology franchise and its innovative, late-stage pipeline. The Medivation Board reached its conclusion about Sanofi’s proposal based on a thorough analysis of the commercial momentum and outlook of the company’s marketed product, XTANDI; its excellent pipeline of prospects; its track record of successful drug development; and its history of delivering superior returns to stockholders.
David Hung, M.D., Founder, President and Chief Executive Officer of Medivation, said, "Medivation’s experienced Board of Directors has been instrumental in overseeing a strategy that has created a leading oncology franchise, delivered consistently strong financial performance, and positioned the company for future growth through its innovative late-stage pipeline. Under the leadership of its Board of Directors, Medivation has achieved great success and rewarded its stockholders with extraordinary results, delivering total stockholder returns of more than 1,440% since 2009. In contrast, Sanofi has no duty to act in the best interests of Medivation or its stockholders. Its proposal to replace our existing directors with its own hand-picked nominees is simply a tactical maneuver to facilitate a transaction that will transfer value that rightly belongs to Medivation stockholders to Sanofi."
Kim Blickenstaff, Chairman of Medivation’s Board of Directors, said, "Sanofi is seeking to take control of our Board in a clear attempt to circumvent objective deliberations over what course of action is in the best interests of all Medivation stockholders. The unattractive economics of Sanofi’s proposal – which the Board has already determined to be substantially inadequate – have not changed. The Medivation Board remains committed to ensuring that our stockholders retain the ability to benefit from the significant value creation potential of our Company."
Evercore and J.P. Morgan are serving as financial advisors to Medivation, and Wachtell, Lipton, Rosen & Katz and Cooley LLP are acting as legal counsel.