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6-K – Report of foreign issuer [Rules 13a-16 and 15d-16]

On July 16, 2015 Cellectis reported the publication of a study in Cancer Research describing the applicability of TALEN-mediated genome editing to a scalable process, which enables the manufacturing of third-party CAR T-cell immunotherapies (Filing, 6-K, Cellectis, JUL 16, 2015, View Source [SID:1234506351]).

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Adoptive immunotherapy using autologous T-cells endowed with chimeric antigen receptors or CARs has emerged as a powerful means of treating cancer. However, a limitation of this approach is that autologous CAR T-cells must be generated on a custom-made basis.

To overcome the limitations of patient-derived CAR T-cell therapies, TALEN mediated gene inactivation can be used to generate non-alloreactive T-cells from third-party donors in a robust, scalable manufacturing process, thus allowing "off-the-shelf" CAR T-cell immunotherapies.

Laurent Poirot Ph.D. and his collaborators use this TALEN-mediated editing approach to develop a process for the large-scale manufacturing of T-cells deficient in expression of both their T-cell receptor (TCR) and CD52, a protein targeted by alemtuzumab, a chemotherapeutic agent. Functionally, T-cells manufactured with this process do not mediate graft-versus-host reactions, and are rendered resistant to destruction by alemtuzumab. These characteristics enable the administration of alemtuzumab concurrently or prior to engineered T-cells, supporting their engraftment.

Furthermore, endowing the TALEN-engineered cells with a CD19 CAR led to efficient destruction of CD19+ tumor targets even in the presence of the chemotherapeutic agent.

CAR T-cell immunotherapies can therefore be used in an "off-the-shelf" manner akin to other biological immunopharmaceuticals.

Laurent Poirot, Ph.D., Head of Early Discovery

Dr. Laurent Poirot studied physics and biology at the Ecole Polytechnique in France, before earning his Ph.D. at the Strasbourg University (France) and the Harvard Medical School in Boston. He then joined the Genomics Institute of the Novartis research foundation in San Diego as a postdoctoral fellow, where he studied the development of high throughput in vivo and in vitro approaches for the study of gene functions in immune cells. He joined Cellectis in 2009 as a Project Leader, and has been working as Head of Early Discovery since 2013.

Multiplex genome edited T-cell manufacturing platform for "off-the-shelf" adoptive T-cell immunotherapies

Laurent Poirot1, Brian Philip2, Cécile Schiffer Mannioui1, Diane Le Clerre1, Isabelle Chion-Sotinel1, Sophie Derniame1, Pierrick Potrel1, Cécile Bas1, Laetitia Lemaire1, Roman Galetto1, Céline Lebuhotel1, Justin Eyquem1,3, Gordon Weng-Kit Cheung2, Aymeric Duclert1, Agnès Gouble1, Sylvain Arnould1, Karl Peggs2, Martin Pule2, Andrew M. Scharenberg4 and Julianne Smith1

1 Cellectis, Paris, France
2 Department of Haematology, UCL Cancer Institute, University College London, London, UK
3 Current address: Memorial Sloan-Kettering Cancer Center, New York, NY
4 Current address: Department of Pediatrics, University of Washington, Seattle Children’s Research Institute, Seattle, WA

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PIQUR raises CHF 18 Million in Series A2 financing

On July 16, 2015 PIQUR Therapeutics AG, a Swiss clinical-stage pharmaceutical company focused on the discovery and development of innovative anti-cancer drugs based on PI3K and mTOR inhibition, reported the closing of an oversubscribed CHF 18 million (USD 19M) round of Series A2 financing (Press release, PIQUR Therapeutics, JUL 16, 2015, View Source [SID1234527274]). This round was backed by several existing investors, including Versant Ventures, as well as new, private investors.

The new funding brings the total capital raised by PIQUR to date to over CHF 55 million (USD 60M). The company plans to use the funding to further strengthen its operational basis and to extend the financing horizon for additional Phase 2 studies for its lead compound PQR309, which has shown preclinical activity in different aggressive cancer cell lines inhibiting the PI3K/mTOR pathway, as well as clinical activity in phase 1. In addition, the new funding will support the preclinical safety and first clinical studies for one of its follow-up compounds.

"We greatly appreciate the continued support provided by our existing shareholders and welcome our new investors who bring valuable perspective, experience, and capital resources to the company," said Vladimir Cmiljanovic, CEO of PIQUR. Gaudenz von Capeller, PIQUR’s CFO, commented: "This financing strengthens our balance sheet as we work to achieve important milestones for our lead candidate as well as the follow-up compound."

Helping patients to survive cancer
PIQUR aims to help patients to survive cancer. Two out of three people are now living at least five years after their cancer has been diagnosed. Despite of significant medical innovations in the treatment of cancer, there remains a high unmet medical need for therapies that prolong patients’ survival and improve their quality of life. PIQUR targets both PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin), two key signaling molecules that are vital to several essential biological processes involved in malignant disease, such as cell growth, proliferation, survival and metastasis, making them attractive targets in cancer therapy.

About PQR309
PIQUR’s lead compound, PQR309, is a novel, oral, balanced pan- PI3K/mTOR inhibitor with excellent prospects to become a powerful anti-cancer drug. PQR309 compares favorably to current and clinically most advanced pan-PI3K/mTOR inhibitors with respect to the drug-like properties. Unlike most of its competitors, PQR309 crosses the blood-brain barrier, expanding its use to oncologic as well as hematologic malignant diseases involving the brain. PQR309 showed preclinical activity in different aggressive cancer cell lines inhibiting the PI3K/mTOR pathway, as well as clinical activity in phase 1.

