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Science Magazine Publishes Results from Preclinical Study on the Activity of Menin-MLL Inhibition for the Treatment of NPM1 Acute Myeloid Leukemia

On January 30, 2020 Syndax Pharmaceuticals, Inc. ("Syndax," the "Company" or "we") (Nasdaq: SNDX), a clinical stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported that Science magazine has published a preclinical report supporting the potential role of MLL1-Menin inhibition in the management of nucleophosmin (NPM1) mutant acute myeloid leukemia (AML) (Press release, Syndax, JAN 30, 2020, View Source [SID1234553703]). The article, "Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia," will be published in the journal’s January 31, 2020 issue and is currently available online.

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This study examined the activity of VTP-50469, an orally-available inhibitor of MLL1-Menin interaction and close analog of the Company’s lead Menin inhibitor, SNDX-5613, for the treatment of established NPM1 AML and the possible prevention of the disease in high-risk populations. Using preclinical models of NPM1 AML, the authors established that the presence of an NPM1 mutation is a clear indicator of pre-leukemic activity and represents a critical step in the development of AML. VTP-50469 was shown to eradicate NPM1 mutant cells at various stages of disease development, suggesting that Menin-MLL inhibition could potentially serve either as a targeted preventive therapy or as a treatment of established disease.

"These unprecedented findings highlight the potential for single agent Menin-MLL inhibition to rapidly eradicate fully developed NPM1 mutant leukemia, even in the case of aggressive relapsed AML," said Scott A. Armstrong, M.D., Ph.D., President, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and Chairman, Department of Pediatric Oncology, Dana-Farber Cancer Institute, and senior author of the study. "In addition, these results provide support for a Menin-MLL inhibitor to serve as a novel strategy to prevent AML development in high-risk patient populations, as NPM1 mutations are acquired in pre-leukemic clones."

"NPM1 mutant AML represents the most common type of cytogenetically normal AML," said Briggs W. Morrison, M.D., Chief Executive Officer of Syndax. "On the heels of our recent Cancer Cell publication, these findings add to the growing body of compelling preclinical data supporting the potential for SNDX-5613 to serve as an effective intervention for both NPM1 mutant AML and MLL-r acute leukemias. We are committed to providing patients with more targeted therapeutic options and are hopeful that these findings will translate into the clinic in our ongoing Phase 1/2 AUGMENT-101 trial."

About SNDX-5613

SNDX-5613 is a potent, selective, small molecule inhibitor of the Menin-MLL binding interaction that is being developed for the treatment of MLL-rearranged (MLL-r) acute leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML); VTP-50469 is a close analog of SNDX-5613. MLL rearrangements occur in approximately 80% of acute leukemia cases in infants and up to 10% of all leukemias. In preclinical models of MLL-r acute leukemias, SNDX-5613 demonstrated robust, dose-dependent inhibition of tumor growth, resulting in a marked survival benefit. Menin-MLL interaction inhibitors have also demonstrated robust treatment benefit in multiple preclinical models of NPM1 mutant AML, which represents the most frequent genetic abnormality in adult AML. SNDX-5613 is currently being evaluated in the Company’s AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias.

About AUGMENT-101

AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the efficacy, safety, tolerability and pharmacokinetics of orally administered SNDX-5613. The Phase 1 dose escalation portion of AUGMENT-101 will enroll adults with R/R acute leukemias and establish a recommended Phase 2 dose. The Phase 2 portion will evaluate efficacy, as defined by Complete Response rate (per International Working Group response criteria), across three expansion cohorts: MLL-r ALL, MLL-r AML and NPM1 mutant AML. The Company expects to report initial clinical data from the trial in 2020. Additional information about the AUGMENT-101 trial is available via Clinicaltrials.gov (NCT 04065399).

About NPM1 Mutant Acute Myeloid Leukemia

NPM1 mutant AML, which is distinguished by point mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a 5-year overall survival rate of approximately 50%. Similar to MLL-r leukemias, NPM1 mutant AML is highly dependent on the expression of specific developmental genes, shown to be negatively impacted by inhibitors of the Menin-MLL interaction. NPM1 mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1 mutant AML.

Quest Diagnostics Reports Record Fourth Quarter And Full Year 2019 Revenues And Earnings; Provides Guidance For Full Year 2020; Increases Dividend 5.7% To $0.56 Per Quarter

On January 30, 2020 Quest Diagnostics Incorporated (NYSE: DGX), the world’s leading provider of diagnostic information services, reported financial results for the fourth quarter and full year ended December 31, 2019 (Press release, Quest Diagnostics, JAN 30, 2020, View Source [SID1234553702]).

