On April 17, 2018 GRAIL, Inc., a life sciences company focused on the early detection of cancer, reported initial results from its Circulating Cell-Free Genome Atlas (CCGA) Study (Press release, Grail, APR 17, 2018, View Source [SID1234525517]). Data from three prototype genome sequencing assays showed it may be feasible to develop a blood test for early detection of multiple cancer types with greater than 99 percent specificity.

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"We are excited that early results with our prototype assays suggest we can develop blood tests for early detection of cancer with a very low rate of false-positive results," said Alexander Aravanis, MD, PhD, Vice President of Research and Development at GRAIL. "These data will be used to inform development of a blood test for early detection of multiple cancer types. Our next steps are to analyze additional data sets from CCGA, including validating these results in an independent data set, and to continue optimizing our assays."

The data were presented today by Dr. Aravanis in a late-breaking research minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago (Abstract LB-343).

Specificity Analyses

When developing early detection tests, high specificity is important to minimize false-positive results. Across all three of the assays evaluated, a "cancer-like" signal was found in less than one percent of participants who entered the study without a cancer diagnosis (5 of 580), suggesting a test with a specificity greater than 99 percent is feasible. Through longitudinal follow-up in the study, it has since been confirmed that two of the five participants who had a cancer-like signal have been diagnosed with cancer. This suggests the signal indicated presence of undiagnosed cancer. Follow-up of the other three participants continues.

Clonal hematopoiesis of indeterminate potential (CHIP) is a known confounding signal present in cell-free DNA (cfDNA) of white blood cells that could increase false-positive results. This CHIP signal is likely due to natural aging processes. Therefore, in this study, paired sequencing of white blood cells and cfDNA was performed to identify these non-cancer mutations. Somatic (non-inherited) mutations from the white blood cells accounted for 66 and 78 percent of all mutations identified in participants with and without cancer, respectively.

Sensitivity Analyses

Initial analyses showed all three prototype assays detected a strong biological signal in cancer types that are typically not screened for and have low survival rates (five-year cancer-specific mortality rate of greater than 50 percent1). These included lung, ovarian, pancreatic, liver, and esophageal cancers. The signal was detected across all stages of cancer, and increased with stage across all three of the assays. The assays evaluating the whole genome performed best, and the whole-genome bisulfite assay showed the strongest detection rates. Additional data showing detection rates for specific cancer types will be presented at an upcoming medical meeting.

In this pre-planned sub-study of CCGA, three prototype sequencing assays were evaluated as potential methods for a blood-based test for early cancer detection. Blood samples from 878 participants with newly diagnosed cancer who had not yet received treatment and 580 participants without diagnosed cancer were sequenced with all three prototype assays. Twenty different cancer types across all stages were included in the sub-study.

The prototype sequencing assays included:

Targeted sequencing of paired cfDNA and white blood cells to detect somatic mutations such as single nucleotide variants and small insertions and/or deletions;
Whole-genome sequencing of paired cfDNA and white blood cells to detect somatic copy number changes; and
Whole-genome bisulfite sequencing of cfDNA to detect abnormal cfDNA methylation patterns.
About CCGA

CCGA is a prospective, observational, longitudinal study designed to characterize the landscape of cell-free nucleic acid (cfNA) profiles in people with and without cancer. The planned enrollment for the study is more than 15,000 participants across 141 sites in the United States and Canada. Approximately 70 percent of participants will have cancer at the time of enrollment (newly diagnosed, have not yet received treatment) and 30 percent will not have a known cancer diagnosis. The groups are demographically similar and representative of a real-world population. The group of participants without cancer includes individuals with conditions that are known to increase cfNA signal, such as inflammatory or autoimmune diseases. Planned follow-up for all participants is at least five years to collect clinical outcomes.

Presentation Details
Abstract LB-343

Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas (CCGA)

Alexander M. Aravanis et al. Tuesday, April 17, 2018: 4:20-4:35pm CDT, Session LBMS01 – Minisymposium: Late-Breaking Research, Room S101 – McCormick Place South (Level 1).

