On April 9, 2019 Oncoceutics reported the publication of an article entitled "First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M–mutant pediatric diffuse intrinsic pontine glioma: a case report" in the Journal of Neurosurgery (authored by Matthew D. Hall, M.D., MBA) (Press release, Oncoceutics, APR 9, 2019, View Source [SID1234558359]). The article summarizes the medical history of a 10-year-old girl with a diffuse intrinsic pontine glioma (DIPG) brain tumor. Following radiation therapy and treatment with ONC201 on a compassionate use basis, she developed near complete resolution of her presenting neurological symptoms for almost one year, enabling her return to school and participation in many normal activities.

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DIPG is a serious and rare disease with a dismal prognosis and no viable treatment options. It predominantly affects children and young adults, and it is the most common form of brainstem glioma in this age group. DIPG.org, a resource network for the disease, summarizes the disease characteristics as follows: "Currently, outcomes for most patients are poor, with a median survival of less than 1 year from diagnosis. Radiation therapy can shrink tumors, temporarily improving some symptoms and delaying the progression of the disease, but in almost all cases, the tumor continues to grow. So far, clinical trials have not shown that currently available chemotherapy drugs, radiosensitizing drugs (drugs that make tumor cells more likely to be killed by radiation therapy), or biologics (medical products created by biological processes, such as vaccines or gene therapy) benefit patients. Because of their location in the brainstem, DIPGs cannot be removed surgically. New approaches to treating DIPG are urgently needed."

ONC201 is an investigational drug developed by Oncoceutics that is being studied in several clinical trials for use against DIPG and other brain tumors. The underlying mechanism of the drug involves the interception of a specific receptor for dopamine, called DRD2. DRD2 is a neurotransmitter that is misused by malignant glioma cells to boost their growth. Tumors that harbor a certain mutation of a highly conserved histone protein, i.e. H3 K27M, are particularly sensitive to ONC201 in spite of the otherwise aggressive growth that this mutation confers. DIPG is one of the tumor types that exhibit a high prevalence of this mutation.

The patient described in the article has shown prolonged clinical benefits and is approaching almost two years from diagnosis, although ONC201 was administered only when symptoms progressed after radiation was completed. This supports further investigation of ONC201 in H3 K27M-mutant gliomas, including DIPG. As a result, Oncoceutics has significantly expanded its pediatric clinical program for ONC201. The company’s ongoing pediatric trial for ONC201 in H3 K27M-mutant high-grade gliomas including DIPG (NCT03416530) was extended with additional treatment arms, a pediatric oral solution formulation was introduced, and ONC201 treatment was extended to newly diagnosed DIPG patients with concomitant radiation.

The company further implemented an intermediate size Expanded Access Protocol (EAP) to provide access to ONC201 for patients that might benefit from the drug but are not eligible for participation in the ongoing clinical trials. The EAP was made possible by the support of the Food and Drug Administration and their high priority effort to facilitate access to promising medicines for patients with serious or immediately life-threatening diseases or conditions when no comparable or satisfactory alternative therapy options are available (see recent FDA statement). The program is also supported by The Musella Foundation, The Cure Starts Now Foundation, The Michael Mosier Defeat DIPG Foundation, Cancer Commons and xCures.

"We are delighted to see a novel concept to treat this horrible disease emerge and show traction in clinical settings," said Keith Desserich, Chairman of the Board and Co-Founder of The Cure Starts Now. "We have followed the development of ONC201 for some time and are excited about the emerging data in both, children as well as young adults that are expected to become public later in this year.

On April 9, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that valemetostat (DS-3201), an investigational and potential first-in-class EZH1/2 dual inhibitor, has received SAKIGAKE Designation for the treatment of adult patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) by the Japan Ministry of Health, Labour and Welfare (MHLW) (Press release, Daiichi Sankyo, APR 9, 2019, View Source [SID1234535072]).