"We had a solid fourth quarter and ended the year by delivering record revenues, earnings and cash from operations," said Steve Rusckowski, Chairman, CEO and President. "Strong volume growth from expanded health plan network access, combined with outstanding execution of our Operational Excellence strategy, helped us offset significant reimbursement pressure.

"Quest is well positioned once again in 2020 to deliver on our commitment to grow revenues and earnings. We have a strong value proposition that supports health care’s triple aim of improving medical quality and the patient experience while reducing the cost of care. Our guidance for 2020 reflects our continued momentum, partially offset by yet another year of meaningful reimbursement pressure."

For further details impacting the year-over-year comparisons related to operating income, operating income as a percentage
of net revenues, income from continuing operations attributable to Quest Diagnostics, and diluted EPS from continuing
operations, see note 2 of the financial tables attached below.

Beginning in 2019, the company has changed how it presents adjusted income measures to additionally exclude amortization
expense for all periods presented. We believe this presentation provides investors with additional insight to evaluate our
performance period over period and relative to competitors, as well as to analyze the underlying trends in our business.

Dividend and Share Repurchase Authority Increased

Quest Diagnostics’ Board of Directors authorized a 5.7% increase in its quarterly dividend from $0.53 to $0.56 per share, or $2.24 per share annually, payable on April 21, 2020 to shareholders of record of Quest Diagnostics common stock on April 7, 2020. This dividend increase is the company’s ninth since 2011.

The Board also increased the company’s share repurchase authorization by $1 billion, bringing the total authorization available to $1.2 billion as of December 31, 2019.

Guidance for Full Year 2020

The company estimates full year 2020 results as follows:

Note on Non-GAAP Financial Measures

As used in this press release the term "reported" refers to measures under accounting principles generally accepted in the United States ("GAAP"). The term "adjusted" refers to non-GAAP operating performance measures that exclude special items such as restructuring and integration charges, amortization expense, excess tax benefits ("ETB") associated with stock-based compensation, the gain associated with the sale and leaseback of a property, and other items.

Non-GAAP adjusted measures are presented because management believes those measures are useful adjuncts to GAAP results. Non-GAAP adjusted measures should not be considered as an alternative to the corresponding measures determined under GAAP. Management may use these non-GAAP measures to evaluate our performance period over period and relative to competitors, to analyze the underlying trends in our business, to establish operational budgets and forecasts and for incentive compensation purposes. We believe that these non-GAAP measures are useful to investors and analysts to evaluate our performance period over period and relative to competitors, as well as to analyze the underlying trends in our business and to assess our performance. The additional tables attached below include reconciliations of non-GAAP adjusted measures to GAAP measures.

Conference Call Information

Quest Diagnostics will hold its quarterly conference call to discuss financial results beginning at 8:30 a.m. Eastern Time today. The conference call can be accessed by dialing 888-455-0391 within the U.S. and Canada, or 773-756-0467 internationally, passcode: Investor; or via live webcast on the company’s website at www.QuestDiagnostics.com/investor. The company suggests participants dial in approximately 10 minutes before the call.

A replay of the call may be accessed online at www.QuestDiagnostics.com/investor or by phone at 866-357-4210 for domestic callers or 203-369-0125 for international callers. No passcode is required. Telephone replays will be available from approximately 10:30 a.m. Eastern Time on January 30, 2020 until midnight Eastern Time on February 13, 2020. Anyone listening to the call is encouraged to read the company’s periodic reports, on file with the Securities and Exchange Commission, including the discussion of risk factors and historical results of operations and financial condition in those reports.

First Patient With Advanced Breast Cancer Receives First Dose in Clinical Trial of GlycoMimetics’ GMI-1359

On January 30, 2020 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that Duke University investigators have dosed the first patient in a proof-of-concept Phase 1b study to evaluate GlycoMimetics’ novel GMI-1359 drug candidate in patients with advanced breast cancer (Press release, GlycoMimetics, JAN 30, 2020, View Source [SID1234553700]). The dose-escalating study will enroll up to 12 individuals with metastatic, hormone receptor positive breast cancer with stable or minimally progressive disease, including bone metastasis. GMI-1359 is a dual inhibitor of both E-selectin and CXCR4. The trial is designed to evaluate safety, pharmacokinetics and pharmacodynamic measures of biologic activity, such as increases in circulating tumor cells and mobilization of CD34+ and immune T-cell subsets. GlycoMimetics expects the trial results to be available in late 2020, the conclusions of which the Company will use to inform future development of GMI-1359.

