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RedHill Biopharma Provides Update on Development Pipeline and Expected Timing for RHB-105 Phase III Top-Line Results

On June 3, 2015 RedHill Biopharma reported an update on its development pipeline and anticipated key milestones (Press release, RedHill Biopharma, JUN 3, 2015, View Source [SID:1234505217]).

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RHB-105 – for H. pylori bacterial infection

Top-line results from the first Phase III clinical study with RHB-105 are expected in the third week of June 2015. The Phase III study (the ERADICATE Hp study) is currently ongoing in the U.S. for the treatment of H. pylori bacterial infection, a major cause of chronic gastritis, peptic ulcer disease, gastric cancer, and mucosa associated lymphoid tissue (MALT) lymphoma

RHB-105 was designated by the FDA as a Qualified Infectious Disease Product (QIDP) under the Generating Antibiotic Incentives Now (GAIN) Act, allowing RedHill to benefit from fast-track development status for RHB-105, priority review, and, if ultimately approved by the FDA, an additional five years of marketing exclusivity, for a total of 8 years

The 2015 global and U.S. market potential for H. pylori eradication therapies, at current branded prices, were recently estimated at approximately $4.83 billion and $1.45 billion, respectively, and could potentially grow with increasing awareness of the health risks associated with H. pylori infection and the benefits of its eradication1

BEKINDA (RHB-102) – for gastroenteritis and gastritis, and for chemotherapy and radiotherapy-induced nausea and vomiting (CINV and RINV, respectively)

Top-line results from the Phase III study with BEKINDA for acute gastroenteritis and gastritis (the GUARD study), currently ongoing in the U.S., are expected either in the fourth quarter of 2015 or the first quarter of 2016. The results are intended to support potential future submissions of marketing applications in both the U.S. and Europe, targeting an estimated potential worldwide market exceeding $650 million annually2

A meeting with the FDA is planned during the third quarter of 2015 to discuss the regulatory path of BEKINDA for the indications of acute gastroenteritis and gastritis, as well as a potential filing of a New Drug Application (NDA) for CINV

RedHill recently received feedback from European regulatory agencies regarding the European Marketing Authorization Application (MAA) submitted by RedHill in December 2014 for the oncology support indications of CINV and RINV. Clinical and manufacturing-related comments have been discussed with the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and a six-month extension was agreed to, in principle, with the MHRA

A Phase IIa Proof of Concept study for a new undisclosed indication is planned to commence in the second half of 2015

RHB-104 – for Crohn’s disease, multiple sclerosis and other inflammatory diseases

Interim analysis of the Phase III study with RHB-104 for Crohn’s disease (the MAP US study) is expected in the second half of 2016, after half of the 270 patients expected to be enrolled in the study have completed 26 weeks of treatment. The primary endpoint is remission at week 26 of treatment

The Phase III MAP US study is currently enrolling patients in approximately 80 sites in the U.S., Canada, Israel and New Zealand, with new sites in Australia, New Zealand and Europe currently being added, for a total of up to 120 clinical sites

Clinical trial applications have been submitted in Europe, and initial comments received and responded to, for RHB-104’s second Phase III Crohn’s disease study (the MAP EU study) with potential European regulatory clearance expected in the third quarter of 2015

RedHill recently received a Notice of Allowance from the U.S. Patent and Trademark Office (USPTO) for two new patents covering RHB-104. Once granted, the patents are expected to be valid until at least 2029

The last patient has been screened in the ongoing Phase IIa Proof of Concept study with RHB-104 for the treatment of multiple sclerosis (MS) (the CEASE-MS study), with interim results expected either in the fourth quarter of 2015 or the first quarter of 2016

ABC294640 – for multiple inflammatory-GI diseases and related oncology indications

ABC294640 is a proprietary, first-in-class, orally administered, new chemical entity (NCE) sphingosine kinase-2 (SK2) inhibitor, which has successfully completed numerous pre-clinical studies and a Phase I study in cancer patients with advanced solid tumors.

ABC294640 targets multiple inflammatory, gastrointestinal and oncology indications within RedHill’s therapeutic focus.

