On January 08, 2016 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for LV305 and G305 for the treatment of soft tissue sarcoma (Press release, Immune Design, JAN 8, 2016, View Source [SID:1234508704]). LV305 and G305 are the complementary agents that comprise CMB305, Immune Design’s "prime boost" cancer immunotherapy product candidate.

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Orphan Drug Designation is granted by the FDA Office of Orphan Drug Products to products that treat rare diseases. The FDA defines rare diseases as those affecting fewer than 200,000 people in the United States. Orphan Drug Designation provides the sponsor certain benefits and incentives, including a period of marketing exclusivity for the first marketing application, if regulatory approval is received for the designated indication, potential tax credits for certain activities and waiver of certain administrative fees.

CMB305 is a cancer immunotherapy product candidate that involves the sequential dosing of LV305 and G305. LV305 is a hybrid vector from the ZVex discovery platform that specifically targets dendritic cells (DCs) in vivo and delivers the RNA for NY-ESO-1, enabling the DCs to express the entire tumor antigen and potentially induce a diverse set of CTLs targeting NY-ESO-1 in tumors. G305, in contrast, is designed to boost the CTL response via the induction of antigen-specific CD4 "helper" T cells. G305 consists of recombinant NY-ESO-1 protein formulated with a proprietary synthetic small molecule called glucopyranosyl lipid A (GLA), the novel TLR4 agonist at the core of the GLAAS platform. CMB305 is intended to be an "off-the shelf" therapy that does not require patient-specific manufacturing or ex vivo manipulation of patient samples. Immune Design has conducted prior studies to establish the safety and individual immunologic activity of LV305 and G305. CMB305 is currently being evaluated in a Phase 1B trial in patients with locally advanced, relapsed or metastatic solid cancers whose tumors express NY-ESO-1 and a randomized Phase 2 trial of CMB305 combined with Genentech’s investigational cancer immunotherapy, atezolizumab (MPDL3280A; anti-PD-L1) in patients with soft tissue sarcoma, pursuant to a collaboration with Genentech.

On January 8 2016 Pfizer Inc. (NYSE: PFE) and Adaptive Biotechnologies Corporation reported that they have entered into a translational research collaboration to leverage next generation sequencing of the adaptive immune system to advance Pfizer’s growing immuno-oncology franchise (Press release, Pfizer, JAN 8, 2016, View Source [SID:1234508703]).

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Under the terms of the agreement, Pfizer and Adaptive will seek to combine drug development and platform technology biomarker expertise to identify patients who may preferentially benefit from immunotherapy.

Understanding and reliably measuring each patient’s immune response to their cancer before and after therapy is critical to defining the most appropriate immunotherapy for that patient. Adaptive’s immunosequencing platform quantitatively and reproducibly measures the patient’s immune-cell repertoire, providing a powerful translational tool to accelerate Pfizer’s immuno-oncology biomarker and drug development programs.

"Immunotherapy is one of the most important advances in cancer therapy and offers the potential for long term disease control for many patients," said Chris Boshoff, Vice President and Head of Early Development, Translational and Immuno-Oncology at Pfizer Oncology. "Pfizer is investing significantly in this space. The collaboration with Adaptive Biotechnologies supports our strategy of accelerating the development of potentially innovative new combination treatments by allowing us to develop a differentiated and competitive understanding of the immune landscape in specific tumor types."

Adaptive Biotechnologies, the leading experts in profiling the immune cell repertoire, will work with Pfizer to apply their proprietary immunosequencing platform technology, bioinformatics capability, and scientific expertise to advance Pfizer’s rapidly expanding immuno-oncology pipeline.

"This collaboration with Pfizer is evidence of the immense impact immune repertoire profiling may have on the immuno-oncology space," said Chad Robins, President, Chief Executive Officer and Co-Founder at Adaptive Biotechnologies. "Adaptive’s ability to precisely measure a patient’s immune response to cancer before and after treatment provides a universal tool that will help bolster our understanding of immuno-oncology approaches."

About Adaptive Biotechnologies

Adaptive Biotechnologies is the pioneer and leader in combining high-throughput sequencing and expert bioinformatics to profile T-cell and B-cell receptors. Adaptive is bringing the accuracy and sensitivity of its immunosequencing platform into laboratories around the world to drive groundbreaking research in cancer and other immune-mediated diseases. Adaptive translates immunosequencing discoveries into clinical diagnostics and therapeutic development to improve patient care.

On January 08, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage company developing novel anti-cancer stem cell and immuno-oncology therapeutics reported the publication of a manuscript in Cancer Research describing OncoMed’s efforts to develop novel therapeutics against R-spondin (RSPO) targets and elucidating the link between expression of the RSPO cancer stem cell pathway and tumor growth (Press release, OncoMed, JAN 8, 2016, View Source [SID:1234508702]). OncoMed is currently conducting a Phase 1a/b clinical trial of its anti-RSPO3 (OMP-131R10) antibody.

