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Astex and Otsuka Announce Results of the Phase 3 ASCERTAIN Study of the Novel Oral Cedazuridine/Decitabine Fixed-Dose Combination (ASTX727) in Patients with Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

On June 6, 2019 Astex Pharmaceuticals, Inc. a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co. Ltd., reported top-line results from the ASCERTAIN phase 3 study evaluating cedazuridine and decitabine fixed-dose combination (ASTX727) vs decitabine IV in adults with intermediate and high-risk MDS or CMML (Press release, Astex Pharmaceuticals, JUN 6, 2019, View Source [SID1234536935]).

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The study met its primary endpoint of decitabine exposure equivalence of 5-day dosing between orally administered ASTX727 and IV decitabine as per the protocol analysis plan. Safety and clinical activity were similar to that observed in a previous phase 1/2 study. The full data will be presented at an upcoming scientific meeting.

Astex plans to file an NDA with the US FDA by the end of 2019.

"We are delighted with the outcome of the ASCERTAIN trial, and the demonstration that the fixed dose combination of cedazuridine with decitabine enables successful oral delivery of decitabine, alleviating the significant burden of five days of monthly IV infusions for patients who may continue to benefit from the drug for several months or even years," said Mohammad Azab, 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 this effort."

About Cedazuridine and Decitabine Fixed-Dose Combination (ASTX727)

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

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study in patients with MDS and CMML to define appropriate doses of the individual components of ASTX727 (cedazuridine and decitabine) so that decitabine exposure after oral administration of ASTX727 is similar to exposure after IV decitabine at the approved daily dose of a 1-hour infusion at 20 mg/m2 (see View Source NCT02103478). This study demonstrated that ASTX727 allowed decitabine to be delivered orally at a dose that emulates parenteral pharmacokinetics, as measured by 5-day area-under-the-curve (AUC).3 The drug’s safety profile was similar to that of IV decitabine. Of particular note was the low level of gastrointestinal adverse events.3

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). ASTX727 may also have potential in all-oral combination regimes for the treatment of a range of different tumor types.

Astex is also expanding the evaluation of cedazuridine – decitabine combinations through a program of investigator-sponsored trials.

ASTX727 is an investigational compound and is not currently approved in any country.

About the ASCERTAIN Study

The ASCERTAIN study was designed to demonstrate that the cedazuridine and decitabine fixed-dose combination (ASTX727) could deliver orally a pharmacokinetically equivalent exposure of decitabine compared to IV decitabine in adults with previously untreated or treated MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, int-2, or high-risk MDS. (see View Source NCT03306264). The study was designed as a randomized, open-label cross-over study in which patients were randomized in a 1:1 ratio to receive ASTX727 daily x 5 in the first 28-day cycle followed by IV decitabine daily x 5 in the second 28-day cycle, or the converse order. Following completion of the first two cycles, patients continued to receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, or the subject decided to discontinue treatment or withdrew from the study. The primary endpoint of the study was total 5-day AUC exposures of decitabine after treatment with ASTX727 versus IV decitabine as measured across the first two cycles. Secondary endpoints included safety assessments, pharmacodynamic measurements, secondary PK parameters, clinical responses, red blood cell transfusion independence, leukemia-free survival, and overall survival. The study was conducted in 138 patients at 46 sites in the US and Canada.

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.

bluebird bio Announces Live Webcast of EHA Data Review and ZYNTEGLO® (autologous CD34+ cells encoding βA-T87Q-globin gene) Approval

On June 6, 2019 bluebird bio, Inc. (Nasdaq: BLUE) reported that the company will host a live webcast to review new data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting, and to discuss the approval of ZYNTEGLO (autologous CD34+ cells encoding βA-T87Q-globin gene) on Friday, June 14 at 8:00 a.m. ET (Press release, bluebird bio, JUN 6, 2019, View Source [SID1234536934]).

Investors may listen to the call by dialing (844) 825-4408 from locations in the United States or +1 (315) 625-3227 from outside the United States. Please refer to conference ID number 2189283.

To access the live webcast of bluebird bio’s presentation, please visit the "Events & Presentations" page within the Investors & Media section of the bluebird bio website at View Source Replays of the webcast will be available on the bluebird bio website for 90 days following the event.

GRAIL Announces Appointment of Hans Bishop as Chief Executive Officer and Strengthens Leadership Team and Board of Directors with New Appointments

On June 6, 2019 GRAIL, Inc., a healthcare company whose mission is to detect cancer early, when it can be cured, reported that Hans Bishop has been appointed as Chief Executive Officer, effective immediately (Press release, Grail, JUN 6, 2019, View Source [SID1234536933]). He succeeds Jennifer Cook, who has stepped down from the Board and her role as Chief Executive Officer for family health reasons. Mr. Bishop has served on GRAIL’s Board of Directors since August 2018 and will continue to serve as a Director on the GRAIL Board.

