On June 29, 2015 Celgene and Juno reported a global collaboration for the development and commercialization of immunotherapies (Press release, Celgene, JUN 29, 2015, View Source [SID:1234506009]). The two companies will leverage T cell therapeutic strategies to develop treatments for patients with cancer and autoimmune diseases with an initial focus on Chimeric Antigen Receptor Technology (CAR-T) and T Cell Receptor (TCR) technologies.

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"This transaction strengthens Celgene’s position in the emerging and transformative area of immuno-oncology," said Bob Hugin, Chairman and CEO of Celgene. "Juno has assembled world class experts and built impressive capabilities and technologies in the areas of T cell biology and cellular therapy; we believe this long-term collaboration enhances the potential of both companies to deliver transformational therapies to patients with significant unmet medical needs."

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"Celgene is the ideal partner for Juno to help us realize the full potential of our science and clinical research while maintaining the independence we, our employees, partners, and investors believe is so critical for true innovation," said Hans Bishop, CEO of Juno. "This unique collaboration is designed to catalyze and create tremendous ongoing scientific and product development synergy by leveraging each company’s strengths and assets. In addition to its established global presence and commercial reach, Celgene has leading small molecule and protein capabilities that complement Juno’s advanced engineered T cell capabilities. By doing this together, we believe we can more quickly and effectively develop potentially disruptive therapies in this new field of medicine and make them more readily available to patients worldwide."

Under the terms of the collaboration, Celgene has the option to be the commercialization partner for Juno’s oncology and cell therapy auto-immune product candidates, including Juno’s CD19 and CD22 directed CAR-T product candidates. B-Cell Maturation Antigen (BCMA) is excluded as a target in this collaboration.

For Juno-originated programs co-developed under the collaboration:

Juno will be responsible for research and development in North America and will retain commercialization rights in those territories;
Celgene will be responsible for development and commercialization in the rest of the world, and will pay Juno a royalty on sales in those territories; and
Celgene has certain co-promotion options:
Celgene will initially be eligible to select two programs, excluding CD19 and CD22, to be subject to a global profit sharing agreement under which the companies will share worldwide expenses and profits equally, except in China; and
Additionally, subject to additional obligations, Celgene may select a third program.
Juno will have the option to enter into a co-development and co-commercialization agreement on certain Celgene-originated development candidates that target T Cells. For any such Celgene-originated programs co-developed under the collaboration:

The parties will share global costs and profits with 70% allocated to Celgene and 30% allocated to Juno; and
Celgene will lead global development and commercialization, subject to a Juno co-promote option in the US and certain EU territories.
Upon closing, Juno will receive an upfront payment of approximately $150 million, and in addition Celgene will purchase 9,137,672 shares of Juno’s common stock at $93.00 per share. In conjunction with this stock purchase:

Celgene will receive the right to nominate a member to Juno’s board of directors;
During the 10-year term of the collaboration, Celgene will have the right to purchase additional equity in Juno during specified windows and at specified market premiums subject to satisfaction of certain conditions by each party including Juno opting in on select Celgene programs, such that, at a maximum, Celgene could own up to 30% of Juno’s common stock then outstanding; and
Celgene has entered into a standstill agreement and agreed to certain lock-up provisions on its share ownership.
This transaction has been approved by the boards of directors of both companies. Celgene and Juno currently expect to complete the transaction during the third quarter of 2015, subject to the expiration or termination of applicable waiting periods under all applicable antitrust laws and satisfaction of other usual and customary closing conditions.

On June 29, 2015 RedHill Biopharma reported that it has initiated a Phase I/II clinical study in the U.S. evaluating ABC294640 in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) (Press release, RedHill Biopharma, JUN 29, 2015, View Source [SID:1234506006]).

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ABC294640 is a proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor, with anti-inflammatory and anti-cancer activities, targeting multiple inflammatory, gastrointestinal (GI) and oncology indications. SK2 is an innovative molecular target for anti-cancer therapy because of its critical role in catalyzing the formation of the lipid-signaling molecule sphingosine 1-phosphate (S1P), which is known to regulate cell proliferation and activation of inflammatory pathways. By inhibiting SK2, ABC294640 could potentially be effective in treating multiple inflammatory, oncologic and gastrointestinal diseases.

