On April 11, 2017 Kyorin Holdings reported that its wholly owned subsidiary, KYORIN Pharmaceutical Co., Ltd. ("Kyorin", Head office: Chiyoda-ku, Tokyo, President & CEO: Mitsutomo Miyashita), has entered into a license agreement with Merck & Co., Inc., Kenilworth, N.J., U.S.A. （ "Merck", Head office: Kenilworth, N.J., U.S.A., CEO: Kenneth C. Frazier ） for Merck’s investigational overactive bladder (OAB) therapeutic agent, KRP-114V (INN: Vibegron) in Asia. (Press release, Kyorin, APR 11, 2017, View Source [SID1234519929]) Under the terms of this agreement, Kyorin will expand the license, which the company acquired from Merck for Japan in July 2014, to also cover Asia. Through this agreement, Kyorin acquires th e licenses to develop, manufacture and commercialize KRP-114V in Korea, Taiwan, Hong Kong and ten member states of ASEAN (Association of South East Asian Nations).

KRP-114V is an investigational selective beta 3 adrene rgic receptor agonist discovered by Merck that is being evaluated as a once-daily therapy for OAB. Kyorin entered into a co-development and co-marketing agreement for this agent with Kissei Pharmaceutical Co., Ltd. in March 2016, and both companies are currently conducting a Phase 3 clinical trial in Japan.

Urology is one of Kyorin’s focus areas, and the comp any is developing this agent in Japan toward the expansion of its product lineup as well as the establishment of its presence in that field. By acquiring the license to KRP-114V for Asia in addition to Jap an, Kyorin is committed to further improving the QOL of the Asian patients with OAB symptoms coupled with Uritos already available in Asia through Kyorin’s alliance partners.

This transaction will have no impact on the comp any’s consolidated earnings forecast in FY2016

On 11 April 2017 4SC AG (4SC, FSE Prime Standard: VSC) reported that 4SC’s collaboration partner Prof. Steven A. Johnsen and his team at the Clinic for General, Visceral and Pediatric Surgery in Göttingen, Germany, published results from a preclinical study providing new insights into the epigenetic mode of action of 4SC’s anti-cancer compound 4SC-202 (Press release, 4SC, APR 11, 2017, View Source [SID1234518595]).

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4SC-202 is an orally administered small molecule for the treatment of cancer. As an epigenetic modulator with a unique mechanism of action, 4SC-202 inhibits both the lysine-specific demethylase (LSD1) and class I histone deacetylases (HDAC 1, 2 and 3), which play roles in the regulation of cancer signaling pathways. Through 4SC-202-mediated changes in the methylation or acetylation pattern of histone proteins (packaging proteins, around which the DNA is wrapped), expression of some genes is promoted, whereas expression of others is suppressed. These changes ultimately lead to more differentiation and less proliferation of cancer cells. The tumor ceases to grow and the immune system is then able to detect and destroy it.

4SC-202 affects gene expression via two well-known molecular cancer players

Prof. Johnsen and his team conducted experiments in multiple pancreatic cancer cell lines. "Mechanistically we observed that the effects on the induction of gene expression mediated by 4SC-202 were elicited by the Bromodomain-containing Protein 4 (BRD4) and MYC, both of which are able to interact with the regulatory sequences located close to the target genes following the changes caused by treatment with 4SC-202," stated Prof. Johnsen.

BRD4 is a well-characterized ‘epigenetic reader’ that recognizes and binds to acetylated lysine residues on both histone and non-histone proteins and plays an important role in maintaining cancer-induced transcriptional programs in the malignant cells. MYC on the other hand is one of the most studied human oncogenes and has been frequently associated with tumor growth and progression due to its involvement in a myriad of biological processes including cell growth, proliferation and cell death.

Prof. Johnsen continued: "Based on the data, we believe that 4SC-202-mediated down-regulation of target gene expression is most likely associated with changes in the acetylation patterns in the regulatory regions located farther from the target genes."