GRAIL also announced the appointment of Joshua Ofman as Chief of Corporate Strategy and External Affairs. In addition, Maykin Ho has joined GRAIL’s Board as an Independent Director. The company also announced that Renée Galá has decided to step down from her role as Chief Financial Officer.

During her tenure as Chief Executive Officer, Ms. Cook led the company through the transition from discovery-stage research to advancing an investigational multi-cancer early detection test into clinical development and toward commercialization. In addition, the company has fully enrolled two of its population-scale clinical studies with approximately 115,000 participants, and initiated a third 50,000-participant clinical study.

"We are very grateful to Jennifer for her important contributions to the company, resulting in the pivotal milestone of the recently presented impressive data from CCGA that support advancement of GRAIL’s investigational multi-cancer early detection test toward commercialization. While we are disappointed to see Jennifer go, we respect and support her decision," said Catherine Friedman, Chair of the GRAIL Board of Directors. "We are thrilled that Hans is stepping into the CEO role to continue building upon this positive trajectory. Hans is a widely respected corporate leader with significant experience building successful companies and guiding novel products through commercialization."

Ms. Friedman continued: "In addition, we are delighted to welcome Josh, an accomplished industry expert in health economics, market access, and health policy with deep experience integrating innovation into healthcare systems, and Maykin, a distinguished biotech leader with unparalleled expertise in healthcare strategy and finance, to GRAIL."

"GRAIL is guided by its bold vision to improve cancer survival rates by creating a single blood test that can detect multiple deadly cancer types at one time," said Mr. Bishop. "For much of my career, I’ve been involved in the fight against cancer, and during that time, I have seen real progress for patients. However, cancer is still the second leading cause of death globally, and I believe early detection is key to changing that. I’m excited to step into the CEO role at a time where the team at GRAIL has delivered such exciting results. I look forward to working with the Board and the entire GRAIL team in this new role to ensure a smooth transition as we advance our test toward commercialization."

Mr. Bishop has more than 30 years of experience in the biotechnology industry. He will continue to serve as the Executive Chair of the Sana Board of Directors and as a Director of Celgene, Agilent Technologies, and Lyell Immunopharma. Mr. Bishop founded Juno Therapeutics in 2013 and served as its President and Chief Executive Officer until the company was acquired by Celgene in March 2018. Prior to this, he served as an Executive in Residence at Warburg Pincus. Earlier, he was Executive Vice President and Chief Operating Officer for Dendreon, Inc. He also previously served as President of Specialty Medicine at Bayer Healthcare, Senior Vice President of Global Commercial Operations at Chiron Corporation, and Vice President and General Manager of European Biopharmaceuticals. Mr. Bishop holds a bachelor’s degree in chemistry from Brunel University in London.

Joshua Ofman, MD, MSHS, joins GRAIL from Amgen where he spent 16 years in several roles, most recently as Senior Vice President, Global Health Policy. Prior to joining Amgen in 2003, Dr. Ofman was a member of the academic faculty in the Department of Medicine and Health Services Research, University of California, Los Angeles (UCLA) School of Medicine, Cedars-Sinai Medical Center. Dr. Ofman also served as Senior Vice President of Zynx Health Inc., a healthcare IT company and subsidiary of the Cerner Corp. Dr. Ofman obtained his undergraduate degree from the University of California, Berkeley and his MD from the University of California, Irvine, School of Medicine. He conducted his internship and residency in internal medicine and fellowship in digestive diseases at the UCLA Department of Medicine. In addition, Dr. Ofman completed a RAND/VA/UCLA fellowship in ambulatory care and health services research, specializing in technology assessment, and obtained his MSHS from the UCLA School of Public Health. He is widely published in health economics and technology assessment, public health program evaluation, and health policy analysis.

Maykin Ho, PhD, has more than 30 years of experience in the healthcare and finance industries. She is a venture partner of Qiming Venture Partners and a member of the Biotech Advisory Panel of the Stock Exchange of Hong Kong. She is also a retired partner of the Goldman Sachs Group, where she served as senior biotechnology analyst, co-head of healthcare for global investment research, and advisory director for healthcare investment banking. Prior to Goldman Sachs, Dr. Ho held various managerial positions in licensing, strategic planning, marketing, and research at DuPont-Merck Pharmaceuticals and DuPont de Nemours & Company. Dr. Ho serves on the Board of Directors for FibroGen, Agios Pharmaceuticals, Parexel International Corporation, the Aaron Diamond AIDS Research Center, and the Institute for Protein Innovation. She was a postdoctoral fellow at Harvard Medical School. Dr. Ho received a PhD in Microbiology and Immunology and a BS from the State University of New York, Downstate Medical Center.

