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Resminostat enhances immune cell cancer cell interaction

On 30 May 2017 4SC AG (4SC, FSE Prime Standard: VSC) reported new preclinical data that demonstrates that resminostat influences the anti-cancer response of natural killer (NK) cells – a subset of our body’s own immune cells (Press release, 4SC, MAY 30, 2017, View Source [SID1234519317]). Resminostat increases the sensitivity of cancer cells to killing by NK cells and enhances the killing activity of NK cells towards cancer cells.

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Roland Baumgartner, Ph.D., Chief Scientific Officer of 4SC, explained the scientific details: "In earlier experiments we established that resminostat increased the sensitivity of cancer cells to NK cell-mediated killing. The addition of resminostat to numerous cancer cell lines induced expression of molecules such as NKG2D ligands – molecules that are specifically recognized by NK cells. In contrast to competing histone deacetylase (HDAC) inhibitors, which negatively affect the viability of NK cells, resminostat increased the proportion of NK cells in the tumor microenvironment.

We now demonstrated that treatment with resminostat enhanced the activity of NK cells. The addition of resminostat to either mixed blood cells or isolated NK cells resulted in strong activation of NK cells – measured by expression of the activation marker CD69. Furthermore, blood cells which were pre-treated with resminostat killed tumor cells more efficaciously than non-treated blood cells."

Jason Loveridge, Ph.D., Chief Executive Officer of 4SC, added: "These new preclinical data add another piece to our understanding of how resminostat affects the interplay between our body’s own immune system and cancer. These new insights are highly valuable and support our clinical development plans to advance resminostat to market authorization."

Oral presentation at the Cancer Immunotherapy and Combinations Congress

Svetlana Hamm, Ph.D., Head of Translational Pharmacology of 4SC, will present the scientific details at the Cancer Immunotherapy and Combinations Congress, as part of the World Preclinical Congress.
Presentation Epigenetic priming with HDAC inhibitor resminostat sensitizes cancer to NK cell based immunotherapy
Time Tuesday, 13 June 2017, 4:05 p.m. EDT
Location Westin Boston Waterfront, Boston, USA
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3 May 2017, Progress update on pivotal RESMAIN study of resminostat in CTCL at 13th Congress of the EADO

24 January 2017, Overall survival benefit for resminostat in first-line liver cancer study subgroup
Further information

Molecular Partners provides additional details on clinical studies of proprietary lead oncology asset MP0250

On May 30, 2017 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies, reported that the first patient was dosed in the phase 2 multiple myeloma study of its lead oncology asset MP0250 (Press release, Molecular Partners, MAY 30, 2017, View Source [SID1234519316]). In the first phase 2 study, the efficacy and safety of MP0250 will be examined in combination with bortezomib (Velcade) and dexamethasone in patients with multiple myeloma who have failed standard therapies. The study will be performed in three different countries: Germany, Poland and Italy. Initial safety data are expected in 2017 and efficacy data in 2018.

In addition, the company announced that MP0250 will also be further evaluated in solid tumors. Molecular Partners intends submit to the FDA in H2 2017 an Investigational New Drug Application (IND) for a phase 1b/2 trial of MP0250 in combination with osimertinib (Tagrisso) in EGFR-mutated T790M-positive Non-Small Cell Lung Cancer (NSCLC) patients. Osimertinib, a third-generation TKI targeting EGFR (Epidermal Growth Factor Receptor), has recently become the standard treatment for those NSCLC patients which harbor a T790M mutation. Despite this novel treatment, patients eventually relapse and treatments become ineffective. MP0250 offers the possibility to target two of the described escape pathways – HGF and VEGF. The combination of MP0250 with osimertinib is expected to continuously block the EGFR-mutated pathway and simultaneously inhibit two additional non-EGFR related pathways of resistance.

"We are pleased and proud to have reached this important milestone to dose the first patient in our multiple myeloma phase 2 study. This is the first step to test our hypothesis that MP0250 can address resistance pathways in various hematological and solid tumors. The submission of an IND for the first solid tumor indication will be another important milestone in the development program of our lead oncology asset MP0250 later this year," commented Dr. Andreas Harstrick, Chief Medical Officer at Molecular Partners.

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics.

The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.

With their good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology, and is advancing a proprietary pipeline of DARPin drug candidates in oncology. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan.

Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and has entered into Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated T790M-positive NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 is currently moving into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

Celyad obtains additional US patent for cancer treatment based on TCR-deficient allogeneic CAR-T cells

On May 30, 2017 Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, reported the issuance of United States Patent No. 9,663,763 relating to Celyad’s method of treating cancer by administering allogeneic primary human T cells that are engineered to be T-Cell Receptor (TCR)-deficient and to express a chimeric antigen receptor (CAR) (Press release, Celyad, MAY 30, 2017, View Source [SID1234519314]).

US Patent 9,663,763 was examined under the Cancer Immunotherapy Pilot Program, also known as the "Patents 4 Patients" initiative, and is the third patent in Celyad’s allogeneic intellectual property portfolio awarded by the United States Patent and Trademark Office (USPTO). This new patent claims specifically methods of treating cancer patients with allogeneic TCR-deficient CAR-T immunotherapies. Earlier patents were related to the allogeneic TCR-deficient CAR-T cells per se, and to methods of producing them. The combination of these granted patents strengthens Celyad’s position and further confirms its leadership in engineered cell therapy, and in the allogeneic CAR-T space.

