On November 09, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of discovering, developing and commercializing novel immuno-oncology product candidates, including both cellular immunotherapy and checkpoint inhibitor platforms, to improve the lives of patients with cancer, reported that a study update from a Phase 1b/2 study of indoximod in combination with temozolomide in temozolomide-refractory glioblastoma patients will be presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology on November 19-22, 2015 at the San Antonio Marriott Rivercenter (Press release, NewLink Genetics, NOV 9, 2015, View Source [SID:1234508119]).

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Details for the presentation follow:

Abstract Title: Updates on phase 1b/2 combination study of the IDO pathway inhibitor indoximod with temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors
Abstract Number: IMCT-21
Time: 7:30-9:30 p.m.
Date: Friday, November 20
Location: Ballroom B
Session Type: Poster

On November 9, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported that two posters detailing preclinical data from its BTK and PDK1 inhibitor programs were presented on Sunday, November 8th at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) being held in Boston, Massachusetts (Press release, Sunesis, NOV 9, 2015, View Source;p=RssLanding&cat=news&id=2110307 [SID:1234508142]).

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The two poster presentations (Abstracts C198 and C186), titled "SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation" and "PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors," are available on the Sunesis website at www.sunesis.com.

"These data represent the first peer-reviewed presentations by Sunesis of our two proprietary kinase inhibitor pipeline programs," said Dan Swisher, Chief Executive Officer of Sunesis. "Each shows compelling, anti-cancer activity and a distinct product profile. SNS-062, our novel, second-generation BTK inhibitor, maintains potent preclinical activity in the presence of a cysteine-481 mutation associated with acquired resistance to ibrutinib. In addition, SNS-062 has a kinase selectivity profile distinct from ibrutinib that may confer additional safety and efficacy advantages that we look forward to uncovering in our upcoming clinical studies. SNS-510 and SNS-229, which belong to a novel class of PDK1 kinase inhibitors, show broad activity in a variety of hematologic cancer cell lines, including cell lines resistant to PI3K and AKT inhibitors, that correlates with significant PDK1 pathway modulation and anti-proliferative activity. We believe this program could soon yield a first-in-clinic selective PDK1 inhibitor to test this important pathway in cancer patients. Near term, we look forward to advancing SNS-062 into the clinic in the first quarter of 2016."

Study Results in Detail

"SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation"

For this study, Sunesis researchers explored the potential of SNS-062, a potent, noncovalent BTK inhibitor, to overcome resistance mechanisms of ibrutinib, a BTK inhibitor with validated anti-cancer efficacy in several B-cell malignancies. These resistance mechanisms include mutation of the cysteine in the BTK active site that ibrutinib requires for covalent binding (C481). SNS-062 has a kinase selectivity profile distinct from ibrutinib showing nM binding affinity for BTK, ITK and Tec kinase family members, but does not meaningfully bind EGFR. A lack of EGFR inhibition by SNS-062 may offer safety advantages over ibrutinib, including reduced diarrhea and rash potentially related to inhibition of EGFR.

Prolonged SNS-062 mediated in vivo inhibition of BTK correlates with potent anti-inflammatory activity in a BTK dependent B-cell mediated collagen induced rat arthritis model. To assess the activity of SNS-062 and ibrutinib against BTK with acquired resistance mutations, inhibition of wild type (WT) and mutant C481S BTK was evaluated in direct kinase assays. SNS-062 inhibits WT and C481S BTK with similar inhibitory concentrations while ibrutinib potency is reduced 40 fold. Similarly, ibrutinib shows a 100 fold loss of potency in inhibiting pBTK levels in C481S BTK expressing cells while SNS-062 activity is unaffected.

SNS-062 shows good oral bioavailability in multiple animal species with a terminal half-life of three to six hours. Pharmacokinetic, pharmacodynamic and toxicity studies demonstrate that SNS-062 plasma concentrations providing >90% inhibition of BTK can be sustained with acceptable tolerability.

"PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors"

Phosphatidylinositol (PI) dependent kinase 1, or PDK1, is a master kinase that activates kinases important in cell growth and survival including members of the AKT, PKC, RSK and SGK families and can interact with its substrates through PI-dependent (PH-mediated) or PI-independent (PIF-mediated) mechanisms. For this study, Sunesis researchers characterized two potent PDK1 kinase inhibitors, SNS-229 and SNS-510, with broad preclinical antitumor activity in hematologic cancers.

