On September 3, 2015 Sandoz, a Novartis company, reported that ZarxioTM (filgrastim-sndz) is now available in the United States (Press release, Sandoz, NOV 20, 2015, View Source [SID:1234508310]). Zarxio is the first biosimilar approved by the US Food and Drug Administration (FDA) and the first to launch in the US."

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As the pioneer and global leader in biosimilars, Sandoz has maintained a commitment to bringing high-quality biosimilar medicines to patients and healthcare professionals around the world," said Richard Francis, Global Head, Sandoz. "With the launch of Zarxio, we look forward to increasing patient, prescriber and payor access to filgrastim in the US by offering a high-quality, more affordable version of this important oncology medicine."

"While biologics have had a significant impact on how diseases are treated, their cost and co-pays are difficult for many patients and the healthcare budget in general. Biosimilars can help to fill an unmet need by providing expanded options, greater affordability and increased patient access to life-saving therapies," said Dr. Ralph Boccia, Medical Director of the Center for Cancer and Blood Disorders, and Chief Medical Officer for the International Oncology Network (ION).

Sandoz understands the importance of providing comprehensive patient support services in the oncology setting. With the launch of Zarxio, Sandoz is also proud to offer Sandoz One SourceTM a patient services center, providing support that connects the patient to the information and resources they need.

The launch follows the FDA approval of Zarxio on March 6, 2015. The approval, via the new biosimilars pathway established under the Biologics Price Competition and Innovation Act, was based on a comprehensive package of analytical, nonclinical, and clinical data, which confirmed that Zarxio is highly similar with no clinically meaningful differences to the US-licensed reference product. The successful Sandoz pivotal head-to-head PIONEER study was the final piece of data contributing to the totality of evidence used by FDA to approve Zarxio as biosimilar to the reference product. Importantly, the data demonstrating high similarity was sufficient to allow extrapolation of use of Zarxio to five indications of the reference product.

Sandoz has an unwavering commitment to increasing patient access to high-quality, life-enhancing biosimilars. Sandoz is the global market leader and currently markets three biosimilars outside the US. Sandoz has a leading pipeline with several biosimilars across the various stages of development, including five programs in Phase III clinical trials/filing preparation.

For more information on Zarxio, please visit www.zarxio.com.INDICATIONS

Patients with Cancer Receiving Myelosuppressive Chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).

Patients with Cancer Undergoing Bone Marrow Transplantation: to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.

Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with Severe Chronic Neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONS
ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim.

WARNINGS AND PRECAUTIONS

Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Patients who report left upper abdominal or shoulder pain should be evaluated.
Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated. Discontinue ZARXIO in patients with ARDS.

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions.

Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.
Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia,hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO.
Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.
Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate treatment.
Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim for SCN. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.

Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

Leukocytosis:

Patients with Cancer Receiving Myelosuppressive Chemotherapy: White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy.

Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to >100,000/3.

Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

The possibility that filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which filgrastim is not approved, cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. Available data is limited and inconclusive.

The safety and efficacy of filgrastim products given simultaneously with cytotoxic chemotherapy have not been established. Do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The safety and efficacy of filgrastim products have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes on nuclear imaging.

ADVERSE REACTIONSMost common adverse reactions in patients:

With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased

With AML (≥ 2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular
With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) are rash and hypersensitivity

Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache

With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia

On November 20, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX)reported mature survival data from the Company’s randomized, double-blind Phase 2 study of RINTEGA (rindopepimut) in patients with EGFRvIII-positive, recurrent glioblastoma (GBM) at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology (SNO) (Press release, Celldex Therapeutics, NOV 20, 2015, View Source [SID:1234508307]). The data were presented in a podium presentation by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School; and President of the Society for Neuro-Oncology, as well as the lead investigator of the ReACT study. RINTEGA is an investigational EGFRvIII specific therapeutic vaccine and was granted Breakthrough Therapy Designation in February 2014. Patients with recurrent glioblastoma that express the EGFRvIII mutation typically have a worse prognosis than the overall glioblastoma population, including poor long-term survival (median time from recurrence to death for EGFRvIII-positive patients is 8.7 months1). As previously reported, the primary endpoint of the study, progression-free survival at six months (PFS6) has been met.