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"There is a need for new and novel treatment approaches for patients with peripheral T-cell lymphoma, a group of heterogenous diseases for which relapse rates tend to be high and options beyond systemic chemotherapy are limited," said Kaszushi Araki, Valemetostat Global Team Leader, Oncology Clinical Development Department, Oncology Function, Daiichi Sankyo. "We look forward to working closely with the Japan Ministry of Health, Labour and Welfare to optimize development of valemetostat and to potentially offer a new, first-in-class targeted therapy option for patients with various subtypes of relapsed/refractory PTCL, including those that are more common in Japan."

The SAKIGAKE Designation System promotes R&D in Japan, driving early practical application for innovative pharmaceutical products, medical devices, and regenerative medicines. As a designated medicine under the SAKIGAKE Designation System, valemetostat will have prioritized consultation, a dedicated review system to support the development and review process, as well as reduced review time from the normal 12 months to 6 months.

Valemetostat targets epigenetic regulation by inhibiting both the EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes that act through histone methylation to regulate gene expression.[1] Reactivation of the silenced genes results in decreased proliferation of EZH2-expressing cancer cells.1 Preclinical research has shown that valemetostat suppressed trimethylation of H3K27 in cells more strongly than EZH2 selective inhibitors.[2] Valemetostat also displayed antitumor activity in various hematological malignancies in preclinical models.2,[3]

SAKIGAKE Designation was granted based on the preliminary results of an ongoing phase 1 study assessing the safety and efficacy of valemetostat in patients with non-Hodgkin lymphomas (NHL) including PTCLs, which were presented at the 2017 annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).[4]

About Peripheral T-Cell Lymphoma (PTCL)

Peripheral T-cell lymphoma (PTCL) is a subtype of non-Hodgkin lymphoma (NHL), a form of cancer that originates in lymphocytes, a type of white blood cell.[5] The two main types of NHL are B-cell lymphomas and T-cell lymphomas, which are classified into subtypes based on the origin and stage of the cancer.[6]

There are at least eight different types of PTCL.[7] Each type is considered rare. Global incidence of PTCL subtypes varies by geographic region.[8] Most, but not all, types of PTCL are aggressive, and patients are usually treated with systemic chemotherapy; relapse is common after initial treatment.8

The incidence of lymphoma, including NHL, is increasing year by year around the world.[9] There were an estimated 509,000 new cases and about 248,000 deaths globally from NHL in 2018.[10] In Japan, there were nearly 21,000 new cases of NHL in 2012.[11] While recent treatment advances have led to improved outcomes for patients with certain types of NHL, patients with aggressive NHL subtypes or relapsed/refractory disease still face a poor prognosis.6,[12]

About Valemetostat

Part of the investigational AML Franchise of the Daiichi Sankyo Cancer Enterprise, valemetostat is an investigational and potential first-in-class EZH1/2 dual inhibitor in phase 1 clinical development for hematologic cancers including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and Non-Hodgkin lymphoma (NHL), including adult T-cell leukemia/lymphoma (ATL/L), peripheral T-cell lymphoma (PTCL), and B-cell lymphomas. Valemetostat is an investigational agent and has not been approved by the FDA or any other regulatory agency worldwide as a treatment for any indication. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science Franchise, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/ immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: DS-8201, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

On April 9, 2019 Foundation Medicine and Flatiron Health reported the publication of study results in the Journal of the American Medical Association validating that real-world clinico-genomic data obtained during the course of routine patient care can yield scientifically and clinically meaningful insights (Press release, Foundation Medicine, APR 9, 2019, View Source [SID1234535090]). These insights can serve as real-world evidence to advance research and discovery in oncology, and may also ultimately inform clinical guidelines. The continuously-updated, de-identified clinico-genomic database includes patient outcomes data processed from patients in Flatiron Health’s network of oncology clinics, linked with comprehensive genomic profiling (CGP) results from Foundation Medicine’s FoundationCORE database.

