On October 12, 2016 RXi Pharmaceuticals Corporation (NASDAQ: RXII), a clinical-stage RNAi company developing innovative therapeutics that address significant unmet medical needs, reported that it has entered into an exclusive option agreement to acquire all outstanding capital stock of MirImmune Inc., a privately-held company focused on the development of next generation immunotherapies for the treatment of cancer, in consideration for a number of shares equal to 19.99% of the then outstanding shares of common stock of RXi, plus additional potential consideration contingent on MirImmune reaching certain milestones (Press release, RXi Pharmaceuticals, OCT 12, 2016, View Source [SID:SID1234515779]). RXi Pharmaceuticals can exercise the option to acquire MirImmune on the terms set forth in the option agreement at any time prior to April 5, 2017 but has no obligation to do so.

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MirImmune was co-founded by Tim Barberich, founder and former Chairman and CEO of Sepracor, Inc. In early 2015, RXi and MirImmune entered into an exclusive license agreement to RXi’s novel and proprietary sd-rxRNA technology for use in developing innovative cell-based cancer immunotherapies. MirImmune’s progress in cell therapy using RXi’s RNAi technology during the past 18 months forms a strong foundation for therapeutic development in the immuno-oncology space. If RXi exercises its option to acquire MirImmune, the acquisition would enable RXi to expand its pipeline and enter into the rapidly expanding field of immuno-oncology using the unique competitive advantages of sd-rxRNA technology.

The advantages of RXi’s RNAi technology, listed below, have been verified in in vitro testing by MirImmune and their partners, and offer support that sd-rxRNA technology is uniquely suited for immune checkpoint modulation in cellular immuno-oncology therapies, such as CAR T-cells.

Multiple immune checkpoints can be targeted at the same time using a combination of sd-rxRNA compounds;
sd-rxRNA have been able to block both extracellular immune check points as well as intracellular targets that are not accessible to antibody therapies; and
Rapid and efficient transfection of T-cells with sd-rxRNA compounds in cell culture (>98%) is obtained while maintaining close to 100% cell viability.
In addition to demonstrating the effectiveness of our sd-rxRNA platform for cell therapy, MirImmune’s progress to date also includes:

Selection of six lead sd-rxRNA compounds against six different extracellular and intracellular immune check points;
Preclinical data that demonstrate silencing of all six targets in vitro, singly and in combinations;
Efficient and long-lasting knockdown of immune checkpoints in vivo;
Demonstrating the applicability of sd-rxRNA transfection in cell therapy to solid tumors in addition to blood cancers by:
Providing preclinical data demonstrating that mesothelin-targeted CAR T-cells modified with the anti-PD1 targeted sd-rxRNA significantly slow in vivo tumor growth in a human ovarian cancer model in mice compared to vehicle control
Generating promising results in ex vivo testing on melanoma cells obtained from a patient-donor, using sd-rxRNA reduction of PD1 in tumor infiltrating lymphocytes (TILs) resulting in destruction of those melanoma cells; and
Filing of intellectual property that covers the use of RNAi compounds for use in cell therapy.
"We are very pleased to have the opportunity to welcome MirImmune into our Company," said Dr. Geert Cauwenbergh, President and CEO of RXi Pharmaceuticals. He added that, "This acquisition would not only allow us to create value for our shareholders; it more importantly sets the stage for what could potentially be a transformational change in the way we treat patients with various malignancies, including solid tumors. Our ultimate goal, through our own efforts as well as through partnerships, is the development of more tolerable treatments resulting in better quality of life and extended survival of family members we would otherwise lose prematurely. This approach is a key first step into the field of cell-based therapies, where sd-rxRNA has numerous advantages over other gene-modulating technologies."

"We are very excited to join our efforts with RXi in the development of RNAi for immunotherapy of cancer," said Dr. Alexey Eliseev, CEO of MirImmune, Inc. He added that, "We at MirImmune have taken first steps in improving the properties of cell-based immunotherapies, such as CAR T‑cells, by RNAi and enabling them to work in the immunosuppressive environment of solid tumors. CAR T‑cell treatments have shown an enormous promise in the treatment of hematological malignancies, but they have been only marginally effective with solid tumors. We treat therapeutic immune cells with RNAi compounds ex-vivo to knock down immune checkpoints, such as PD-1, LAG-3 and others. This treatment boosts the anti-tumor activity of the cells when they are subsequently administered to the patients. RXi’s sd-rxRNA is arguably the best RNAi technology for such ex vivo treatment of cells. Our plan is to develop sd-rxRNA as a more safe and effective alternative to gene editing of the immune cells or checkpoint blockade with monoclonal antibodies."

About RXi’s Proprietary Self-delivering RNAi (sd-rxRNA) Technology Platform

RNAi is a powerful molecular tool that has the ability to "silence" or down-regulate the expression of a specific gene that may be overexpressed in a disease condition. Scientists at RXi developed a robust RNAi therapeutic platform that includes self-delivering RNA (sd-rxRNA) compounds where drug-like properties are built into the RNAi compound itself. These proprietary compounds are novel RNAi compounds with enhanced properties for therapeutic use including: efficient spontaneous cellular uptake, stability, reduced potential for immune stimulation, and potent, long-lasting intracellular activity. All cell types tested (primary, neuronal and non-adherent) internalize sd-rxRNA compounds uniformly and efficiently, resulting in potent and long lasting silencing. sd‑rxRNA compounds have the ability to selectively block the expression of any target in the genome providing applicability to a broad spectrum of therapeutic areas.