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Mature overall survival (OS) data continue to show a marked benefit [hazard ratio = 0.53 (0.32, 0.88); p=0.0137] with a long-term survival benefit clearly seen in the RINTEGA arm. In May, the Company reported a hazard ratio of 0.57 (0.33, 0.98) (p=0.0386) for OS in the study.

Nine of 10 patients (one patient lost to follow up) on the RINTEGA arm remain alive since the Company last presented data in May compared to only two out of five patients on the control arm.

At two years, the survival rate for RINTEGA patients is 25% versus 0% for control patients in the intent to treat (ITT) population, with five patients extending beyond two years.

Five patients in the RINTEGA arm continue survival follow-up without progression per central review, compared to only one patient on the control arm.

A clear advantage continues to be demonstrated across multiple, clinically important endpoints including overall survival (OS), long-term progression-free survival (PFS), objective response rate (ORR) and need for steroids.
33% of patients on the RINTEGA arm who were receiving steroids at baseline were able to stop steroids for six months or longer compared to none on the control arm.

"The results of the ReACT study change the way we think about glioblastoma—offering patients and their families new hope in the face of one of the most difficult to treat cancers and upending the notion that the brain, masked behind the blood brain barrier, is beyond the reach of the promise of immunotherapy," said David A. Reardon, M.D. "The long-term survival benefit observed in this study is unprecedented as it is exceedingly rare for patients with highly aggressive, EGFRvIII-positive glioblastoma—even in the newly diagnosed setting—to live beyond two years. Most striking perhaps is that not only are patients living considerably longer, they are also living better, with minimal side effects and a reduced need for steroids. The ReACT data also build considerable anticipation for the ACT IV study in newly-diagnosed glioblastoma as these patients typically present with much stronger immune systems and stand to derive an even greater benefit."

"Patients with glioblastoma—especially those who are EGFRvIII-positive—face a staggering diagnosis, and in the face of this news, making the decision to participate in a clinical trial—especially a randomized study—is never an easy decision," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex. "To this end, we are extremely gratified on behalf of our ReACT patients, their families and physicians that RINTEGA continues to tell a very consistent, impressive story across multiple, clinically relevant endpoints including, most importantly, long-term survival. These results replicate what we have seen in earlier RINTEGA studies conducted in newly-diagnosed patients, supporting our belief that RINTEGA will be an important treatment option for all patients with EGFRvIII-positive glioblastoma."

Presentation Details

ReACT is a randomized, controlled Phase 2 exploratory study designed to determine if adding RINTEGA to standard of care bevacizumab (BV; Avastin) improves outcomes for patients with EGFRvIII-positive, recurrent glioblastoma across multiple measures. Patients [n=73, intent to treat (ITT)] were bevacizumab-naïve at study entry. Tumor responses were evaluated in accordance with RANO criteria by an independent expert review committee blinded to treatment group assignment. Data for this long-term update included study results through September 1, 2015.

PFS6: As previously reported, the primary endpoint of PFS6 was met. 10 out of 36 (28%) patients were alive at six months without progression on the RINTEGA arm compared to 6 out of 37 (16%) on the control arm (p=0.1163). Given the exploratory nature and size of the trial, the ReACT study required a PFS6 1-sided p-value of 0.2 (powered at 80%) for positivity.

SURVIVAL: RINTEGA+BV demonstrated a statistically significant, clinically meaningful overall survival benefit compared to BV alone. Consistent with previous studies of RINTEGA and the published data observed for immune-mediated therapeutics, this survival benefit includes a "tail" on the RINTEGA survival curve with multiple patients exceeding what is customary survival for EGFRvIII-positive glioblastoma. Nine patients on the RINTEGA arm continue to be followed for survival, including five without disease progression per central review. Two patients on the control arm continue to be followed for survival, including one without disease progression per central review. At two years, the survival rate for RINTEGA patients in the ITT population is 25% versus 0% for control patients.

