1stOncology™: Cancer Intelligence Service – Page 15603 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Sunesis Pharmaceuticals Announces Presentation of The Ohio State University-Sponsored Preclinical Study of BTK Inhibitor SNS-062 at AACR Annual Meeting

On April 3, 2017 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported results from an Ohio State University-sponsored preclinical study evaluating the efficacy of non-covalent BTK inhibitor SNS-062 in chronic lymphocytic leukemia (CLL) proprietary cell lines and patient samples (Press release, Sunesis, APR 3, 2017, View Source [SID1234518447]). The study demonstrated that, unlike ibrutinib, SNS-062 inhibition of BTK signaling is unaffected by the presence of the C481S mutation and may address acquired resistance to covalent BTK inhibitors. The results are being presented today in a poster session titled "Reversal of Drug Resistance" on Monday, April 3, 2017 from 8:00 AM to 12:00 PM ET at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

"B-cell receptor signaling is exceptionally active in CLL and is vital for the proliferation and survival of CLL cells, making BTK inhibition an effective target. However, a subset of patients acquire resistance to ibrutinib, the current standard of care BTK inhibitor," said Amy Johnson, PhD, Associate Professor, Hematology, The Ohio State University. "A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S. In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients."

"Preclinical and healthy volunteer data continue to reveal a unique profile for SNS-062, one distinct from ibrutinib and other covalently binding BTK inhibitors," said Judy Fox, PhD, Chief Scientific Officer of Sunesis. "SNS-062 has the potential to become an important new treatment for CLL, addressing what is an increasingly well-defined and prevalent unmet patient need. With an active IND, we remain on track to dose the first patient in our planned Phase 1B/2 study in patients with advanced B-cell malignancies this quarter."

For the study, primary CLL B-cells were isolated from the whole blood of consenting patients with CLL. In these cells, SNS-062 was found to decrease surface expression of B-cell activation markers and patient CLL cell viability in a dose-dependent manner, with BTK inhibition by SNS-062 comparable to ibrutinib. Further, SNS-062 was found to inhibit BTK wild type (WT) and BTK C481S, while ibrutinib and acalabrutinib show reduced activity toward BTK C481S. SNS-062 has a unique kinase selectivity profile, affecting a limited number of kinases outside the TEC kinase family. SNS-062 was also found to diminish stromal cell protection in patient CLL cells, an important observation given the role of tumor microenvironment in this malignancy.

The poster (Poster Number 22, Abstract Number 1207, Convention Center, Halls A-C, Poster Section 6) titled "SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated Bruton tyrosine kinase" is available on the Sunesis website at www.sunesis.com.

About SNS-062

SNS-062 is a novel, second-generation BTK inhibitor, a class of kinase inhibitors that selectively inhibits the enzyme Bruton’s tyrosine kinase (BTK). This target mediates signaling through the B-cell receptor, which is critical for adhesion, migration, proliferation and survival of normal and malignant B-lineage lymphoid cells. Unlike other drugs in its class, SNS-062 has a distinct kinase selectivity profile and binds non-covalently to the BTK enzyme. This alternate binding site potentially provides an opportunity to address the leading resistance mechanism, a mutation in the enzyme’s binding site required for covalent binding. In preclinical studies, SNS-062 demonstrated potent activity against Cys-481S mutated B-cell malignancies, and has been studied in healthy subjects in a Phase 1A, randomized, double-blind, placebo-controlled dose-ranging study to investigate the drug’s safety, pharmacokinetics, and pharmacodynamics. With the reported successful study outcome, SNS-062 is proceeding to a Phase 1B/2 study in patients with B-cell malignancies.

Peregrine Pharmaceuticals Announces Presentation of Preclinical Study Results Highlighting Potential of PS-Targeting Antibodies to Enhance Anti-Tumor Activity of Adoptive T Cell Transfer Therapy with No Added Off-Target Toxicities

On April 3, 2017 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, reported the presentation of positive new data from the company’s ongoing collaboration with researchers from Memorial Sloan Kettering Cancer Center (MSK) (Press release, Peregrine Pharmaceuticals, APR 3, 2017, View Source [SID1234518444]).

