On November 3, 2016 BioLineRx Ltd. (NASDAQ/TASE: BLRX), a clinical-stage biopharmaceutical company dedicated to identifying, in-licensing and developing promising therapeutic candidates, reported positive Phase 2a correlative data, as well as detailed mechanism-of-action data, for BL-8040, the Company’s leading oncology platform, that will be presented at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exhibition in San Diego, California, taking place December 3-6, 2016. Schedule your 30 min Free 1stOncology Demo! In a poster titled, "The Selective Anti Leukemic Effect of BL-8040, a Peptidic CXCR4 Antagonist, is Mediated by Induction of Leukemic Blast Mobilization, Differentiation and Apoptosis: Results of Correlative Studies from a Ph2a Trial in Acute Myeloid Leukemia", BioLineRx reports the final correlative results from its Phase 2a trial in acute myeloid leukemia (AML). The trial consisted of 45 AML patients receiving BL-8040 monotherapy on days 1-2, followed by the same dose of BL-8040 plus chemotherapy (Cytarabine) on days 3-7. All patients had poor-risk disease and had been heavily pretreated, with 19% having relapsed after a short first remission (≤12 months), 17% having 2 or more relapses, while 45% were refractory to 1-2 induction treatments.
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As previously reported, the composite complete remission rate, including both complete remission (CR) and complete remission with incomplete blood count recovery (CRi), was 38% in subjects receiving BL-8040 dose ≥1.0 mg/kg (n=39). In the 1.5 mg/kg dose selected for the expansion phase of the study (n=22), the composite complete remission rate was 41%. These response rates are superior to the historical response rate of approximately 20% reported for high-risk AML patients treated with Cytarabine alone. The ongoing follow-up of responding patients (n=19) showed median Event Free Survival of 9.3 months (range of 4.3-12.8 months).
Results further show that BL-8040 monotherapy had a substantial therapeutic effect. Treatment with BL-8040 as a single agent triggered robust mobilization of AML blasts from the bone marrow to the peripheral blood stream, and the extent of mobilization was correlated with a positive response to treatment. The preferential mobilization of AML blasts over normal cells (4.7-fold vs. 1.4-fold, respectively) was further confirmed by FISH analysis in a subset of patients. In addition, BL-8040 monotherapy resulted in a 40% increase in AML blast apoptosis.
In an oral presentation at ASH (Free ASH Whitepaper), entitled "The High Affinity CXCR4 Inhibitor, BL-8040, Induces Apoptosis of AML Blasts and their Terminal Differentiation by Blocking AKT/ERK Survival Signals and Downregulating BCL-2, MCL-1 and Cyclin-D1 through Regulation of miR-15a/16-1 Expression", delivered by Prof. Amnon Peled from the Hadassah Medical Center and Biokine Therapeutics, BioLineRx reports detailed data on the mechanism-of-action by which BL-8040 directly induces apoptosis of AML cells. The data presented are from in vitro studies using human AML cell lines and human primary AML samples, as well as in vivo studies using human primary AML cells engrafted in NOD scid gamma (NSG) mice.
The results of the pre-clinical studies show that BL-8040 treatment in vivo triggered mobilization of AML blasts from their protective bone marrow microenvironment and induced their terminal differentiation, further supporting the data presented by BioLineRx at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual conference earlier this year.
In addition, the studies illustrate how BL-8040 increases the expression and activity of a special class of microRNA precursors termed miR-15a/16-1. These microRNA molecules have been previously linked to cancer, and shown to suppress the activity of several tumor-related pro-survival proteins. Therefore, by increasing the expression of miR-15a/16-1 microRNA molecules, BL-8040 decreases the expression of tumor-survival proteins and promotes tumor cell death. Importantly, in both in vitro and in vivo experiments, BL-8040 was found to synergize with a selective Bcl-2 inhibitor (Venetoclax) and an FLT3 inhibitor (Quizartinib, also known as AC220) in inducing AML cell death, pointing at potential drug combination treatments.