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The findings demonstrate the feasibility of creating a de-identified clinico-genomic database (CGDB) and validate the potential of such real-world data for understanding and optimizing personalized cancer care, including, for example, biomarkers of response to immunotherapy treatment. The study linked clinical data from the electronic health records (EHRs) of 28,998 patients from 275 oncology practices in Flatiron Health’s network across the United States with genomic data from Foundation Medicine CGP testing. Among 4,064 patients with non-small cell lung cancer (NSCLC), exploratory analyses recapitulated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between tumor mutation burden (TMB) and response to immunotherapy.

"The publication of our validation study in a high-profile journal not only validates the ability of a real-world clinico-genomic database to yield scientifically and clinically-relevant findings, but also the potential for this novel approach to significantly impact our understanding of personalized medicine. This represents a major milestone in our mission to leverage regulatory-grade, real-world data to advance cancer care," stated Gaurav Singal, MD, chief data officer at Foundation Medicine. "As the dataset continues to grow, we expect it will advance therapeutics development, optimize clinical trial design and execution, and ultimately even support clinical decision making, enabling a more efficient way to evaluate new medicines and accelerate their availability for patients who need them."

In addition to demonstrating the scientific validity of the database for rigorous research, the study findings confirmed and extended several biomarker hypotheses in oncology. Corroborating recent clinical trial data, high TMB was shown to be associated with both longer duration on anti-PD-1/PD-L1 therapy and improved overall survival (OS) from treatment initiation. In addition, this retrospective real-world analysis re-demonstrated the importance of genomic biomarker-guided targeted treatment in NSCLC: among patients with genomic alterations known to drive tumor growth, treatment with agents targeted to these mutations was associated with prolonged survival. These findings may be extended in the future to identify additional factors associated with response to targeted therapies and immunotherapies.

"Our proof-of-principle study validated the importance of marrying tumor genomic data with clinical outcomes recorded during routine care, which represents a huge stream of data that is being generated and recorded every day, but has not yet been used meaningfully outside of patient care," said Vineeta Agarwala, MD, PhD, director of product management at Flatiron Health. "These data can inform treatment guidelines, clinical trial design, and precision drug development."

Since launching in November 2016, the CGDB now includes linked, de-identified data for more than 50,000 patients (over 6,000 with non-small cell lung cancer) and helps researchers and biopharmaceutical partners accelerate the development of targeted therapeutics and immunotherapies to treat cancer. The CGDB includes de-identified clinical data (demographic data, medication history, laboratory testing, and outcomes including survival) from Flatiron Health linked to genomic data (comprehensive genomic profiling of tumors, including genomic findings, variant annotations, and computational biomarkers such as tumor mutational burden [TMB], microsatellite instability [MSI], and loss of heterozygosity [LOH]) from Foundation Medicine across a variety of tumor types, allowing for a continuously updated, longitudinal view of a patient’s clinical, diagnostic and therapeutic journey.

On April 9, 2019 BioAtla , LLC, a global clinical-stage biotechnology company focused on the development of Conditionally Active Biologic (CAB) protein therapeutics, and BeiGene, Ltd. (Nasdaq: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that the two companies have entered into a global co-development and collaboration agreement for the development, manufacturing and commercialization of BioAtla’s investigational CAB CTLA-4 antibody (BA3071) (Press release, BeiGene, APR 9, 2019, View Source;p=RssLanding&cat=news&id=2393908 [SID1234535074]). BA3071 is a novel, CTLA-4 inhibitor that is designed to be conditionally activated in the tumor microenvironment in order to reduce systemic toxicity and potentially enable safer combinations with checkpoint inhibitors such as BeiGene’s investigational anti-PD-1 antibody, tislelizumab, a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages.

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Under the terms of the collaboration, BioAtla will co-develop the CAB-CTLA-4 antibody to defined early clinical objectives and BeiGene will then lead the parties’ joint efforts to develop the product candidate and be responsible for global regulatory filings and commercialization. Subject to the terms of the agreement, BeiGene will hold a co-exclusive license with BioAtla to develop and manufacture the product candidate globally and an exclusive license to commercialize the product candidate globally. BeiGene will be responsible for all costs of development, manufacturing and commercialization in Asia (ex-Japan), Australia and New Zealand, and the parties will share development and manufacturing costs and commercial profits and losses upon specified terms in the rest of the world. BioAtla will receive an upfront payment of $20 million and a milestone payment upon reaching the defined early clinical objectives. BioAtla is also eligible to receive up to $249 million in subsequent development and regulatory milestones globally and commercial milestones in the BeiGene territory, together with tiered royalties on sales in the BeiGene territory. Additional terms of the agreement were not disclosed.