Presented preclinical study results highlighted the potential of the company’s phosphatidylserine (PS)-targeting antibodies to enhance the anti-tumor activity of adoptive T cell transfer therapy without triggering any off-target toxicities. Data were presented this morning by MSK researchers at the 2017 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which is being held April 1-5, 2017 in Washington, D.C.

For this study, a team of MSK researchers led by cancer immunotherapy thought-leaders, Taha Merghoub, Ph.D. and Jedd D. Wolchok, M.D., Ph.D., evaluated and compared the anti-tumor activity and off-target toxicities of adoptive T cell transfer therapy in combination with either PS-targeting antibodies or anti-OX40 antibodies in mice with advanced melanomas. Whereas PS-targeting and anti-OX40 demonstrated comparable tumor regression when administered in combination with transferred adoptive T cells, only the PS-targeting combination achieved these results without any off-target toxicities. By contrast, the anti-OX40 treatment combination triggered off-target inflammatory destruction of healthy tissues.

"While adoptive T cell transfer remains one of the most exciting new approaches to treating cancer, to date the toxicity associated with the treatment has limited its potential. We are encouraged that these study results showed that the combination of anti-PS and adoptive T cell treatment led to enhanced anti-tumor effect without any evidence of additional off-target side effects," said Taha Merghoub, Ph.D., co-director of the Ludwig Collaborative Laboratory at MSK. "We believe that these findings may support potential applications for this combination in solid tumors in the future."

Additional study results demonstrated that the PS-targeting antibodies decreased tumor-induced immunosuppression as evidenced by a decrease in immunosuppressive regulatory T cells (Tregs) and M2 macrophages. This finding is consistent with Peregrine’s belief that bavituximab may modulate the immunosuppressive tumor microenvironment and enhance the activity of immunotherapy agents.

"These study results provide further support for our belief that anti-PS agents such as bavituximab can play an important role as part of combination cancer treatments. This is directly tied to the agents’ ability to modulate the tumor microenvironment to combat the immunosuppression that limits the activity of CAR T and immunotherapies," said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. "Importantly, we are now also seeing evidence that this targeted modulation of the tumor microenvironment by anti-PS allows for enhanced activity of these other treatments without triggering any off-target toxicities. This is opposed to other conventional immunotherapies such as anti-OX40 with systemic mechanisms of action. We believe this advantageous tolerability profile will be a key benefit in positioning anti-PS agents for inclusion in optimal combination cancer regimens."

Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. PS-targeting antibodies have demonstrated an ability to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. Bavituximab is believed to override PS immunosuppressive signaling by blocking the engagement of PS with its receptors and sending an alternate immune activating signal.

Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations. These trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination.

Additionally, Peregrine continues to advance its pre-clinical collaboration with MSK with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab’s combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.

OncoMed Presents Preclinical Data for Anti-TIGIT Program at the American Association for Cancer Research Annual Meeting 2017

On April 3, 2017 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported data from multiple preclinical studies detailing the mechanism and anti-tumor activity of anti-TIGIT alone and in combination with checkpoint inhibitors at the AACR (Free AACR Whitepaper) Annual Meeting 2017 (Press release, OncoMed, APR 3, 2017, View Source [SID1234518443]). These are the first data from OncoMed’s anti-TIGIT program to be shared publicly. OncoMed plans to initiate a Phase 1a single-agent study of its anti-TIGIT antibody (OMP-313M32) in the first half of 2017.