Philip Serlin, CEO of BioLineRx, commented, "We are pleased to be presenting additional positive results about BL-8040, our lead oncology platform. In particular, clinical studies show that BL-8040 acts selectively on chemotherapy-resistant cells, which may be beneficial in reduction of residual disease and supports the incorporation of BL-8040 in front-line treatment settings such as AML consolidation. Such studies are currently ongoing. We are also encouraged to see, in pre-clinical models, a synergistic effect between BL-8040 and Venetoclax, and between BL-8040 and Quizartinib, drugs which are also being investigated as AML treatments. Given the high percentage of patients experiencing a relapse or that are refractory to available treatments, we anticipate that BL-8040, in combination with a growing repertoire of drugs, will be able to offer hope to AML patients around the world."
About BL-8040
BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and certain hematological indications. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells from the bone marrow, thereby sensitizing these cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing apoptosis. In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, and T, B and NK cells. Furthermore, scientific findings in the field of immuno-oncology suggest that CXCR4 antagonists may be effective in inducing the infiltration of anti-tumor T cells into the tumor. Therefore, when combined with immune checkpoint inhibitors, BL-8040 has the potential to enable activated T cells to better reach tumor cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.
Author: [email protected]
http://www.medivir.com/investors/press-releases/2016/medivir-strengthens-its-clinical-pipeline-by-entering-into-agreement-to-acquire-a-portfolio-of-clinical-stage-oncology-programs
November 2, 2016 Medivir AB (Nasdaq Stockholm: MVIR) reported that it has entered into an agreement to acquire two clinical stage oncology programs from Tetralogic Pharmaceuticals Corporation (Nasdaq: TLOG), advancing and expanding its clinical pipeline (Press release, Medivir, NOV 2, 2016, View Source [SID1234528400]). The acquisition includes remetinostat, a skin-directed HDAC inhibitor, and birinapant, a bivalent SMAC mimetic, and all intellectual property and data associated with Tetralogic’s HDAC inhibitor and SMAC mimetic projects.
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Remetinostat Clinical Program
Remetinostat is a topical, skin-directed inhibitor of histone deacetylases (HDACs) and has a strong link to Medivir´s existing expertise in protease inhibition. The compound was designed to effectively inhibit HDACs within cutaneous lesions, but to be rapidly broken down in the bloodstream, preventing the side effects associated with systemically administered HDAC inhibitors.
Remetinostat is currently in a late phase II program aimed to treat early stage cutaneous T-cell lymphoma (CTCL), a chronic, orphan hematologic cancer that presents in the skin. There are few drugs available for the treatment of the disease, and those currently available have generally poor tolerability. As a result, patients are in need of safe and effective new treatment options which remetinostat may represent. The estimated addressable market for early-stage CTCL in the US alone is approximately USD 900m annually.
Medivir currently plans to start a phase III trial with remetinostat in the second half of 2017.
Birinapant Clinical Program
Birinapant is a bivalent, second mitochondrial activator of caspases (SMAC) mimetic that binds cellular inhibitor of apoptosis proteins (cIAPs) and induces their degradation. cIAPs are part of the ubiquitin proteasome system, and birinapant therefore ties in well to Medivir’s existing interests in modulators of protein ubiquitination. Medivir currently plans to start two different clinical studies with birinapant:
A phase I study in combination with KeytrudaTM(pembrolizumab), a PD-1 inhibitor from Merck & Co., Inc. (MSD outside of the US and Canada, "MSD"), in patients with solid tumours, subject to transfer to Medivir of the clinical trial agreement between Tetralogic and MSD and receipt of KeytrudaTMsupply. Preclinical studies have shown that SMAC mimetics such as birinapant are able to enhance the response of T-cells to tumour antigens, and the objective of the planned phase I study is to investigate the safety of the combination and the potential of birinapant to enhance response rates seen with KeytrudaTMalone. PD-1 inhibitors such as KeytrudaTMare immuno-oncology products that have substantially improved treatment outcomes for patients with solid tumours. Revenues of PD-1 inhibitors as reported by MSD and Bristol-Myers Squibb in the last twelve months have totalled approximately USD 3.2b. The PD-1 inhibitor market is expected to continue to grow from increasing use and expansion of the number of indications for which they are approved.
