On September 3, 2019 Astex Pharmaceuticals, Inc., a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan, reported that the US Food & Drug Administration (FDA) has granted orphan drug designation for the company’s orally administered fixed-dose combination of cedazuridine and decitabine (ASTX727 or C-DEC) for the treatment of myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML) (Press release, Astex Pharmaceuticals, SEP 3, 2019, View Source [SID1234539239]). The designation follows on from the recent announcement that the phase 3 ASCERTAIN study of ASTX727 in adults with intermediate and high-risk MDS or CMML met the primary endpoint of decitabine exposure equivalence of total 5-day dosing between oral ASTX727 and IV decitabine. The data from the study will be presented at an upcoming scientific meeting. The designation provides for seven years of marketing exclusivity in the US following product approval, as well as certain tax incentives and grants.

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"We are delighted that the FDA has granted orphan drug designation for the fixed dose combination of cedazuridine with decitabine," said Mohammad Azab, MD, Astex Pharmaceuticals’ president and chief medical officer. "Subject to regulatory review and approvals, ASTX727 could bring a new treatment option to patients with these deadly diseases. We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who contributed to the clinical development program of ASTX727."

ASTX727 is an investigational compound and is not currently approved in any country. Astex plans to file an NDA with the US FDA by the end of 2019.

Astex’s parent company, Otsuka Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd. previously announced that, subject to regulatory approvals, commercialization of ASTX727 in the US and Canada will be conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc. respectively. Astex, Otsuka and Taiho are all members of the Otsuka group of companies.

About Cedazuridine and Decitabine Fixed-Dose Combination (ASTX727)

ASTX727 is a novel, orally administered fixed dose combination of cedazuridine, an inhibitor of cytidine deaminase,1 with the anti-cancer DNA hypomethylating agent, decitabine.2 By inhibiting cytidine deaminase in the gut and the liver, ASTX727 is designed to allow for oral delivery of the approved DNA hypomethylating agent, decitabine, at exposures which emulate exposures achieved with the approved intravenous form of decitabine administered over 5 days.3

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study in patients with MDS and CMML (see View Source NCT02103478) and a pivotal phase 3 study (ASCERTAIN) (see View Source NCT03306264) conducted at investigator sites in the US and Canada and designed to confirm the results from the phase 1/2 study. The phase 3 study is being extended to include patients with acute myeloid leukemia (AML) unsuitable to receive intensive induction chemotherapy.

The concept of using cedazuridine to block the action of cytidine deaminase is also being evaluated in a low dose formulation of cedazuridine and decitabine for the treatment of lower risk MDS (see View Source NCT03502668).

About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. US incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.4,5 The prevalence has been estimated to be from 60,000 to 170,000 in the US.6 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.7 The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML. CMML is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the US is approximately 1,100 new cases per year,8 and CMML may transform into AML in 15% to 30% of patients.9 The hypomethylating agents decitabine and azacitidine are effective treatment modalities for hematologic cancers and are FDA-approved for the treatment of higher risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections.

On September 3, 2019 Boehringer Ingelheim and Lupin Limited (Lupin) reported a licensing, development and commercialization agreement for Lupin’s MEK inhibitor compound (LNP3794) as a potential targeted therapy for patients with difficult-to-treat cancers (Press release, Boehringer Ingelheim, SEP 3, 2019, View Source [SID1234539238]). The partnership aims to develop Lupin’s lead MEK inhibitor compound in combination with one of Boehringer Ingelheim’s innovative KRAS inhibitors for patients with gastrointestinal and lung cancers harboring a broad range of oncogenic KRAS mutations.

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"The licensing of Lupin’s novel MEK inhibitor enables us to pair with our innovative KRAS inhibitors to develop new combination treatment concepts providing more effective and durable responses for patients with cancers driven by activated KRAS who currently have limited treatment options available," said Norbert Kraut, Ph.D., Head of Global Cancer Research at Boehringer Ingelheim. "We believe this collaboration will significantly strengthen our KRAS program. We have developed comprehensive approaches to successfully tackle the oncogenic KRAS–RAF–MEK–ERK pathway from the ground up and this partnership is another key building block in our long-term strategy to bring novel treatments to patients in our quest to defeat intractable cancer types."

Commenting on the partnership, Nilesh Gupta, Managing Director, Lupin Limited said, "With the success of our second new drug discovery program in oncology, we have made a significant mark in bringing novel treatments to patients. Lupin’s MEK Inhibitor program successfully cleared early clinical stages, demonstrating our capabilities in delivering world class innovation. We are proud of the achievements of our team and the capabilities we have built which enable us to further our new drug discovery program. We are delighted to partner with Boehringer Ingelheim in developing treatments that will truly benefit patients in need".