OBJECTIVE RESPONSE RATE (ORR): Nine out of 30 evaluable ITT patients (30%) on the RINTEGA arm experienced a confirmed objective response versus six out of 34 evaluable patients (18%) on the control arm. Five patients on the RINTEGA arm experienced durable responses greater than six months, and three of these patients experienced durable responses greater than 18 months (range of 18.6+ to 22.2 months). In contrast, only two patients on the control arm experienced a durable response greater than six months, and none experienced a response greater than 7.4 months.

STEROID USE: Further emphasizing the level of disease control, 50% of the 18 patients on the RINTEGA arm who were on steroids at the start of treatment were able to stop steroids for at least two months during treatment versus only 26% of the 19 patients on the control arm who were on steroids at the start of treatment. 33% of patients on the RINTEGA arm were able to stop steroids for more than six months, and, of these, three were able to stop for more than one year versus none on the control arm for either time point.

IMMUNE RESPONSE: Prolonged survival was associated with high anti-EGFRvIII humoral responses that were predominantly of the cell killing IgG1 isotype, and recent in vivo experiments have shown those immune responses had tumor killing function through antibody dependent cellular cytotoxicity (ADCC) of EGFRvIII-expressing tumor cells. This biologic effector function is rarely proven for immune therapies. Importantly, rapid generation of anti-EGFRvIII humoral response correlated with longer survival; however, even those with slower development of immune responses benefitted. No patient in the control arm had detectable EGFRvIII specific antibody response. This effect is consistent with RINTEGA’s proposed mechanism of action as a targeted immunotherapeutic vaccine.

OTHER: Multiple subgroup and adjusted analyses have concluded that the consistent survival benefit observed in the study was not influenced by potential imbalances in patient demographics.
SAFETY: RINTEGA was very well tolerated without unexpected additive toxicity to bevacizumab.
RINTEGA is a registered trademark of Celldex Therapeutics. Avastin is a registered trademark of Genentech, Inc.
1Data provided the Radiation Therapy Oncology Group (RTOG).

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 2014, the U.S. Food and Drug Administration (FDA) granted RINTEGA Breakthrough Therapy Designation for the treatment of adult patients with EGFRvIII-positive glioblastoma. The first interim analysis for ACT IV occurred in June 2015, and the study’s Data Safety and Monitoring Board recommended continuation of the study as planned. The Company anticipates that ACT IV will reach the required 75% of events (deaths) to perform the second interim analysis in late 2015 and that the analysis will occur in early 2016.

On November 20, 2015 the U.S. Food and Drug Administration reported that it has granted approval for Ninlaro (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy (Press release, , NOV 20, 2015, View Source [SID:1234508303]).
Multiple myeloma is a form of blood cancer that occurs in infection-fighting plasma cells (a type of white blood cell) found in the bone marrow. These cancerous cells multiply, produce an abnormal protein and push out other healthy blood cells from the bone marrow. The disease may result in a weakened immune system and cause other bone or kidney problems. The National Cancer Institute estimates there will be 26,850 new cases of multiple myeloma and 11,240 related deaths in the United States this year.

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"As we learn more about the underlying biology of multiple myeloma, we are encouraged to see the development of new ways to treat this disease," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. "Today’s approval is the third drug for multiple myeloma approved this year and provides patients with a new oral treatment that slows disease progression when other therapy has failed." The FDA approved Farydak (panobinostat)in February and Darzalex (daratumumab) earlier this month.

Ninlaro is a type of cancer drug called a proteasome inhibitor and works by blocking enzymes from multiple myeloma cells, hindering their ability to grow and survive. Ninlaro is the first oral proteasome inhibitor and is approved in combination with another FDA-approved treatment for multiple myeloma called Revlimid (lenalidomide) and dexamethasone (a type of corticosteroid).

