On June 22, 2020 TG Therapeutics, Inc. (NASDAQ: TGTX), reported preclinical data presentation for TG-1701, the Company’s highly selective, BTK inhibitor, at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, being held virtually (Press release, TG Therapeutics, JUN 22, 2020, View Source [SID1234561282]).

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer stated, "We are encouraged by the preclinical data presented today which showed TG-1701 to be just as active and more selective for BTK than ibrutinib, a currently approved BTK inhibitor. Importantly, we are pleased to see the additive anti-tumor inhibition seen when TG-1701 was combined with umbralisib plus ublituximab (U2), supporting our combinatorial approach to development. The proprietary triple combination regimen of U2 + TG-1701 has shown strong responses clinically in an ongoing Phase 1 study, and we look forward to continuing this research and presenting updated data on TG-1701 as a monotherapy and as a triple regimen with U2."

Highlights from the data presentation are included below.

Title: TG-1701, a novel irreversible Bruton’s kinase (BTK) inhibitor, does not inhibit anti-CD20-driven ADCC and ADCP in vitro, and cooperates with the glycoengineered anti-CD20 mAb, ublituximab, in in vivo mantle cell lymphoma models

In vitro and in vivo studies were undertaken to evaluate the activity of TG-1701 alone and in combination with ublituximab and umbralisib in models of lymphoma
TG-1701 showed greater selectivity for BTK than, and similar activity to, ibrutinib in mantel cell lymphoma (MCL) models
TG-1701, in contrast to ibrutinib, did not block ublituximab-driven antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cell phagocytosis (ADCP) in vitro
In vivo xenograft studies suggested that TG-1701 synergized with the U2 combination, resulting in greater anti-tumor activity than either TG-1701 or U2 alone

On June 22, 2020 Onconova Therapeutics, Inc. (NASDAQ: ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with an initial focus on myelodysplastic syndromes (MDS) reported an investigator-initiated Phase 1/2a trial of oral rigosertib plus nivolumab in advanced metastatic KRAS mutated (KRAS+) lung adenocarcinoma has begun enrolling patients (Press release, Onconova, JUN 22, 2020, View Source [SID1234561322]).

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"Over half of non-small cell lung cancers are classified as lung adenocarcinomas; of these, the largest subset has a KRAS mutation as the predominant genetic driver," said Dr. Steven Fruchtman, President and CEO, Onconova Therapeutics. "Despite discovering the KRAS mutation over 30 years ago, little progress has been made in KRAS+ directed treatments. The work under Dr. Rajwanth Veluswamy’s leadership at the Icahn School of Medicine is an important step towards determining if rigosertib, as a RAS-mimetic, can change that."

The investigator-initiated trial is an open-label, dose-escalating Phase 1 study followed by a Phase 2a dose-expansion phase to study the combination of oral rigosertib and nivolumab in metastatic KRAS+ lung adenocarcinoma patients who have progressed on standard frontline treatment. The study will assess safety and efficacy. Additional details are available on www.clinicaltrials.gov (NCT04263090).

"The novel combination of rigosertib with an anti-PD-1 antibody targets two of the most important oncogenic pathways in cancer biology," said Dr. Rajwanth Veluswamy, Assistant Professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai. "This study will evaluate the safety and tolerability of this combination in KRAS mutated NSCLC in which patients have failed frontline immunotherapy. The study will explore efficacy of the combination in this common lung cancer subset and will also determine if rigosertib may restore sensitivity to the PD-1 blockade."

About Rigosertib

Rigosertib, Onconova’s lead candidate, is a proprietary Phase 3 small molecule. A key publication in a preclinical model reported rigosertib’s ability to block cellular signaling by targeting RAS effector pathways (Divakar, S.K., et al., 2016: "A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling." Cell 165, 643). Onconova is currently in the clinical development stage with oral and IV rigosertib, including clinical trials studying single agent IV rigosertib in second-line higher-risk MDS patients (pivotal Phase 3 INSPIRE trial) and oral rigosertib plus azacitidine in HMA naive and refractory higher-risk MDS patients (Phase 2). Patents covering oral and injectable rigosertib have been issued in the US and are expected to provide coverage until at least 2037.