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The Phase I/II study is intended to evaluate the safety and tolerability of ABC294640, as well as provide a preliminary evaluation of efficacy of the drug in patients with refractory/relapsed DLBCL, primarily patients with HIV-related DLBCL. Up to 33 patients are expected to be enrolled in the study, which will be conducted at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans. The study is funded primarily by a grant awarded by the National Cancer Institute (NCI) Small Business Technology Transfer (STTR) program. Dr. Chris Parsons, MD, an associate professor in the Departments of Medicine and Microbiology, Immunology & Parasitology at LSUHSC, is the lead investigator for the study.

Dr. Terry Plasse, MD, RedHill’s Medical Director, said: "We are excited to initiate this translational study with ABC294640, carrying Dr. Parson’s laboratory evaluations into an important clinical population of patients with refractory/relapsed diffuse large B-cell lymphoma, primarily patients with HIV-related DLBCL, a group of patients with substantial unmet medical needs. RedHill continues to advance towards additional Phase II clinical studies with ABC294640 as a radioprotectant in cancer patients undergoing therapeutic radiotherapy and, subject to a pending NCI/SBIR grant, multiple myeloma."

DLBCL is the most common subtype of non-Hodgkin’s lymphoma, accounting for an estimated 30% of the 70,000 projected non-Hodgkin’s lymphoma cases diagnosed in the U.S. in 20151. Many DLBCLs are etiologically linked to the human viruses which encode unique oncogenes contributing to tumor onset and progression. Standard treatments for DLBCL exhibit limited efficacy and incur significant toxicities.

The Phase I/II study was initiated following positive pre-clinical studies, led by Dr. Parsons, indicating the therapeutic activity of ABC294640 for virus-associated DLBCL, in an established xenograft model for Kaposi’s sarcoma-associated herpesvirus-associated DLBCL, including reversal of disease progression for established tumors. The pre-clinical studies were performed in parallel with a successful Phase I study that demonstrated the drug’s safety and assessed its pharmacokinetics and pharmacodynamics in cancer patients with advanced solid tumors.

RedHill acquired the rights to ABC294640 in March 2015 from U.S.-based Apogee Biotechnology Corporation ("Apogee"). Prior to the acquisition, Apogee completed numerous successful pre-clinical studies with ABC294640 in GI, inflammation, radioprotection and oncology models, as well as a successful Phase I clinical study in cancer patients with advanced solid tumors. The open-label, dose-escalation, Phase I clinical study demonstrated the drug’s safety and assessed its pharmacokinetics and pharmacodynamics in cancer patients with advanced solid tumors. The development of ABC294640 was funded to date primarily through grants and contracts in excess of $14 million from U.S. federal and state government agencies, such as the FDA, Department of Defense (DoD) and the National Institutes of Health (NIH), including the National Cancer Institute and BARDA.

A second Phase II study of ABC294640 is planned to evaluate ABC294640 as a radioprotectant to prevent mucositis in cancer patients undergoing therapeutic radiotherapy. RedHill also plans a third Phase II clinical study for the treatment of multiple myeloma, subject to funding by a pending grant from the National Cancer Institute.

The Phase I/II study with ABC294640 for refractory/relapsed diffuse large B-cell lymphoma is registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health which provides public access to information on publicly and privately supported clinical studies: View Source

About ABC294640:

ABC294640 is a first-in-class, proprietary sphingosine kinase-2 (SK2) selective inhibitor, administered orally, with anti-cancer and anti-inflammatory activities, targeting multiple potential inflammatory, oncology and gastrointestinal indications. By inhibiting the SK2 enzyme, ABC294640 blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid that promotes cancer growth and pathological inflammation. ABC294640 was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in inflammatory, GI, radioprotection and oncology models, as well as a Phase I clinical study in cancer patients with advanced solid tumors. A Phase I/II clinical study evaluating ABC294640 in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has been initiated in the U.S. The development of ABC294640 was funded to date primarily through grants and contracts in excess of $14 million from U.S. federal and state government agencies.