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The article "Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates beta-Catenin Signaling and Tumorigenesis in Multiple Cancer Types" (released online December 30, 2015) describes the generation of neutralizing monoclonal antibodies against RSPO-1, -2 or -3 and the successful use of these antibodies to treat diverse types of patient-derived xenografts, including colon, ovarian, pancreas and lung tumors. Of note, these anti-RSPO antibodies were effective in the tumor models regardless of whether the tumors overexpressed RSPO because of gene translocations or because of other tumor-intrinsic pathways. OncoMed is utilizing biomarker assays to prospectively screen patients for RSPO gene expression as part of its Phase 1a/b clinical program.

Mechanistically, the paper establishes a functional link between RSPO expression and tumor growth. Tumor-derived RSPO can activate beta-catenin, and antibody-mediated blocking of RSPO binding to its receptor potently inhibits tumor growth. This anti-tumor activity is associated with the modulation of beta-catenin and cancer stem cell pathways.

"R-spondins are emerging as an important cancer target. As key stimulators of beta-catenin activity in a variety of human tumor types, targeting the RSPO pathway may prove to be an effective approach to modulating this fundamental signaling axis," said John Lewicki, Ph.D., OncoMed’s Chief Scientific Officer. "Our first anti-RSPO candidate is being studied in Phase 1a/b clinical trials with a strong biomarker hypothesis and we expect to establish a single-agent dose and treat biomarker-positive patients this year."

About Anti-RSPO3
OncoMed’s anti-RSPO3 (OMP-131R10) is the first drug in its class to target the R-spondin-LGR pathway, an important cancer stem cell pathway identified by OncoMed researchers. The company’s ongoing Phase 1a/1b clinical trial is initially enrolling patients with advanced refractory solid tumors to assess the safety, pharmacokinetics, pharmacodynamics and initial evidence of efficacy of the anti-RSPO3 antibody. Once a single-agent dose has been identified, biomarker-selected patients will be enrolled in a Phase 1a expansion arm to evaluate possible anti-tumor activity. In the Phase 1b portion of the trial, anti-RSPO3 will also be tested in second-line colorectal cancer patients in combination with chemotherapy.

In preclinical studies OncoMed’s anti-RSPO3 antibody demonstrated robust in vivo anti-tumor efficacy as a single agent and in combination with standard of care across a range of solid tumors, including colon, lung, ovarian, and pancreatic cancers, among others. The anti-RSPO3 antibody delayed tumor recurrence following termination of chemotherapy, and decreased the frequency of cancer stem cells. Anti-RSPO3 antibody represents the third product candidate in the clinic that is part of OncoMed’s collaboration with Celgene.

On January 8, 2016 Otsuka Pharmaceutical Co., Ltd. (Headquarters: Chiyoda-ku, Tokyo; President and CEO: Tatsuo Higuchi; "Otsuka")reported that it has filed the NDA in Japan for "ponatinib (brand name outside Japan is Iclusig), a known tyrosine kinase inhibitor (TKI) developed by ARIAD Pharmaceuticals, Inc. (Headquarters: Massachusetts, United States; "ARIAD") used to treat resistant and intolerant chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (Press release, Otsuka, JAN 8, 2016, View Source [SID:1234508699]).

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ARIAD conducted a multicenter Phase I / II trial in Japan to confirm efficacy, safety and tolerability of ponatinib. Otsuka filed the NDA based on these results and the results of overseas clinical trials. Furthermore, ponatinib was designated in Japan to be an orphan drug in September 2015.

Ponatinib is a TKI discovered and developed by ARIAD that targets BCR-ABL expressed in CML and Ph+ ALL. This drug is a new chemically synthesized oral TKI, and is specifically designed to inhibit unmutated BCR-ABL as well as T315I mutation, a mutant-type BCR-ABL that manifests and induces resistance after patients are treated with other TKIs. Ponatinib demonstrates efficacy in currently available TKI-resistant and in patients who are intolerable CML as well as relapsed or refractory Ph+ ALL, but it also demonstrates efficacy for isoforms of BCR-ABL that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs. Ponatinib was approved by the US FDA in December 2012, and was approved in Europe in July 2013.

