On April 17, 2018 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical results in two posters, including late-breaking data being presented today, for its Checkpoint kinase 1 (Chk1) inhibitor SRA737, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago, Illinois (Press release, Sierra Oncology, APR 17, 2018, View Source [SID1234525426]).

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"The data presented within these posters demonstrate that SRA737, as monotherapy and in combination with a poly ADP-ribose polymerase inhibitor (PARPi) such as niraparib, has anti-tumor activity across a broad range of settings. Anti-tumor activity was observed both in homologous recombination repair (HRR) proficient cancers which are poor candidates for PARPi alone, and in HRR deficient tumor cells that have acquired resistance to either PARPi and/or platinum agents," said Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. "We also observed inhibition of tumor growth in aggressive CCNE1-driven high grade serous ovarian cancer (HGSOC) patient-derived xenografts. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. Analogous to PARPi, which first exhibited robust activity in patients harboring BRCA mutations, Chk1 inhibitors such as SRA737 may prove effective in defined genetic backgrounds of high replication stress, such as CCNE1 amplification."
The efficacy of SRA737 monotherapy is currently being investigated in an ongoing Phase 1/2 clinical trial (NCT02797964) in replication stress-driven cancer including a patient cohort with CCNE1 amplified HGSOC.
Sierra is also planning to investigate SRA737 in combination with niraparib in a multicenter Phase 1b/2 study in subjects with metastatic castration-resistant prostate cancer (mCRPC), anticipated to be initiated in the fourth quarter of 2018. Janssen Research & Development, LLC will supply TESARO’s ZEJULA (niraparib) for the trial, which is to be led by Professor Johann de Bono, Regius Professor of Cancer Research, Head of the Division of Clinical Studies and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.
The two posters will be available on the company’s website at www.sierraoncology.com.
SRA737 AACR (Free AACR Whitepaper) 2018 Late-Breaker: The Novel Oral Chk1 Inhibitor, SRA737, Is Active in Both PARP Inhibitor Resistant and CCNE1 Amplified High Grade Serous Ovarian Cancers
Data being presented in this late-breaking poster is from research conducted in the laboratory of Dr. Fiona Simpkins, Assistant Professor of Obstetrics and Gynecology at The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Approximately 20% of HGSOCs harbor CCNE1 gene amplification. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. These tumors show intrinsic resistance to PARPi and frequently are, or become resistant to, platinum therapy, leaving patients without effective treatment options. In this research, Chk1 inhibition by SRA737 as monotherapy in CCNE1 amplified ovarian cancer models was shown to: a) increase levels of replication stress and DNA double strand breaks, b) in turn leading to excessive genomic instability, c) resulting in subsequent tumor cell death, tumor regression and a profound survival benefit.

A distinct subgroup comprising approximately 50% of HGSOC have defective HRR genes (e.g. BRCA1/2 mutation). HRR deficient HGSOC are initially sensitive to PARPi but drug resistance ultimately emerges, frequently involving genetic reversion of BRCA mutated genes and partial restoration of HRR. HRR deficiency may also elevate sensitivity to Chk1 inhibition, given the well-established role of Chk1 in HRR, as well as other aspects of the replication stress response. In this research, SRA737 demonstrated activity as a single agent, as well as in combination with PARPi, in acquired PARPi-resistant cells. Furthermore, SRA737 in combination with PARPi demonstrated preliminary evidence of synergistic tumor growth inhibition in a HGSOC patient-derived xenograft model.

SRA737 AACR (Free AACR Whitepaper) 2018 Poster: The Chk1 Inhibitor, SRA737, Synergizes with the PARP Inhibitor, Niraparib, to Kill Carcinoma Cells via Multiple Cell Death Pathways
Sierra presented a second poster at AACR (Free AACR Whitepaper) with data from research conducted in the laboratory of Dr. Paul Dent, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia. The results demonstrate that the combination of SRA737 and niraparib was effective in HRR proficient ovarian and breast tumor cell lines and that both autophagic cell death and apoptotic pathways contribute to SRA737/niraparib-induced tumor cell killing. PARPi monotherapy is known to be substantially less effective in treating patients with HRR proficient tumors, making the combination with SRA737 a novel and potentially more effective treatment option. Moreover, the involvement of multiple cell death mechanisms may decrease the potential for tumors to develop resistance to these agents.