Dr. Raj Kamboj, President of Lupin’s Novel Drug Discovery and Development (NDDD) stated, "The success of our second NDDD program in Oncology has added to our confidence in bringing highly differentiated and best-in-class innovation from India for patients globally. Carrying forward our founder, Dr. Desh Bandhu Gupta’s dream in shaping true innovation, we have delivered a novel treatment from conceptualization to clinical stage development with promising results that can be a potential combination treatment for precision oncology."

The collaboration has a strategic goal to focus on patients with gastrointestinal or lung cancers defined by KRAS mutations, sub-populations that currently need more effective therapeutic options. KRAS mutations occur in 1 in 7 of all human metastatic cancers making it the most frequently mutated cancer-causing gene, with mutation rates of more than 90 percent in pancreatic cancers, more than 40 percent in colorectal cancers and more than 30 percent in lung adenocarcinomas. Preclinical data has shown that the combination of Boehringer Ingelheim’s novel KRAS inhibitors with MEK inhibitors results in increased anti-tumor activity based on their complementary mechanisms of action in keeping KRAS-driven cancers in check.

Lupin’s MEK inhibitors developed as part of its oncology pipeline have shown pre-clinical activity as a single agent as well as in combination. Furthermore, they have also shown early clinical benefit in a small subset of patients. Lupin’s Novel Drug Discovery and Development team is focused on building a pipeline of highly differentiated and innovative new chemical entities in the therapeutic areas of oncology, immunology and metabolic disorders. Lupin’s NDDD activities were started with the vision to use cutting-edge research in bringing novel molecules that address unmet medical needs in multiple therapeutic areas to market globally.

Lupin will receive an upfront payment of $20 million and potential additional payments for successful achievement of defined clinical, regulatory and commercial milestones for a total deal value of more than $700 million. Additionally, Lupin will be entitled to receive double-digit royalties on the sales of the product.

On September 3, 2019 Physicians’ Education Resource (PER), a worldwide leading resource for continuing medical education, reported that it will present the 4th Annual International Congress on Immunotherapies in Cancer: Focus on Practice-Changing Application on Saturday, Dec. 14, at the InterContinental New York Times Square in New York City (Press release, Physicians’ Education Resource, SEP 3, 2019, View Source [SID1234539237]).

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The program will be co-chaired by Naiyer A. Rizvi, M.D., professor of medicine; director, thoracic oncology; co-director, cancer immunotherapy program; and the Price Family Professor of Medicine, Columbia University Medical Center; and Mario Sznol, M.D., professor of medicine; leader, melanoma disease related translational team; co-director, YALE SPORE in skin cancer; and co-director, cancer immunology program, Yale Cancer Center.

"We look forward to this year’s International Congress on Immunotherapies in Cancer," said Phil Talamo, president of PER. "This annual educational program brings together oncologists, nurses and pharmacists to highlight the fundamental principles and pivotal advancements within the past year surrounding the evolving role of immunotherapies and their role in cancer treatment."

The 4th Annual International Congress on Immunotherapies in Cancer is a one-day interactive program that will provide attendees with a comprehensive review of the key data sets that are most relevant to the application of these novel strategies for the clinician who manages some of the most difficult-to-treat forms of cancer. Top experts will lead discussions that focus on the practical application of recent clinical trial results that have shaped current and evolving clinical management, evolving biomarker information, the latest basic science findings and the most highly anticipated clinical trials in the field. As an exciting, fast-paced congress, this meeting will provide a multimodule, curriculum-based program that focuses exclusively on immunotherapies and their application to the management of cancer.

On September 3, 2019 CEL-SCI Corporation (NYSE American: CVM), a Phase 3 cancer immunotherapy company, reported that Geert Kersten, Chief Executive Officer, is scheduled to present at the H.C. Wainwright 21st Annual Global Investor Conference on Tuesday, September 10th at 11:15 a.m. Eastern Time (Press release, Cel-Sci, SEP 3, 2019, View Source [SID1234539236]).

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A live webcast of Mr. Kersten’s presentation will be available in the Investors section of the Company’s website at View Source The webcast will be available for 90 days following the presentation.

On September 3, 2019 Veracyte, Inc. (Nasdaq: VCYT) reported the publication of new data that further define the genomic landscape around thyroid cancer (Press release, Verastem, SEP 3, 2019, View Source [SID1234539235]). The study findings help characterize the role of specific gene alterations known as variants and fusions in predicting thyroid cancer and also reinforce the potential for Veracyte’s Afirma Xpression Atlas (XA) genomic test to help guide personalized surgery and treatment decisions for patients with suspected or confirmed thyroid cancer. The new study appears online in the journal Thyroid.

