BVD-AB1 is a therapeutic antibody under development by BioMed Valley for the treatment of cancer (Company Pipeline BioMed Valley Discoveries, NOV 14, 2014, View Source [SID:1234500980]).

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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.

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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On November 12, 2014 Advaxis reported that the Company has submitted an Investigational New Drug application (IND) to the United States Food and Drug Administration (FDA) to conduct a Phase 1/2 study of ADXS-HPV (ADXS11-001) alone or in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, for the treatment of advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer (Press release Advaxis, NOV 12, 2014, View Source [SID:1234500957]).

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This follows the press release issued in July 2014 announcing the clinical trial collaboration between Advaxis and MedImmune, the global biologics research and development arm of AstraZeneca.

ADXS-HPV is Advaxis’s lead Lm-LLO immunotherapy designed for the treatment of HPV-associated cancers. Preclinical evidence suggests that the combination of ADXS-HPV with a checkpoint inhibitor, such as MEDI4736, can enhance overall anti-tumour response.

Pending FDA’s acceptance of the IND submission, the proposed Phase 1/2 protocol is designed to evaluate the safety and efficacy of ADXS-HPV as monotherapy and in combination with MEDI4736. Specifically, the Phase 1 part of the trial is expected to establish a recommended dose regimen of ADXS-HPV with MEDI4736, and the Phase 2 portion will assess the safety and efficacy of the combination. The study is planned to begin in early 2015.

"The filing of our ADXS-HPV + MEDI4736 IND for HPV associated cervical and head and neck cancers is another significant advance in Advaxis’s clinical strategy as it adds to our rapidly growing pipeline and positions Advaxis as a clear leader in the immunotherapy-checkpoint inhibitor combination therapy market," commented Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. "Additionally, the filing of this IND and the recently announced filing of the ADXS-PSA + KEYTRUDA (pembrolizumab) IND demonstrate Advaxis’s ability to rapidly transition partnering agreements to clinical programs. Since announcing our agreements with MedImmune and Merck in July and August, respectively, we have worked diligently with both companies’ research teams to develop IND filings involving each company’s checkpoint inhibitor that, upon acceptance by FDA, should enable us to initiate two Phase 1/2 trials in early 2015."

Within 30 calendar days of the IND filing, FDA will notify Advaxis of any questions it has or protocol revisions it requests which may delay this timing. Advaxis plans to work with the FDA review team to address any questions or requests that arise within this 30-day window.

On November 12, 2014 Clovis Oncology reported that the Phase 2 portion of the seamless Phase 2/3 TIGER-1 (Third-Generation Inhibitor of Mutant EGFR in Lung Cancer) study has commenced with the dosing of the first patient at a U.S. study site (Press release Clovis Oncology, NOV 12, 2014, View Source;p=RssLanding&cat=news&id=1989119 [SID:1234500959]). Rociletinib is the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations as well as the primary resistance mutation T790M.

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"I am pleased to lead the US trial of first-line rociletinib in patients with EGFR-mutant NSCLC," said Ross Camidge, MD, PhD, Associate Professor, Division of Medical Oncology, University of Colorado School of Medicine and the lead investigator for the TIGER-1 study in the United States. "The rociletinib clinical data observed to date in the second-line EGFR-mutant population after failure of drugs like erlotinib have been highly encouraging and consistent, really making the case to try this drug in these patients from the outset. The absence of side effects associated with wild-type EGFR inhibition from this drug is also likely to be welcomed by patients."

"It is exciting that less than five years after the initial TKI was confirmed as standard first-line treatment for EGFR-mutant NSCLC, we are ready to begin the first randomized study proving the role of a third-generation EGFR inhibitor in this population," said Tony Mok, Professor of Clinical Oncology, the Chinese University of Hong Kong, and the lead investigator for the TIGER-1 study in Asia. "Rociletinib is a very promising compound which targets both the activating mutations and the resistant exon 20 T790M mutation. It is our objective to prove a higher efficacy with rociletinib in the TIGER-1 study. With the high incidence of EGFR mutations in this region, I trust TIGER-1 will roar in Asia."

"Patients with EGFR-mutant lung cancer are hungry for a new treatment option that can extend progression-free survival beyond what is seen with the first-generation EGFR inhibitors available today, particularly an option without the rash that make current treatments difficult for many patients," said Bonnie J. Addario, founder of The Bonnie J. Addario Lung Cancer Foundation, one of the largest philanthropies (patient-founded, patient-focused, and patient-driven) devoted exclusively to eradicating Lung Cancer through research, early detection, education, and treatment. "The evident activity and clear lack of rash and other side effects associated with wild-type EGFR inhibition makes us very enthusiastic about the potential for this drug and this study. I believe the development of targeted therapies like rociletinib represents one of the most important scientific advances of this decade."

In pre-clinical testing, rociletinib demonstrated significant reductions in tumor volume in subcutaneous xenograft and genetically-engineered mouse models with each of the two activating mutations (exon 19 deletion, L858R mutation), collectively observed in approximately 85 percent of EGFR-mutant NSCLC patients. Consistent with rociletinib sparing wild-type EGFR, there was no reduction in body weight in the animals treated with rociletinib whereas body weight loss was observed in the animals treated with erlotinib or afatinib.

In approximately 60 percent of patients with EGFR-mutant NSCLC, acquired resistance to current EGFR TKIs is driven by a secondary T790M mutation in EGFR. In a front-line PC-9 (EGFRDel19) model rociletinib and erlotinib were compared over time to determine when resistance emerged. Resistant tumors emerged around day 30 in erlotinib-treated mice whereas no tumor regrowth was observed in mice treated up to 86 days with rociletinib.