A Phase Ib/II study of ABC294640 for refractory/relapsed diffuse large B cell lymphoma, primarily funded by the National Cancer Institute/STTR, is planned to commence either in the second or third quarter of 2015

A Phase II study in multiple myeloma is planned, subject to a pending National Cancer Institute/SBIR grant

A Phase II study to assess ABC294640 as a radio-protectant and radiation enhancer in cancer patients receiving radiotherapy is being planned by RedHill

RHB-106 – bowel cleanser pill

In February 2014, RedHill and Salix Pharmaceuticals, Inc. ("Salix") entered into a license agreement under which Salix acquired worldwide exclusive rights to RHB-106 and other purgative developments. In April 2015, Valeant Pharmaceuticals International, Inc. ("Valeant") announced the completion of its acquisition of Salix. The RHB-106 program is under review by Valeant following its acquisition of Salix

MESUPRON – for pancreatic cancer and other solid tumors

RedHill is preparing nonclinical studies to further evaluate the mechanism of action and define the patient population for MESUPRON, a Phase II orally-administered small molecule drug targeting pancreatic cancer and other solid tumors. MESUPRON is a first-in-class urokinase-type plasminogen activator (uPA) inhibitor

RP101 – for pancreatic cancer and other solid tumors

RedHill is preparing nonclinical studies to further evaluate the mechanism of action and define the patient population for RP101, a Phase II orally-administered small molecule drug targeting pancreatic cancer and other solid tumors. RP101 is a first-in-class heat shock protein 27 (Hsp27) inhibitor

Ebola virus disease – early stage development program

As part of a previously disclosed nonclinical research collaboration with a U.S. government agency, initial nonclinical studies have been completed, and RedHill is currently planning the next stage of development

RIZAPORT (RHB-103) – for acute migraines

Regulatory feedback regarding the MAA submitted in October 2014 is expected either in the fourth quarter of 2015 or the first quarter of 2016

RedHill and its Canadian co-development partner IntelGenx Corp. continue to work with the FDA to address the remaining Chemistry, Manufacturing and Controls (CMC) matters, and to secure a compliant source of raw material. The existing source of raw material for RIZAPORT has been successfully audited in recent months by non-U.S. regulatory agencies, as well as an independent auditor on behalf of RedHill, and is currently awaiting another FDA inspection, after which, and subject to a successful audit, a new FDA PDUFA date is expected

NICE recommends VARGATEF® (nintedanib*) in combination with docetaxel as an option for patients with non-small cell lung cancer of adenocarcinoma histology within its licensed indication

On June 3, 2015 Boehringer Ingelheim reported that following a review by the National Institute for Health and Care Excellence (NICE) in the UK, VARGATEF (nintedanib*) in combination with docetaxel has been recommended for use within the National Health Service (NHS) in England and Wales (Press release, Boehringer Ingelheim, JUN 3, 2015, View Source [SID:1234505215]).1 This is positive news for patients with locally advanced metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma histology who have had limited treatment options that have been shown to extend survival after first-line chemotherapy.

Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "We are delighted with this announcement from NICE which represents an important milestone in the effort to extend survival for patients with adenocarcinoma of the lung following initial treatment with chemotherapy. The survival advantage demonstrated by VARGATEF, in combination with docetaxel, has been shown with a predictable and generally manageable safety profile."

NICE has issued a Final Appraisal Determination (FAD) for VARGATEF and, subject to any appeal by consultees, the FAD may be used as the basis for the institute’s guidance on the use of the appraised technology in the NHS in England and Wales.1 Nintedanib, in combination with docetaxel, is the first and only triple angiokinase inhibitor available for EU patients with advanced NSCLC of adenocarcinoma histology after first-line chemotherapy.

Since the launch of VARGATEF in January 2015 it has also been:

accepted for use without restriction within NHS Scotland, as per its licensed indication2

accepted by the Swedish Dental and Pharmaceutical Benefits Agency to be subsidised as a treatment of advanced lung cancer patients with adenocarcinoma in combination with docetaxel after first-line chemotherapy3

assessed by the German IQWiG who indicated an added benefit for the treatment of advanced lung cancer patients with adenocarcinoma in combination with docetaxel after first-line chemotherapy without brain metastases4

These announcements are based on the outcomes of the LUME-Lung 1 study which demonstrated:5

nintedanib, plus docetaxel, significantly prolonged progression-free survival compared to docetaxel alone for patients with
adenocarcinoma (PFS: primary endpoint; 4.0 vs 2.8 months)

nintedanib, plus docetaxel, significantly extended overall survival to beyond one year for patients with adenocarcinoma, compared to docetaxel alone (OS: key secondary endpoint; 12.6 vs 10.3 months)

nintedanib, plus docetaxel, enabled 1 in 4 patients with adenocarcinoma to live for at least two years after first-line chemotherapy