Kelly Marcom, M.D., and Dorothy Sipkins, M.D., Ph.D., both of the Duke Cancer Institute, are the trial’s co-principal investigators.This clinical trial builds on published findings from Dr. Sipkins on the key roles of both E-selectin and CXCR4 in the trafficking of metastatic cancer cells and of their establishment as micro-metastases in bone. Dr. Sipkins’ research suggests that both E-selectin and CXCR4 mediate key mechanisms that promote progression and migration of cancer cells to protective niches in the bone marrow micro-environment, and reveals the potential for an E-selectin and CXCR4 inhibitor like GMI-1359 to molecularly excise disseminated breast cancer cells.1

"The initiation of enrollment is an important milestone in our exploration of GMI-1359 and its potential as a novel approach to treating metastatic cancer," said GlycoMimetics Senior Vice President of Clinical Development and Chief Medical Officer Helen Thackray, M.D., FAAP. "We’re pleased to have such distinguished researchers at Duke University begin to explore the use of this investigational therapy and look forward to learning more about its potential impact as clinical study advances."

More information on this clinical trial can be found at www.clinicaltrials.gov.

About GMI-1359

GMI-1359 is designed to simultaneously inhibit both E-selectin and CXCR4. E-selectin and CXCR4 are both adhesion molecules involved in tumor trafficking and metastatic spread. Preclinical studies indicate that targeting both E-selectin and CXCR4 with a single compound could improve efficacy in the treatment of cancers that involve the bone marrow such as acute myeloid leukemia and multiple myeloma or in solid tumors that metastasize to the bone, such as prostate cancer and breast cancer, as well as in osteosarcoma, a rare pediatric tumor. GMI-1359 has completed a Phase 1 clinical trial in healthy volunteers. The newly initiated Phase 1b clinical study in breast cancer patients is designed to enable investigators to identify an effective dose of the drug candidate and to generate initial biomarker data around the drug’s activity.

UPenn scientists receive ACGT grant to accelerate CAR T-Cell clinical trial

On January 30, 2020 University of Pennsylvania reported a scientific team is developing a new CAR T-cell gene therapy treatment for advanced metastatic prostate cancer with a $500,000 grant from Alliance for Cancer Gene Therapy (ACGT) (Press release, University of Pennsylvania, JAN 30, 2020, View Source [SID1234553699]).

The ACGT grant was awarded to Joseph Fraietta, PhD, assistant professor of microbiology and a T-cell biologist with expertise in tumor immunology and translational medicine, and Naomi Haas, MD, director of the Prostate and Kidney Cancer Program, associate professor of medicine, and nationally renowned expert in the field of prostate and kidney cancer. The goal of the ACGT-funded study is to overcome prostate cancer’s stubborn resistance to CAR T-cell therapy, a therapy that has been successful in treating blood cancers. Drs. Fraietta and Haas are exploring approaches for re-engineering T-cells to enable them to induce safe, long-term remission for advanced, metastatic prostate cancer patients.

"The grant from ACGT will help us advance our clinical work in a very novel way," said Dr. Fraietta. "If we can unlock the epigenetic code that controls the fate and function of T-cells, it could be a game changer."

"The ACGT Scientific Advisory Council is impressed with the potential of this research team and their successful innovations in the use of T-cell therapy," noted Kevin Honeycutt, CEO and president of ACGT. "Because Drs. Fraietta and Haas are building on direct results already achieved with patients, there may be less transition time required to get a promising new treatment into the clinic for prostate cancer patients. Plus, we believe this research could provide a tumor-attack roadmap to help fight other cancers, including lung, pancreatic, ovarian and brain."

In the ACGT-funded study, Drs. Fraietta and Haas are going from the bedside back to the benchtop to employ new insight into how to better enable T-cells to battle cancer cells in solid tumors. Drs. Haas and Fraietta will explore the connection between nutrient availability and epigenetic programming, and how these factors influence the viability of T-cells and their anti-tumor functionality. This research builds on durable results being achieved by Dr. Haas in related prostate cancer clinical trials. In these trials, different doses of CAR T-cell gene therapies are being used to treat metastatic patients for whom traditional hormonal therapies, chemotherapies, radiation and surgery have failed.

"For so many years, chemotherapy, radiation and surgery were the traditional treatments for cancer. For prostate cancer, there’s also hormone therapy," said Honeycutt. "Unfortunately, as the cancer progresses, it often stops responding to these traditional treatments. New cell and gene therapy approaches like the ones Drs. Fraietta and Haas are employing offer new hope to all cancer patients. ACGT has been dedicated to funding innovative science that harnesses the power of cell and gene therapy and transforms how cancer is treated. The work of Drs. Fraietta and Haas is a great example of this promise."

ACGT has been instrumental in funding some of the decade’s most transformative research, including breakthroughs in the use of CAR T-cell gene therapy for leukemia by the University of Pennsylvania’s Carl H. June, MD. "Dr. June received his first ACGT grant in 2004 and a second in 2008, back when gene therapy was considered a risky proposition," says Honeycutt. "Fast forward to today and the field has changed dramatically with major pharmaceutical companies and research institutions vying for the next big discovery using gene therapy or immunotherapy."