Frank Hermann, MD, Chief Development Officer of 4SC, commented, "These data provide valuable new insights into 4SC-202’s molecular mode of action in cancer cells. In addition to these direct effects on cancer cells, we know that 4SC-202 has various biologic effects, especially enhancing the immune response against cancer tissue. Considering these multiple biological effects, we believe that 4SC-202 is a very attractive partner for combination treatment approaches in hematology and oncology with a special focus on immuno-oncology therapies such as checkpoint inhibitors. Therefore, we plan to investigate this very promising combination in cancer patients who are not responding to treatment with checkpoint inhibitors alone. In these patients, the epigenetic effects of 4SC-202 have the potential to modulate the cancer tissue and help to reactivate the immune system to fight the cancer."

– Press release ends –

Original publication

Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner.
Mishra VK, Wegwitz F, Kosinsky RL, Sen M, Baumgartner R, Wulff T, Siveke JT, Schildhaus HU, Najafova Z, Kari V, Kohlhof H, Hessmann E, Johnsen SA.
Nucleic Acids Research, View Source

Related articles

21 March 2017, 4SC-202 – a promising combination partner for cancer treatment
View Source

2 June 2016, 4SC at ASCO (Free ASCO Whitepaper): 4SC 202 and checkpoint inhibitors – strong partners in cancer treatment

21 March 2016, Epigenetic compound 4SC-202 strengthens endogenous immune response to cancer



Further information

About 4SC-202

4SC-202 is an orally administered small molecule for the treatment of cancer. 4SC-202 is an epigenetic modulator with a unique mechanism of action that inhibits both the lysine-specific demethylase (LSD1) protein and class I histone deacetylase proteins (HDAC 1, 2 and 3), which play significant roles in the regulation of signaling pathways in cancer cells.

4SC-202 has been investigated in a Phase I study with 24 intensively pretreated patients with several types of highly advanced hematologic cancers, and has proven to be tolerated. Positive signs of anti-tumor efficacy were observed with one complete remission for 28 months and one partial responder for 8 months.

Data from preclinical investigations showed that 4SC-202 strengthens the anti-tumor immune response. Treatment with 4SC-202 alters the tumor microenvironment and increases infiltration of immune cells into the tumor. Further preclinical investigations showed that the combination of 4SC-202 with checkpoint inhibitors resulted in better anti-tumor activity than treatment with checkpoint inhibitors alone, suggesting a very promising clinical development path for 4SC-202 in both refractory and non-responding patients to treatment with checkpoint inhibitors.

On April 11, 2017Moleculin Biotech, Inc., (NASDAQ: MBRX) ("Moleculin" or the "Company"), a preclinical pharmaceutical company focused on the development of anti-cancer drug candidates, some of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center ("MD Anderson"), reported that it has appointed Theradex Systems, Inc. as its contract research organization ("CRO") for its planned Phase I/II clinical trial for Annamycin for the treatment of relapsed or refractory acute myeloid leukemia ("AML") (Press release, Moleculin, APR 11, 2017, View Source [SID1234518526]).

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Walter Klemp, Chairman and CEO of Moleculin stated: "We are pleased to announce this key milestone. We selected Theradex for their extensive US and international expertise with clinical research and development of pharmaceutical compounds in the areas of oncology and life-threatening diseases, including considerable experience with AML. Engaging Theradex is a key step in preparing to initiate our Phase I/II clinical trial for Annamycin and we look forward to moving ahead with them as we continue to work with the FDA on our IND, which must go into effect for clinical trials to begin. We are confident in Theradex’s ability to assist us in executing a high-quality and efficient trial."

About AML
Leukemia is a cancer of the white blood cells and the acute forms of leukemia can manifest quickly and leave patients with limited treatment options. AML is the most common type of acute leukemia in adults. It occurs when a clone of leukemic progenitor white blood cells proliferates in the bone marrow suppressing the production of normal blood cells. In order to qualify for a curative bone marrow transplant, patients must first undergo induction therapy. The current standard of care is the combining of 2 chemotherapeutic drugs, always including an anthracycline intended to induce a CR or complete response, which has not improved since it was first used in the 1970’s. We estimate that it has the same cure rate of about 20% as then. Currently, the only viable long term option for acute leukemia patients is a bone marrow transplant for those 20%, which is successful in a significant number of patients. For more information on AML click: View Source

About Annamycin
Annamycin is an anthracycline intended for the treatment of relapsed or refractory AML. Annamycin is a unique liposome formulated anthracycline (also referred to in literature as "L-Annamycin") that has been designed to produce little to no cardiotoxicity and avoid the multidrug resistance mechanisms that often defeat current anthracyclines. It has been tested in 114 patients in 6 clinical trials, 3 of which focused on leukemia, with little to no cardiotoxicity. The Company is working with the FDA on an investigative new drug application for a Phase I/II trial for second line treatment of relapsed or refractory AML, for which no approved therapy currently exists.

On April 11, 2017 Idera Pharmaceuticals, Inc. (Nasdaq:IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, reported successful completion of the phase 1 portion of the ongoing Phase 1/2 clinical trial of intratumoral IMO-2125 (Press release, Idera Pharmaceuticals, APR 11, 2017, View Source [SID1234518523]). Intratumoral IMO-2125 is an agonist of TLR9, in combination with ipilimumab for the treatment of anti-PD-1 refractory metastatic melanoma. Enrollment has begun for the Phase 2 portion of the trial with the 8mg dose of intratumoral IMO-2125. The Phase 1 dose escalation of IMO-2125 in combination with pembrolizumab is ongoing.

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"We are very pleased with the progress to date in the Phase 1 dose escalation trial of IMO-2125 in combination with ipilimumab, and with the outcomes observed," stated Joanna Horobin, M.B., Ch.B., Idera’s Chief Medical Officer. "IMO-2125 in combination with ipilimumab demonstrated preliminary evidence of meaningful clinical activity in this anti-PD-1 refractory metastatic melanoma patient population which represents a high unmet medical need. All dose levels have been well tolerated and did not exacerbate the safety issues commonly observed with ipilimumab. Furthermore, data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of trial."

The Phase 2 portion of the trial utilizes a Simon two-stage design to evaluate the objective response rate of IMO-2125 in combination with ipilimumab, compared to historical data for ipilimumab alone in the anti-PD-1 refractory metastatic melanoma population. The ipilimumab arm of IMO-2125-204 has already met the pre-specified futility assessment to advance immediately into the second stage of the Phase 2 portion of the trial given that 2 patients treated at the Phase 2 dose experienced confirmed responses, including one complete response (CR).

All dose levels of IMO-2125 in the Phase 1 portion of the trial have been well tolerated; however the 8 mg dose level has been selected for the Phase 2 portion of the trial based on its safety, clinical efficacy, and data from multiple translational immune parameters supporting the mechanism. Phase 2 will evaluate twenty-one patients dosed at 8mg, of which 9 are already enrolled. The MD Anderson Cancer Center will continue to lead the trial and will be joined by additional centers. In addition to potential interim updates, the company expects to have overall response rate (ORR) data available in the first quarter of 2018.

Additionally, the company has begun and will continue to engage in discussions with regulatory authorities regarding the path to registration for IMO-2125 in combination with ipilimumab in PD-1 refractory metastatic melanoma patients.

The Phase 1 clinical trial of intratumoral IMO-2125 in combination with pembrolizumab in PD-1 refractory melanoma patients is enrolling as expected, and patient enrollment in a phase 1 trial of intratumoral IMO-2125 monotherapy in multiple tumor types has been activated and the first patient is expected to enroll early this quarter.

"I am very encouraged by the tremendous progress that has been made to date to advance us to this important stage in IMO-2125’s development cycle," stated Vincent Milano, Idera’s Chief Executive Officer. "There is a very clear unmet medical need for those patients for whom current checkpoint inhibitor therapies are not providing adequate solutions. We are incredibly focused on advancing this program as rapidly as possible for these patients, and we are also looking forward to exploring areas outside of melanoma in which intratumoral IMO-2125 may also serve an important role through its unique mechanism of action within the tumor microenvironment."

About the Phase 1/2 trial of IMO-2125 in combination with ipilimumab
The Phase 1/2 trial of intratumoral IMO-2125 in combination with ipilimumab is being conducted in patients who are refractory to anti-PD-1 therapy. The phase 1 portion of the trial was conducted at MD Anderson Cancer Center and the phase 2 portion of the trial will expand to include additional centers. In the Phase 1 portion of the trial, four dose levels of IMO-2125 (4, 8, 16 and 32 mg) have been administered intratumorally in one targeted lesion at weeks 1, 2, 3, 5, 8 and 11, in combination with the standard dosing regimen of ipilimumab, beginning on week 2. The Phase 2 expansion portion of the trial utilizes a Simon two-stage design. If at least 2 of the first 10 patients treated at the Phase 2 dose experience confirmed response the futility hurdle has been met and the trial may continue to enroll. Phase 2 will evaluate 21 patients at the phase 2 dose. Tumor biopsies have been collected pre- and post-24 hours of the first dose of IMO-2125, as well as at 8 and 13 weeks to evaluate multiple immune markers. Clinical activity has been evaluated by the RECIST v1.1 criteria. Clinical data from this study has been presented at SITC (Free SITC Whitepaper) 2017, ASCO (Free ASCO Whitepaper)-SITC 2017 and AACR (Free AACR Whitepaper) 2017, and can be found also on Idera’s corporate website at View Source