The safety and efficacy of Ninlaro were demonstrated in an international, randomized, double-blind clinical trial of 722 patients whose multiple myeloma came back after, or did not respond to, previous treatment. Study participants received either Ninlaro in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Those taking Ninlaro lived longer without their disease worsening (average 20.6 months) compared to participants taking the other regimen (14.7 months).

The most common side effects of Ninlaro are diarrhea, constipation, low blood platelet count (thrombocytopenia), peripheral neuropathy (numbness and pain from nerve damage, usually in the hands and feet), nausea, peripheral edema (fluid under the skin causing swelling), vomiting and back pain.

The FDA granted priority review and orphan drug designations for Ninlaro. Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

Ninlaro is marketed by Takeda Pharmaceuticals based in Osaka, Japan. Farydak is marketed by East Hanover, New Jersey-based Novartis Pharmaceuticals. Darzalex is marketed by Janssen Biotech of Horsham, Pennsylvania. Revlimid is marketed by Celgene Corporation, based in Summit, New Jersey.

On November 20, 2015 Kancera reported an operational update on the PFKFB3 and HDAC6 projects as well as the EU-funded epigenetically targeted parasitic project A-PARADDISE (Press release, Kancera, NOV 20, 2015, View Source;releaseID=1076542 [SID:1234508302]).

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The PFKFB3 project
Recent studies conducted within the framework of the collaboration with Prof. Thomas Helleday show that treatment with Kancera’s PFKFB3 inhibitor KAN0438757 alone inhibits an aggressive breast cancer tumor formed by the cell line MB231 (triple negative breast cancer). The human cancer cells were transplanted into zebra fish and four days treatment with KAN0438757 reduced the size of the tumor by more than 50% in comparison with the control treatment. The results support that Kancera’s PFKFB3 inhibitor is effective when reaching the tumor in sufficient concentration. Previously reported results show that Kancera’s PFKFB3 inhibitor KAN0438757 is able to counteract cancer cell repair of the DNA. Hence there are grounds to examine whether a more potent effect of PFKFB3 inhibitors can be achieved against triple negative breast cancer by combining the treatment with e.g. DNA damaging radiation. However, such a combination effect remains to be demonstrated in vivo.

The HDAC6 project
Since May 2015, when Kancera’s first patent application in the HDAC6 project entered the international stage, new series of potent and selective inhibitors of the enzyme has been developed. An additional patent application that covers these new HDAC6 inhibitors will be registered before the end of January, 2016. In order facilitate the filing of the new patent application, Kancera has decided to postpone the publication of the first patent application for one year.

In June 2015, Vinnova announced that Kancera’s HDAC6 project had been awarded a grant of SEK 2,000,000 for the further development of HDAC6 inhibitors against cancer. The first installment of SEK 436,000 was paid in July. Vinnova has now decided to bring forward the second installment of SEK 750,000 to December 2015.

EU projektet mot parasitsjukdomar – A-PARADDISE
In February 2014 Kancera received an initial payment from the EU amounting to € 523,655 for the execution of the A-PARADDISE project. This project is a collaboration between 15 research groups on three continents to develop drugs against severe parasitic diseases: malaria, schistosomiasis, leishmaniasis and Chagas disease. The project issued an interim report which now has been approved by the EU. This means that a further installment of the grant will be paid to Kancera at year-end according to plan. This installment amounts to € 285,000.

For further information, please contact,

Thomas Olin, CEO: +46 (0) 735 20 40 01
Address:
Kancera AB (publ)
Karolinska Institutet Science Park, Banvaktsvägen 22
SE 171 48 Solna

Please visit the company website; View Source

About the PFKFB3 project
By blocking mechanisms which enable the cancer cells to adapt to periods of oxygen deprivation, possibilities open for new treatment strategies. Kancera’s project is based on a specific inhibition of the enzyme PFKFB3 resulting in a decreased metabolism in cancer cells, and decreased cell growth. In addition, research shows that PFKFB3 is involved in the regulation of both angiogenesis and division of cells, two critical processes that contribute to tumor growth. PFKFB3 is more common in oxygen-deficient tumor tissue compared to healthy tissue, which makes a targeted effect therapy with fewer side effects than traditional chemotherapy possible. Inhibition of PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This is a way to overcome the current problems of tumor resistance to radiation and chemotherapy.

