On November 14, 2014 ImmunoCellular Therapeutics reported the presentation of updated efficacy data from the Phase II trial of dendritic cell-based immunotherapeutic vaccine ICT-107 at the 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, being held in Miami, FL (Press release ImmunoCellular Therapeutics, NOV 14, 2014, View Source [SID:1234500964]). Patrick Y. Wen, MD, Director of the Center for Neuro-Oncology at Dana Farber Cancer Institute and Professor of Neurology at Harvard Medical School, and principal investigator on the trial, will present the maturing data set in patients with newly diagnosed glioblastoma multiforme (GBM) in an oral presentation.

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Consistent with prior data presentations in December 2013 and June 2014, the results demonstrate a statistically significant progression-free survival (PFS) benefit, and a numeric overall survival (OS) benefit in ICT-107 treated patients compared to the control group. The ICT-107 treatment effect continues to be strongest in the pre-defined HLA-A2 subgroup of patients in which the MGMT methylated patients showed the largest treatment effect, with a significant PFS advantage over the control group, and continued potential for the OS advantage to move toward significance as more events occur. There were no differences in adverse events between the ICT-107 treated group and the control group.

"ICT-107 continues to hold promise for patients with newly diagnosed glioblastoma, as no other immunotherapy has shown statistical benefit for a clinical outcome in a controlled trial in this patient population," said Dr. Wen. "I think that the data from the phase II trial strongly support advancing to a registrational program."

"With this second update of the original trial results, we remain confident that there is a meaningful treatment benefit in HLA-A2 patients. In the per-protocol population, OS hazard ratios are in the 0.6-0.7 range for all HLA-A2 patients as a group as well as for each of the MGMT subgroups. If our upcoming phase III program generates statistically significant results in this range, ICT-107 could represent a clinically meaningful advance for GBM patients," said Andrew Gengos, ImmunoCellular’s Chief Executive Officer. "The US FDA and three national European regulators have indicated support for phase III testing. We anticipate hearing shortly from the EMA, and then expect to be in position to finalize our phase III design and move into trial execution in 2015."

Updated ICT-107 Phase II OS and PFS Results

As of October 2014, a total of 88 events (patient deaths) had been recorded from the 124 randomized patients, representing 9 additional events since these data from the phase II trial were last updated in June 2014. There were 25 active and 11 control patients alive for a total of 36 patients available for additional follow-up.
Median PFS for the HLA-A2 methylated MGMT per-protocol (PP) population was 24.1 months for the ICT-107 treated group and 8.5 months for control, representing a statistically significant 15.6-month PFS benefit for the ICT-107 treated group (age stratified HR = 0.257 [0.095-0.697], p = 0.004).
Median OS for the HLA-A2 methylated MGMT PP population was 23.9 months for the control group, and the median has not yet been reached for the ICT-107 treated group. At the time of the analysis, 65% of ICT-107 patients and 50% of the control patients were alive (age stratified HR = 0.631 [0.212-1.880], p = 0.404), suggesting the potential for long-term survival with ICT-107 treatment.
Median PFS for the HLA-A2 unmethylated MGMT PP population was 10.5 months for the ICT-107 treated group and 6.0 months for the control group, representing a 4.5-month median PFS benefit for the ICT-107 treated group (age stratified HR = 0.720 [0.351-1.474], p = 0.364).
Median OS for the HLA-A2 unmethylated MGMT PP population, was 15.8 months for ICT-107 patients, and 11.8 months for the control group, representing a 4-month median OS benefit for the ICT-107 treated group (age stratified HR = 0.652 [0.320-1.325], p = 0.233).
Median PFS in the intent-to-treat (ITT) population (all phase II patients) was 11.4 months for the ICT-107 treated group and 10.1 months for the control group, representing a statistically significant benefit in the ICT-107 treated group (age stratified HR = 0.640 [0.423-0.968], p = 0.033).
Median OS in the ITT population was 18.3 months for the ICT-107 treated group and 16.7 for the control group, representing a numeric, but not statistically significant, advantage for the treatment group (age stratified HR = 0.854 [0.547-1.334], p = 0.487).

The Company is utilizing all available information from the controlled phase II trial to design phase III testing in order to increase its probability of success, including the timing of randomization within the standard-of-care treatment these patients receive, in an attempt to limit the number of patients who are "early progressors" and unlikely to respond to therapy.