A phase II program, to investigate birinapant in combination with platinum-based chemotherapy for the treatment for high-grade serous carcinomas (HGSCs), including ovarian cancer, in collaboration with clinical investigators at UCLA. The UCLA team have identified that platinum-resistant cells in HGSCs are highly susceptible to birinapant-platinum co-therapy in approximately half of patients, and have developed a bioassay to enable patient selection. High-grade serous carcinomas are tumours that are believed to be derived from cells in the fallopian tube and can present as ovarian, endometrial, tubal or peritoneal cancer. The majority of ovarian cancer cases are high-grade serous carcinomas and these patients have a very poor survival rate. The ovarian cancer market size overall is estimated to be USD 840m, with those patients resistant to platinum treatments representing the group with highest unmet need.
Financial Consideration and Third-Party Arrangements
The acquisition has been structured to provide an upfront cash payment, but with the majority of financial consideration tied to successful clinical development, regulatory approvals and sales milestones. Medivir will also assume agreements or certain obligations with other third parties, including the MSD agreement regarding KeytrudaTM, subject to confirmation from MSD.
The acquisition includes the following potential payments to Tetralogic and other third party licensees:
Upfront cash consideration of USD 12m;
Remetinostat development milestones through regulatory filings of up to USD 20m;
Remetinostat regulatory approval milestones of up to USD 45m;
Remetinostat tiered royalties capped at an aggregate of 13%;
Additional remetinostat commercialization milestones of up to USD 31m, primarily based on substantial sales achievement levels;
Birinapant development milestones and research support of up to USD 20m;
Birinapant tiered royalties capped at an aggregate of 10%; and
Additional birinapant commercialization milestones of up to USD 110m, primarily based on substantial sales achievement levels.
Strategic Overview
"This is a transformative transaction for Medivir and an important part of our strategy to expand our pipeline with programs in later stage clinical phases, shifting the balance from research to clinical development. The acquisition enables Medivir to build critical mass in development and secures visible value generation, with expected near-term and continuous news flow from multiple studies. These assets are complementary to our oncology efforts in early phases. Both programs have an excellent fit with the Medivir scientific platforms and we are uniquely positioned to recognize the value of both of Tetralogic’s clinical assets." says Niklas Prager, CEO & President of Medivir.
Richard Bethell, CSO of Medivir continues, "We are excited to have acquired these two projects, both of which have the potential to meaningfully advance the care of cancer patients. Medivir has a track record of discovering and developing drugs that are targeted to specific tissues, so we are well placed to rapidly progress remetinostat for the treatment of early-stage CTCL. Many patients with this disease are urgently in need of new treatments that are both safe and effective. We also believe that birinapant, through its effects on both immune and tumour cells, offers the potential to improve the treatment of a number of different cancers. We look forward to rapidly advancing both of these agents into the next round of clinical studies."
Closing Conditions
The transaction is subject to confirmation by MSD of agreement transfer to Medivir, the consent of the Tetralogic Senior Noteholders, approval of the Tetralogic shareholders and other customary closing conditions. Medivir expects the transaction to close by year end 2016.
10-Q – Quarterly report [Sections 13 or 15(d)]
Aduro Biotech has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 10-Q, Aduro BioTech, NOV 2, 2016, View Source [SID1234516172]).
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Anti-tumor cell therapies, signed an agreement with Bellicum Pharmaceutical
On November 2, 2016 Bellicum Pharmaceuticals and Hospital Bambino Gesù , the European reference point for the care and in pediatric research, announced the beginning of an extended collaboration centered on the development of new therapies with genetically modified cells for treating onco-hematological diseases (Press release, OPBG, NOV 2, 2016, View Source [SID1234516577]).