UNC Lineberger discovery would allow researchers to fine-tune activity of cancer-hunting immune cells

On January 30, 2020 A discovery by University of North Carolina Lineberger Comprehensive Cancer Center researchers could allow scientists to fine-tune genetically engineered immune cells to heighten their killing power against tumors or to decrease their activity level in the case of severe side effects (Press release, Lineberger Comprehensive Cancer Center, JAN 30, 2020, View Source [SID1234553698]).

Gianpietro Dotti is the Director of the Cancer Cellular Immunotherapy Program at UNC Lineberger.
UNC Lineberger’s Gianpietro Dotti, MD.

In a study published in Cancer Cell, researchers led by UNC Lineberger’s Gianpietro Dotti, MD, reported new findings about the regulation of co-stimulatory molecules that could be used to activate cancer-killing immune cells – chimeric antigen receptor T-cells, or CAR-T – or decrease their activity.

"In immunology, it’s always about balance; you don’t want to have too much T-cell activation, and you don’t want T-cell activation to be too low," said Peishun Shou, PhD, postdoctoral research associate at UNC Lineberger and the study’s co-first author. "We wanted to keep the T-cell activation and tumor killing at a suitable or sustainable level."

Cellular immunotherapy
Cellular immunotherapy, or CAR-T immunotherapy, involves extracting specific immune cells from patients, engineering the cells in the lab to hunt tumor cells displaying a specific molecular target, and then re-infusing them to fight their cancer.

Through the Clinical Immunotherapy Program, UNC Lineberger researchers have designed novel investigational CAR-T therapies for Hodgkin and non-Hodgkin lymphoma, multiple myeloma, neuroblastoma and leukemia that are being studied in clinical trials.

"We are conducting and developing clinical studies with CAR-T cells in both liquid and solid tumors. In these studies, we are testing what we call the ‘new generation’ of CAR-T cells, hoping to further enhance the therapeutic index of this technology," said Dotti, the study’s corresponding author, a professor in the UNC School of Medicine Department of Microbiology and Immunology and director of the UNC Lineberger Cellular Immunotherapy Program. "This latest study highlights how when translational and basic science come together, we can hopefully improve therapeutic strategies."

CAR-T immunotherapy study findings
In the Cancer Cell study, researchers revealed new strategies for engineering investigational CAR-T to either increase the activity of modified T-cells to more effectively kill tumor cells, or decrease their activity in case the therapies trigger severe side effects.

They developed strategies for improving two different types of modified T-cells. These two types of CAR-T cells are differentiated by the signals that activate them. First, they have a receptor that recognizes a specific marker on the tumor – the first signal. They also need a second signal that helps to fully activate them and increase their response. There are two different types of T-cells that have different "second signals" that activate them.

Peishun Shou is a postdoctoral researcher at UNC Lineberger.
UNC Lineberger’s Peishun Shou, PhD.
One type of CAR-T is co-stimulated by the CD28 protein, and another is stimulated by 4-1BB. UNC Lineberger researchers wanted to find a way to regulate these proteins in order to "fine-tune" the cells’ disease-fighting response, since researchers reported each type of CAR-T has differences in terms of how long it typically lasts in the body to fight cancer, how quickly it responds and the strength of its response.

"T-cells have to be activated to kill tumor cells," Shou said. "If you have better activation, you have more cytokine release … and the cells can better target a tumor and kill it. In some cases, we want to make the T-cells stronger, more active, and depending on the tumor type, we may want to tune down the T-cell activation to help the T-cells survive and expand."

For CAR-T co-stimulated by 4-1BB, scientists found they could increase expression of the LCK molecule to increase the cells’ activity.

"What we found is that the LCK molecule can bind to the CAR, enhancing the CAR-T cell activation and signaling transduction, which therefore will help CAR-T cells get a better tumor-killing effect," Shou said.

CAR-T safety switch feature
They also reported on the discovery of a new "safety switch" mechanism to reduce activity of CAR-T co-stimulated by CD28. Doctors could use the safety switch should patients experience severe side effects from the experimental therapy.

They found they could use a molecule called SHP1 to reduce T-cell activity. When they added a certain drug, SHP1 bound to the CAR to reduce the activity of CAR-T cells.

"In the presence of the drug, we can cool down or tune down the CAR-T cell activation," Shou said. "The advantage of this switch is that it will not kill the CAR-T cells; it’s just temporarily tuning down the activity."

Researchers want to investigate using these findings to improve CAR-T treatments against blood cancers like leukemia, and to potentially improve experimental treatments for solid tumors.

"Researchers in the CAR-T immunotherapy field now want to solve the solid tumor problem," Shou said. "Solid tumors have an immunosuppressive microenvironment, so you need stronger CAR-T activation."