On April 17, 2018 Torque, an immuno-oncology company developing Deep Primed cellular therapies with pharmacologic control to direct immune power deep within the tumor microenvironment, reported preclinical data for the company’s Deep-Primed IL-15 and Deep-Primed IL-12 programs demonstrating their activity compared to systemically administered IL-15 and IL-12 (Press release, Torque Therapeutics, APR 17, 2018, View Source [SID1234525537]). These data were presented at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago.

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Torque is developing a new class of Deep-Primed immune cell therapeutics to dramatically expand cell therapy cures for cancer. Deep-Priming uses advanced material engineering to anchor immune-stimulatory drugs directly to the surface of multi-targeted, antigen-primed T cells to activate both the adaptive and innate immune system with pharmacologic control in the tumor microenvironment. This approach does not require genetic engineering and enables tunable loading of precise doses of cytokines onto the surface of T cells to deliver sustained and controlled immune activation.

"Both Il-15 and IL-12 are potent cytokines capable of inducing strong anti-tumor immune responses, yet their clinical use as systemic therapies is limited by the potential for severe toxicities," said Thomas Andresen, PhD, Chief Scientific Officer of Torque. "Anchoring these powerful immune activators to the surface of T cells that traffic to tumors is a unique approach to direct immune power in the tumor microenvironment. These preclinical studies demonstrate superior efficacy for this approach compared to systemic administration of these same cytokines and are the foundation for the first clinical trials that will begin later this year for Deep IL-15."

Highlights of the three preclinical presentations follow, and copies of the posters are available for download on the Torque website: https://bit.ly/2FZtPOW

Abstract 3575 / Poster 13: "Cell therapy with surface-tethered IL-12 provides immune system priming and strong anti-tumor activity"
Presenter: Jon Nardozzi, PhD, Torque; Session: Adoptive Cell Therapy 3
Key findings from the study:

Deep IL-12 Priming technology enables high loading of IL-12 doses on the surface of tumor-specific T cells.
Deep IL-12 Priming substantially increases tumor killing survival with adoptively transferred tumor-specific T cells in an aggressive solid tumor model and is superior to systemically administered IL-12.
Administration of repeat doses of Deep IL-12 Primed T cells without pre-conditioning (lymphodepletion) further increases tumor killing and survival with adoptively transferred T cells in this aggressive solid tumor model.
Deep IL-12 Primed T cells activate an endogenous immune response but do not induce overt toxicities such as weight loss or sustained systemic cytokine release.
Abstract 3577 / Poster 15: "Deep IL-15 provides autocrine stimulation and expansion of autologous T cells driven by controlled concentrated release of IL-15"
Presenter: Pengpeng Cao, PhD, Torque; Session: Adoptive Cell Therapy 3
Key findings from the study:

Deep IL-15 Priming technology loads IL-15 on T cells with a highly controlled dose per cell and provides slow release of IL-15 for autocrine stimulation and sustained adoptive T cell therapy expansion.
In contrast to systemically delivered IL-15, Deep IL-15 substantially increases target CD8 T cell concentration in the tumor, without significant systemic IFNg levels or endogenous CD8 and NK cell expansion, due to lack of systemic exposure.
Torque’s fully closed manufacturing process that uses a proprietary dendritic cell priming process generates several billion, antigen-primed human T cells with an average of 20% reactivity and >95% T cell purity (demonstrated with autologous cells from healthy human donors).
Clinical trials using this manufacturing process for Deep IL-15 Primed multi-target T cells are expected to initiate in 2018.

Also at AACR (Free AACR Whitepaper), the Irvine Lab of the Koch Institute at MIT presented data on IL-12 and IL-15 formulated in nanogels and anchored to T cells using technology developed in the Irvine Lab. Torque has built upon the Irvine Lab’s work to create the Deep-Priming technology platform. The Irvine Lab is directed by Darrell Irvine, PhD, who is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board, Professor at the Massachusetts Institute of Technology, and an Investigator of the Howard Hughes Medical Institute.