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In detail, the arrangement concerns the preclinical and clinical development of products advanced cell therapy engineered with the suicide gene new CaspaCIDe of Bellicum, for the production of lymphocytes through modified chimeric and T-lymphocyte receptors artificial receptor (CAR T and TCR) specific for certain antigens , including CD19.
The two entities will jointly develop T cells modified with chimeric receptors (CAR T) and other cellular therapies developed by the Child Jesus and engineered with the safety switch CaspaCIDe of Bellicum, designed to reduce or eliminate the cells, when necessary, that is, presence of possible side effects related to the same cells.
Under the agreement, Bellicum will provide the necessary financial support in exchange for worldwide commercialization rights to certain developed cell therapies, while the Baby Jesus will keep the rights for the purpose of ricerc a. The Hospital of the Holy See will perform clinical research and studies for the application of advanced cell therapies in pediatric patients, initially through two clinical trials based on the use of genetically modified lymphocytes with specific chimeric receptors and CD19 antigens GD2 , respectively, in patients pediatric suffering from acute lymphoblastic leukemia, and neuroblastoma.
The trial will begin in the first half of 2017 . In addition, the Baby Jesus will produce, within its pharmaceutical plant, genetically modified cells necessary for European experiments , including T lymphocytes transduced with PRAME (Preferentially Expressed Protein in Melanoma) and employable in patients with acute myeloid leukemia or bone cancer.
Xencor Reports Third Quarter 2016 Financial Results
On November 2, 2016 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of autoimmune diseases, asthma and allergic diseases and cancer, reported financial results for the third quarter ended September 30, 2016 and provided a review of pipeline and corporate highlights (Filing, Q3, Xencor, 2016, NOV 2, 2016, View Source [SID1234516344]).
"During the third quarter, we initiated clinical trials across our internal pipeline of XmAb programs, including Phase 1 studies of subcutaneously administered XmAb5871 and XmAb7195, and a first-in-human Phase 1 study of our lead immuno-oncology bispecific antibody candidate, XmAb14045," said Bassil Dahiyat, Ph.D., president and chief executive officer of Xencor. "With these milestones complete and a strong cash position, we expect to report data from multiple clinical trials in the year ahead, while also initiating studies of additional bispecific oncology candidates and continuing to explore the breadth of our Fc engineering technology."
Pipeline Highlights:
XmAb5871: XmAb5871 is a first-in-class monoclonal antibody that targets CD19 with its variable domain and that uses Xencor’s XmAb immune inhibitor Fc domain to target FcγRIIb, a receptor that inhibits B-cell function. In March 2016, Xencor initiated Phase 2 clinical studies of XmAb5871 for the treatment of IgG4-Related Disease (IgG4-RD) and systemic lupus erythematosus (SLE), and in July 2016, Xencor initiated a Phase 1 trial of subcutaneously administered XmAb5871.
· Preliminary data from IgG4-RD Phase 2 trial to be presented at the American College of Rheumatology (ACR) 2016 Annual Meeting on November 13, 2016 in Washington, DC; additional data expected in 2017
· Initial data from subcutaneous administration trial expected in 2017
· Initial data from SLE Phase 2 trial expected in 2018
XmAb7195: XmAb7195 is a first-in-class monoclonal antibody that targets IgE with its variable domain and uses Xencor’s XmAb Immune Inhibitor Fc domain to target FcγRIIb, resulting in three distinct mechanisms of action for reducing IgE levels. In September 2016, Xencor initiated a Phase 1b multi-dose trial of subcutaneously administered XmAb7195 for the treatment of allergic disease.
· Initial data from subcutaneous administration Phase 1b trial expected in 1H17
Bispecific Oncology Pipeline: Xencor’s initial bispecific antibody programs are tumor-targeted antibodies that contain both a tumor antigen binding domain and a cytotoxic T-cell binding domain. These bispecific antibodies activate T cells for highly potent and targeted killing of malignant cells. Their XmAb Fc domains confer long circulating half-lives, stability and ease of manufacture. In September 2016, Xencor initiated a Phase 1 trial of XmAb14045 in acute myeloid leukemia (AML) and other CD123-expressing hematologic malignancies.
