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Calithera Announces First Patient Dosed in a Phase I Study of CB-1158, the First-in-Class Inhibitor of the Immuno-Oncology Target Arginase

On September 15, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that the first patient has been dosed in a Phase I clinical trial assessing the safety and efficacy of CB-1158, a first-in-class arginase inhibitor for the treatment of advanced solid tumors (Press release, Calithera Biosciences, SEP 15, 2016, View Source [SID:SID1234515171]). Arginase is an enzyme in myeloid-derived suppressor cells (MDSCs), which prevents T-cell and natural killer (NK) cell activation in tumors.

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"Arginase, when released by MDSCs, plays an important role in the inhibition of T-cell and NK-cell activation and proliferation, preventing immune-mediated anti-tumor activity. For example, in many solid tumors, including lung, colorectal, esophageal, bladder, head and neck, and kidney cancer, arginase-expressing MDSCs accumulate, establishing an immunosuppressive microenvironment by blocking the ability of T-cells and NK-cells to kill cancer cells. We believe that inhibitors of arginase can promote an anti-tumor immune response and augment the activity of checkpoint inhibitors," said Susan M. Molineaux, Ph.D., founder, Chief Executive Officer and President of Calithera Biosciences. "We look forward to reporting initial clinical results with this compound in 2017."

Arginase exerts its immunosuppressive effect by depleting the amino acid arginine in the tumor microenvironment and preventing activation and proliferation of the immune system’s cytotoxic T-cells and NK-cells. We believe that inhibitors of arginase activity promote an anti-tumor immune response by restoring arginine levels in the tumor and reversing this immunosuppressive metabolic checkpoint. The Phase I clinical trial will enroll patients with advanced solid tumors treated with CB-1158 as a monotherapy, as well as in combination with an anti-PD1 therapy.

Epizyme Earns $6 Million Milestone Payment from GlaxoSmithKline for Initiation of Clinical Development with First-in-Class PRMT5 Inhibitor

On September 15, 2016 Epizyme, Inc. (NASDAQ:EPZM), a clinical-stage biopharmaceutical company creating novel epigenetic therapeutics, reported it has earned a $6 million milestone payment from GlaxoSmithKline (GSK) (Press release, Epizyme, SEP 15, 2016, View Source [SID:SID1234515153]). The milestone payment follows GSK’s initiation of patient dosing in a Phase 1 clinical trial of GSK3326595 (formerly EPZ015938), a first-in-class protein arginine methyltransferase-5 (PRMT5) inhibitor discovered by Epizyme and licensed to GSK. PRMT5 is a protein methyltransferase that is associated with a number of human cancers.

"Epizyme has pioneered the discovery and development of epigenetic therapies for the treatment of cancer, with three agents discovered by Epizyme now in clinical development," said Robert Bazemore, President and Chief Executive Officer, Epizyme. "Our collaboration with GSK represents an important part of our strategy of partnering with industry leaders to extend the breadth of our epigenetic therapies while providing resources to help us accelerate our portfolio of assets. We look forward to GSK’s continued progress with this program."

GSK has initiated a Phase 1, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in patients with solid tumors and non-Hodgkin lymphoma.

"The introduction of this PRMT5 inhibitor into the clinic by GSK is an exciting scientific achievement for Epizyme," said Robert A. Copeland, Ph.D., President of Research and Chief Scientific Officer, Epizyme. "This milestone reinforces the strength of our scientific capabilities, which have enabled us to expand our platform into new epigenetic target classes of potentially high importance in oncology. Through our collaborations with GSK and other biopharmaceutical companies, as well as our in-house research efforts, we have developed a number of novel epigenetic programs that we believe hold tremendous potential, including this first-in-class PRMT5 inhibitor."

About the Epizyme-GSK Collaboration

About PRMT5 and GSK3326595
PRMT5 is a protein arginine methyltransferase (PRMT) that is reported to have a role in diverse cellular processes, including tumorigenesis. PRMT5 overexpression is observed in cell lines and primary patient samples derived from a number of cancers, including lymphomas, lung cancer, breast cancer and colorectal cancer. GSK3326595 (formerly EPZ015938), a highly selective and orally bioavailable small molecule, is the first PRMT5 inhibitor and the third epigenetic investigational therapy derived from Epizyme’s proprietary discovery platform to enter the clinic.

