On March 1, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, (Press release, RedHill Biopharma, MAR 1, 2016, View Source [SID:1234509323]) selected key research and development milestones and events anticipated in 2016.

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RedHill’s pipeline includes several Phase III and Phase II-stage programs, as well as earlier-stage development programs. Selected potential highlights for 2016 include:

RHB-104 – Crohn’s disease (Phase III) and multiple sclerosis (Phase IIa)

RedHill has completed enrollment of over half of the planned 270 patients in the Phase III MAP US study for Crohn’s disease in the U.S. and additional countries. Interim analysis of the MAP US study is expected in the second half of 2016, after half of the patients enrolled in the study complete 26 weeks of treatment. If approved for marketing, RHB-104 is expected to become a potential paradigm changer in the treatment of Crohn’s disease, targeting a worldwide market estimated to exceed $6 billion in 20171.

Interim top-line results from the CEASE-MS study, an open label Phase IIa, proof-of-concept clinical study exploring RHB-104 as an add-on therapy to interferon beta-1a in patients treated for relapsing-remitting multiple sclerosis (RRMS), are expected in the coming weeks.

RedHill and Quest Diagnostics (Q Squared Solutions LLC) continue to make progress with the development of the Mycobacterium avium subspecies paratuberculosis (MAP) companion diagnostic test following a pre-submission meeting held with the U.S. Food and Drug Administration (FDA) in 2015.
RHB-105 – H. pylori bacterial infection (Phase III)

A meeting with the FDA is scheduled for April 2016 to discuss the planned confirmatory Phase III study with RHB-105 in the U.S. for the treatment of H. pylori infection.

The FDA meeting follows positive top-line results from the ERADICATE Hp first Phase III study with RHB-105, conducted in the U.S., which successfully met its primary endpoint, demonstrating 89.4% efficacy in eradicating H. pylori with high statistical significance (p < 0.001). The Complete Study Report (CSR) is expected in the coming weeks.

The FDA has granted RHB-105 Qualified Infectious Disease Product (QIDP) designation under the GAIN Act, allowing for a total of eight years of market exclusivity, Fast-Track development and Priority Review status which shortens review time for future marketing applications. RHB-105 is targeting a potential worldwide market estimated at approximately $4.83 billion in 20152.
BEKINDA (RHB-102) – acute gastroenteritis (Phase III) and IBS-D (Phase II)

Top-line results from the GUARD Phase III study with BEKINDA 24 mg in the U.S. for acute gastroenteritis and gastritis are expected in the second half of 2016. If approved for marketing by the FDA, BEKINDA is expected to be the first-ever 5-HT3 antagonist drug indicated for acute gastroenteritis, targeting a potential worldwide market estimated to exceed $650 million annually3.

A Phase II study with BEKINDA 12 mg for diarrhea-predominant irritable bowel syndrome (IBS-D) is planned to be initiated in the U.S. in the coming weeks, subject to regulatory clearance. The U.S. potential market for IBS-D treatments is estimated to exceed $1.3 billion by 20204.

RedHill is also pursuing potential marketing approval of BEKINDA in Europe for the oncology support indications of chemotherapy and radiotherapy-induced nausea and vomiting, pending additional discussions and feedback from European Member States as to whether additional clinical and CMC work is required.
YELIVA (ABC294640) – diffuse large B-cell lymphoma (Phase I/II), refractory or relapsed multiple myeloma (Phase I/II) and radioprotection (Phase II)

A Phase I/II clinical study was initiated to evaluate YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL). The study is being conducted at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans and is supported by a grant awarded to Apogee Biotechnology Corp. ("Apogee"), from which RedHill acquired the rights to YELIVA, from the NCI Small Business Technology Transfer (STTR) program, as well as additional support from RedHill.

A Phase I/II study with YELIVA for the treatment of refractory or relapsed multiple myeloma is planned to be initiated during the second quarter of 2016. The study will be conducted at Duke University Medical Center and is supported by a $2 million grant from the NCI Small Business Innovation Research Program (SBIR) awarded to Apogee in conjunction with Duke University, with additional support from RedHill.

A Phase II clinical study to evaluate YELIVA as a radioprotectant to prevent mucositis in cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the U.S. during the second half of 2016, subject to regulatory and other conditions.

RedHill is pursuing additional oncology and gastrointestinal indications with YELIVA and plans to initiate additional clinical programs, subject to regulatory and other conditions.
MESUPRON and RP101 – orally-administered oncology drug candidates (Phase II-stage)

RP101 – Results from the ongoing pre-clinical studies conducted in collaboration with the Fraunhofer Institute for Cell Therapy and Immunology (IZI), are expected during the first half of 2016. The research collaboration tests RP101 in pre-clinical oncology models, including pancreatic cancer, in combination with standard-of-care chemotherapies, and is intended to support the existing Phase I and Phase II clinical data with RP101 and to assess the drug’s clinical development path.