About the HDAC6 project
Histone deacetylases (HDACs) are primarily involved in removing acetyl groups from the so-called histones and thereby affect how our genes are stored and activated in the cell nucleus. Some HDACs also affect the cell function outside the cell nucleus. HDAC6 belongs to this group of HDACs with a major biological role in the regulation of the cancer cell´s ability to migrate and to form metastases. The use of HDAC inhibitors in the treatment of cancer patients has so far yielded promising results, but has been limited due to severe side effects. For this reason, the pharmaceutical industry is now looking for more selective inhibitors of individual HDAC enzymes. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution on how health care could take advantage of the anti-cancer effects of HDAC inhibitors without causing the patient severe side effects.

About the EU-project against parasitic diseases – A-PARADDISE
A-PARADDISE (Anti-Parasitic Drug Discovery in Epigenetics) is an EU-funded project (contract n° 602080), which aims to identify new drug targets for anti-parasitic drug discovery as well as to develop already available lead compounds to candidate drugs against schistosomiasis. The project will also develop lead compounds and possibly drug candidates against targets in the following parasites (diseases): Leishmania (Leishmaniasis), Trypanosoma cruzi (Chagas disease) and Plasmodium falciparum (malaria). The A-PARADDISE project builds on the completed and highly successful SEtTReND project which was focused against schistosomiasis.

On November 20, 2015 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT:IMUC) reported the presentation today of recently updated overall survival (OS) results and immune response data from the phase 2 trial of ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, NOV 20, 2015, View Source [SID:1234508298]). ICT-107 is a dendritic cell-based immunotherapy targeting multiple tumor-associated antigens on glioblastoma stem cells. The data are being presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, being held in San Antonio, TX. The data from the phase 2 trial continue to indicate a survival advantage in the ICT-107 treated group compared to the control group. The data also show a significant association between immune response and survival, especially in HLA-A2 positive (HLA-A2+) patients, which is the target patient population for the phase 3 registration trial.

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IOS results were analyzed at three years after the last patient enrolled. For the 124-patient intent-to-treat population (ITT), median OS was 1.6 months or 10% better for ICT-107 patients than control. The difference in the Kaplan-Meier (KM) survival curves for this patient population was not statistically significant.

Updated OS results for the pre-specified subgroup of HLA-A2+ patients continue to support selecting this patient population alone for a well powered phase 3 trial. For the MGMT methylated, HLA-A2+ PP population, median OS was 13.8 months or 58% better for ICT-107 treated patients than control. For the MGMT unmethylated, HLA-A2+ per-protocol (PP) population, median OS was 4.0 months or 34% better for ICT-107 treated patients than control. The differences in the KM survival curves for these two pre-specified phase 2 sub-populations were not powered for, and did not achieve, statistical significance.

ELISPOT evaluation of antigen-specific immune response demonstrated a more frequent immune response in HLA-A2+ patients compared with HLA-A1 patients, and this difference was statistically significant. This increased immune response in HLA-A2+ patients further supports the selection of HLA-A2+ patients exclusively for inclusion in the phase 3 trial.

In HLA-A2+ patients, immune response was shown to be associated with survival. 60% of ICT-107 treated patients demonstrated a statistically significant immune response compared to only 36% of control patients. In a KM comparison of OS for immune responders versus non-responders, the responder curve showed a statistically significant survival benefit with a log-rank p-value of 0.0084. For ICT-107 treated patients, the KM comparison of OS for responders versus non-responders showed a statistically significant survival benefit with a log-rank p-value of 0.0147. The Company believes that the relationship between immune response and OS supports the phase 3 design improvement of adding more ICT-107 doses for patients in the first year of the protocol.