On November 13, 2014 Isis Pharmaceuticals and AstraZeneca reported a strategic alliance to discover and develop novel delivery methods for antisense oligonucleotides (Press release Isis Pharmaceuticals, NOV 13, 2014, View Source;p=RssLanding&cat=news&id=1989207 [SID:1234500960]). The new delivery approaches seek to target the desired tissue more effectively. The agreement builds on an existing collaboration between AstraZeneca and Isis Pharmaceuticals, a leader in the field of antisense, and supports AstraZeneca’s research and development capabilities in the area of antisense oligonucleotide-based therapeutics and RNA biology. Initial project areas will be oncology and cardiovascular and metabolic diseases (CVMD).

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Antisense oligonucleotides are short, single strands of DNA or RNA molecules. Rather than modulating the activity of already-formed proteins, antisense oligonucleotides act before proteins are produced at the level of messenger RNA in the cell, thus opening up new opportunities for therapeutic intervention. The new delivery methods will aim to enhance the access of antisense oligonucleotides into specific organs and cells. The methods build on Isis Pharmaceuticals’ successful Ligand Conjugation Antisense (LICA) technology. The first example of this technology being Isis’ GalNac-conjugated antisense oligonucleotides targeting liver hepatocytes, which lowers the therapeutic dose needed for liver targets by approximately 10-fold.

Under the terms of the agreement, each party will fund its own contribution and commit investigators to the collaboration. In line with AstraZeneca’s open innovation approach, the companies will work together on an agreed programme and share rights to the results. Isis can apply learnings from this collaboration broadly across its antisense technology platform and AstraZeneca can similarly apply learnings across its broader RNA-based, small molecule and antibody research and development activities.

Isis Pharmaceuticals and AstraZeneca entered into a collaboration, development and license agreement in 2012 in oncology, subsequently expanded in 2013 to include CVMD. Under the 2012 agreement, one of the molecules being developed is AZD9150 (ISIS-STAT3Rx), a first-in-human, first-in-class, antisense oligonucleotide inhibitor of STAT3, which is being developed as an immunomodulatory agent in combination with MEDI4736, AstraZeneca’s investigational anti-PD-L1 immune checkpoint inhibitor. A second product of that collaboration, an antisense oncology compound targeting the androgen receptor AZD5312 (ISIS-ARRx), is in Phase I trials. The new delivery collaboration announced today builds on this existing relationship and is expected to also bring benefits to these programs.

"This exciting collaboration very much supports AstraZeneca’s research and development in the area of RNA-based therapeutics. If successful, we’ll have a way to selectivity modulate therapeutic targets in specific cell types that are intractable to small molecules and antibodies. This could lead to a number of ground breaking drugs for both oncology and cardiovascular and metabolic diseases," said Susan Galbraith, Head of the Oncology Innovative Medicines Unit, AstraZeneca.

Brett Monia, Senior Vice President of Antisense Drug Discovery, Isis Pharmaceuticals said, "The collaboration expansion announced today builds upon an already successful agreement between Isis and AstraZeneca. Together, we have advanced ISIS-STAT3Rx and ISIS-ARRx in clinical development, both of which are being evaluated in patients with cancer. This opportunity also complements our internal efforts to expand the use of our technology and develop drugs with broad therapeutic applicability."

"RNA molecules play an increasingly important role in our research portfolio. We are delighted to be expanding our existing, strong collaboration with Isis Pharmaceuticals, who are leading players in RNA biology, with the aim of improving the delivery of antisense oligonucleotides to specific cardiovascular and metabolic tissue targets," said Marcus Schindler, Head of the CVMD Innovative Medicines Unit, AstraZeneca.

An analysis from Adam Feuerstein at TheStreetis skeptic on Oxigene’s positive Phase II ovarian cancer data (External Source FierceBiotech, OXiGENE, NOV 12, 2014, View Source;utm_source=internal [SID:1234500966]). A decision on using Avastin for ovarian cancer is looming, but hasn’t arrived yet, complicating any analysis of a combination drug study like this. Avastin, by the way, achieved a solid PFS but not a statistically significant overall survival benefit for ovarian cancer patients, which may not prevent its approval. If Avastin plus chemo becomes the standard of care in this area, then Oxigene will face some big challenges in designing a Phase III trial, notes Feuerstein. If the biotech decides to run a non-inferiority study, it will need a big and expensive patient population to examine. If it tries to beat Avastin/chemo, it faces a very tall order. And if Avastin is rejected, that makes Oxigene’s task even more difficult. Perhaps, suggests Feuerstein, the company should go a different route and try a combination with Votrient.

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Oncoethix, the Swiss-based specialist in oncology drug development, reported that the first patient has been enrolled in an international, open-label, non-randomized, multicenter Phase 1b trial of OTX015 in advanced solid tumors (Press release OncoEthix, NOV 12, 2014, View Source [SID:1234501220]). The trial will be coordinated by Dr Lillian Siu, MD, of the Princess Margaret Hospital, Toronto, Canada, who is Professor of Medicine at the University of Toronto, and Director of the Phase 1 program.