Nintedanib in combination with docetaxel demonstrated a generally manageable side-effect profile without further compromising patients’ overall, health-related, quality of life compared to chemotherapy alone. The most common adverse events for patients taking docetaxel vs nintedanib plus docetaxel included: nausea 18% vs 24%; vomiting 9% vs 17%; diarrhoea 22% vs 42% and elevated liver enzymes 8% vs 29%.5

Adenocarcinoma is the most common type of lung cancer and the majority of patients are diagnosed in an advanced stage.6 Most patients will experience disease progression during or after first-line chemotherapy and there is a significant need for new, effective second-line treatments.5

VARGATEF was granted EU marketing authorisation in November 2014 and in combination with docetaxel is indicated for use in adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology, after first-line chemotherapy.

Celgene and bluebird bio to Develop Anti-BCMA Product Candidates; bluebird bio Regains Rights to CAR T Programs Outside of BCMA

On June 3, 2015 bluebird bio reported that its existing global collaboration agreement with Celgene Corporation (Nasdaq: CELG) has been amended and restated to focus on developing product candidates targeting B-cell maturation antigen (BCMA) during a three-year collaboration term (Press release, bluebird bio, JUN 3, 2015, View Source [SID:1234505224]).

The original collaboration, initiated in 2013, was focused on applying gene therapy technology to genetically modify a patient’s own T cells to target and destroy cancer cells. BCMA is the first target selected to advance to the clinic under this collaboration. BCMA is a cell surface protein that is expressed in normal plasma cells and in most multiple myeloma cells, but is absent from other normal tissues.

Celgene and bluebird bio will work collaboratively on the initial, lead anti-BCMA product candidate (bb2121), with a Phase 1 clinical trial expected to begin enrollment in early 2016, and develop next-generation anti-BCMA product candidates. bluebird bio retains sole rights to develop all other chimeric antigen receptor (CAR) T cell programs developed by bluebird bio under the collaboration, including ongoing undisclosed preclinical programs with opportunities in both solid tumors and hematologic malignancies.

Under the terms of the amended and restated collaboration agreement:

bluebird bio will receive a $25 million payment to develop the lead anti-BCMA product candidate through a Phase 1 clinical trial and develop next-generation anti-BCMA product candidates.

bluebird bio will be responsible for the development of all anti-BCMA product candidates through the completion of Phase 1 studies.

Additionally, on a product-by-product basis within the anti-BCMA product program, Celgene has an option to develop and commercialize each product candidate worldwide, and bluebird bio has the option to share equally in the development, promotion and profits of each product candidate in the United States. In addition to the payments described above and consistent with the prior agreement, Celgene would also pay bluebird bio specified development and regulatory milestone payments as well as royalty payments on net sales.

"We have successfully achieved the initial goal of our collaboration with Celgene —identifying a promising lead development candidate in the CAR T cell field — and we are excited to focus our Celgene collaboration on the development of anti-BCMA products," said Nick Leschly, chief bluebird. "Celgene is a leader in developing and commercializing therapies for multiple myeloma, and we believe they are the best global partner for our first CAR T program. Together we look forward to entering the clinic early next year with bb2121 and continuing our collaboration around next-generation BCMA products."
"Our collaboration with bluebird bio has collectively made strong progress advancing a lead product candidate, targeting BCMA, toward the clinic in hematologic malignancies. We look forward to continuing to work with bluebird and build on the recent success to advance the anti-BCMA program and ultimately, to succeed on the goal of delivering a high-impact therapeutic in the CAR T arena," said Tom Daniel, M.D., President of Research and Early Development at Celgene.

A Unique Position in Immuno-oncology
Outside of BCMA, bluebird bio is independently pursuing the development of a broad portfolio of novel immuno-oncology therapeutics. This portfolio will leverage bluebird bio technology, including its lentiviral vector platform, gene editing capabilities and internal gene therapy and immuno-oncology expertise.

"Consistent with the long-term vision for bluebird bio, we are expanding our immuno-oncology T cell-based efforts in parallel with our late-stage hematopoietic stem cell-based programs," said Rob Ross, M.D., senior vice president, clinical development, bluebird bio. "Our goal is to initiate multiple clinical trials over the next several years against novel targets in both solid and hematologic malignancies by integrating our proprietary lentiviral and gene editing platforms with our immuno-oncology expertise and experience in implementing multi-center, industry-sponsored gene therapy studies. This is an exciting step in bluebird bio’s evolution and an opportunity for us to further realize the value that gene therapy can bring to patients and families in need."