Abstract 3565 / Poster 3: "T cell receptor signaling-responsive single chain IL-12 and IL-15 superagonist nanogel ‘backpacks’ to enhance adoptive cell therapy in solid tumors"
Presenter: Michael Fichter, PhD, Koch Institute for Integrative Research at MIT; Session: Adoptive Cell Therapy 3
Key findings from the study:

IL-15 nanogels anchored to tumor-targeted T cells induces significant and specific expansion of the adoptively transferred T cells in tumors and lymph nodes that is superior to systemic IL-15.
IL-15 nanogels anchored to T cells substantively improved the efficacy of an adoptive T cell therapy against solid tumors while reducing cytokine-induced side effects triggered by systemically administered IL-15.
In a separate experiment, IL-12 nanogels anchored to CD8 effector cells induced substantial cell activation.
About Deep-Primed Immune Cell Therapeutics
Torque’s Deep-Priming platform is based on 10 years of research and development to combine very potent immunomodulatory drugs with T cells to drive a powerful immune response with pharmacologic control in the tumor microenvironment. We are developing Deep-Primed T cells using a focused set of immunomodulators—initially IL-15, IL-12, and TLR agonists—that activate both innate and adaptive immunity. Administering these immunomodulators systemically to a patient can cause lethal toxicity by activating immune cells throughout the body. Deep-Primed therapeutics are designed to activate T cells and focus the immune response to target the tumor, without systemic exposure. This is achieved by:

Anchoring the immunomodulators to the surface of T cells to activate and direct the immune response in the tumor microenvironment
Modular antigen priming of T cells to target multiple, tumor-associated antigens using a proprietary cell-processing technology
In hematologic cancers, this new class of immune therapeutics has the potential to improve on the initial success of single-target CAR-T therapeutics. For solid tumors, Deep-Primed T-cells have the potential to enable efficacy against tumors with heterogeneous antigens protected by hostile microenvironments, which are not readily addressable with the first generation of immune cell therapies.

On April 17, 2018 Rigel Pharmaceuticals, Inc. reported that the U.S. Food and Drug Administration (FDA) approved TAVALISSE (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment (Press release, Rigel, APR 17, 2018, View Source [SID1234605501]). TAVALISSE is an oral spleen tyrosine kinase (SYK) inhibitor that targets the underlying autoimmune cause of the disease by impeding platelet destruction, providing an important new treatment option for adult patients with chronic ITP. Rigel plans to launch TAVALISSE in the United States in late May 2018.

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"Chronic ITP is challenging to treat because the heterogeneity of the disease makes it difficult to predict how an individual patient will respond to available treatments and not all patients can find a treatment that works well for them," said James Bussel, M.D., professor emeritus of pediatrics at Weill Cornell Medicine and the principal study investigator on the FIT Phase 3 program. Dr. Bussel has served as a consultant and paid member of the advisory board for Rigel Pharmaceuticals, Inc. "The FDA approval of fostamatinib arms physicians with a new treatment option, which works via a novel mechanism."

The FDA approval of TAVALISSE was supported by data from the FIT clinical program, which included two randomized placebo-controlled Phase 3 trials (Studies 047 and 048) and an open-label extension (Study 049), as well as an initial proof of concept study. The New Drug Application (NDA) included data from 163 ITP patients and was supported by a safety database of more than 4,600 subjects across other indications in which fostamatinib has been evaluated.

"People living with chronic ITP often feel they have an invisible disease — one that can not only impact quality of life, but also be life threatening," said Caroline Kruse, executive director of the Platelet Disorder Support Association, a patient advocacy organization dedicated to ITP patients. "That’s why we encourage members of our community to learn about their disease, understand treatment strategies, and seek support so that they can advocate for their best care. The availability of a new treatment option provides the ITP community with more choices."

Different Treatment Approach
TAVALISSE is designed to inhibit SYK, a key signaling component in the body’s immune process that can lead to platelet destruction in ITP patients. TAVALISSE may address an underlying autoimmune cause of ITP by impeding platelet destruction.