"TIGIT is a highly desirable target in immuno-oncology with similarities in structure and function to PD1 and broad expression of its ligands on a wide variety of tumor tissues. We believe that by blocking TIGIT signaling our anti-TIGIT antibody may enable T-cell activation and facilitate a potent anti-tumor immune response, potentially halting the growth and recurrence of tumors," said Austin Gurney, Ph.D., OncoMed’s Senior Vice President of Molecular and Cellular Biology and co-Chief Scientific Officer. "In multiple preclinical studies with anti-TIGIT antibodies we have observed immune activation and robust anti-tumor activity — both as a single agent and in combination with other cancer immunotherapeutics. Notably, the effect on inhibiting tumor growth persists upon re-challenging cured animals with re-injection of tumor cells, indicating that we are inducing a long-term immune memory response that we hope will translate into long-term clinical benefit. We look forward to advancing our anti-TIGIT antibody into the clinic in the first half of 2017."

Anti-TIGIT AACR (Free AACR Whitepaper) Annual Meeting 2017 Highlights

Anti-TIGIT demonstrates single-agent activity in multiple models

TIGIT (T cell immune-receptor with Ig and ITIM domains) is an inhibitory checkpoint receptor that binds to PVR ligand, a protein broadly expressed on tumor cells and tumor-infiltrating cells, and, in doing so, blocks T-cell activation. In order to test the immune response and anti-tumor activity of anti-TIGIT, OncoMed researchers developed a surrogate TIGIT-blocking antibody that could be tested in syngeneic mouse models. Potent single-agent, dose-dependent anti-tumor efficacy was observed on large established tumors in multiple murine models, including colorectal, breast and melanoma. In a separate set of experiments using patient-derived xenograft models in humanized mice containing human lymphocytes derived from hematopoietic stem cells, anti-TIGIT inhibited human melanoma tumor growth.

Anti-TIGIT induces immune memory responses

In another set of experiments, the surrogate anti-TIGIT antibody inhibited the growth of kidney and colon tumors in immune-competent mice, causing complete tumor regression. When mice were re-challenged with the same tumor cells after having achieved complete regression, tumors did not regrow and the mice remained tumor free, indicating that single-agent anti-TIGIT induces powerful Th1-type immune memory response and increases cytotoxic lymphocyte activity.

Anti-TIGIT plus anti-PD1 or anti-PDL1 results in potent anti-tumor activity

Anti-TIGIT demonstrated combination activity when combined with checkpoint inhibitors anti-PD1 and anti-PDL1 in preclinical models. In colon cancer models, the combination inhibited tumor growth and resulted in complete rejection of the tumors, significantly increasing mice survival as compared to control or to anti-TIGIT, anti-PD1 or anti-PDL1 alone. Further, when mice whose tumors achieved complete regression following treatment with anti-TIGIT plus anti-PD1 or anti-TIGIT plus anti-PDL1 were re-challenged with increasing number of tumor cells, they remained protected from tumor growth, suggesting the induction of immunologic memory against the tumor cells.

Anti-TIGIT activates cytotoxic immune responses directed at tumors; pharmacodynamics markers identified going into the clinic

In vivo studies of anti-TIGIT’s anti-tumor activity provided insight into its mechanism of action. In preclinical studies, anti-TIGIT increased cytotoxic T-cell activity against tumor cells and decreased T-cell suppression. More specifically, anti-TIGIT promoted dose-dependent increases in T and NK cell activation in tumors, as well as increased infiltration of T cells into the tumor. Consistent with the mechanism of action, anti-TIGIT treatment promoted upregulation of immune genes associated with activation of T and NK cells, Th1 response and cytotoxic activity. Blood and tumor samples analyzing pharmacodynamic (PD) markers of immune responses were consistent, suggesting that blood may be a potential surrogate tissue for measuring PD markers of anti-TIGIT activity. Immunohistochemistry (IHC) profiling of a large human tumor panel including multiple indications showed the highest TIGIT expression on immune cells associated with tumors at varying levels, while it was generally low on tumor cells.