"BeiGene is a recognized leader in China-inclusive global clinical development, with broad oncology clinical programs, which include tislelizumab," said Scott Smith, President of BioAtla. "This collaboration complements our strategy of building our pipeline of innovative CAB oncology candidates, advancing combination product therapies, and effectively addressing markets with strong growth potential and high unmet medical need."

"BioAtla has developed an exciting proprietary protein discovery and expression platform to generate CABs, which in turn have been applied to BA3071, a novel, investigational CTLA-4 inhibitor that is designed to be conditionally activated in the tumor microenvironment," commented Dr. Lai Wang, Senior Vice President, Asia Pacific Clinical Development, Global Research, Clinical Operations and Biometrics, for BeiGene. "The unique nature of BA3071 provides an exciting opportunity to combine this CTLA-4 antibody with our anti-PD-1 antibody, tislelizumab. We look forward to working with BioAtla through proof-of-concept, followed by global development of this potentially unique cancer therapy as a single agent or in combination with other therapies."

"We believe that our collaboration with BeiGene will accelerate the global development and potential commercialization of BA3071 and advance the prospects and potential of safer and more effective combination therapies for the treatment of several cancer indications," stated Jay M. Short, Ph.D., Chairman, CEO and co-founder of BioAtla. "The application of BioAtla’s CAB technology to CTLA-4 inhibition may offer greater potency and safety, thereby improving this important cancer therapy and expanding its potential applications."

About BA3071

BA3071 is a novel, investigational conditionally active CTLA-4 inhibitor. The first investigational new drug (IND) filing is currently planned for mid-2019. Subject to regulatory clearance of the IND, a Phase 1/2 multi-center, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and antitumor activity of BA3071 alone and in combination with BeiGene’s tislelizumab, an investigational anti-PD-1 inhibitor, is anticipated to start in the second half of 2019.

The cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an inhibitory receptor expressed on T cells. The CTLA-4 pathway is a key immune checkpoint pathway that provides a downregulating signal to T cells. The blockade of CTLA-4 is intended to induce an antitumor immune response by promoting the activation and proliferation of tumor-specific T cells. Although inhibition of CTLA-4 has been shown to significantly improve antitumor response, it may also lead to immune attack of healthy cells. To minimize on-target off-tumor toxicity, BioAtla has applied its proprietary CAB technology with the intent to activate binding to the CTLA-4 receptor only on T cells in the tumor microenvironment.

Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti-CTLA-4 monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and are among the most promising components of treatment approaches for many other cancers. Employing BioAtla’s proprietary CAB technology, BA3071 is designed to improve the efficacy and safety of anti-CTLA-4 therapy, as a monotherapy and in combination with other therapies, by restricting its activation and that of tumor specific T cells to the tumor microenvironment.

About Conditionally Active Biologics (CABs)

Conditionally Active Biologics are proteins generated using BioAtla’s proprietary protein discovery, evolution and expression technologies. These proteins can be monoclonal antibodies, enzymes and other proteins designed with functions dependent on changes in micro physiological conditions (e.g., pH level, oxidation, temperature, pressure, presence of certain ions, hydrophobicity and combinations thereof) both outside and inside cells.