Immune response did not differ statistically for MGMT methylated compared to unmethylated patients. This result supports including both MGMT types of patients in phase 3 testing.

Of particular interest was the unexpected finding that there was an increased immune response in some control patients post-treatment. One potential explanation is that the phase 2 control (activated dendritic cells without peptide loading) was immunologically active. The phase 3 design employs a different control comprising the patients’ own monocytes, which are less immunologically active than dendritic cells. This control could help clarify a potential survival difference between ICT-107 and control treated patients.

The data are being presented at SNO by John S. Yu, MD, Founder of ImmunoCellular Therapeutics. Dr. Yu commented: "The final data from the phase 2 trial continue to demonstrate the therapeutic value of ICT-107 as a potential treatment for patients with newly diagnosed glioblastoma, and strongly support advancing to phase 3 testing. The clear association between immune response and survival is an important finding that we believe validates the immunotherapeutic mechanism of ICT-107 and strengthens our optimism for the phase 3 trial."

Andrew Gengos, ImmunoCellular Chief Executive Officer, said: "Based on these newly updated phase 2 survival results and the supporting immune response data, we are confident of the design improvements we have built into the phase 3 trial, and look forward to treating our first patient in the coming weeks. The phase 3 trial initiation represents a major milestone in the company’s path toward building a leading cancer immunotherapy company."

Phase 3 Registration Trial Sites Open; First Patient Anticipated to be Treated Soon

The phase 3 registrational trial of ICT-107 is designed as a randomized, double-blind, placebo-controlled study of over 400 HLA-A2+ subjects, which will be conducted at about 120 sites in the US, Canada and the EU. The primary endpoint in the trial is overall survival, which the FDA and EU regulators have stated is the appropriate endpoint for registrational clinical studies in glioblastoma. Secondary endpoints include progression-free survival and safety, as well as overall survival in the two pre-specified MGMT subgroups.

Multiple clinical trial sites have been opened for patient enrollment in the US, with additional sites anticipated to open in Canada and Europe in the coming weeks and months.

ImmunoCellular has reached agreement with the US FDA on a Special Protocol Assessment (SPA) relative to the primary and secondary endpoints as well as the statistical plan for the phase 3 trial. ImmunoCellular has also been awarded a $19.9 million grant from the governing Board of the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency, to implement the phase 3 registration trial.

Background on the ICT-107 Phase 2 Trial

The ICT-107 phase 2 trial was a randomized, double-blind, placebo-controlled phase 2 study of the safety and efficacy of ICT-107 in patients with newly diagnosed glioblastoma multiforme following resection and chemoradiation. ICT-107 is an intradermally administered autologous immunotherapy consisting of the patient’s own dendritic cells pulsed with six synthetic tumor-associated antigens: AIM-2, MAGE-1, TRP-2, gp100, HER-2, IL-13Rα2. The placebo control consisted of the patient’s unpulsed dendritic cells.

A total of 124 patients were randomized at 25 clinical trial sites in the US. One third of the patients or 43 patients were treated with placebo, and the treatment arm included two thirds or 81 patients. All patients in the trial received standard-of-care temozolomide. The regimen was four induction doses of ICT-107 after chemoradiation, and then maintenance doses until the patient progresses. The primary endpoint of the trial was OS, defined as the time from randomization until date of death or the last date the patient is known to be alive. Secondary endpoints included PFS, defined as the time from randomization until the date of documented progressive disease or death, whichever occurs first, or the last date the patient is known to be alive and progression-free if progression or death is not observed. Other secondary endpoints included the rates of OS and PFS at six months after surgery, then assessed every three months until the end of the study. Safety and immune response were additional secondary endpoints.

For patients, families and physicians seeking additional information about the ICT-107 phase 3 trial, please consult www.clinicaltrials.gov.