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The trial seeks to enrol up to 98 patients across seven centers in five countries (Belgium, Canada, France, Spain and Switzerland), including the Institut Gustave-Roussy in Paris, where Professor Jean-Charles Soria is the Principal investigator. Three patients have already been enrolled. The trial aims to determine, in a first step, the suitability of five solid tumor indications under investigation (BRD-NUT Midline Carcinoma, Triple Negative Breast Cancer, Non-Small Cell Lung Cancer harbouring a rearrangement ALK gene/fusion protein or KRAS mutation, and Castrate-Resistant Prostate Cancer and Pancreatic Ductal Carcinoma) to be progressed into the Phase 2a part of the trial.

Dr Esteban Cvitkovic, MD, Founder and Chief Scientific Officer, Oncoethix, commented: "This multicenter Phase 1b trial is an important step for OTX015, as it will provide key safety and efficacy data in several solid tumor types, after having characterized its single agent safety and activity profile in the Acute Leukemias and Lymphomas in Phase 1 trial (OTX015_104). The solid tumor indications approach selected for OXT015 is based on compelling data from our own preclinical pharmacology program. We have also initiated a multicentric (France, Switzerland) Phase 2a trial in recurrent glioma."

OTX015 is a novel first-in-class synthetic small molecule inhibitor of BET bromodomain proteins 2/3/4. These proteins are considered potential cancer targets, as they play a pivotal role in regulating the transcription of growth-promoting and cell cycle regulators.

Coordinating investigator Dr Lillian Siu commented: "OTX015 is a promising drug that has shown outstanding early results in hematologic cancer studies and we are delighted to have commenced the solid tumor trial at the Princess Margaret Cancer Centre in Canada."

Bertrand Damour, Chief Executive Officer at Oncoethix, added "We believe that OTX015 has the potential to be an important new drug across a number of advanced solid tumors and the start of the Phase 1b is a key milestone for the Company. We are also ahead of schedule in our hematologic cancer program and will be releasing further data from this program at NCI/EORTC/AACR in November and the American Society of Hematology (ASH) (Free ASH Whitepaper) in December."

On November 12, 2014 Blueprint Medicines reported the completion of a $50 million Series C financing (Press release Blueprint Medicines, NOV 12, 2014, View Source [SID:1234500956]). Proceeds from the financing will be used to advance Blueprint Medicines’ two lead product candidates through clinical trials in 2015 and fund the continued development of Blueprint Medicines’ kinase discovery platform and pipeline.

"The proceeds from this financing provide us with the financial strength to initiate clinical trials for our FGFR4 and KIT Exon 17 inhibitors in 2015 with the goal of establishing proof of concept rapidly and ultimately improving the lives of patients," said Jeffrey Albers, chief executive officer of Blueprint Medicines. "We are incredibly pleased to welcome such highly respected public investors to our shareholder base. Their investment provides strong endorsement for the quality of the platform, pipeline and team we’ve built at Blueprint Medicines over the past three years."

Blueprint Medicines’ Series C financing was led by Partner Fund Management and included additional new investors, Wellington Management Company, RA Capital, Tavistock Life Sciences, Perceptive Advisors, Sabby Capital, Cowen Investments and Redmile Group. The Company’s existing shareholders – Biotechnology Value Fund, Casdin Capital, Fidelity Biosciences, Nextech Invest and Third Rock Ventures – also participated in the financing.
"Blueprint Medicines’ proprietary kinase platform, which combines a first-of-its-kind chemical library and a novel genomics-based target discovery engine, holds significant value creation potential," said Alex Virgilio, Ph.D. of Partner Fund Management. "The team has achieved impressive results to date by rapidly discovering and advancing two first-in-class product candidates toward clinical development. We believe the team can sustainably replicate this success based on the strength of the platform in producing exquisitely selective inhibitors to novel genomically defined kinase targets."

Blueprint Medicines expects to initiate clinical trials in 2015 with its two lead product candidates:
 BLU-285 is the first known selective inhibitor of KIT Exon 17 mutants. The Company intends to initiate two clinical studies, including one for the underserved systemic mastocytosis patient population and another for genomically defined subsets of patients with gastrointestinal stromal tumors (GIST).
 BLU-554 is the first known selective FGFR4 inhibitor. Blueprint Medicines anticipates initiating a clinical study for patients suffering from hepatocellular carcinoma with aberrant FGFR4 pathway activation.

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