"We are excited to bring this new medicine to the population of adult patients with chronic ITP in need of additional therapies. I want to thank the patients, caregivers and physicians who contributed to our fostamatinib clinical program, and also the Rigel team for all of their dedication and hard work to bring the company to this historic day," said Raul Rodriguez, president and CEO of Rigel Pharmaceuticals. "This regulatory milestone, our first product approval, validates the therapeutic effect of SYK inhibition in an autoimmune disease."

Rigel will be providing product information at the ASCO (Free ASCO Whitepaper) Annual Meeting being held June 1-5, 2018 in Chicago, Booth #24160, or you can visit www.TAVALISSE.com.

About ITP
In patients with ITP, the immune system attacks and destroys the body’s own blood platelets, which play an active role in blood clotting and healing. Common symptoms of ITP include excessive bruising, bleeding and fatigue. People suffering with chronic ITP may live with an increased risk of severe bleeding events that can result in serious medical complications or even death. Current therapies for ITP include steroids, blood platelet production boosters (TPOs) and splenectomy. However, not all patients have an adequate treatment response with existing therapies. As a result, there remains a significant medical need for additional treatment options for patients with ITP.

About TAVALISSE
Indication
TAVALISSE (fostamatinib disodium hexahydrate) tablets is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Important Safety Information
Warnings and Precautions

Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.
Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST increase to >3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation.
Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE.
Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation.
TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose.
Drug Interactions

Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the major active metabolite of TAVALISSE (R406), which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose.
It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406.
Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction of the CYP3A4 substrate drug.
Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp) substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug.
Adverse Reactions

Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).
Common adverse reactions (≥5% and more common than placebo) from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea, dizziness, ALT and AST increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia.
Please see www.TAVALISSE.com for full Prescribing Information.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

Trademarks for TAVALISSE are owned by or licensed by Rigel.

Conference Call and Webcast Today at 5:00PM Eastern Time
Rigel will hold a live conference call and webcast today at 5:00pm Eastern Time (2:00pm Pacific Time).

Participants can access the live conference call by dialing (855) 892-1489 (domestic) or (720) 634-2939 (international) and using the Conference ID number 5189918. The slide presentation accompanying the conference call can be accessed from Rigel’s website at www.rigel.com/webcasts. The webcast will be archived and available for replay after the call via the Rigel website.

Genprex has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission (Filing, 10-K, Genprex, 2018, APR 17, 2018, View Source [SID1234527531]).

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On April 17, 2018 Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy, reported preclinical data on the immune activating antibody ATOR-1015 at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 taking place in Chicago, Illinois American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 taking place in Chicago, Illinois. ATOR-1015 is a first-in-class bispecific tumor-directed antibody, targeting CTLA-4 and OX40, designed to selectively activate the immune system in the tumor, without increasing systemic toxicity.

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The preclinical data demonstrate that ATOR-1015 physically localizes to the tumor and selectively activates the immune system in the tumor area, confirming the intended ATOR-1015 mechanism of action.

ATOR-1015 is primarily designed for combination therapy with a PD-1 blocking antibody, and the potential of this approach is supported with preclinical data reporting enhanced anti-tumor effect of ATOR-1015 in combination with an anti-PD-1 antibody, as compared to anti-PD-1 monotherapy. In addition, ATOR-1015 demonstrated superior efficacy compared to mono-targeting CTLA-4 and OX40 antibodies.

"The results presented in Chicago confirm that our CTLA-4 bispecific antibody ATOR-1015 selectively activates the immune system in the tumor area. This offers great potential for an improved benefit/risk profile for cancer patients. We are more and more excited about the significant prospects for this unique compound, particularly in combination with PD-1 blockers, and are looking forward to initiate clinical development later in the year", said Per Norlén CEO of Alligator Bioscience.

Alligator is planning to initiate an ATOR-1015 Phase I study during the second half of 2018.

A poster with the title "CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation" is showcased today at 8-12 a.m. EDT and is also available on the company web page View Source

For further information, please contact:
Cecilia Hofvander, Director Investor Relations & Communications
Phone +46 46 286 44 95
E-mail: [email protected]

The information was submitted for publication, through the agency of the contact person set out above, at 3 p.m. CEST on 17 April 2018.