On November 18, 2020 Genoscience Pharma, a clinical stage biotechnology company developing unique lysosomotropic drug candidates for the treatment of cancer, autoimmune and infectious diseases through autophagy modulation, reported the successful completion of a phase 1b clinical study with GNS561, its lead candidate, in primary and secondary liver cancer patients (Press release, GenoScience, NOV 18, 2020, View Source [SID1234571329]). The company is planning to start phase 2 trials in 2021.

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"Safety and biomarker data from the GNS561 phase 1b study in primary and secondary liver cancers support moving the drug into later stage clinical studies with the aim of addressing patients with liver cancer that have a fatal progression," said Thomas Decaens, M.D., chief hepatogastroenterologist & oncologist and investigator in the GNS561 phase 1 trial at Grenoble-Alpes Centre Hospitalier Universitaire (France).

A recommended phase 2 dose has been selected and validated by the Safety Monitoring Committee (SMC). Genoscience Pharma plans to conduct a phase 2 study using GNS561 as a monotherapy. In parallel, Genoscience Pharma is planning to conduct combination trials with immune checkpoint inhibitors. It has been shown that autophagy is a key mechanism implicated in the immune evasion of immune checkpoint inhibitor therapies. By combining both treatments, in addition to its own anti-tumor activity, GNS561 has been shown to sensitize the tumor to immune checkpoint inhibitors in preclinical models.

"This is a major step for Genoscience Pharma. We are looking forward to continuing our drug development work in liver cancers and broadening the current treatment options. Data from our completed phase 1b study encourages us to pursue our efforts to treat patients that have no other satisfactory therapeutic options," said Philippe Halfon, M.D., CEO and founder of Genoscience Pharma.

Phase 1b results:
The study,which took place in the US and several European countries, enrolled 26 patients in six cohorts: 50mg, 100mg, 200mg, 400mg (three times per week), and 200mg and 300mg twicedaily. The primary objective of the trial was to assess the safety of GNS561 in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) that is not deemed appropriate for a curative therapy, in patients with locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA), in patients with pancreatic adenocarcinoma (PDAC) and liver metastasis, and in patients with colorectal cancer (CRC) and liver metastasis. All patients were previously exposed to one or more anti-tumor therapies (to which they were found to be refractory or intolerant). Secondary objectives of the study were to identify the recommended phase 2 dose (RD) and to characterize the pharmacokinetics. Some exploratory objectives were evaluated such as pharmacodynamics (PD) biomarker expression in blood and in liver biopsy.

Safety data: Analysis of all the safety data to date demonstrates that GNS561 has generally been well-tolerated with no dose-limiting toxicities or unexpected safety signals. The most frequent adverse events observed are manageable gastro-intestinal events, as determined by the SMC.

Pharmacokinetics: The data observed on day one of each cycle shows an absorption profile typical of an oral administration. A long half-life has been measured and linear pharmacokinetics. As expected, there was a higher concentration of GNS561 in the liver than in the plasma.

Preliminary disease stabilization: While the phase 1b trial was a safety trial and not intended to demonstrate efficacy, the investigator-assessed best response (RECIST v1.1) to GNS561 across all cohorts supports promising clinical activity. All patients were advanced; almost half of the total number treated and 60% of HCC enrolled patients were previously exposed to three lines or more of anti-cancer therapies. A disease stabilization was observed in three patients (two in seven evaluable HCC patients and one iCCA patient). "We are investigating all the data obtained from this phase 1 and some of the trends observed are interesting. Disease stabilization observed is a starting point, we look forward to seeing the potential of the compound in a dedicated efficacy trial. The team is writing an article to describe more of the phase 1b results we obtained; we will publish soon," said Eric Raymond, M.D., chief medical officer of Genoscience Pharma.

About GNS561 GNS561 is a PPT-1 (Palmitoyl Protein Thioesterase-1) inhibitor that blocks autophagy. Autophagy is activated in tumor cells in response to certain conditions, due to a tumor cell growth in advanced cancers. By entering the lysosomes and binding to its target, GNS561 has an important inhibiting activity on late stage autophagy, which leads to tumor cell death.

On November 18, 2020 Cellaria Inc (Wakefield, MA, USA) and the Spring Lab, Northeastern University, reported the successful receipt of a National Institutes of Health (NIH) R01 grant to extend and advance the application of innovative new photomedicine-based therapies for hard-to-treat cancers (Press release, Cellaria, NOV 18, 2020, View Source [SID1234571325]). The grant highlights the close working relationship of the two organizations and will provide $3.2M funding to develop precision therapeutics closely tailored to the requirements of specific patient populations. Cellaria’s contribution to the partnership is next generation, patient-derived, customized cell models that boost the effectiveness of ​in vitro studies, helping researchers to identify where the technology can have the most impact. Dr Bryan Spring, Assistant Professor of Biomedical Physics credits Cellaria with a vital role in accelerating his research.