Analysis of Newly Expanded Cumulative Cohort Demonstrates that DecisionDx-Melanoma Improves Risk Prediction for Patients with Cutaneous Melanoma

On June 6, 2019 Castle Biosciences, Inc., a skin cancer diagnostics company providing personalized genomic information to improve cancer treatment decisions, reported the presentation of newly expanded performance results for DecisionDx-Melanoma at the 2019 Fall Clinical Dermatology Conference for PAs & NPs held in Scottsdale, Arizona (Press release, Castle Biosciences, JUN 6, 2019, View Source [SID1234536932]). The poster, titled "The prognostic 31-gene expression profile (31-GEP) test improves risk prediction in cutaneous melanoma (CM) patients within current AJCC stages," demonstrated the utility of DecisionDx-Melanoma in identifying risk for patients with cutaneous melanoma beyond traditional staging.

Using a newly expanded performance cohort of 901 archival cutaneous melanoma samples (211 of which were not previously reported) from 22 centers, the analysis was designed to examine whether incorporating the DecisionDx-Melanoma test result in treatment decisions improves upon traditional melanoma staging methods. Patients assessed in the expanded cohort had a median age of 60 years and a median Breslow thickness of 1.4 mm. Forty-four percent of melanomas were American Joint Committee on Cancer (AJCC) Stage I, 24% were Stage II and 32% were Stage III.

Key Study Findings

DecisionDx-Melanoma was a significant and independent predictor of recurrence-free survival, distant metastasis-free survival and melanoma-specific survival (MSS) in the cumulative cohort of 901 cutaneous melanoma patients.
Within each AJCC stage, DecisionDx-Melanoma further stratified risk of melanoma-specific mortality. Using AJCC staging alone, patients with Stage I melanoma have an estimated 5-year MSS rate of 98%. Within that group, those with a Class 1A (lowest risk) DecisionDx-Melanoma test result had an estimated 5-year MSS rate of 99.7%, a risk equivalent to AJCC Stage IA. Stage I, Class 2B (highest risk) patients had a 92.8% 5-year MSS rate, lower than patients with Stage IIIA disease.
Patients with Stage II cutaneous melanoma have an estimated 5-year MSS rate of 90% using AJCC staging alone. Stage II patients who had a Class 1A DecisionDx-Melanoma test result had a 5-year MSS rate of 97%, equivalent to Stage IB. The MSS rate for Stage II patients with a Class 2B test result was 87.4%, aligned with risk estimates for AJCC Stage IIB.
"Accurate risk assessment in cutaneous melanoma is important because most treatment decisions are based on the patient’s expected risk of metastasis or recurrence," commented study co-author Darrell S. Rigel, M.D., M.S., Clinical Professor at New York University School of Medicine. "These results show that DecisionDx-Melanoma provided a more comprehensive assessment of patient risk compared to AJCC staging alone, supporting its utility in developing individualized patient management plans."

The poster can be found in the Publications section of the Castle Biosciences website.

About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous melanoma metastasis or recurrence, as well as sentinel lymph node positivity, independent of traditional staging factors, and has been studied in more than 3,100 patient samples. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in four archival risk of recurrence studies of 901 patients and five prospective risk of recurrence studies including more than 780 patients. Prediction of the likelihood of sentinel lymph node positivity has also been validated in two prospective multicenter study cohorts that included more than 1,400 patients. Impact on patient management plans for one of every two patients tested has been demonstrated in four multicenter and single-center studies including more than 560 patients. The consistent performance and accuracy demonstrated in these studies provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results.

More information about the test and disease can be found at www.SkinMelanoma.com.

ARVINAS TO PRESENT AT THE GOLDMAN SACHS 40TH ANNUAL GLOBAL HEALTHCARE CONFERENCE

On June 6, 2019 Arvinas Inc. (Nasdaq: ARVN), a biotechnology company creating a new class of drugs based on protein degradation, reported that Ian Taylor, Ph.D., Chief Scientific Officer, will participate in a fireside chat at the Goldman Sachs 40th Annual Global Healthcare Conference on Wednesday, June 12 at 3:20 p.m. PT in Palos Verdes, CA (Press release, Arvinas, JUN 6, 2019, View Source [SID1234536931]).

A live audio webcast of the presentation will be available here and at www.arvinas.com on the Events page. A replay of the webcast will be archived on the Arvinas website for 30 days following the presentation.