In Japan, CML occurs in approximately 1 out of 100,000 people among all age groups. It is estimated that there are approximately 11,000 patients.*3 Although the mortality rate has decreased with the advancement of TKI treatment, the number of patients is steadily increasing with an aging population. Initial symptoms are rarely seen in CML patients from disease onset to the chronic phase (5-6 years); however, white blood cell count and the blast cell ratio increase and, as the disease progresses, patients begin experiencing symptoms such as general malaise, weight loss, and bloating due to hepatosplenomegaly. In the accelerated phase (6-9 months), patients experience bone pain and exacerbation of hepatosplenomegaly; in the blast phase (3-6 months), patients experience anemia, bleeding tendencies, infections, etc. For CML, symptoms gradually worsen and risk of treatment resistance increases as the disease progresses*4. In contrast, Ph+ALL is seen in pediatric and elderly patients, and prognosis is extremely poor for patients who relapse after receiving initial ALL treatment and is an area where needs are still unmet.*5,6

Although TKI is used as a first-line drug for CML and Ph+ ALL, resistance to treatment can develop as the disease progresses because of amplification, overexpression or mutation of BCR-ABL genes, which are causal factors of the disease. In such cases, an adequate patient response to therapy may not be obtained even after several TKI products are used. In addition, there are patients who must discontinue treatment as they become intolerant of the side effects of other TKIs. A new TKI treatment is desired in Japan and other Asian countries in order to treat such resistant or intolerant patients.

Otsuka is currently expanding its product portfolio and is focusing on CNS (neuropsychiatry), cardiovascular, ophthalmology, and oncology fields. The company will continue to develop and commercialize pharmaceuticals aimed to improve survival of hematological cancer patients with insufficient treatment options by undertaking operations to provide a wide range of products from diagnostics to treatment.

On January 8, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported updated results from the pivotal phase II study, IMvigor 210, of the investigational cancer immunotherapy atezolizumab (MPDL3280A) in people with locally advanced or metastatic urothelial carcinoma (mUC) (Press release, Hoffmann-La Roche , JAN 8, 2016, View Source [SID:1234508698]).

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Median overall survival (mOS) in this heavily pre-treated population was 11.4 months [95% CI: 9.0, NE] in people with higher levels of PD-L1 expression, and 7.9 months [95% CI: 6.6, 9.3] in the overall study population. The study also showed that 84% (n=38/45) of people who responded to atezolizumab continued to respond regardless of their PD-L1 status, when the results were assessed with longer median follow-up of 11.7 months. Median duration of response has not yet been reached. Atezolizumab was well tolerated and adverse events were consistent with those observed in previous updates. These data were presented at the 2016 Genitourinary Cancers Symposium of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (ASCO GU).1

"It is encouraging to see that the majority of people with advanced bladder cancer who responded to atezolizumab maintained their response with longer follow up," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "We are looking forward to sharing these results with the US FDA and other health authorities in the hope that we may bring atezolizumab to treating physicians and their patients as soon as possible."

Roche is planning to submit these data imminently to Global health authorities and the U.S. Food and Drug Administration (FDA) under Breakthrough Therapy designation. This designation is designed to expedite the development and review of medicines that may demonstrate substantial improvement over existing therapies for serious diseases.

About the IMvigor 210 study
IMvigor 210 is an open-label, multicentre, single-arm phase II study that evaluated the safety and efficacy of atezolizumab in people with locally advanced or mUC, regardless of PD-L1 expression. People in the study were enrolled into one of two cohorts. Cohort 1 comprised those who had received no prior therapies for locally advanced or mUC, but who were ineligible for first-line cisplatin-based therapy. The results for this cohort are not yet mature. Cohort 2, for which updated results were announced today, included people whose disease had progressed during or following previous treatment with a platinum-based chemotherapy regimen(heavily pretreated), 41 percent of people in the study had 2 or more treatments in the metastatic setting. People received a 1200-mg intravenous dose of atezolizumab on day 1 of 21-day cycles until progressive disease (Cohort 1) or loss of clinical benefit (Cohort 2).

Co-primary endpoints of the study included confirmed RECIST v1.1 ORR per central IRF and investigator-assessed modified RECIST ORR. Secondary endpoints included duration of response, overall survival, progression-free survival and safety. People were selected by histology, prior lines of therapy and PD-L1 expression on tumour-infiltrating immune cells (IC), using an investigational immunohistochemistry test that is being developed by Roche Tissue Diagnostics.

In addition to IMvigor 210, Roche has an ongoing randomised phase III study, IMvigor 211, comparing atezolizumab with standard-of-care chemotherapy in people who have mUC that worsened after initial treatment. All studies include the evaluation of a companion test developed by Roche Tissue Diagnostics to determine PD-L1 status.

About metastatic urothelial cancer
Metastatic urothelial cancer is associated with a poor prognosis and limited treatment options. It is a disease that has seen no major advancements for nearly 30 years. Urothelial cancer is the ninth most common cancer worldwide, with 430,000 new cases diagnosed in 2012, and it results in approximately 145,000 deaths globally each year. Men are three times more likely to suffer from urothelial cancer compared with women, and it is also three times more common in developed countries than in less developed countries.

About atezolizumab
Atezolizumab (also known as MPDL3280A) is an investigational monoclonal antibody designed to target and bind to a protein called PD-L1, which is expressed on TCs and tumour-infiltrating ICs. PD-L1 interacts with PD-1 and B7.1, both found on the surface of T cells, causing inhibition of T cells. By blocking this interaction, atezolizumab may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells.