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U.S. FDA Grants Fast Track Designation for HER2-Targeting Antibody Drug Conjugate DS-8201 for HER2-Positive Metastatic Breast Cancer

On December 1, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to its investigational HER2-targeting antibody drug conjugate DS-8201 for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including ado-trastuzumab emtansine
(T-DM1) (Press release, Daiichi Sankyo, DEC 1, 2016, View Source [SID1234516875]).

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Fast Track designation is designed to facilitate the development and expedite the review of drugs that treat serious conditions and address an unmet medical need. The designation enables early and frequent communication with the FDA and is intended to accelerate drug approval and patient access to novel treatment options.

"This is an important milestone for DS-8201 that underscores the critical need to develop new and effective therapeutic options for patients with metastatic breast cancer whose tumors are no longer controlled by currently approved targeted HER2 treatments," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "It’s our obligation to drive science forward to help bring innovative treatment options to cancer patients with the greatest unmet needs and we look forward to working closely with the FDA to optimize development of DS-8201."
Fast Track designation was granted based on results from the dose escalation part of a two-part phase 1 study that assessed the safety, tolerability and preliminary efficacy of DS-8201. These results were recently presented during a late-breaking poster discussion at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress and further highlighted in the concluding summary session.1
The second part (dose expansion) of the ongoing phase 1 study is enrolling patients in Japan and the United States to evaluate the safety and efficacy of DS-8201 in four different cohorts of HER2 expressing cancers: patients with HER2+ metastatic breast cancer previously treated with T-DM1; patients with HER2+ gastric or gastroesophageal junction adenocarcinoma previously treated with trastuzumab; patients with HER2 low expressing breast cancer; and patients with other solid cancers that express HER2. For more information about the study visit ClinicalTrials.gov.

About DS-8201
DS-8201 is an investigational HER2-targeting antibody drug conjugate (ADC) currently in phase 1 clinical development for HER2+ advanced or metastatic breast cancer or gastric cancer, HER2 low expressing breast cancer and other HER2 expressing solid cancers.

DS-8201 is comprised of a humanized anti-HER2 antibody attached by a peptide linker to a novel topoisomerase I inhibitor that utilizes Daiichi Sankyo’s proprietary linker-payload technology, offering a unique mechanism of action.2 This linker-payload combination of DS-8201 allows for a higher drug-to-antibody ratio (DAR) of about 8, which may help target low expressing HER2 tumors by supplying more payload per antibody to a tumor.2

About HER2+ Metastatic Breast Cancer
Human epidermal growth factor receptor 2 (known as HER2) is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells.3 About one in five breast cancers overexpress the HER2/neu gene, which causes these cancers to grow more aggressively.3 Several unmet needs remain today in HER2+ metastatic breast cancer. Many tumors advance to the point where no currently approved HER2-targeted treatment continues to control the disease.4 Additionally, there are no existing options indicated for HER2 low expressing tumors (IHC2+/FISH- or IHC1+), which generally have poor prognosis.2,5

IBM and Pfizer to Accelerate Immuno-oncology Research with Watson for Drug Discovery

On December 1, 2016 IBM (NYSE: IBM) Watson Health and Pfizer Inc. (NYSE: PFE) reported a collaboration that will utilize IBM Watson for Drug Discovery to help accelerate Pfizer’s research in immuno-oncology, an approach to cancer treatment that uses the body’s immune system to help fight cancer (Press release, Pfizer, DEC 1, 2016, View Source [SID1234516872]). Pfizer is one of the first organizations worldwide to deploy Watson for Drug Discovery, and the first to customize the cloud-based cognitive tool – tapping in to Watson’s machine learning, natural language processing, and other cognitive reasoning technologies to support the identification of new drug targets, combination therapies for study, and patient selection strategies in immuno-oncology.

Immunotherapies, which modify a patient’s immune system to recognize and target cancer cells using a combination of vaccines, immunomodulators, and small/large molecules, are reshaping the field of oncology. Oncology researchers at Pfizer will use Watson for Drug Discovery to analyze massive volumes of disparate data sources, including licensed and publicly available data as well as Pfizer’s proprietary data. With this new tool, Pfizer researchers will analyze and test hypotheses to generate evidence-based insights for real-time interaction. The customized technology can also support efficient safety assessments.

Cancer is one of the leading causes of death worldwide, and is arguably one of the most complex diseases known to mankind.1 Many researchers believe that the future of immuno-oncology lies in combinations tailored to unique tumor characteristics, which could transform the cancer treatment paradigm and enable more oncology patients to be treated.

"Pfizer remains committed to staying at the forefront of immuno-oncology research," said Mikael Dolsten, President, Pfizer Worldwide Research & Development. "With the incredible volume of data and literature available in this complex field, we believe that tapping into advanced technologies can help our scientific experts more rapidly identify novel combinations of immune-modulating agents. We are hopeful that by leveraging Watson’s cognitive capabilities in our drug discovery efforts, we will be able to bring promising new immuno-oncology therapeutics to patients more quickly."

Laurie Olson, Executive Vice President, Strategy, Portfolio and Commercial Operations, Pfizer, said, "At Pfizer, we are entering a new frontier in data innovation in which we are investing in a range of new technologies and digital solutions to help us dynamically mine both internal and external data sources to find new connections in science, as well as help us better understand how diseases progress and how they could potentially be treated. Applying the power of cognitive computing to an area that is a core part of our DNA – discovering new medicines – is helping Pfizer to learn how we can most efficiently discover those immuno-oncology therapies that have the best chance of successful outcomes for patients."

The newly launched Watson for Drug Discovery is a cloud-based offering that aims to help life sciences researchers discover new drug targets and alternative drug indications. The average researcher reads between 200 and 300 articles in a given year2, while Watson for Drug Discovery has ingested 25 million Medline abstracts, more than 1 million full-text medical journal articles, 4 million patents and is regularly updated. Watson for Drug Discovery can be augmented with an organization’s private data such as lab reports and can help researchers look across disparate data sets to surface relationships and reveal hidden patterns through dynamic visualizations.

"We believe that the next great medical innovations will emerge as researchers and scientists find new patterns in existing bodies of knowledge. In order to do this, they need access to R&D tools that can help them efficiently navigate the opportunities and challenges presented by the explosion of data globally," said Lauren O’Donnell, Vice President of Life Sciences, IBM Watson Health. "IBM is honored to collaborate with Pfizer, and put Watson for Drug Discovery to work to support efforts in bringing life-saving immunotherapies to doctors and patients worldwide."

CTI BioPharma Presents Nonclinical Pharmacology Study Demonstrating Pacritinib Has Distinct Profile Amongst JAK Inhibitors At EORTC-NCI-AACR Molecular Targets And Cancer Therapeutics Symposium

On December 1, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported the results of a translational pharmacology study comparing biomarker activity profiles for three JAK inhibitors: pacritinib, ruxolitinib and momelotinib, using the BioMAP Diversity PLUS panel of in vitro human primary cell-based systems (Press release, CTI BioPharma, DEC 1, 2016, View Source [SID1234516869]). The results demonstrated distinct profiles amongst these JAK inhibitors and suggest that clinical responses are likely to be distinct with each agent. The results were presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium, November 29 – December 2 in Munich, Germany.

At clinically relevant concentrations, each of the JAK inhibitors reduced inflammatory mediators associated with myelofibrosis such as TNF and IL-6, however they had divergent effects on other immunological and inflammatory pathways. When tested on human lymphoid cells, pacritinib had the strongest inhibitory activities on sIL-17A, sIL-2 and sIL-6, mediators involved in autoimmune responses, while ruxolitinib had the broader inhibitory activities in multiple systems. Both ruxolitinib and pacritinib were inhibitory to B cells, but only ruxolitinib inhibited T cells that are associated with cell-mediated immunity. Only pacritinib was anti-proliferative to endothelial cells and fibroblasts, effects commonly seen in agents with anti-cancer properties. The resulting distinct phenotypic profiles of pacritinib, ruxolitinib and momelotinib, illustrate that although all were developed as JAK2-ATP binding site inhibitors, they have divergent biological effects and likely will have distinct clinical activities.

The poster for Abstract #P094: "Comparative Biomarker Profiles of Pacrtitinib, Momelotinib, Pexidartinib and Ruxolitinib Using BIOMAP Diversity Plus Panel" is available at www.ctibiopharma.com.

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.

Kura Oncology Presents Preclinical Data on KO-947 and Menin-MLL Inhibitor Program at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

On December 1, 2016 Kura Oncology, Inc. (Nasdaq:KURA), a clinical stage biopharmaceutical company, reported preclinical data highlighting the identification and characterization of KO-947, its development candidate targeting ERK1/2 kinases (Press release, Kura Oncology, DEC 1, 2016, View Source [SID1234516867]). The company has also presented preclinical data relating to the identification and optimization of potent and selective inhibitors of the menin-MLL interaction. Both presentations took place at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics (EORTC) in Munich, Germany.

"We are excited to present preclinical data from these two innovative programs at EORTC, both of which showed compelling activity in preclinical models of cancer," said Yi Liu, Ph.D., Chief Scientific Officer. "Looking forward, we anticipate nominating a development candidate for our menin-MLL program by the end of 2016, and initiating a Phase 1 clinical trial for KO-947 in the first half of 2017."

KO-947 – A potent and selective inhibitor of ERK1/2 kinases

The RAS/RAF/MEK pathway is estimated to be activated in more than 30% of human cancers, including cancers arising from mutations in KRAS, NRAS and BRAF. Although inhibitors of both BRAF and MEK have been approved for treatment of melanoma, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples due to reactivation of ERK1/2 kinases.

In preclinical studies presented today at EORTC, KO-947 showed potent inhibition of ERK signaling pathways and proliferation of tumor cells exhibiting dysregulation of MAPK pathway, including mutations in BRAF, NRAS or KRAS. KO-947 also inhibits MAPK signaling and cell proliferation in preclinical models that are resistant to BRAF and MEK inhibitors. Results obtained from screening a large panel of PDX models demonstrate that KO-947 induces tumor regressions in BRAF or RAS mutated tumor models as well as in tumor models lacking BRAF/RAS mutations but characterized by other dysregulation of the MAPK pathway.

KO-947 appears to be differentiated from other published ERK inhibitors by an extended residence time and prolonged pathway inhibition in vitro and in vivo. The data further suggest that the drug properties of KO-947 may allow Kura to maximize the therapeutic window with flexible administration routes and schedules, including intermittent dosing.

Inhibitors of the Menin-MLL Interaction

Chromosomal translocations that affect the mixed lineage leukemia (MLL) gene result in aggressive acute myeloid and lymphoid leukemias that are often resistant to standard chemotherapy. Approximately 5-10% of acute leukemias in adults, and 70% of acute leukemias in infants, are characterized by tumors with abnormal MLL fusions. MLL fusion proteins require menin for leukemogenic activity and selective disruption of the menin-MLL interaction represents a potential therapeutic approach for the treatment of acute leukemias with MLL rearrangements.

In preclinical studies presented at EORTC, inhibitors of the menin-MLL interaction showed potent inhibition of the proliferation of MLL leukemic cells. Inhibitors of the menin-MLL interaction displayed a greater than 50-fold reduction in potency in non-MLL-fusion leukemia cell lines and induced regression in a MV4:11 mouse xenograft model. The data show that the anti-tumor activity of menin-MLL inhibitors correlates with target engagement in tumors as well as inhibition of expression of downstream genes under the regulation of the fusion protein. Moreover, the inhibitors demonstrated potent efficacy in subcutaneous and disseminated models of MLL-fusion leukemias.

Both of the posters presented at EORTC can be found on Kura’s website in the Scientific Presentations and Papers section or by clicking here.

IGNYTA ANNOUNCES COMPELLING PHASE 1/1b CLINICAL DATA ON RXDX-105, ITS VEGFR-SPARING RET INHIBITOR, AT THE 2016 EORTC-NCI-AACR ANNUAL MEETING

On December 1, 2016 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported data from an ongoing Phase 1/1b study of RXDX-105—Ignyta’s VEGFR-sparing, potent RET inhibitor—at the 2016 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Molecular Targets and Cancer Therapeutics Symposium in Munich, Germany, highlighting RXDX-105’s clinical activity in patients harboring RET molecular alterations, with five out of nine patients with RET fusion-positive cancers who were RET inhibitor-naïve achieving a RECIST response (1 complete response, 3 partial responses, and 1 unconfirmed partial response), for a preliminary objective response rate (ORR) of 56% (Abstract number 437, Poster number P116) (Filing, 8-K, Ignyta, DEC 1, 2016, View Source [SID1234516866]).