MESUPRON – Nonclinical studies are currently ongoing and are intended to support the clinical data from previous Phase I and Phase II studies with MESUPRON.
RIZAPORT (RHB-103) – acute migraines

In 2015, the Federal Institute for Drugs and Medical Devices of Germany (BfArM) granted marketing authorization of RIZAPORT 5 mg and 10 mg under the European Decentralized Procedure (DCP), in which Germany served as the Reference Member State. RedHill and IntelGenx Corp. ("IntelGenx") continue to work together to obtain national-phase approvals of RIZAPORT in additional European DCP territories.

RedHill and IntelGenx also continue to work together to bring RIZAPORT to the U.S. market. The companies expect to re-submit the RIZAPORT New Drug Application (NDA) to the FDA and receive a new PDUFA (Prescription Drug User Fee) date in the fourth quarter of 2016.
Ebola virus disease – early stage, non-clinical development program

Following positive initial non-clinical studies, RedHill continues to advance its collaboration with a U.S. government agency to test the antiviral activity of its proprietary experimental combination therapy of orally-administered actives for the treatment of Ebola virus disease.

On March 1, 2016 Amgen (NASDAQ:AMGN) reported the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for BLINCYTO (blinatumomab) to include new data supporting the treatment of pediatric and adolescent patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Amgen, MAR 1, 2016, View Source [SID:1234509321]).

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BLINCYTO, the first-and-only FDA-approved bispecific CD19-directed CD3 T cell engager (BiTE) immunotherapy, is currently available under an accelerated approval in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL, a rare and rapidly progressing cancer of the blood and bone marrow impacting both adults and children.1,2

ALL is the most common type of cancer in children.3 While 95 percent of children with ALL achieve a complete remission with first-line treatment, approximately 650 children in the U.S. each year will relapse or be refractory to treatment.4-6 Pediatric patients with relapsed or refractory ALL have poor long-term outcomes, with an overall survival of less than 10 percent.7 New approaches are needed to improve response rates and help certain patients meet eligibility requirements to receive an allogeneic hematopoietic stem cell transplantation (alloHSCT), the only potentially curative option for patients with relapsed or refractory disease.

"Children with relapsed or refractory ALL have very poor long-term outcomes and currently there are limited available therapies to induce remission," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We look forward to collaborating with regulatory authorities to make BLINCYTO available to this ultra-orphan patient population with a high unmet medical need."

The sBLA is based on data from the Phase 1/2 ‘205 single-arm trial, which found that treatment with BLINCYTO induced complete remission in a clinically meaningful number of pediatric patients with Ph- relapsed or refractory B-cell precursor ALL. Overall, the types of serious adverse events (AEs) reported in the pediatric population are consistent with the known BLINCYTO safety profile. The FDA approved prescribing information for BLINCYTO includes a boxed warning for cytokine release syndrome and neurologic toxicities.

About Study ‘205
Study ‘205 evaluated BLINCYTO in a Phase 1/2 single-arm, multicenter, dose-finding, efficacy trial in patients less than 18 years of age with Ph- B-cell precursor ALL that was refractory, had relapsed at least twice or relapsed after an alloHSCT. Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data will be submitted for publication.

The most frequently reported serious AEs were pyrexia, febrile neutropenia, cytokine release syndrome, sepsis, device-related infection, overdose, convulsion, respiratory failure, hypoxia, pneumonia and multi-organ failure.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BLINCYTO was granted breakthrough therapy and priority review designations by the FDA, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

BLINCYTO was also recently granted conditional marketing authorization in the European Union for the treatment of adults with Ph- relapsed or refractory B-precursor ALL.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

BLINCYTO U.S. Product Safety Information

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

This safety information is specific to the current U.S. approved indication.

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): Life-threatening or fatal CRS occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).

Neurological Toxicities: Approximately 50% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to onset of any neurological toxicity was 7 days. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.

Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.

Tumor Lysis Syndrome (TLS): Life-threatening or fatal TLS has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.

Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.

Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment. The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.

Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy. Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).

Adverse Reactions
The most commonly reported adverse reactions (≥ 20%) in clinical trials were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), diarrhea (20%) and constipation (20%).

Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.