On June 29, 2015 Juno reported the U.S. Food and Drug Administration (FDA) accepted the Company’s investigational new drug (IND) application for JCAR017 for patients with relapsed/refractory (r/r) B cell non-Hodgkin lymphoma, or NHL (Press release, Juno, JUN 29, 2015, View Source [SID:1234506005]). JCAR017 is a chimeric antigen receptor (CAR) T cell product candidate targeting CD19, a protein expressed on the surface of most B cell leukemias and lymphomas.

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The IND enables Juno to initiate a multi-center Phase I trial exploring JCAR017 for r/r NHL, scheduled to begin in 2015, with the potential to advance to a registration trial in 2016.

"Based on the encouraging results of JCAR017 in pediatric acute lymphoblastic leukemia, we are excited to begin investigating this product candidate in non-Hodgkin lymphoma," said Mark Frohlich, M.D., Juno EVP of development and portfolio strategy. "FDA acceptance of the JCAR017 IND for this multi-institutional study is an important milestone for Juno. Together with our planned fully-human CD19 CAR-T cell trial, combination study with AstraZeneca’s anti-PDL-1 antibody, and ongoing translational clinical trial with JCAR014, it will provide important biologic insights that will inform our future strategies."

In collaboration with Seattle Children’s Research Institute, Juno continues to investigate JCAR017 in pediatric patients with r/r acute lymphoblastic leukemia (ALL). Results of a Phase I study to date demonstrated 91 percent of patients achieved a complete remission, all of which were documented by flow cytometry. Adverse events were consistent with what has been previously reported. The results were presented in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2015 in Philadelphia.

About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s chimeric antigen receptor (CAR) and T cell receptor technologies (TCR) genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell.

On June 29, 2015 CytRx reported the presentation of interim results from its ongoing open-label Phase 2 pilot study evaluating the efficacy and safety of aldoxorubicin for the treatment of Kaposi’s Sarcoma (KS) in HIV-infected patients (Press release, CytRx, JUN 29, 2015, View Source [SID:1234506004]). The data will be presented on Wednesday, July 1, 2015 during a poster session at the 18th International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents in Hollywood, Florida.

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For the study, patients with biopsy-confirmed KS were administered 100 or 150 mg/m2 aldoxorubicin (75 or 112 mg/m2 doxorubicin equivalents) IV every three weeks. At the time of presentation, preliminary analyses were available for nine patients who received at least six cycles of drug (mean = 6.3 cycles). Four patients had received prior Doxil chemotherapy. Of these 9 patients, 6 (67%) demonstrated a partial response (PR) to aldoxorubicin at the end of study visit (EOS), and 7 (78%) demonstrated PR within 4 months of EOS. Doxorubicin could be detected in all tumor biopsies and higher doxorubicin concentrations were demonstrated within KS lesions relative to skin next to the lesions for 3/4 (75%) patients for whom adequate tissue was available for analysis. Five of 6 (83%) patients receiving aldoxorubicin and for whom data are available exhibited reduced intratumoral viral loads during therapy. A subset of patients also exhibited improvements in quality of life during treatment, and all patients exhibited either improvement or stability in immunologic and virologic HIV treatment parameters. Aldoxorubicin was well-tolerated, with only 2 patients (22%) experiencing a grade 4 adverse event (transient neutropenia and anemia), and overall AEs (44%) were mild and compared favorably with AE rates from other trials enrolling KS patients representing urban, minority-predominant populations.

"KS remains an important cause of morbidity and mortality for HIV-infected patients worldwide, yet significant toxicities limit drug exposure and outcomes for many patients when antiretroviral therapy is combined with standard treatments like liposomal doxorubicin (Doxil)," said Chris Parsons, MD, Associate Professor in the Departments of Medicine and Microbiology, Immunology, & Parasitology at the Louisiana State University Health Sciences Center, and principal investigator of the study. "These data demonstrate aldoxorubicin’s ability to leverage cancer biology to preferentially release chemotherapeutic drugs in tumors, thereby limiting toxicity, increasing drug exposure and improving outcomes. We remain highly encouraged by the activity and tolerability of aldoxorubicin in this study, and look forward to its continued enrollment and final results."