On October 12, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that a presentation on the results of a Phase Ib clinical study of its in-house developed multiple receptor tyrosine kinase inhibitor lenvatinib mesylate (lenvatinib) in combination with the anti-PD-1 antibody pembrolizumab developed by Merck & Co., Inc (Press release, Eisai, OCT 12, 2016, View Source [SID:SID1234515765]). (Kenilworth, New Jersey, U.S.A.), known as MSD outside the United States and Canada, in patients with selected solid tumors was given at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress held from October 7 to 11. Development of this combination regimen is being conducted jointly under the cooperation of both companies.

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This investigational study is a multicenter, open-label Phase Ib/II clinical study to evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab. In the Phase Ib part of the study, which was conducted to determine and confirm the maximum tolerated dose (MTD), 13 patients with selected solid tumors (8 patients with renal cell carcinoma, 2 patients with endometrial cancer, 2 patients with non-small cell lung cancer and 1 patient with melanoma) that had progressed after treatment with approved therapies or for which there are no standard effective therapies available were administered lenvatinib (either 24 mg or 20 mg daily) and pembrolizumab (200 mg intravenously every three weeks).

According to the latest results of the Phase Ib part of the study as of August 2016, dose-limiting toxicities (DLTs) were reported in 2 of 3 patients in the lenvatinib 24 mg / pembrolizumab 200 mg group. No DLTs were reported in the lenvatinib 20 mg / pembrolizumab 200 mg group (10 patients), and the MTD was confirmed as 20 mg of lenvatinib per day / 200 mg of pembrolizumab every three weeks. The objective response rate, one of the study’s secondary endpoints, was 69.2% (n of 13 patients). Grade 3 or higher Treatment-Emergent Adverse Events (TEAEs) were observed in 69.2% of patients, and no patients had discontinued treatment due to TEAEs. The three most frequently observed adverse events were decreased appetite, diarrhea and fatigue.

Takashi Owa, Ph.D, Chief Medicine Creation Officer of Eisai’s Oncology Business Group, commented "From the results of this study for patients who had progressed after treatment with approved therapies or for which there are no standard effective therapies available, we are encouraged to further explore the combination of lenvatinib and pembrolizumab in the next stage of clinical development." Currently, the Phase II part of the study is underway in the United States, while preparations to initiate a Phase Ib clinical study in Japan are also underway.

Eisai regards oncology as a key therapeutic area and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai remains committed to providing further clinical evidence for lenvatinib aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

About lenvatinib mesylate ("lenvatinib", generic name, product names: Lenvima , Kisplyx )
Discovered and developed in-house, lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation. Currently, Eisai has obtained approval for lenvatinib as a treatment for refractory thyroid cancer in over 45 countries including in the United States, Japan, in Europe, Korea, Canada, and Mexico, and is undergoing regulatory review in countries throughout the world including South Africa and Malaysia. Specifically, Eisai has obtained approval for the agent indicated in the United States for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively.Lenvatinib was also approved in the United States in May 2016 for an additional indication in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. Furthermore, lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe in August 2016. Lenvatinib has been launched in Europe under the brand name Kisplyx for this indication. Meanwhile, Eisai is conducting clinical studies of lenvatinib in several other tumor types such as hepatocellular carcinoma (Phase III), endometrial carcinoma (Phase II), biliary tract cancer (Phase II), and in combination with pembrolizumab for various types of cancer (Phase Ib/II). In addition, Eisai has initiated a Phase III clinical study of lenvatinib in combination with pembrolizumab and everolimus in renal cell carcinoma (first-line therapy).

About the Phase Ib/II Clinical Study (Study 111)

Study 111 is a multicenter, open-label Phase Ib/II clinical study to evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab. In the Phase Ib part of the study, which was to determine and confirm the maximum tolerated dose (MTD), 13 patients with selected solid tumors (8 patients with renal cell carcinoma, 2 patients with endometrial cancer, 2 patients with non-small cell lung cancer and 1 patient with melanoma) who had progressed after treatment with approved therapies or for which there are no standard effective therapies available were administered 24 mg (3 patients) or 20 mg (10 patients) of lenvatinib orally daily as well as 200 mg of pembrolizumab intravenously every three weeks. Objective response rate, overall survival and progression-free survival are also assessed as secondary endpoints. Currently, the Phase II part of the clinical study is underway in the United States.

On October 12, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that its amended protocol using its NY-ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell therapy in ovarian cancer patients with treatment resistant or refractory metastatic ovarian cancer is now actively recruiting (Press release, Adaptimmune, OCT 12, 2016, View Source [SID:SID1234515760]).