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"This personalized information helps guide surgery and treatment decisions and is derived from the same minimally invasive sample that the Afirma GSC uses in thyroid cancer diagnosis, meaning the patient can avoid additional fine needle aspiration procedures."

For the new analysis, researchers evaluated data from 61 published studies involving 4,648 thyroid nodule samples to determine the frequency of specific variants and fusions and the likelihood of cancer when they are detected in preoperative patient samples. The study focused on thyroid nodule samples that were indeterminate – not clearly benign or malignant – following traditional diagnostic testing.

Key findings include:

More than one quarter (26%) of the total thyroid nodules were positive for at least one gene alteration, and of those, 94% were DNA sequence variants and 6% were RNA fusions;
Only five specifically reported gene alterations appeared in 10 or more nodules in the collective cohort and less than one percent of the total thyroid nodules had more than one variant or fusion;
The positive predictive value (PPV) – or likelihood that a variant or fusion was found in thyroid nodules that ultimately proved cancerous – varied significantly among the five most prevalent gene alterations [BRAFV600E (98%), PAX8/PPARG (55%), HRASQ61R (45%), BRAFK601E (42%) and NRASQ61R (38%)]; and
The cumulative PPV for these five gene alterations was 77%; the PPV decreased to 47% when BRAFV600E was excluded.
"A key takeaway from our analysis is that gene variants and fusions carry different levels of cancer risk and should therefore be considered individually in thyroid cancer diagnosis and treatment decision-making. This means that use of multiple-gene panels to rule in or rule out cancer may be too blunt a tool in the emerging era of precision medicine," said Whitney S. Goldner, M.D., of the University of Nebraska Medical Center and lead author on the new paper. "We also found inconsistencies in the details reported about specific gene variants and fusions in the studies we evaluated. As researchers increasingly focus on the role of individual gene alterations in thyroid cancer, standardized reporting of this information will be very important."

"In the near future, knowing cancer’s molecular profile will be at least as important as knowing its histological subtype. Our study findings reinforce the value of the Afirma XA in identifying the presence, as well as clinical relevance, of specific gene alterations found in preoperative thyroid nodules," said Richard T. Kloos, M.D., medical director of endocrinology for Veracyte and an author of the new study. "This personalized information helps guide surgery and treatment decisions and is derived from the same minimally invasive sample that the Afirma GSC uses in thyroid cancer diagnosis, meaning the patient can avoid additional fine needle aspiration procedures."

The study findings support the use of the Afirma XA, an RNA whole-transcriptome sequencing-based test that detects expressed DNA variants and RNA fusion partners in over 500 genes that are associated with thyroid cancer. DNA variants are alterations in the most common DNA nucleotide sequences and RNA fusions are chromosomal rearrangements that juxtapose two different genes together to form a fusion gene. The Afirma XA is performed on fine needle aspiration (FNA) samples of thyroid nodules deemed suspicious for cancer by Veracyte’s Afirma Genomic Sequencing Classifier (GSC), as well as those that are suspicious for or have been diagnosed as cancer based on cytopathology.

About Afirma Genomic Testing

The Afirma GSC and Xpression Atlas provide physicians with a comprehensive solution for a complex landscape in thyroid nodule diagnosis and individualization of care. Veracyte developed the Afirma GSC with RNA whole-transcriptome sequencing and machine learning. The test helps identify patients with benign thyroid nodules among those with indeterminate cytopathology results in order to help patients avoid unnecessary diagnostic thyroid surgery. The Afirma XA provides physicians with genomic alteration content from the same fine needle aspiration samples that are used in Afirma GSC testing and may help physicians make decisions about the surgical or therapeutic pathway for their patients with greater confidence. The Afirma XA includes 761 variants and 130 fusion partners in over 500 genes that are associated with thyroid cancer.

About Thyroid Cancer

The American Cancer Society estimates that 54,070 people in the United States will be diagnosed with thyroid cancer in 2019. Each year in the United States approximately 525,000 patients undergo FNA biopsies to evaluate thyroid nodules for cancer. Up to 30 percent of these patients receive indeterminate results – meaning they are not clearly benign or malignant – and, historically, most were directed to diagnostic surgery even though 70 percent to 80 percent of the time the nodules ultimately proved to be benign. For patients diagnosed with thyroid cancer, multiple precision medicine therapies are now available or in development to treat the cancer based on its genomic profile.