On April 20, 2016 Kuros Biosciences Ltd. ("Kuros" or the "Company"), reported that Checkmate Pharmaceuticals Inc., Cambridge, MA, USA ("Checkmate") has dosed its first first melanoma patient in a Phase 1b clinical trial with CMP-001, formerly known as CYT003 (Press release, Kuros Biosciences, APR 20, 2016, View Source [SID1234516801]). The trial is designed as a multi-center, open-label study of CMP-001 in combination with pembrolizumab for patients with advanced melanoma who have either progressed on anti-PD1 therapy or have failed to respond to at least 12 weeks of therapy.

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In August 2015, Checkmate acquired exclusive access to Cytos’ clinically validated product candidate CYT003 as well as its VLP platform and to technology related to oligonucleotide synthesis for multiple products in the field of oncology. As a result of the first dosing of a patient with this licensed product candidate, Kuros will receive a milestone payment of USD 1 million from Checkmate. In this collaboration Kuros may receive up to USD 90 million in development milestones and may receive up to double-digit royalties on net sales from successfully developed products.

Didier Cowling, Chief Executive Officer of Kuros, commented: "We are very pleased that Checkmate has already advanced CMP-001 into a phase 1b clinical trial. Reaching this milestone only 10 months after signing the license agreement is a significant achievement. We wish to congratulate Checkmate on its progress and are eager to see how intra-tumoral therapy with CPM-001 will perform in combination with pembrolizumab in patients with advanced melanoma. "

For further information, please contact:

Kuros Biosciences Ltd

Harry Welten, MBA

Chief Financial Officer

Tel: +41 44 733 46 46

[email protected]

Developing effective vaccines against Ebola virus is a global priority.
To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo).
Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015.
Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 1010 viral particles) or MVA-BN-Filo (1 × 108 median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later.
The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations.
Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses.
In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies.
clinicaltrials.gov Identifier: NCT02313077.

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Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.

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On April 20, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that its drug candidate neratinib was highlighted in three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Puma Biotechnology, APR 20, 2016, View Source [SID:1234511151]). The AACR (Free AACR Whitepaper) Annual Meeting was held at the Ernest N. Morial Convention Center in New Orleans from April 16 to April 20.

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Abstract Number 298: Amplification of mutant ERBB2 drives resistance to the irreversible kinase inhibitor neratinib in ERBB2-mutated breast cancer patients.

On Sunday April 17th, preclinical data was presented from studies performed to identify possible mechanisms of acquired resistance to neratinib therapy in ERBB2-mutated breast cancers. Data from three breast cancer patients in the ongoing phase II SUMMIT basket study of neratinib in ERBB2-mutant cancers who progressed following initial benefit from neratinib treatment identified a common genomic alteration in their tumors. More specifically, targeted exome sequencing of biopsies collected at time of disease progression revealed increased copy number of the ERBB2-mutant allele. In addition, enhanced receptor activity in the ERBB2-mutant cells correlated with increased formation of ERBB2/ERBB3 dimers, activation of the PI3K/AKT pathway and in vivo tumorigenic potential. Combined ERBB2 and ERBB3 inhibition efficiently inhibited phosphorylation of ERBB2/ERBB3 and cell proliferation. These studies indicate that amplification of mutated ERBB2 may promote increased ERBB2/ERBB3 dimerization, ERBB3 activation, and subsequent downstream signaling activation and that dual ERBB2/ERBB3 blockade may be a potential strategy to delay or prevent resistance to neratinib in ERBB2-mutant breast tumors.

Abstract Number 3140: Differential clonal selection in tumor tissue and cell-free DNA from a neratinib-treated refractory breast cancer patient harboring an activating ERBB2 (HER2) mutation.

On Tuesday April 19th, data was presented from a patient who was part of the ongoing Copenhagen Prospective Personalized Oncology (CoPPO) research program. This program aims to offer patients with limited treatment options targeted treatments against actionable driver mutations that have been identified in circulating cell free DNA in patients by using whole exome sequencing. The poster presented data from a patient with metastatic HER2-negative and estrogen receptor (ER)-positive breast cancer (Luminal A) who had previously been exposed to seven lines of chemotherapy as well as ER antagonists and aromatase inhibitors. After examination by whole exome sequencing, an activating mutation in ERBB2 (S310Y) was found and consequently the patient was treated with neratinib through a compassionate use program. Neratinib caused a rapid decrease in the allelic frequency of ERBB2 (S310Y) cell free DNA after 2 days, with a continuous decline during the next 7 days. Consistent with this neratinib treatment effect, MRI scans showed regression of the liver metastases. After 5 months on neratinib, the patient progressed with the appearance of brain metastases, which were surgically removed and subject to whole exome sequencing. The ERBB2 mutation observed in the liver metastasis could not be identified in the brain metastases. However, more than 300 new variants were exclusively identified in the brain metastases, among these ERBB3 as well as new PIK3CA, and ESR1 mutations, that were not present in the pre-treatment cell free DNA samples. In conclusion, neratinib was able to suppress an activating ERBB2 mutation in a heavily pre-treated ER+ breast cancer patient. However, refractory tumor clones harboring ERBB3, PIK3CA and ESR1 mutations developed in brain. The poster indicated that combining neratinib with fulvestrant or inhibitors of the HER3/PI3K/AKT/mTOR pathway might prove beneficial to overcome potential resistance mechanisms to therapy.

Abstract Number 4760: Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations.

On Wednesday April 20th, preclinical studies to better understand effects of HER2 mutations were presented. Patient-derived xenograft (PDX) tumor models representing colorectal, ovary, pancreas and endometrial cancers were evaluated in vivo, testing the antitumor activity of neratinib, afatinib, lapatinib, trastuzumab and T-DM1 administered on standard treatment regimens. In vivo treatment with neratinib or afatinib resulted in tumor growth inhibition in some tested models including ST022 (HER2G366R/R678Q) ovary and ST204 (HER2A386D) pancreas and tumor regressions were reported with either agent in the ST427 (HER2V777L) colorectal line. Neratinib or afatinib were also found active in one each of four tested endometrial models. Lapatinib, trastuzumab and T-DM1 were inactive in all tested HER2-mutant models.

The abstracts of the three presentations described above are available online at: View Source;DetailItemID=363#.Vusrr-IrKUk.

On April 20, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported, in partnership with its collaborators, early clinical data from two oral presentations for two product candidates at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana (Press release, Juno, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158810 [SID:1234511172]).

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JCAR018 is a chimeric antigen receptor (CAR) T cell product candidate targeting CD22, and had data from a Phase I trial in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r ALL). JTCR016, a T cell receptor (TCR) cell product candidate targeting Wilms tumor-1 (WT-1), had data from a Phase I trial in patients with acute myelogenous leukemia (AML) at high risk of relapse following an allogeneic hematopoietic stem cell transplant and patients with either mesothelioma or non-small cell lung cancer.

"As we advance our CD19-directed portfolio, we are encouraged by the early signs of clinical activity from product candidates against different targets," said Mark J. Gilbert, M.D., Juno’s Chief Medical Officer. "The data from JCAR018 suggest two paths to improve outcomes – use in patients with CD19 negative disease and a combination of CD19 and CD22 to decrease the risk of resistant cells and increase the percentage of patients that demonstrate a long-term durable remission in B cell malignancies. Additionally, JTCR016 continues to show an encouraging safety profile and signals of clinical activity, including evidence of tumor reduction as well as significant T cell expansion and persistence in a patient with mesothelioma."

In an oral presentation on Monday, April 18, 2016, Terry J. Fry, M.D., Investigator, Pediatric Oncology Branch and Head of Hematologic Malignancies Section, National Cancer Institute, National Institutes of Health, presented "CD22 CAR Update and Novel Mechanisms of Leukemic Resistance." Dr. Fry reported on CD22-directed CAR T cell therapy (JCAR018) in pediatric and young adult patients with r/r B-cell ALL. Key takeaways include:

Data from nine enrolled and treated patients were reported in this Phase I dose-escalation trial. (JCAR018; Clinical Trials Identifier: NCT02315612).

As previously reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in December 2015, six patients were treated at the lowest dose, with one patient achieving a complete remission (CR) and complete molecular remission as measured by flow cytometry (CmR). This patient relapsed after three months.

Three patients have enrolled at dose level 2 (1 x 106 cells/kg), which is in the dose range of CD19-directed CAR T programs. All three patients achieved a CR and CmR. These patients remain in complete remission with follow-up ranging from 3 to 6 months.
The complete remissions have been seen in both patients naïve to CAR T therapies as well as those with CD19 negative relapse after prior CD19-directed CAR T therapy.

Limited cytokine release syndrome (CRS) was seen at dose level 2, with two patients at Grade 1 and one patient at Grade 2. No severe neurotoxicity was observed in these treatment cohorts. Dose limiting toxicity was observed at higher doses, so dosing continues at dose level 2 (1 x 106 cells/kg).

In an oral presentation on Wednesday, April 20, 2016, Phil Greenberg, M.D., Head of Program in Immunology at the Fred Hutchinson Cancer Research Center and Professor, Medicine/Oncology and Immunology, University of Washington, presented "Targeting Cancer with Engineered T Cells." Dr. Greenberg reported on WT-1 TCR cell therapy (JTCR016) in refractory mesothelioma and AML. Key takeaways include:

In a Phase I/II study designed to evaluate genetically modified T cells targeting WT-1 in WT-1-expressing non-small cell lung cancer (NSCLC) and mesothelioma using a WT-1-specific T-cell receptor, WT-1 TCR (JTCR016; Clinical Trials Identifier: NCT02408016), there have been five patients enrolled.

Three patients have been treated to date. Preliminary data show one mesothelioma patient with an ongoing partial response to the WT-1 TCR and one with stable disease. The responses appear to correlate with the pharmacokinetics of the engineered T cells, as the patient with the partial response had the best T cell expansion and persistence. The patient had progressed after multiple therapies, including chemotherapy and radiation, prior to receiving JTCR016.

JTCR016 was generally well-tolerated in these three patients, with no evidence of severe CRS or severe neurotoxicity.
In a Phase I dose-escalation trial in patients with AML following allogeneic hematopoietic stem cell transplantation, 11 patients with no measurable disease but at high risk of relapse have been treated to date. JTCR016 continues to be relatively well-tolerated with prolonged persistence of the engineered T cells and no relapses to date.

This AACR (Free AACR Whitepaper) 2016 Major Symposium presentation also highlighted encouraging pre-clinical data from a mesothelin-directed TCR for the treatment of pancreatic cancer, demonstrating the potential of these therapies in treating solid tumors, and next-generation strategies to make these T cells more potent.

About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s CAR and TCR technologies genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell. JCAR018 and JTCR016 are investigational product candidates and their safety and efficacy have not been established.