Studies have shown that cancerous tumors create highly specific conditions at their site that are not present in normal tissue. These cancerous microenvironments are primarily a result of the well understood unique glycolytic metabolism associated with cancer cells, referred to as the Warburg Effect in aerobic cancer cells. CAB proteins are designed to deliver their therapeutic payload and/or recruit the immune response in specific and selected locations and conditions within the body and to be active only in the presence of a particular cellular microenvironment. In addition, the activation is designed to be reversible to repeatedly switch ‘on and off’ should the CAB move from a diseased to a normal cellular microenvironment and vice versa. CABs can be developed in a variety of formats, including antibodies, antibody drug conjugates (ADCs), bispecifics, chimeric antigen receptor T-cells (CAR-Ts) and combination therapies.

About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologic program, and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

Clinical trials of tislelizumab include a global Phase 3 clinical trial in patients with second-line non-small cell lung cancer (NSCLC); a global Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a global Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a global Phase 3 clinical trial in first-line patients with gastric cancer (GC); a global Phase 3 clinical trial in first-line patients with ESCC; a global Phase 3 trial in patients with Stage III NSCLC; a global Phase 2 clinical trial in second- or third-line patients with HCC; a global Phase 1 clinical trial in patients with relapsed/refractory (R/R) NK/T-cell lymphomas; and a global Phase 1 clinical trial in patients with solid tumors. In China, BeiGene has completed a pivotal Phase 2 clinical trial in patients with R/R classical Hodgkin’s lymphoma (cHL), and is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 2 clinical trial in second-line urothelial cancers (UC); and a Phase 2 clinical trial in patients with MSI-H or dMMR solid tumors.

The new drug application (NDA) in China for R/R cHL has been accepted by the China National Medical Products Administration (NMPA) and granted priority review.

BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).

On April 9, 2019 Forbius, a clinical-stage company that develops novel biologics for the treatment of cancer and fibrosis, reported that Dr. Maureen O’Connor-McCourt, Chief Scientific Officer of Forbius, will be presenting an overview of AVID100, a novel, tumor-selective, anti-EGFR antibody-drug conjugate (ADC), at PEGS Boston’s 9th Annual Clinical Progress of Antibody-Drug Conjugates (Press release, Forbius, APR 9, 2019, View Source [SID1234535091]).

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Details and highlights of Dr. O’Connor-McCourt’s presentation:

Discovery of Next-Generation ADCs: Preclinical and Clinical Development of AVID100, an EGFR-Targeting ADC

Presentation Friday, April 12th at 11:35 AM ET, Harborview 1 & 2

AVID100 is highly potent and selectively cytotoxic against EGFR-expressing cancer cells, while sparing normal EGFR-positive keratinocytes
AVID100 was well-tolerated in a Phase 1 dose-escalation study in patients with advanced solid tumors of epithelial origin (any EGFR status)
Only modest skin toxicity observed, in line with preclinical findings
Phase 2 trial (AVID100-01; NCT03094169) ongoing to evaluate AVID100 efficacy, safety, and tolerability in patients with EGFR-overexpressing (IHC 3+) SCCHN and sqNSCLC
About AVID100 and the AVID100-01 Trial
AVID100 is a highly potent EGFR-targeting antibody-drug conjugate (ADC) that was engineered to achieve enhanced anti-tumor efficacy without a corresponding increase in toxicity against skin and other EGFR-expressing normal tissues. In preclinical studies, AVID100 demonstrated significant anti-cancer activity, including in EGFR-overexpressing tumor models that are resistant to marketed EGFR inhibitors. AVID100 is the only anti-EGFR ADC in clinical development that targets both wild-type and mutant forms of EGFR.

In a successfully completed Phase 1 study, AVID100 reported a recommended Phase 2 dose (RP2D) of 220 mg/m2 (~6mg/kg), which is expected to be in the therapeutically active range based on preclinical efficacy studies. Treatment was generally well-tolerated, with the majority of treatment-related adverse events in the Phase 1 trial at the RP2D being grade 1 or 2 in severity.

AVID100-01 (NCT03094169) is an open label, multicenter study to evaluate the efficacy, safety, and tolerability of AVID100 in patients with confirmed EGFR-overexpressing tumors (more than 50% of cells with EGFR 3+ or more than 75% of cells with EGFR 2+ staining by a validated immunohistochemistry assay).