Currently, bluebird bio has active pre-clinical research programs targeting multiple different, novel oncology antigens, including BCMA. These programs include various T cell therapies with significant academic and industry collaborations. bluebird bio recently announced a strategic collaboration with Five Prime Therapeutics, which marries Five Prime’s antigen discovery platform and certain human antibodies with bluebird bio’s immuno-oncology and gene therapy capabilities, with the potential for development candidates in both hematologic malignancies and solid tumors.

Merck Extends Immuno-Oncology Collaboration with Agenus

On June 3, 2015 Agenus reported that Merck, known as MSD outside the United States and Canada, through a subsidiary, has extended its collaborative research term under its existing collaboration and license agreement with Agenus, for the discovery and development of therapeutic antibodies to Merck proprietary immune checkpoints for the treatment of cancer (Press release, Agenus, JUN 3, 2015, View Source [SID:1234505219]).

Under the terms of the original agreement, Agenus will discover and optimize fully human antibodies against two undisclosed Merck checkpoint targets using the Retrocyte Display platform. Merck will be responsible for the further development and commercialization of candidates generated under the collaboration. The discovery phase has been extended to April 2016. As previously disclosed, under the terms of the agreement, Agenus is eligible to receive approximately $100 million in milestone payments as well as royalties on worldwide product sales.

"This collaboration has resulted in encouraging outcomes, and we’re delighted that a leader in the rapidly developing immuno-oncology space has elected to extend this discovery phase of our collaboration," said Robert Stein, MD, PhD, Chief Scientific Officer of Agenus Inc. "We believe our antibody generating technology is now the most extensive in vitro platform in the industry with significant advantages for creation of high quality antibody candidates."

Aptose Biosciences Granted Orphan Drug Designation by the U.S. FDA for APTO-253 in Acute Myeloid Leukemia

On June 2, 2015 Aptose Biosciences reported that the U.S. Food and Drug Administration (FDA) has granted the company orphan drug designation for APTO-253 for the treatment of acute myeloid leukemia (AML) (Press release, Aptose Biosciences, JUN 2, 2015, View Source [SID:1234505214]). APTO-253, a first-in-class inducer of the KLF4 gene, is the company’s lead product candidate in a Phase Ib clinical trial in patients with AML, high-risk myelodysplastic syndrome (MDS) and other hematologic malignancies in which KLF4 silencing is reported as operative.

"AML is a particularly challenging cancer of the blood and bone marrow for which there are currently few treatment options," said William G. Rice, Ph.D., Chairman, President and CEO. "APTO-253, with its unique mechanism of action, has the potential to emerge as an entirely new therapeutic approach for this patient population, and receiving orphan drug designation is a key regulatory milestone along the path."

Epigenetic suppression of the Krüppel-like factor 4 (KLF4) gene has been reported in the scientific literature as a key transforming event in AML. APTO-253 is a first-in-class, targeted inducer of the KLF4 tumor suppressor gene, and has demonstrated a favorable safety profile with no evidence of suppression of the normal bone marrow. Preclinical studies have shown potent single-agent activity to kill AML cells and strong synergy as part of a combination strategy with various marketed and investigational agents. APTO-253 is currently in a Phase 1b clinical study in patients with relapsed or refractory hematologic malignancies.

Orphan drug designation is granted by the FDA to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States. Orphan drug status provides research and development tax credits, an opportunity to obtain grant funding, exemption from FDA application fees and other benefits. If APTO-253 is approved to treat AML, the orphan drug designation provides Aptose with seven years of marketing exclusivity.

About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a cancer derived from myeloid progenitor or stem cells that typically mature into red blood cells, white blood cells or platelets. AML initiates in the bone marrow when stem or progenitor cells lose cell cycle control, anti-apoptotic factor or other means to limit rampant proliferations. Leukemic cells have the ability to rapidly spread from the marrow to the bloodstream. Further, these rapidly proliferating cells quickly crowd out normal cells as they infiltrate other organs and tissue systems.

AML is the most common type of acute leukemia among adults, with an annual incidence of more than 18,000 patients, and causing more than 10,000 deaths each year in the U.S. It is a particularly devastating blood cancer, with less than 25 percent of newly diagnosed patients surviving beyond five years.