Allogeneic technology has the potential to broaden the therapeutic applications of CAR T-Cell immunotherapies as it does not depend on cells derived from the patient. TCR-deficient CAR-T cells are aimed at avoiding or greatly reducing adverse immune reactions (such as a graft- versus-hostdisease (GVHD) response) which would greatly benefit patients.

Dr. Christian Homsy, CEO of Celyad: "We are pleased to have obtained this new patent. The combination of this patent with the earlier granted US Patents consolidates our strong IP position in the CAR-T field and strengthens our IP portfolio covering key elements in the allogeneic TCR-deficient CAR-T cells production value chain."

Dr. Georges Rawadi, VP Business Development & IP at Celyad: "Allogeneic CAR-T cells are of increasing interest to many Pharma and BioPharma companies involved in cell-based cancer immunotherapies. We are looking to maximize the significant value of our allogeneic CAR-T assets through strategic collaborations and partnerships such as the ones we have established with ONO Pharma and Novartis."

Sierra Oncology Granted US and EU Patents for Chk1 inhibitor SRA737

On May 30, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported it has been issued a selection patent for its Chk1 inhibitor, SRA737, from the U.S. Patent and Trademark Office (Press release, Sierra Oncology, MAY 30, 2017, View Source [SID1234519311]). The patent explicitly covers SRA737 and extends its protection out to 2033 in the U.S., before any patent term extensions.

The company also reported that a similar European Patent (No. 2855448) was previously issued for SRA737 on February 8, 2017. SRA737 is currently being evaluated in two Phase 1 clinical trials.

"These issuances further build on our intellectual property position for SRA737 and establish a solid foundation for the potential future commercialization of this promising drug candidate," said Dr. Nick Glover, President and CEO of Sierra Oncology. "We anticipate generating additional intellectual property claims as we advance our DDR-focused research activities and our innovative genetics-driven clinical programs."

U.S. Patent No. 9,663,503 pertains to SRA737, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit Chk1 kinase function, and in the treatment of diseases and conditions that are mediated by Chk1, including proliferative conditions such as cancer. The patent also covers the use of SRA737 in combination with other agents.

SRA737-01, a Monotherapy trial prospectively enrolling patients with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition via synthetic lethality into five indication-specific cohorts: colorectal, ovarian, non-small cell lung, prostate, and head and neck cancers. In cancer cells, replication stress induced by oncogenes (e.g., MYC or RAS) or genetic mutations in DNA repair machinery (e.g., BRCA1 or FA) combined with loss of function in tumor suppressors (e.g., TP53 or ATM) results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. Targeted inhibition by SRA737 may therefore be synthetically lethal to these cancer cells and have utility as a monotherapy in a range of tumor indications.

SRA737-02, a Chemotherapy Combination trial evaluating SRA737 in combination with low-dose gemcitabine in indication-specific cohorts of prospectively-selected, genetically-defined subjects with bladder or pancreatic cancer. Profound mechanistic potentiation has been reported when Chk1 inhibition is combined with DNA damaging cytotoxic agents or radiation. The widely-used chemotherapy gemcitabine is a strong exogenous inducer of replication stress and preclinical modeling demonstrates robust synergistic anti-tumor activity for SRA737 potentiated by gemcitabine.

Sierra Oncology is also advancing SRA141, a potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7) undergoing preclinical development. Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types. For more information, please visit www.sierraoncology.com.

Loxo Oncology Announces FDA Clearance of Investigational New Drug (IND) Application for Next-Generation TRK Inhibitor, LOXO-195

On May 30, 2017 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported that the United States Food and Drug Administration cleared the Investigational New Drug (IND) application for LOXO-195, Loxo Oncology’s next-generation TRK inhibitor (Press release, Loxo Oncology, MAY 30, 2017, View Source [SID1234519310]). LOXO-195 was developed to treat patients with TRK fusion cancers who become resistant while receiving another TRK inhibitor, such as larotrectinib.

"We hope that LOXO-195 can extend the period of durable disease control for patients with TRK fusion cancers," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "Today, there are patients receiving larotrectinib in ongoing clinical trials who have ongoing clinical responses. We have an obligation to these patients, and all patients with TRK fusion cancers, to be ready when they need a new treatment option."

Informed by internal research and the medical literature, LOXO-195 was designed to address anticipated mechanisms of acquired resistance in cancers exposed to a prior TRK inhibitor, including "solvent front" mutations (e.g. NTRK1 G595R, NTRK3 G623R), which are not well-addressed by existing investigational agents. LOXO-195 will be developed as a sequential treatment, to follow larotrectinib or another TRK inhibitor, to extend the total time of benefit from TRK inhibition.

LOXO-195 will initially be studied in a multi-center Phase 1/2 trial. The primary objective of the trial is to determine the maximum tolerated dose or recommended dose for further study. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Objective Response Rate and Duration of Response, as determined by RECIST v1.1). The trial will include a dose escalation phase and dose expansion phase.

About LOXO-195
LOXO-195 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that have acquired resistance to initial TRK therapy such as larotrectinib. Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. Though drugs such as larotrectinib can induce durable responses in these patients, the cancer may eventually begin to grow again. This phenomenon is called "acquired resistance," in that the cancer has acquired features conferring resistance to the initial therapy that was once effective. Emerging data in the field of TRK inhibition suggest that acquired resistance may emerge due to TRK kinase point mutations, such as those in the solvent front domain, xDFG domain, or gatekeeper region. LOXO-195 was designed to address these new point mutations and induce a new response in the patient’s cancer. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or email [email protected].