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To date, no objective clinical responses have been reported in the ovarian cancer patients who received NY-ESO SPEAR T-cell therapy in the initial iteration of this trial. Of note, these initial patients received a preconditioning regimen which consisted of cyclophosphamide alone, rather than including fludarabine. Data from Adaptimmune’s studies of its NY-ESO SPEAR T-cell therapy in synovial sarcoma patients have indicated the importance of including fludarabine in the preconditioning regimen. The use of fludarabine appears to be required for expansion, response and persistence of transduced cells. As a result, this trial will enroll patients under a revised protocol including a pre-conditioning regimen that includes fludarabine in combination with cyclophosphamide.

"Based on our clinical experience to date, we have amended the protocol for this trial to include both fludarabine and cyclophosphamide in the conditioning regimen," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We hope that, as previously observed in synovial sarcoma, this lymphodepleting regimen will enable anti-tumor immune responses mediated by NY-ESO SPEAR T-cell therapy in these patients with advanced chemotherapy relapsed or refractory ovarian cancer."

This is a Phase I/IIa, open-label study of autologous T-cells genetically engineered with an enhanced affinity NY-ESO-1 T-cell receptor in ovarian cancer patients with the HLA-A*0201, HLA-A*0205, and/or HLA-A*0206 allele and whose tumor expresses the NY-ESO-1 tumor antigen. Though the prevalence of HLA sub-types varies from population to population, the most common in the western world is HLA-A2. Among the HLA-A2 variants, the most prevalent are HLA-A*0201 and HLA-A*0206.

This multi-center study is intended to enroll up to 10 additional patients under the revised protocol, and will assess the safety and tolerability of Adaptimmune’s NY-ESO SPEAR T-cell therapy in patients with treatment resistant or refractory metastatic ovarian cancer expressing the NY-ESO-1 antigen. Secondary objectives will include the assessment of clinical efficacy, measurements of durability of persistence of NY-ESO SPEAR T-cells in the blood, and exploratory tumor biomarker studies, and evaluations of the phenotype and functionality of NY-ESO-1 SPEAR T-cells.

For more information on this clinical trial, visit ClinicalTrials.gov at: View Source (Identifier: NCT01567891).

About Ovarian Cancer
As reported by the American Cancer Society, epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and the country’s fifth most common cause of cancer mortality in women. It is estimated that in 2016 in the United States, 22,280 women will receive a new diagnosis of ovarian cancer, and approximately 14,240 women will die of this disease. Overall, the five-year relative survival rate is 45 percent. If the cancer is detected and treated early, at the localized stage when the cancer is only in the part of the body where it started, the five-year relative survival rate is 92 percent. However, only 15 percent are detected at the localized stage. No treatment is available for patients with refractory or resistant metastatic ovarian cancer.

On October 12, 2016 Celgene Corporation (NASDAQ:CELG) and Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) reported each company has entered into collaboration agreements with Abbott (NYSE: ABT), a leader in diagnostic technologies, to develop and commercialize companion diagnostic tests on Abbott’s m2000 RealTime System to identify isocitrate dehydrogenase (IDH) mutations in acute myeloid leukemia (AML) patients (Press release, Agios Pharmaceuticals, OCT 12, 2016, View Source [SID1234515759]). Celgene is currently developing enasidenib (AG-221/CC-90007), an IDH2 mutant inhibitor, for the treatment of patients with relapsed or refractory AML who have an IDH2 mutation. Agios is developing AG-120, an IDH1 mutant inhibitor, for the treatment of patients with relapsed or refractory AML who have an IDH1 mutation.

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IDH1 and IDH2 mutations occur in approximately 20% of AML patients. An article published online this week in the journal Leukemia (Medeiros, Leukemia 2016) concluded that advances in the understanding of the genetics underlying myeloid malignancies are driving an era of development for targeted treatments such as IDH mutant inhibitors. The authors recommend that IDH mutational analysis should become part of the routine AML diagnostic workup and repeated at relapse to identify patients who may be eligible for targeted investigational treatments currently under clinical study.

"AML is a complex and heterogeneous disease, making it difficult to treat," said Han Myint, M.D., Vice President, Global Medical Affairs, Myeloid for Celgene. "IDH mutations lead to aberrant DNA methylation, causing a block in myeloid differentiation that leads to disease progression. Molecular profiling is important to identify genomic mutations which may have prognostic and potential treatment implications for patients with AML."

Abbott’s m2000rt RealTime System, is a polymerase chain reaction (PCR) instrument designed to enable clinical laboratories to automate PCR and results analysis, simplifying the complex and manual steps often associated with molecular diagnostics. Both Celgene and Agios have incorporated this screening into clinical trial designs, including the recently initiated Phase 3 IDHENTIFY trial comparing enasidenib with conventional therapy in older patients with an IDH2 mutation and relapsed or refractory AML (NCT02577406).

"The field of personalized medicine is advancing at a rapid pace for a broad range of medical conditions, especially within hematology-oncology," said Chris Bowden, M.D., chief medical officer at Agios. "Our collaboration with Abbott will provide a test to help identify AML patients with IDH mutations who are in need of treatment options."

The m2000 system has not been FDA cleared or approved for use with enasidenib or AG-120.

Enasidenib and AG-120 have not been approved for any use in any country.