On April 17, 2018 Novocure (NASDAQ: NVCR) reported positive top-line results from its STELLAR phase 2 pilot trial in mesothelioma demonstrating clinically meaningful improvements in overall survival and progression free survival among patients who received Tumor Treating Fields plus standard of care chemotherapy, pemetrexed and cisplatin or carboplatin, compared to historical control data of patients who received standard of care chemotherapy alone (Press release, NovoCure, APR 17, 2018, View Source [SID1234525444]).

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The final data exceeded the results of the interim analysis presented in December 2016 at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer for all efficacy endpoints. No device-related serious adverse events were reported. Novocure will submit the full data for presentation at an upcoming medical conference.

"We are extremely pleased with these top-line results, which bring us one step closer to realizing the potential for a new treatment for mesothelioma patients in desperate need," said Dr. Eilon Kirson, Novocure’s Chief Science Officer and Head of Research and Development. "Mesothelioma is the first torso indication for which Novocure will pursue FDA approval. The STELLAR data reinforce our belief that Tumor Treating Fields may be a broadly applicable platform technology for the treatment of solid tumors. We look forward to sharing the detailed results of the study with the lung cancer community at an upcoming medical conference."

Novocure previously received Humanitarian Use Device (HUD) designation for the use of Tumor Treating Fields for the treatment of pleural mesothelioma. Based upon the final STELLAR data, Novocure plans to submit a Humanitarian Device Exemption (HDE) application to the FDA for approval. An approved HDE would allow Novocure to market Tumor Treating Fields in combination with standard of care chemotherapy as a treatment for pleural mesothelioma in the United States.

Tumor Treating Fields in combination with standard of care chemotherapy is an investigational treatment for pleural mesothelioma and is not approved for this indication. These results are preliminary top-line data and are subject to further analysis.

About STELLAR

The STELLAR trial is a phase 2 pilot single-arm, open-label, multi-center trial designed to test the efficacy and safety of Tumor Treating Fields in combination with standard of care chemotherapy, pemetrexed combined with cisplatin or carboplatin, in 80 patients with unresectable, previously untreated malignant pleural mesothelioma. The historical control for this trial is the results of the 2003 pemetrexed phase 3 FDA registration trial.

An interim analysis of the first 42 patients enrolled in the trial with an average follow-up time of 11.5 months was presented at the International Association for the Study of Lung Cancer in December 2016. The one-year survival rate of patients treated with Tumor Treating Fields combined with pemetrexed and cisplatin or carboplatin was 80 percent (compared to 50 percent in pemetrexed and cisplatin-alone historical controls). Median progression free survival in the Tumor Treating Fields-treated group was 7.3 months (compared to 5.7 months in pemetrexed and cisplatin-alone historical controls) and one-year survival rate was 79.7 percent (compared to 50.3 percent in pemetrexed and cisplatin-alone historical controls). Median overall survival had not yet been reached. No device-related serious adverse events had been reported to date.

About Mesothelioma

Malignant mesothelioma is a rare thoracic solid tumor cancer that has been strongly linked to asbestos exposure. It has a long latency period of at least 20-30 years following exposure, and global incidence is still increasing in countries where asbestos is still in use. There are approximately 3,000 new cases of mesothelioma annually in the United States. The prognosis of mesothelioma patients is very poor, with a median overall survival of approximately 12 months in most reported studies.

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 March 17, 2018 Zymeworks Inc. (NYSE/TSX: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported that presented preclinical data on ZW49, its lead bispecific antibody-drug conjugate candidate (ADC) and its ZymeLink ADC platform (Press release, Zymeworks, APR 17, 2018, View Source [SID1234525407]). As previously reported, Zymeworks expects to file an Investigational New Drug (IND) application this year in order to begin clinical trials with ZW49 for patients with HER2-expressing cancers.

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Abstract Number: 3914; ZW49, A HER2 Targeted Biparatopic Antibody Drug Conjugate for the Treatment of HER2 Expressing Cancers

Summary: ZW49, which incorporates Zymeworks’ Azymetric bispecific and ZymeLink ADC technology platforms, was shown to be active and well tolerated in a series of preclinical studies. The unique biparatopic (ability to simultaneously bind two distinct locations on a single target) properties of ZW49 enable highly efficient delivery of its cancer cell killing payload while its ZymeLink-enhanced tolerability allows higher doses to be administered leading to improved anti-tumor activity. In models of both high and low HER2-expressing cancers, administration of ZW49 resulted in complete regression of the tumors. Importantly, ZW49 was well tolerated in preclinical safety studies at the same exposure levels that demonstrated efficacy in tumor models, without the toxicities generally associated with this class of ADC payloads.

Abstract Number: 3912; Towards Development of Next Generation Biparatopic ADCs Using a Novel Linker-Toxin with Expanded Therapeutic Window
Summary: Many ADCs in development ultimately fail to demonstrate efficacy in clinical testing due to dose-limiting toxicities. Zymeworks’ approach to ADC development is focused on efficient payload delivery and improving tolerability to enable greater exposures at the tumor rather than the conventional approach of solely increasing ADC potency. Preclinical data demonstrate that ZymeLink improved the tolerability of ADCs against four known clinical targets compared to the corresponding ADC platforms used in clinical trials. This enabled ZymeLink ADC exposures of at least seven-fold higher than benchmark ADCs which translated to increased anti-tumor activity in preclinical models. Ongoing efforts are focused on evaluating biparatopic versions of these ZymeLink ADC candidates to expand the therapeutic window even further.

"Combining our complementary Azymetric and ZymeLink technology platforms gives us a foundation to create active and well tolerated ADCs," said Ali Tehrani, Ph.D., Zymeworks’ President & CEO. "ZW49 is the first of many of ADCs that we plan to develop as part of our diverse pipeline of new medicines to overcome the limitations of current therapies and ultimately, defeat cancer."

About ZW49
ZW49 is a biparatopic (a bispecific antibody that can simultaneously bind two non-overlapping epitopes on a single target) anti-HER2 ADC based on the same antibody framework as ZW25, Zymeworks’ lead clinical candidate being evaluated in a Phase 1 study, but armed with the company’s proprietary ZymeLink cytotoxic (potent cancer-cell killing) payload. ZW49 may mediate its therapeutic effect through a combination of mechanisms, including: increased HER2 receptor-antibody clustering and internalization leading to toxin-mediated cytotoxicity; increased binding and removal of HER2 protein from the cell surface; and potent effector function.

About Antibody-Drug Conjugates
Antibody-drug conjugates (ADC) are a class of anti-cancer therapies intended to precisely target tumor cells in order to avoid the significant toxicities routinely associated with cancer treatments while simultaneously improving their efficacy. An ADC is an antibody that is connected, or conjugated, to a small molecule drug. It has three critical components: the antibody for targeting of specific cells, the cytotoxin (or payload) being delivered to induce cancer cell death, and the linker, which connects the two components together.

About the ZymeLink Platform
The ZymeLink platform is a modular suite of site-specific conjugation technologies, customizable linkers, and proprietary cytotoxic payloads designed for the targeted delivery of therapeutics with optimal tolerability and efficacy. The ZymeLink platform is compatible with traditional antibodies and with the Azymetric platform and is intended to facilitate the development of next-generation therapeutics.

About the Azymetric Platform
The Azymetric platform enables the transformation of monospecific antibodies into bispecific antibodies, giving them the ability to simultaneously bind two different targets. Azymetric bispecific technology enables the development of multifunctional biotherapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering degradation, and increase tumor-specific targeting. These features are intended to enhance efficacy while reducing toxicities and the potential for drug-resistance. Azymetric bispecifics have been engineered to retain the desirable drug-like qualities of naturally occurring antibodies, including low immunogenicity, long half-life and high stability. In addition, they are compatible with standard manufacturing processes with high yields and purity, potentially significantly reducing drug development costs and timelines.