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"We’ve demonstrated proof of concept and seen significant interest from clinicians," said Dr Spring. "However, we initially targeted just a single ovarian cancer biomarker. To capture the heterogeneity of the disease and efficiently study multiple biomarkers we needed to upgrade our cell models. Developing new models in-house would have taken years and instead we chose to work with Cellaria. This has really accelerated progress by providing rapid access to rigorously characterized cell models for specific molecular subtypes and patient populations."

Dr Spring’s research focuses on the use of antibody-photosensitizer conjugates to make cancer cells susceptible to light-induced destruction, targeting microscopic cancer cell deposits left behind by conventional therapies. Primary areas of application are pancreatic and ovarian cancer. With these cancers, cells left behind by surgery and other conventional therapies can metastasize in the peritoneal cavity and abdomen, attacking other organs and increasing the severity of the disease. The new NIH research grant is entitled "Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers".

Cellaria provides cell models, complete with comprehensive omics data, that help the researchers to determine which biomarkers are most actionable when it comes to targeting drug resistant cells and applying the photomedicine. These cell models robustly represent the full heterogeneity of the cancers, which is essential for the development of precision therapies. Dr Spring has been using Powder, a high grade serous ovarian cancer cell model developed from the carcinoma of a 65 – 69 Caucasian, stage IV patient. New models for pancreatic cancer have recently been added to the Cellaria portfolio. All have a robustly authenticated lineage and are provided with protocols to maintain specific biomarker expression. Cellaria’s unrivalled expertise in cell line growth, stabilization and characterization underpin the company’s ability to supply customised models that enable researchers to identify the specific biomarkers of most relevance to their work.

"Cellaria have all the -omics in place and are highly responsive in terms of refining models to our requirements," said Dr Spring. "The Cellaria team are experts in their field and great to work with. The bottom line is that via this collaboration we get to concentrate on our science, rather than the tools we need to support it, which is just as we prefer it."

On November 18, 2020 Cernostics, Inc. the GI Precision Medicine company, reported two newly completed clinical studies confirming the ability of the TissueCypher Barrett’s Esophagus Assay to identify patients at high risk for progression to cancer (Press release, Cernostics, NOV 18, 2020, View Source [SID1234571324]). The two independent peer-reviewed studies, both authored by Prof. Jacques Bergman and Dr. Nicola Frei (University Medical Center, Amsterdam, the Netherlands), have further validated Cernostics’ TissueCypher Barrett’s Esophagus Assay to accurately and objectively predict which patients with Barrett’s esophagus will develop esophageal cancer. These studies confirm the accuracy of the assay in patients with NDBE and LGDBE, and support clinical adoption of the assay to help providers make better-informed clinical decisions. TissueCypher has the potential to improve patient care by identifying patients at high risk for development of esophageal cancer who will benefit from early intervention or increased surveillance, as well as identifying patients at low risk for progression who can avoid unnecessary procedures.

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• Independent Validation of TissueCypher to Predict Future Progression in Non-Dysplastic Barrett’s Esophagus: A Spatial-Temporal Analysis, published in Clinical and Translational Gastroenterology. This blinded independent validation study confirms the ability of TissueCypher to accurately predict incident/future progression to esophageal cancer in patients with NDBE. The study also demonstrated that sampling multiple endoscopic levels across the Barrett’s segment further increases the detection rate for NDBE patients at high-risk for incident progression to esophageal cancer. This study validated findings from previous studies that TissueCypher identifies a high-risk subset of patients with NDBE who progress at a rate that is higher than published estimates for expert pathologist-confirmed LGD. A TissueCypher high-risk score in patients with NDBE may support a management approach similar to the approach for confirmed LGD, which includes endoscopic eradication therapy or increased surveillance to prevent development of cancer. This is a crucial finding as these are the "at-risk" group who may be missed by the current standard of care. This is the fourth study to independently validate the TissueCypher assay, and provides a critical level of evidence to support clinical adoption of the assay to risk stratify patients with non-dysplastic BE.

• Tissue Systems Pathology Test Objectively Risk Stratifies Barrett’s Esophagus Patients with Low-Grade Dysplasia, accepted in American Journal of Gastroenterology This blinded cohort study evaluated the TissueCypher Barrett’s Esophagus Assay in the screening cohort of a randomized controlled trial of SUveillance versus RadioFrequency ablation (SURF) for BE patients with community-based diagnosis of LGD. This is the fifth study to independently validate the risk stratification of TissueCypher, and a key strength is the study design in which the cohort was prospectively enrolled and followed. The results independently validated the ability of TissueCypher to objectively risk-stratify patients with LGD. TissueCypher provided objective risk stratification, whereas there was significant variability between the expert pathologists whose diagnoses were concordant for only 51.7% of cases in this study. In addition to risk stratifying patients with expert pathologist-confirmed LGD, TissueCypher also identified approximately 50% of the progressors that were downstaged to NDBE by expert pathologists. These patients are a high-risk subset who may be missed by the current standard of care, but could be identified early by TissueCypher and undergo management similar to LGD to prevent progression to cancer.