On June 12, 2020 Personalis, Inc., (Nasdaq: PSNL) a leader in advanced genomics for cancer, reported that the company will present new data in scientific posters to be presented at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, which will be held online, June 22-24, 2020 (Press release, Personalis, JUN 22, 2020, View Source [SID1234561338]).

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These abstract showcases data from ImmunoID NeXT, the first platform to enable comprehensive analysis of both a tumor and its immune microenvironment from a single sample. The ImmunoID NeXT Platform can be used to investigate the key tumor- and immune-related areas of cancer biology, consolidating multiple oncology biomarker assays into one and maximizing the biological information that can be generated from a precious tumor specimen.

Following are details and links to the scientific posters that will be presented at the online meeting.

Abstract Number, Session Category and Session Title

Title & Presenter

Date

Location

2085 / 2

Bioinformatics and Systems Biology

Machine Learning

Precision neoantigen discovery using a pan-allelic machine learning model for enabling the development of composite biomarkers and personalized immunotherapy

Presenter: Datta Mellacheruvu

June 22, 2020

Online

1989 / 26

Clinical Research

Circulating Markers 2

Enhanced whole exome profiling of tumor circulating cell-free DNA enables sensitive assessment of tumor mutations

Presenters: Mengyao Tan and Simo V. Zhang

June 22, 2020

Online

1334 / 29

Molecular and Cellular Biology/Genetics

Genomic Profiling of Tumors 2

A diagnostic platform for precision cancer therapy enabling composite biomarkers by combining tumor and immune features from an enhanced exome and transcriptome

Presenter: Robert Power

June 22, 2020

Online

2512 / 28

Molecular and Cellular Biology/Genetics

Genomic Profiling of Tumors 3

Pan-cancer characterization of the tumor and immune microenvironment facilitates identification of cancer-specific biological signatures

Presenter: Sean M. Boyle

June 22, 2020

Online

4430 / 25

Bioinformatics and Systems Biology

Tumor Heterogeneity and Microenvironment: Next-Generation Sequencing, Single Cell, and Imaging

Quantification of tumor-infiltrating immune cell populations with an augmented transcriptome

Presenter: Eric Levy

June 22, 2020

Online

4278 / 2

Clinical Research

Predictive Biomarkers for Treatment Efficacy 3

A composite neoantigen score is more strongly associated with therapeutic response than tumor mutational burden in a cohort of late-stage anti-PD-1-treated melanoma patients

Presenter: Charles Abbott

June 22, 2020

Online

6678 / 24

Immunology

Immune Response to Therapies 2

Sensitive HLA loss of heterozygosity detection reveals allele-specific neoantigen expansion as resistance mechanism to anti-PD-1 therapy

Presenter: Rachel Marty Pyke

June 22, 2020

Online

852 / 2

Bioinformatics and Systems Biology

Machine Learning and Artificial Intelligence for Omics, Imaging, and Diagnostics

Improved tumor-only somatic variant calling using a gradient boosted machine learning algorithm

Presenter: Nick Phillips

On June 22, 2020 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, and BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, reported preclinical data demonstrating high cure rates in solid tumors of BT-001, an anti-CTLA4 antibody-encoding oncolytic virus (Press release, Transgene, JUN 22, 2020, View Source [SID1234561354]).

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Cure rates exceeding 70% were seen in multiple mouse models, demonstrating the powerful therapeutic effect of BT-001 when used as a single agent, providing a solid basis for BT-001’s upcoming clinical development, with a Phase 1 clinical trial expected to start before the end of 2020.

BT-001 is a next-generation oncolytic virus (OV) being co-developed by Transgene and BioInvent. It was generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode a Treg-depleting, anti-CTLA4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, as well as the cytokine GM-CSF.

BT-001 has multiple mechanisms of action. It has been designed to combine the killing of cancer cells (oncolysis), and the production of the anti-CTLA4 antibody and GM-CSF directly in the tumor site, while also generating an immune response against tumor cells.

These data indicate that BT-001 has the potential to make a significant difference in the treatment of solid tumors and as such, underpin the effectiveness of both Transgene’s and BioInvent’s technology platforms.