Amgen Announces Positive BLINCYTO® (blinatumomab) Phase 2 Study Results In Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Cell Precursor Acute Lymphoblastic Leukemia

On July 16, 2015 Amgen reported the top-line results of a Phase 2 open-label, single-arm, multicenter trial to evaluate the efficacy and safety of BLINCYTO (blinatumomab) in adults with relapsed or refractory Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Amgen, JUL 16, 2015, View Source [SID:1234506350]).

The investigational study showed blinatumomab monotherapy induced a complete remission or complete remission with partial hematological recovery within two cycles of treatment in a clinically meaningful number of patients. Overall safety results from this study were consistent with the known blinatumomab safety profile.

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The data will be submitted to a future medical conference and for publication.

"These top-line results are encouraging and support blinatumomab as a potential treatment option for patients with relapsed or refractory Philadelphia chromosome-positive B-cell precursor ALL," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We are hopeful that our comprehensive ALL development program for blinatumomab, the first clinical and regulatory validation of the BiTE platform, will continue to demonstrate clinical effectiveness for patients with this serious disease."

Philadelphia chromosome-positive B-cell precursor ALL
Approximately one-fourth of adult ALL expresses the oncogenic protein BCR-ABL1 that results from the t (9;22) chromosome translocation known as the Philadelphia chromosome.

Trial Design (NCT02000427)
This study enrolled adult subjects with relapsed or refractory Ph+ B-cell precursor ALL. This was an open-label, single-arm, multicenter study consisting of a screening period, an induction treatment period (two cycles of blinatumomab), a consolidation treatment period (up to three additional cycles of blinatumomab for applicable subjects), and a safety follow-up visit 30 days after treatment. Following the safety follow-up visit, subjects were followed for response duration and survival every 3 months for 18 months or death, whichever occurred first.

About BLINCYTO (blinatumomab)
BLINCYTO (blinatumomab) is the first bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct product, and the first single-agent immunotherapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL, a rare and rapidly progressing cancer of the blood and bone marrow.1,2 Prior to approval, BLINCYTO was granted breakthrough therapy and priority review designations by the FDA. BLINCYTO has a BOXED WARNING in its product label regarding Cytokine Release Syndrome (CRS) and Neurological Toxicities. (Please see Important Safety Information below).

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.

Important U.S. Product Information
BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

IMPORTANT SAFETY INFORMATION

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 are 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. 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 (26%), febrile neutropenia (26%), nausea (25%), hypokalemia (23%), rash (21%), tremor (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.

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 Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com

10-Q – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-Q, MultiCell Technologies, JUL 15, 2015, View Source [SID:1234506346])

Apogenix Enters into Licensing Agreement with CANbridge Life Sciences for Immuno-Oncology Candidate APG101 in China

On July 15, 2015 Apogenix, a next generation immuno-oncology company, reported that it has entered into an exclusive licensing agreement with CANbridge Life Sciences, a biopharmaceutical company focused on developing Western drug candidates in China and North Asia, for the development and commercialization of lead immuno-oncology drug candidate APG101 in China, Macao, and Hong Kong (Press release, Apogenix, JUL 15, 2015, View Source [SID1234524582]). Under the terms of the agreement, Apogenix will receive upfront and milestone payments, as well as royalty payments at tiered, double-digit royalty rates following commercial launch of APG101 in China .

APG101 is a CD95 ligand inhibitor which restores the immune response against tumors and inhibits invasive tumor cell growth. The drug candidate is being developed for the treatment of solid tumors and malignant hematological diseases. In a controlled phase II proof-of-concept trial in patients with recurrent glioblastoma, treatment with APG101 in combination with radiotherapy has demonstrated clinical superiority in all study endpoints compared to treatment with radiotherapy alone.

"The licensing agreement with CANbridge represents an important milestone in our goal to develop and commercialize our immuno-oncology compound APG101 as a new therapy for difficult-to-treat tumor indications on an international level," said Thomas Hoeger, Ph.D., Chief Executive Officer of Apogenix. "We are delighted to have found a strong and committed partner with a seasoned management team and extensive drug development expertise in these important Asian markets. We look forward to working with CANbridge to obtain approval for APG101 in China, Macao, and Hong Kong, so we can provide patients suffering from glioblastoma with a novel, much-needed therapeutic option as soon as possible."

In the phase II trial, glioblastoma patients expressing a certain biomarker associated with the CD95 ligand experienced the greatest benefit from treatment with APG101. The trial showed a statistically significant prolongation of overall survival in biomarker-positive patients treated with APG101, with a median overall survival of 16.1 months compared to 7.3 months in patients treated with radiotherapy alone. Apogenix is developing a companion diagnostic test based on this biomarker to identify those patients most likely to benefit from APG101.

"Development of this targeted therapeutic fits the CANbridge mission of bringing promising Western treatments to China and other Asian territories, where patients’ severe medical needs are going unmet," said James Xue, CANbridge Chairman and CEO. "The mortality rate of malignant glioma is one of the top ten among all cancers in China. With very limited treatment options, the outcomes for Chinese patients are even more grim than in the West. The potential to develop a targeted immuno-oncology product represents a tremendous advance for glioblastoma treatment in China."

"The CANbridge and Apogenix missions and cultures are perfectly aligned, which bodes well for the success of this partnership," said Henri Termeer, CANbridge’s Advisor and former Chairman and CEO of Genzyme Corporation. "Each company is dedicated to bringing forth treatments in their respective markets for patients with few options. Together, CANbridge and Apogenix can move this exciting program forward more effectively than either could alone in China."