About IMO-2125
Toll-like receptors (TLRs) play a central role in the innate immune system, the body’s first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue. Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. Checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 (PD1) are designed to enable the immune system to recognize tumor cells. In this setting, intratumoral TLR9 agonist administration may increase the tumor-infiltrating lymphocytes (TILs), and thereby potentiate anti-cancer activity of checkpoint inhibitors in the injected tumor as well as systemically.

IMO-2125, Idera’s TLR9 agonist, has been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown in various scientific presentations and publications to activate dendritic cells and induce interferon. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In previously completed clinical trials, subcutaneous administration of IMO-2125 was very well tolerated in about 114 patients with hepatitis C. Idera has conducted further preclinical and clinical research evaluating the potential of IMO-2125 to enhance the anti-tumor activity of other checkpoint inhibitors in cancer immunotherapy with data has been presented at several scientific and medical conferences during the past few years. The posters from these presentations can be found at View Source

About Metastatic Melanoma
Melanoma is a type of skin cancer that begins in a type of skin cell called melanocytes. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread beyond the skin to other parts of the body such as by through the lymphatic system (metastatic disease). Melanoma accounts for only one percent of skin cancer cases, but causes a large majority of skin cancer deaths. The American Cancer Society estimates that in 2017, there will be 87,110 new cases of melanoma in the U.S., and about 9,730 will die of this disease. Based on proprietary Idera research, the company anticipates by the year 2025, there will be roughly 13,000 anti-PD-1 refractory metastatic melanoma patients.

On April 11, 2017 – ArQule, Inc. (Nasdaq: ARQL) reported that it has received clearance from the U.S. Food and Drug Administration (FDA) for the Investigational New Drug (IND) application to conduct a phase 1 clinical trial with ARQ 531 in patients with B-cell malignancies who are refractory to other therapeutic options (Press release, ArQule, APR 11, 2017, View Source [SID1234518522]). ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK).

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ArQule plans to initiate a phase 1a/b dose escalation and signal generation trial by Q3 of 2017. The phase 1a portion will be a dose escalation study open to patients with B-cell malignancies, with the aim of establishing a recommended dose. Upon completion of the phase 1a trial, the company plans to begin a phase 1b trial in a number of expansion cohorts that will include patients with the C481S mutation who are refractory to other therapies. The goal would be to establish target engagement and early proof of concept.

"Given the emerging data on BTK resistance and the extensive preclinical work the team at The Ohio State University have done with ARQ 531, we are looking forward to moving this drug from the bench to the bedside," said Dr. Jennifer Woyach, M.D., of The Ohio State University College of Medicine. "A clear need is emerging for a BTK inhibitor that addresses resistance."

"There is an emerging body of evidence that is defining the potential clinical need related to BTK resistance, and new molecules are needed to treat patients who have developed resistance," said Dr. Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "We have been working with The Ohio State University in the preclinical development of ARQ 531, and we are looking forward to extending that partnership into clinical testing."

B-cell malignancies, like chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma and mantle cell lymphoma are driven by BTK. The only approved BTK inhibitor, ibrutinib, is irreversible and makes a covalent bond with the C481 residue of the targeted protein. Although ibrutinib has demonstrated excellent responses in patients with elevated B-cell receptor signaling, clinical resistance has been observed, and the BTK C481S mutation is emerging as a predominant mechanism of resistance. As a reversible inhibitor, ARQ 531 does not require interaction with the C481 residue, a binding site essential for irreversible ibrutinib binding to BTK, thus positioning ARQ 531 as a targeted therapy for patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.


About BTK and ARQ 531

ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies ARQ 531 has demonstrated high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to initiate a phase 1 trial by the third quarter of 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.