Main points from the presentation included:

The anti-CTLA4 antibody and GM-CSF accumulate in tumors with low systemic exposure. Concentrations of the anti-CTLA4 antibody in the tumor after intratumoral injection of BT-001 is more than 10-fold higher than after intraperitoneal injection of 3 mg/kg of the recombinant antibody in a xenograft tumor model.
When tumor cells were re-implanted in mice that had been cured after a first BT-001 treatment, a strong tumor-specific response and long-lasting immune memory were developed by these mice.
BT-001, even at sub-optimal dose, reinforced the therapeutic activity of an anti-PD-1 antibody – opening up potential combinations for powerful dual checkpoint blockade treatment regimens.
These promising findings are available in a poster being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, on June 22-24, 2020. It can be downloaded from the AACR (Free AACR Whitepaper) website and from both Transgene’s and BioInvent’s websites.

Title of the poster: "BT-001, an oncolytic Vaccinia virus armed with a Treg-depletion-optimized recombinant human anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment."
Authors: Jean-Baptiste Marchand, Monika Semmrich, Laetitia Fend, Matilda Rehn, Nathalie Silvestre, Ingrid Teige, Johann Foloppe, Linda Mårtensson, Eric Quéméneur, Björn Frendeus
Session Date: June 22-24, 2020
Poster Session Title: Inflammation, Immunity, and Cancer / Modifiers of the Tumor Microenvironment 2
Poster Number: 5602// Abstract Number: 2902

On June 22, 2020 Ascentage Pharma (6855.HK), a global, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and senescence diseases, reported a clinical collaboration with Acerta Pharma, the hematology research and development center of excellence of AstraZeneca (LSE/STO/NYSE: AZN) (Press release, Ascentage Pharma, JUN 22, 2020, View Source [SID1234561370]). Under the terms of the collaboration, Ascentage will sponsor a clinical trial to study the combination of Ascentage Pharma’s APG-2575, a selective Bcl-2 inhibitor, and Acerta’s CALQUENCE (acalabrutinib), a Bruton’s Tyrosine Kinase (BTK) inhibitor, evaluating the efficacy and safety of this combination therapy in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

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This global, multicenter, open-label Phase Ib/II dose-escalation and dose-expansion study is designed to evaluate the safety, tolerability, and anticancer activity of APG-2575 as a single agent or in combination with CALQUENCE in patients with r/r CLL/SLL. The study has already initiated in US with the dosing of first patient, and planned to expand in Europe, and Australia.

CLL/SLL is a hematologic malignancy caused by mature B-cell neoplasms and constitutes the most common form of adult leukemia in North America and Europe, accounting for about 30% of all new leukemia cases. Despite significant initial responses to current first-line treatments, many patients with CLL need ongoing treatment to maintain these responses, and relapse often portends a poor prognosis. Recent studies in CLL showed that combining a BTK inhibitor with another Bcl-2 inhibitor can deepen responses and even shorten cyclic treatment, enabling patients to achieve complete remission and therefore discontinue treatment.1,2 These findings have provided a compelling rationale for exploring APG-2575 in combination with BTK inhibitors.

"We are delighted to enter this collaboration with Acerta. APG-2575 is a key drug candidate in our development pipeline targeting apoptosis, with great potential in the treatment of hematologic malignancies. Collaborating with Acerta helps to accelerate our global clinical development program for APG-2575," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "Combination therapy is becoming more important in cancer treatment, and the rationale of a Bcl-2 inhibitor combined with a BTK inhibitor is sound. We hope that APG-2575 combined with CALQUENCE will show synergistic effects in the treatment of CLL/SLL, offering additional treatment options for patients with otherwise limited treatment options around the world."

References

1. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med 2019;380:2095-2103.
2. Wiestner A. Ibrutinib and venetoclax — doubling down on CLL. N Engl J Med 2019;380:2169-2171.

About APG-2575

APG-2575 is a novel, orally administered Bcl-2‒selective inhibitor being developed by Ascentage Pharma. APG-2575 is designed to treat a variety of hematologic malignancies by selectively blocking Bcl-2 to restore the normal apoptosis process in cancer cells. Since March 2020, the company has received approvals and clearances for several Phase Ib/II studies of APG-2575 in China, Australia, and the US, and is advancing clinical development of APG-2575 for a variety of hematologic malignancy indications.