"This substantial update of our Phase 1/1b clinical data on RXDX-105 provides compelling evidence of its potent anti-tumor activity with promising durability and acceptable safety in patients with RET-fusion positive tumors," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "With approximately 500-fold higher potency against RET than VEGFR2 in vitro, RXDX-105 has the potential to address a critical unmet medical need in RET-positive patients for whom the clinical utility of multikinase inhibitors with both RET and VEGFR activity is constrained by safety liabilities and limited efficacy. We look forward to the continuation of the study to further explore the safety and efficacy of RXDX-105."
As of the November 2016, data cut-off, the findings showed:
Safety
A total of 91 patients with a range of solid tumors have been treated in the Phase 1/1b clinical trial, with 55 patients treated in the Phase 1 study and 36 patients treated in the Phase 1b study.

• RXDX-105 continues to demonstrate a safety profile similar to what has been previously reported: across both studies, the most common treatment-related adverse events (>10% incidence) were rash (31%), fatigue (22%), diarrhea (20%), nausea (18%), hypophosphatemia (14%), vomiting (14%), muscle spasms (13%), and decreased appetite (10%);

• The majority of treatment-related adverse events were Grade 1 or 2, and were reversible with dose modification;

• The most common Grade 3 treatment-related adverse events (>5% incidence) were rash (9%), hypophosphatemia (7%), and ALT increase (6%);

• One patient experienced a Grade 3 drug reaction with eosinophilia and systemic symptoms, in which the patient recovered with drug discontinuation. One patient experienced Grade 3 rash complicated by fatal alveolar hemorrhage. No other treatment-related Grade 4 or higher events were observed.

• Toxicities commonly associated with VEGFR inhibition, such as hypertension, hypothyroidism, proteinuria, and neurotoxicity, were rarely observed (<5%).
Efficacy
Of the 36 patients treated in the Phase 1b study, 35 had RET or BRAF molecular alterations.
Nine RET inhibitor-naïve patients (n = 8 in the Phase 1b cohort; n = 1 in the Phase 1 cohort) with RET fusion-positive tumors were treated at a daily dose of 275 mg or 350 mg in the fed state, and were evaluable for response.

• A preliminary ORR of 56% was observed in patients with RET fusion-positive solid tumors who were RET inhibitor-naïve (five out of nine treated patients had a RECIST response);

• Of the five patients demonstrating a RECIST response, one patient with metastatic colorectal cancer (mCRC) achieved a complete response; three patients, all with non-small cell lung cancer (NSCLC), achieved a partial response; and one patient with NSCLC had an unconfirmed partial response;

• Among the seven patients with RET fusion-positive NSCLC who were RET inhibitor-naïve, three achieved a partial response and one achieved an unconfirmed response (a second scan had not been obtained at the date of data cutoff), for a preliminary ORR of 57%;

• Duration of response to RXDX-105 ranged from 2+ to 7+ months, with all responder patients currently continuing on treatment in active response; median duration of response, therefore, has not yet been determined;

• Additionally, a previously disclosed Phase 1 patient with RET-mutated M918T medullary thyroid cancer had a confirmed partial response and continues on treatment after ten cycles.

• These data confirm that RXDX-105 is active across a range of different histologies, with confirmed RECIST responses now observed in medullary thyroid cancer, NSCLC, and mCRC, and across a range of RET molecular alterations, including the M918T point mutation, and CCDC6-, EML4-, and PARD3-RET fusions.
Among the remaining patients treated in Phase 1b who were either RET fusion-positive and received prior RET inhibitor treatments (n = 4) or had BRAF molecular alterations (n = 23), durable disease control but no objective responses have been observed to date.
Based on the promising efficacy data observed thus far in patients with RET fusion-positive solid tumors who are RET inhibitor-naïve, this population will remain the primary focus of future development of RXDX-105. Enrollment in the Phase 1b study is ongoing to further explore the safety and efficacy of RXDX-105 in various molecular baskets at several doses.