· Initial data from XmAb14045 Phase 1 trial expected in 2017
· Initiation of Phase 1 trial for XmAb13676 in B-cell malignancies expected in 1Q17; initial data expected in 2018
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· Investigational New Drug (IND) application filing for XmAb18087 in neuroendocrine tumors expected in 2017
· IND application filing for XmAb20717, a PD-1 x CTLA-4 dual checkpoint inhibitor, in multiple oncology indications expected in 2018
Partnered XmAb Programs: Nine pharmaceutical companies and the National Institutes of Health (NIH) are advancing novel drug candidates either discovered at Xencor or that rely on Xencor’s proprietary XmAb technology. Seven such programs are currently undergoing clinical testing.
· In September, MorphoSys announced that it began dosing in the safety evaluation portion of a Phase 2/3 combination trial of XmAb5574/MOR208 with bendamustine in patients with relapsed or refractory diffuse large B-cell lymphoma (B-MIND trial). Following the Phase 2 safety evaluation, the study is expected to transition into a pivotal Phase 3 part in 2017.
Third Quarter Ended September 30, 2016 Financial Results
Cash, cash equivalents and marketable securities totaled $301.9 million as of September 30, 2016, compared to $193.3 million on December 31, 2015. The increase reflects the $150 million upfront payment received from Novartis in July 2016, net of spending for the nine months ended September 30, 2016.
Revenues for the third quarter ended September 30, 2016 were $7.8 million compared to $3.5 million for the same period of 2015. Revenues for the nine months ended September 30, 2016 were $81.1 million, compared to $6.0 million for the same period in 2015. Revenues in the three and nine-month period ended September 30, 2016 were earned primarily from the Company’s Novartis and Amgen collaborations, compared to revenues for the same period in 2015, which were earned primarily from the Company’s Novo Nordisk, Alexion and CSL collaborations.
Research and development expenditures for the third quarter ended September 30, 2016 were $14.1 million, compared to $10.6 million for the same period in 2015. Total research and development expenses for the nine-month period ended September 30, 2016 were $38.5 million, compared to $23.3 million for the same period in 2015. The increased spending on research and development for the three and nine months ended September 30, 2016 is primarily due to additional spending on Xencor’s XmAb5871 clinical programs and bispecific technologies, including its initial bispecific oncology clinical candidates, XmAb14045 and XmAb13676.
General and administrative expenses in the third quarter ended September 30, 2016 were $3.0 million compared to $3.2 million for the same period in 2015. Total general and administrative expenses for the first nine months of 2016 were $10.0 million, compared to $8.5 million in the first nine months of 2015. Decreased spending on the general and administration areas for the three months ended September 30, 2016 over the same period in 2015 is due to lower stock-based compensation charges in the quarter, while the increased spending for the nine months ended September 30, 2016 over the same period in 2015 reflects additional legal and accounting fees for compliance related activities and additional stock-based compensation charges.
Non-cash, share-based compensation expense for the first nine months of 2016 was $5.9 million compared to $3.4 million for the first nine months of 2015.
Net loss for the third quarter ended September 30, 2016 was $8.1 million, or $(0.20) on a fully diluted per share basis, compared to a net loss of $10.0 million, or $(0.25) on a fully diluted per share basis, for the same period in 2015. For the nine months ended September 30, 2016, net income was $32.7 million or $0.78 on a fully diluted per share basis, compared to net loss of $25.3 million, or $(0.66) on a fully diluted per share basis, for the same period in 2015. The lower loss for the three months ended September 30, 2016 over the loss reported for the same period in 2015 is primarily due to revenue earned from the Company’s Amgen collaboration, while the income earned for the nine months ended September 30, 2016 over the same period in 2015 is primarily due to revenue earned from the Company’s Novartis collaboration.
The total shares outstanding was 41,138,851 as of September 30, 2016, compared to 40,477,003 shares outstanding as of September 30, 2015.
Financial Guidance
Based on current operating plans, Xencor expects to have cash to fund research and development programs and operations beyond the end of 2019.