Celsion Corporation Announces Positive DSMB Review of Phase 1b OVATION Study in Ovarian Cancer

On September 15, 2016 Celsion Corporation (NASDAQ:CLSN) reported that the independent Data Safety Monitoring Board (DSMB) has completed its safety review of data from the first three patient cohorts in the ongoing Phase Ib OVATION Study (Press release, Celsion, SEP 15, 2016, View Source [SID:SID1234515152]). Based on the DSMB’s recommendation, the study will continue as planned and the Company will proceed with dosing in its fourth and final patient cohort at an escalated dose. The OVATION Study is a dose-escalating clinical trial combining GEN-1, the Company’s DNA-based immunotherapy, with the standard of care for the treatment of newly-diagnosed patients with advanced ovarian cancer who will undergo neoadjuvant chemotherapy followed by interval debulking surgery.

"The DSMB’s recommendation and the lack of any dose limiting toxicities in the trial to date underscore the improved tolerability of GEN-1 over recombinant IL-12 protein-based therapies," said Nicholas Borys, M.D., senior vice president and chief medical officer of Celsion. "The favorable safety profile we have seen thus far is consistent with the translational data that we reported earlier this year, which show that GEN-1 produces a sustained, localized secretion of IL-12 protein and avoids the high levels of systemic exposure which have limited the development of recombinant IL-12 therapies in the past."

"We could not be more excited to progress with the OVATION Study and look forward to reporting clinical findings from the third patient cohort, as well as translational data from the first two cohorts, early in the fourth quarter. Furthermore, we expect to report final data from this highly promising study in the first quarter of 2017," said Michael H. Tardugno, Celsion’s chairman, CEO and president. "We have been encouraged, as have been our Investigators, by the findings to-date in this difficult-to-treat patient population. As we have previously reported, all six patients in the first two cohorts experienced a clinically meaningful response, ranging from stable disease to one pathologically confirmed complete response. In addition, we saw sustained decreases of 90% or greater of the prospective indicator of the presence of ovarian cancer cells, CA-125 protein, in all patients, as well as highly impressive pathologically responses, which is associated with prolonged survival."

The OVATION Study is designed to enroll three to six patients per dose cohort at escalating doses of GEN-1 with the goal to identify a safe, tolerable and therapeutically active dose of GEN-1 by recruiting and maximizing an immune response. The first three cohorts each enrolled three patients. Enrollment in the fourth and final cohort is underway, and Celsion expects to report full data from the OVATION Study by the first quarter of 2017. Future studies of GEN-1 will include a Phase I/II study combining GEN-1 with Avastin and Doxil.

ArQule Announces Publication of Manuscript Highlighting Preclinical Activity of FGFR Inhibitor, ARQ 087, in Peer Reviewed Journal

On September 15, 2016 ArQule, Inc. (Nasdaq: ARQL) reported the publication of a paper detailing the preclinical profile of ARQ 087, an orally available fibroblast growth factor receptor (FGFR) inhibitor (Press release, ArQule, SEP 15, 2016, View Source [SID:SID1234515151]). The findings, published on-line by PLOS ONE, View Source, demonstrate that ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations.

ARQ 087 is being dosed in intrahepatic cholangiocarcinoma (iCCA) patients with FGFR2 genetic alterations as part of the phase 2 portion of a biomarker driven phase 1/2 trial. The company has been granted orphan drug designation by the U.S. Food and Drug Administration and European Medicines Agency for ARQ 087 in this indication.

About Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC)1. Depending on the anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). iCCA originates from the intrahepatic biliary ductal system and forms an intrahepatic mass. The average age adjusted incidence rate for iCCA is approximately one in 100,000 per year in the United States and Europe2,3.

About FGFR and ARQ 087

ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor ("FGFR") family with demonstrated activity in FGFR2 genetic alterations. The FGFR pathway is disrupted in several ways in human cancer, thus providing numerous therapeutic targets for an inhibitor of this pathway. ARQ 087 has demonstrated in vivo inhibition of tumor growth and downstream signaling in tumors whose growth is driven by FGFR targets.

Signals of single agent activity with this drug were observed in phase 1a testing. Phase 1b expansion cohorts with ARQ 087 include patients with cholangiocarcinoma and adrenocortical tumors, as well as those with FGFR translocations, amplifications and mutations. Clinical development of ARQ 087 has advanced into phase 2 for intrahepatic cholangiocarcinoma (iCCA) following the observation of two confirmed responses in this patient population in the phase 1 portion of the program.

EISAI RECEIVES LICENSE FOR NEW INDICATION FOR ANTICANCER AGENT KISPLYX(R) ? (LENVATINIB MESYLATE) FOR TREATMENT OF ADVANCED RENAL CELL CARCINOMA

On September 15, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its European regional headquarters Eisai Europe Ltd. (Location: U.K.) has received license from the European Commission for anticancer agent Kisplyx ▼ (generic name: lenvatinib mesylate, "lenvatinib") in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy (Press release, Eisai, SEP 15, 2016, View Source [SID:SID1234515149]). Following the United States, Europe marks the second region where lenvatinib has been licensed for the advanced renal cell carcinoma indication.