U.S. Dosage and Administration Guidelines
BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

Please see full U.S. Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

On March 1, 2016 Celsion Corporation (NASDAQ: CLSN), a fully-integrated oncology company focused on the development of a portfolio of innovative cancer treatments, including directed chemotherapies, immunotherapies and RNA- or DNA-based therapies for the treatment of cancer and other difficult-to-treat diseases, reported that the U.S. Patent and Trademark Office (USPTO) issued a key patent (U.S. Patent No. 9,254,334 B2) which provides broad intellectual property protection covering the therapeutic use of the Company’s proprietary TheraSilence lung-specific delivery system in a broad range of therapeutic entities, including the delivery of synthetically-generated inhibitory RNA (RNAi) such as small inhibitory RNAs (siRNAs), microRNAs, microRNA mimics, anti-microRNAs and related molecules that can regulate protein expression at the transcript level by exploiting endogenous cell mechanisms (Press release, Celsion, MAR 1, 2016, View Source [SID:1234509317]).

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This new patent further strengthens previously issued patents directed at the composition of the Company’s proprietary TheraSilence family of delivery systems.

"This newly granted patent enhances our strong IP protection surrounding the novel composition of matter claims for our TheraSilence lung-specific delivery system and expands our use claims covering a broad range of therapeutic RNA entities to provide unique treatment options for lung diseases that are not addressable by conventional drugs," said Michael H. Tardugno, chairman, president and chief executive officer of Celsion Corporation. "Our strategy is to seek to maximize the value of this platform in the near-term by pursuing collaborations and development agreements, while focusing internal development efforts on our two clinical stage candidates, ThermoDox and GEN-1, our DNA-based immunotherapy for the localized treatment of ovarian cancer."

Celsion previously announced compelling preclinical findings confirming that the Company’s TheraSilence technology platform can safely and effectively deliver RNA to the lungs in non-human primates. In the study, TheraSilence-formulated signaling RNA resulted in preferential expression in the lungs, with expression in the liver at less than 15% of expression levels observed in the lungs. Expression levels in tissues other than the lung, spleen and liver were very low or at background levels. These data build on previous preclinical studies indicating the preferential delivery of RNA to the lung using the TheraSilence RNA delivery system.

A murine study demonstrated that the delivery of TheraSilence-formulated siRNA molecules designed to target vascular endothelial receptor 2 (VEGFR2), a protein that is critical for the growth of new blood vessels in tumors, significantly inhibited VEGFR2 expression and lung tumor growth.
Delivery of a TheraSilence-formulated anti-micro RNA molecule into rats with experimentally induced pulmonary arterial hypertension appeared to normalize vascular remodeling that occurs in the lung and help restore cardiac function that is compromised as a result of the disease.

On March 1, 2016 EUSA Pharma, a newly-established specialty pharmaceutical business, and AVEO Oncology (NASDAQ:AVEO) reported the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency for tivozanib for the first-line treatment of advanced renal cell carcinoma (RCC) (Press release, AVEO, MAR 1, 2016, View Source [SID:1234509302]).

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The filing is based on tivozanib’s existing dataset and follows positive interactions with the Rapporteur and Co-Rapporteur during 2015 which indicated support for a filing using the phase III TIVO-1 trial as the pivotal study. EUSA Pharma submitted the application under the European Union’s centralized procedure, which permits the agency to issue a single marketing authorization that is valid across all EU countries.

Under the companies’ license agreement announced in December 2015, EUSA holds exclusive commercialization rights to tivozanib in RCC in Europe and in a number of other territories outside North America, including South America and South Africa, in addition to a range of further indications. Under the terms of the agreement, EUSA Pharma will undertake and fund the commercialization of the product in its territories, assuming approval.

"Survival rates in advanced renal cancer remain low and current therapies can be associated with treatment-limiting toxicities, resulting in significant unmet need where tivozanib has the potential to become an important new first-line therapy," said Lee Morley, Chief Executive Officer of EUSA Pharma. "We are delighted to have achieved the submission of our Marketing Authorization Application to the European Medicines Agency so soon after licensing this exciting product, and we look forward to the outcome of the regulators’ review. In our short history, we have made great strides in building a strong portfolio of specialist medicines, and our filing of tivozanib in Europe is another milestone in EUSA’s journey to become a leading specialty pharmaceutical business."

"Filing of an MAA by our partner EUSA Pharma is an important step toward the potential commercialization of tivozanib in territories around the world," said Michael Bailey, President and Chief Executive Officer of AVEO. "We continue to leverage strong partnerships to advance our pipeline, including tivozanib in areas outside of North America and oncology, while we focus on the development and regulatory path forward for tivozanib in North America. We look forward to making progress on this path in the near-term, including the potential initiation of a Phase 3 trial of tivozanib in third line RCC to potentially enable registration in the first- and third-lines in the U.S."

About Tivozanib

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.