This open-label Phase 2 clinical trial is expected to enroll up to 30 patients, randomly assigned to two equally sized treatment arms which will receive aldoxorubicin at 100 or 150 mg/m2 by 30-minute intravenous infusion. Because the KS patients in the study have compromised immune systems, the aldoxorubicin dosages administered in the trial are lower than those administered in the Company’s clinical testing of aldoxorubicin in patients with soft tissue sarcomas. Patients with advanced KS receive aldoxorubicin on day 1, then every 3 weeks until evidence of tumor progression, unacceptable toxicity or withdrawal of consent. The primary objectives of preliminary efficacy include evaluation of the size, number and nodularity of skin lesions, change in size and number of lung lesions and changes in the number of tumor cells that express viral DNA (Kaposi sarcoma-associated herpesvirus, the etiologic agent of KS). The Company is also evaluating the level of aldoxorubicin uptake into lesions. Safety is being assessed through monitoring of adverse events and the ability to remain on assigned treatment. The trial is being conducted at the Louisiana State University Health Sciences Center in New Orleans, LA.

KS is an orphan indication in the U.S.

About Kaposi’s Sarcoma

Kaposi sarcoma is a cancer that causes lesions (abnormal tissue) to grow in the skin; the mucous membranes lining the mouth, nose, and throat; lymph nodes; or other organs. The lesions are usually purple and are made of cancer cells, new blood vessels, red blood cells, and white blood cells. Kaposi sarcoma is different from other cancers in that lesions may begin in more than one place in the body at the same time. KS remains the most common HIV-associated tumor worldwide. The condition is also endemic in certain parts of Central Africa and Central and Eastern Europe.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

On June 29, 2015 Celldex Therapeutics that an independent Data Safety and Monitoring Board (DSMB) recommended continuation of the Phase 3 ACT IV study of RINTEGA (rindopepimut) in patients with newly diagnosed glioblastoma (Press release, Celldex Therapeutics, JUN 29, 2015, View Source [SID:1234506002]).

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The ACT IV study is a randomized, double-blind, placebo controlled study of rindopepimut plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. 745 patients were enrolled into ACT IV to reach the required 374 patients with minimal residual disease (assessed by central review) needed for analysis of the primary overall survival endpoint. All patients, including those with disease that exceed this threshold, will be included in a secondary analysis of overall survival as well as analyses of progression-free survival, safety and tolerability, and quality of life. The timing of the overall survival primary endpoint data is event-driven. Interim analyses assessing safety, futility and efficacy conducted by an independent DSMB were prespecified at 50 percent and 75 percent of events.

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As previously announced, the second interim analysis is expected to occur in late 2015/early 2016.

RINTEGA is a registered trademark of Celldex Therapeutics.

About RINTEGA

RINTEGA is an investigational therapeutic vaccine that targets the tumor specific oncogene EGFRvIII, a functional and permanently activated variant of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long term survival in clinical studies of patients with glioblastoma (GBM). In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in GBM. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in tumors in about 30% of patients with GBM. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues.

Three Phase 2 trials of RINTEGA—ACTIVATE, ACT II, and ACT III—have been conducted in newly diagnosed EGFRvIII-positive GBM and have shown consistent improvements in both overall survival and progression-free survival compared to matched historical controls. The most common adverse events for RINTEGA include injection site reactions, fatigue, rash, nausea and pruritus. RINTEGA is currently being studied in two clinical trials in EGFRvIII-positive GBM—an international Phase 3 study called ACT IV in newly diagnosed GBM and a Phase 2 study called ReACT in recurrent GBM. In February 2015, the U.S. Food and Drug Administration (FDA) granted RINTEGA Breakthrough Therapy Designation for the treatment of adult patients with EGFRvIII-positive glioblastoma (GBM).