SNS-229 and SNS-510 belong to a novel class of PDK1 inhibitors that bind the inactive conformation of PDK1 as determined by X-ray crystallography and induce a conformational change that perturbs the PIF-pocket, thereby inhibiting PIF-mediated substrate binding, in contrast to the ATP-competitive PDK1 inhibitor tool compounds GSK2334470 and BX-320.

SNS-229 and SNS-510 were evaluated in more than twenty cell lines derived from hematologic cancers including acute myeloid leukemia, multiple myeloma, B-cell lymphoma, and mantle cell lymphoma. SNS-510 shows strong anti-proliferative activity and induces apoptosis in PI3K and AKT inhibitor resistant cell lines. SNS-229 and SNS-510 are compared to the PDK1 inhibitor GSK2334470 and were up to 30 fold more potent at inhibiting PDK1, S6K, RSK and AKT phosphorylation and up to 50 fold more potent in cancer cell viability assays.

In vivo, SNS-510 shows dose and time dependent inhibition of PDK1 autophosphorylation and up to 90% inhibition of RSK2 and AKT phosphorylation after eight hours, whereas GSK-2334470 and the pan-PI3K inhibitor GDC0941 only show moderate PDK1 and RSK2 inhibition and no AKT inhibition. In PK studies in CD/1 mice, SNS-229 and SNS-510 have good pharmacokinetic properties, with a terminal half-life of four to five hours and an oral bioavailability of >90%.

In an AML xenograft mouse model, both SNS-229 and SNS-510 show dose-related efficacy with >95% tumor growth inhibition and partial regression (>50% tumor shrinkage) in 70% and 100% of animals at the highest dose after 21-day dosing. These studies show that targeting the inactive conformation of PDK1 leads to potent and sustained pathway inhibition resulting in strong tumor growth inhibition and regression.

(Filing, 10-Q, Bellicum Pharmaceuticals, NOV 9, 2015, View Source [SID:1234508147])

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(Filing, 10-Q, Portola Pharmaceuticals, NOV 9, 2015, View Source [SID:1234508173])

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On November 9, 2015 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, reported financial results for the third quarter ended September 30, 2015, and also provided an overview of certain corporate developments (Press release, Verastem, NOV 9, 2015, View Source;p=RssLanding&cat=news&id=2110303 [SID:1234508120]).

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"Our mission is to improve survival and the quality of life for patients battling cancer through the combination of our cancer stem cell-targeting agents with current and emerging standard of care treatments," said Robert Forrester, President and Chief Executive Officer of Verastem. "We are supported by a strong balance sheet, three clinical compounds and a team of talented and dedicated professionals. We continue to believe in our pipeline candidates and are focused on executing their clinical development."
Mr. Forrester continued: "We are working with thought-leading researchers on innovative anti-cancer applications for our compounds. For example, researchers from the University of Edinburgh recently published a ground-breaking paper in "Cell" which highlights the potential of focal adhesion kinase (FAK) inhibition to enable the body’s immune system to better fight cancer. While this is early stage data, it provides support for the thesis that FAK inhibitors may be useful in combination with immuno-oncology agents with the goal of yielding more durable responses for a greater number of cancer patients."

Recent Developments
Stopped Enrollment in the COMMAND Study Evaluating VS-6063 in Mesothelioma Due to Futility – In September 2015, Verastem announced its decision to stop enrollment in the Phase 2 registration-directed, double-blind, placebo-controlled study (COMMAND) of VS-6063 for patients with mesothelioma. The decision to stop enrollment followed a Data Safety Monitoring Board (DSMB) review of a pre-planned interim analysis. The results of the analysis demonstrated that VS-6063 had a generally well tolerated safety profile but that there was not a sufficient level of efficacy to warrant continuation of the study.

New Research Published in the Journal "Cell" Highlighting the Potential of FAK Inhibition to Enhance the Efficacy of Anti-Tumor Immunotherapy – In September 2015, Verastem announced that researchers from the University of Edinburgh published a study in the journal "Cell" which discusses results from preclinical research showing that focal adhesion kinase (FAK), a protein which is often overproduced in tumors, enables cancer cells to evade attack by the body’s immune system. In this study, researchers discovered that FAK inhibition can favorably modulate the balance of immune cells in the tumor, inducing immune-mediated tumor elimination in preclinical models.

Presented Data on VS-6063, VS-4718 and VS-5584 at Key Oncology-Focused Medical Meetings – In November 2015, Verastem presented a total of six posters at the 2015 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) and the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 30th Anniversary Annual Meeting. The presented data described the results of preclinical research showing that FAK inhibitors may enhance the effects of anti-cancer immunotherapy for both typically responsive and non-responsive tumors.

During the third quarter, Verastem also gave several oral and poster presentations at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper)/18th European Cancer Congress (ECC) and at the 16th World Conference on Lung Cancer (WCLC) describing clinical and preclinical data relating to its pipeline product candidates.

All of the posters and presentations can be found on the Presentations page of Verastem’s website.

Third Quarter 2015 Financial Results
As of September 30, 2015, Verastem had cash, cash equivalents and investments of $120.5 million compared to $92.7 million as of December 31, 2014. Verastem used $11.6 million for operating activities in the third quarter ended September 30, 2015 (the "2015 Quarter").

Net loss for the 2015 Quarter was $15.4 million, or $0.42 per share, as compared to a net loss of $13.3 million, or $0.52 per share, for the same period in 2014 (the "2014 Quarter"). Net loss includes stock-based compensation expense of $2.1 million and $2.8 million for the 2015 Quarter and 2014 Quarter, respectively.

Research and development expense for the 2015 Quarter was $11.3 million compared to $9.0 million for the 2014 Quarter. The $2.3 million increase from the 2014 Quarter to the 2015 Quarter was primarily related to an increase of $2.3 million in contract research organization expense for outsourced biology, chemistry, development and clinical services, which includes our clinical trial costs, an increase in consulting fees of approximately $299,000, an increase in personnel related costs of approximately $115,000 due to increased headcount and salaries, and an increase of approximately $102,000 in lab supplies due to increased research activity. These increases were partially offset by a decrease of approximately $537,000 in stock-based compensation.

General and administrative expense. General and administrative expense for the 2015 Quarter was $4.2 million compared to $4.3 million for the 2014 Quarter. The decrease of approximately $100,000 from the 2014 Quarter to the 2015 Quarter primarily resulted from a decrease in professional fees of approximately $249,000, primarily related to lower IP and general legal costs, and a decrease in stock-based compensation expense of approximately $245,000. These decreases were partially offset by increases in personnel related costs of approximately $247,000, primarily due to an increase in headcount and salaries, and in consulting fees of approximately $164,000.

The number of outstanding common shares as of September 30, 2015, was 36,934,804.

Financial Guidance
We expect our existing cash, cash equivalents and investments will enable us to fund our current operating plan and capital expenditure requirements at least through the first half of 2017.

About VS-6063
VS-6063 (defactinib) is an orally available compound designed to target cancer stem cells through the potent inhibition of focal adhesion kinase (FAK). Cancer stem cells are an underlying cause of tumor resistance to chemotherapy, recurrence and ultimate disease progression. Research has demonstrated that FAK activity is critical for the growth and survival of cancer stem cells. VS-6063 is currently being studied in the "Window of Opportunity" study in patients with mesothelioma prior to surgery, a Phase 1/1b study in combination with paclitaxel in patients with ovarian cancer, a trial in patients with KRAS-mutated non-small cell lung cancer and a trial evaluating the combination of VS-6063 and VS-5584 in patients with relapsed mesothelioma.

About VS-4718
VS-4718 is an orally available compound designed to target cancer stem cells through the potent inhibition of focal adhesion kinase (FAK). VS-4718 is currently being studied in a Phase 1 dose escalation study in patients with advanced cancers.

About VS-5584
VS-5584 is an orally available compound that has demonstrated potent and highly selective activity against class 1 PI3K enzymes and dual inhibitory actions against mTORC1 and mTORC2. In preclinical studies, VS-5584 has been shown to reduce the percentage of cancer stem cells and induce tumor regression in chemotherapy-resistant models. Verastem is currently conducting a dose escalation trial of VS-5584 in patients with advanced solid tumors as a single agent and a combination trial of VS-5584 and VS-6063 in patients with relapsed mesothelioma. VS-5584 has been granted orphan drug designation for use in mesothelioma in the U.S. and EU.