AACR Presentations

These data were presented in three posters during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, DC:

Title: "Pharmacodynamic biomarkers for anti-TIGIT treatment and prevalence of TIGIT expression in multiple solid tumor types"
Abstract: 599

Title: "Antibody against TIGIT (T-cell immunoreceptor with Ig and ITIM domains) induces anti-tumor immune response and generates long-term immune memory"
Abstract: 2003

Title: "Anti-TIGIT induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity"
Abstract: 2612

About Anti-TIGIT
TIGIT (T cell immunoreceptor with Ig and ITIM domains) blocks T cells from attacking tumor cells, similar to the inhibitory protein PD-1. OncoMed’s anti-TIGIT antibody (OMP-313M32) is intended to activate the immune system through multiple mechanisms and enable anti-tumor activity. A Phase I clinical trial of anti-TIGIT is expected to begin enrolling patients during the first half of 2017.

This program is part of OncoMed’s Celgene collaboration. Upon the completion of certain enrollment criteria in the Phase I clinical trial, Celgene will have the option to obtain an exclusive license to anti-TIGIT.

Merrimack Launches as New, Refocused Research & Clinical Development Company with Resources to Advance Prioritized Lead Pipeline Candidates MM-121, MM-141 and MM-310

On April 3, 2017 Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK) reported that it has commenced operating as a new, refocused research and clinical development company in connection with the completion today of its previously announced transaction with Ipsen S.A. valued at up to $1.025 billion (Press release, Merrimack, APR 3, 2017, View Source [SID1234518442]). Under the terms of the agreement, Merrimack sold to Ipsen its first commercial product, ONIVYDE, including U.S. commercialization rights and its licensing agreement with Shire plc, and its development, license and supply agreement with Actavis for a generic version of doxorubicin hydrochloride (HCI) liposome injection that is marketed in the United States as DOXIL.

Merrimack received $575 million in cash upon closing and is eligible to receive up to $450 million in additional regulatory approval-based milestone payments. Merrimack will also retain the rights to receive net milestone payments pursuant to its exclusive licensing agreement with Shire plc for the ex-U.S. development and commercialization of ONIVYDE for up to $33 million.

"The completion of this sale marks our first day as a new Merrimack: a refocused research and clinical development company, with a promising pipeline that is poised for continued long-term success and stockholder value creation," said Richard Peters, M.D., Ph.D., President and Chief Executive Officer. "Today, we have a more sustainable financial structure than at any point in Merrimack’s history, which will allow us to deliver significant cash returns to our stockholders while also funding our long-term corporate objectives and strategies into the second half of 2019. We are also moving forward focused on MM-121, MM-141 and MM-310, our three clinical programs that we believe have the highest probability of success and the highest expected return on investment. The Board of Directors and the management team are confident in the tremendous opportunities for success in our focused pipeline on behalf of cancer patients around the world and as a means to deliver additional value to our stockholders."

With the completion of the Ipsen transaction, Merrimack is now prioritizing three clinical programs:

MM-121 (seribantumab) is a first-in-class fully human monoclonal antibody that binds to the HER3 receptor and targets heregulin positive cancers. Merrimack is currently conducting the Phase 2 randomized SHERLOC study evaluating MM-121 in HRG+ non-small cell lung cancer patients in combination with docetaxel or pemetrexed and plans to initiate another Phase 2 randomized study this year in Her2 negative, hormone receptor, and heregulin positive breast cancer patients.
MM-141 (istiratumab) is a bispecific tetravalent antibody and a potent inhibitor of the PI3K/AKT/mTOR pathway by targeting IGF1-R and HER3. Currently, Merrimack is conducting the CARRIE study, a Phase 2 randomized trial evaluating MM-141 in previously untreated metastatic pancreatic cancer patients with high levels of free IGF1 in combination with nab-paclitaxel and gemcitabine.
MM-310 is an antibody-directed nanotherapeutic (ADN) that contains a novel prodrug of docetaxel and targets the EphA2 receptor, which is highly expressed in most solid tumor types. MM-310 was designed to improve the therapeutic window of docetaxel in major oncology indications, such as prostate, ovarian, bladder, gastric, pancreatic and lung cancers. A first-in-human Phase 1 study to evaluate safety and preliminary activity of MM-310 was initiated in the first quarter of 2017.
As previously announced, Merrimack intends to use the $575 million upfront payment, net of tax reserves and transaction-related and other costs, to:

Invest $125 million to develop Merrimack’s streamlined oncology pipeline such that Merrimack will be able to fund itself into the second half of 2019;
Extinguish the $175 million in outstanding Senior Secured Notes due in 2022, plus approximately $20 million of costs associated with the redemption; and
Return $140 million to Merrimack’s stockholders through a special cash dividend. The Board of Directors plans to approve the special cash dividend and announce a record date and ex-dividend date in due course.
Advisers

BofA Merrill Lynch and Credit Suisse Securities (USA) LLC are serving as financial advisers to Merrimack and Skadden, Arps, Slate, Meagher & Flom LLP is serving as legal adviser.

Jazz Pharmaceuticals Completes Rolling Submission of New Drug Application for Vyxeos™ (CPX-351), an Investigational Treatment for Acute Myeloid Leukemia

On April 3, 2017 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported the completion on March 31, 2017 of a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the approval of Vyxeos (cytarabine and daunorubicin) liposome for injection, an investigational treatment for acute myeloid leukemia (AML), a rapidly progressing and life-threatening blood cancer (Press release, Jazz Pharmaceuticals, APR 3, 2017, View Source [SID1234518440]). 1 The company has requested a priority review for the Vyxeos NDA, which, if granted, would accelerate the expected timing of the FDA’s review.

Vyxeos utilizes CombiPlex technology, which encapsulates a fixed ratio of drugs in a nano-scale delivery complex. Vyxeos received Breakthrough Therapy Designation from the FDA in May 2016 for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes. Vyxeos was also granted Fast Track Designation for the treatment of elderly patients with secondary AML by the FDA, and Orphan Drug Designation by the FDA and the European Commission for the treatment of AML. The FDA grants Breakthrough Therapy Designation to expedite the development and review of new medicines that are intended to treat serious or life-threatening diseases when the clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on at least one clinically significant endpoint.

"The completion of our NDA submission for Vyxeos marks a significant milestone for the company as we continue to advance our pipeline of products for hematology and oncology diseases with high unmet medical needs," said Karen Smith, M.D., Ph.D., global head of research and development and chief medical officer at Jazz Pharmaceuticals. "We look forward to working closely with the FDA toward the goal of obtaining approval of Vyxeos for patients with AML as little has changed in the pharmacologic treatment of AML in more than 40 years."

The NDA submission includes clinical data from five studies, including the pivotal Phase 3 study. Data from the Phase 3 study, which met its primary endpoint, were previously presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2016.

About Vyxeos (CPX-351)

Vyxeos (cytarabine and daunorubicin) liposome for injection, or CPX-351, is an investigational product being evaluated for the treatment of AML, and is a combination of cytarabine and daunorubicin encapsulated within a nano-scale liposome at a 5:1 molar ratio. The proposed trade name, Vyxeos, is conditionally approved by the FDA and is subject to confirmation upon approval of the NDA.

About Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a rapidly progressing and life-threatening blood cancer that rises in frequency with age.1 The American Cancer Society estimates that there will be approximately 21,380 new cases of AML and 10,590 deaths from AML in the United States in 2017.1 The median age at diagnosis is 67 and with rising age there is progressive worsening of prognosis.1,2 Advancing age is associated with increasing risk of specific chromosomal/mutational changes and risk of pre-malignant marrow disorders, which give rise to more aggressive and less responsive forms of AML.3,4 As patients age there is also reduced tolerance for intensive chemotherapy.5 As a consequence, advances in supportive care, intensive chemotherapy and bone marrow transplantation have primarily benefitted younger patients.3,5 The five-year survival rate has not improved in older patients despite of 40 years of research.5,6