This license was based on a Phase II clinical study (Study 205)1 that evaluated the safety and efficacy of lenvatinib in combination with everolimus in patients with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted therapy. From the results of the study, the lenvatinib plus everolimus group (n=51) demonstrated a significant extension in the study’s primary endpoint of progression free survival (PFS) compared to the everolimus alone group (n=50) (median PFS for the lenvatinib plus everolimus group: 14.6 months vs median PFS for the everolimus alone group: 5.5 months; Hazard Ratio (HR) 0.40 [95% CI: 0.24-0.68], p=0.0005). Furthermore, updated median overall survival in the study population was 25.5 months in the lenvatinib plus everolimus group compared with 15.4 months in the everolimus alone group (HR 0.59 [95% CI: 0.36-0.97]).2 The most common treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) were diarrhea, hypertension and fatigue.

The number of patients with renal cancer is estimated to be approximately 338,000 worldwide, including approximately 115,000 in Europe, 58,000 in the United States and 17,000 in Japan.3 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney,4 and originates from malignant cells in the lining of the tubules of the kidney. The incidence of renal cell carcinoma in people over 55 years of age is rising, and it is more likely to affect men than women. For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment is molecular targeted drug therapy, however with low 5-year survival rates, this remains a disease with significant unmet medical need.

In Europe, lenvatinib has been designated as an orphan drug for thyroid cancer and is marketed as Lenvima for this indication. In Europe, renal cell carcinoma does not meet the criteria for orphan drug designation. Accordingly, under European regulations, any licensed medicine that previously received orphan drug designation for an indication and subsequently receives license for a non-orphan indication must be marketed under a different trade name. As such, lenvatinib will be marketed as Kisplyx ▼ in the European Union for the indication covering renal cell carcinoma.

Eisai positions 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.

*Please refer to the following notes for the licensed indications in the United States, Japan and Europe

Media Inquiries:
Public Relations Department,
Eisai Co., Ltd.
+81-(0)3-3817-5120

1. About lenvatinib mesylate (generic name, "lenvatinib")
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 license 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 has submitted applications for regulatory review in countries throughout the world including South Africa and Malaysia. Specifically, Eisai has obtained license for the agent indicated in the United States for treatment for 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.
Furthermore, lenvatinib was also licensed 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.
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 an immune checkpoint inhibitor for various types of cancer (Phase Ib/II).
Lenvatinib is marketed globally for use in the treatment of thyroid cancer and also in the United States for use in the treatment of renal cell carcinoma under the brand name Lenvima. Lenvatinib has been designated as an orphan drug for thyroid cancer by the regulatory authorities in Japan, the United States and Europe. Under European regulations, any licensed medicine that previously received orphan drug designation for an indication and now received license for a non-orphan indication must be marketed under a different trade name. As such, lenvatinib will be marketed as Kisplyx ▼ in the European Union for the indication covering renal cell carcinoma.

About the Phase II Clinical Study (Study 205)1
Study 205 was a multicenter, randomized, open-label study of the combination of lenvatinib (18 mg) plus everolimus (5 mg), lenvatinib alone (24 mg), and everolimus alone (10 mg) in patients with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted therapy, and was conducted in Europe and the United States. 153 patients were randomized in a 1:1:1 ratio to one of three treatment arms to compare the efficacy and safety of these three regimens.
From the results of the study, the combination of lenvatinib plus everolimus group demonstrated a significant extension in the study’s primary endpoint of progression free survival (PFS) compared to the everolimus alone group (median PFS for the lenvatinib plus everolimus group: 14.6 months vs median PFS for the everolimus alone group: 5.5 months; Hazard Ratio (HR) 0.40 [95% CI: 0.24-0.68], p=0.0005). Additionally, median PFS for the lenvatinib alone group was 7.4 months, demonstrating an extension in PFS compared to the everolimus alone group (HR: 0.61 [95% CI: 0.38-0.98]).
The study also assessed objective response rate (ORR) and overall survival (OS) as secondary endpoints. Regarding ORR, both the lenvatinib plus everolimus group and the lenvatinib alone group showed an improvement in ORR compared to the everolimus alone group (lenvatinib plus everolimus: 43%, lenvatinib alone: 27%, everolimus alone: 6%). Furthermore, regarding OS, updated median overall survival in the study population was 25.5 months in the lenvatinib plus everolimus group compared with 15.4 months in the everolimus group (HR 0.59; 95% CI 0.36 – 0.97).2
The most common any-grade treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) were diarrhea, hypertension and fatigue.