"Key opinion leaders from around the world continue to validate the potential for TissueCypher to improve care for patients with Barrett’s esophagus," commented Cernostics CEO Mike Hoerres. "We appreciate Prof. Jacques Bergman’s continued commitment to evaluating our innovative technology, and we anticipate additional studies from thought-leading institutions in the coming months that further validate the unique ability of TissueCypher to predict progression in patients with BE. Our momentum in growing clinical evidence and adoption bodes well for patients afflicted with this disease state and their physicians."

About Barrett’s Esophagus and TissueCypher

Barrett’s esophagus, which affects more than three million Americans, occurs when chronic exposure to acid from the stomach causes the esophageal cell lining to deteriorate, creating an environment for cancer. Without treatment, BE can lead to esophageal adenocarcinoma, the fastest-rising cancer in the U.S. The current approach to managing BE is surveillance, involving regular endoscopic procedures with biopsies, monitoring for disease progression, and GERD-related drug therapy to control symptoms and prevent injury to the esophagus. Cernostics has developed and commercialized the world’s first precision medicine test that predicts risk of developing esophageal cancer in patients with Barrett’s esophagus. The patent-protected technology platform – TissueCypher Barrett’s Esophagus Assay – uniquely analyzes whole slide digital images with multiplexed fluorescence, providing greater information and accuracy than traditional subjective tissue diagnostics. TissueCypher provides actionable information to gastroenterologists, eliminating the uncertainty related to the management of Barrett’s esophagus patients.

On November 18, 2020 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported the final results from its PLX9486 + sunitinib Phase 1/2 study in patients with advanced gastrointestinal stromal tumors (GIST) (Press release, Cogent Biosciences, NOV 18, 2020, View Source [SID1234571323]). The data will be presented, summarized and discussed in a live oral session on Friday, November 20th from 11:30 a.m. to 12:30 p.m. ET at the Connective Tissue Oncology Society (CTOS) 2020 virtual meeting.

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PLX9486 is a selective tyrosine kinase inhibitor designed to potently inhibit KIT exon 17 mutations, including D816V. Most patients with imatinib-resistant GIST have both primary and secondary KIT mutations, often including secondary mutations on exon 17 and exon 13, making it difficult to achieve broad therapeutic KIT inhibition. These data suggest that treatment with a combination of PLX9486, a type 1 KIT inhibitor with activity against exon 17 mutations, and sunitinib, a type 2 KIT inhibitor with activity against exon 13 mutations, may provide substantial clinical benefit over treatment with type I or type II inhibitors alone.

"We are pleased to share final results from our Phase 1/2 trial of PLX9486 + sunitinib and are excited to advance this combination into a Phase 3 GIST trial in the second half of 2021," said Andrew Robbins, President and CEO of Cogent Biosciences. "With a median progression free survival (PFS) of 12 months in a heavily pre-treated population of advanced GIST patients, this combination holds significant promise for these patients with unmet medical need."

Oral Presentation:

Abstract: 3458521

Title: The potent and selective kit inhibitor PLX9486 dosed in combination with sunitinib demonstrates promising progression free survival (PFS) in patients with advanced gastrointestinal stromal tumor (GIST): final results of a phase 1/2 study.

Date: November 20, 2020

Time: Session 8: 11:30 a.m. – 12:30 p.m. ET

"The final results from this Phase 1/2 trial are highly encouraging for GIST patients who have limited treatment options due to secondary resistance KIT mutations," said Jonathan Trent, M.D., Ph.D., Associate Director for Clinical Research, Sylvester Comprehensive Cancer Center, University of Miami Health System. "I look forward to participating in the upcoming trial of this promising combination for imatinib-resistant GIST patients."

Results:

Out of the 18 patients with advanced GIST enrolled in the trial, all patients had received prior treatment, including 67% of patients with at least three prior lines of therapy. Doses for this study included 3 levels:

Level 1: PLX9486 500mg + sunitinib 25mg (3 patients)
Level 2: PLX9486 1000mg + sunitinib 25mg (5 patients)
Level 3: PLX9486 1000mg + sunitinib 37.5mg (10 patients)
Among the 15 patients who had not previously received PLX9486 as a single agent, the median progression free survival (PFS) was 12 months, the confirmed ORR was 20% and the clinical benefit rate (CR+PR+SD) was 80%, with 27% of patients remaining on therapy out 27-34 months. Importantly, there were no dose limiting toxicities in the three dose levels tested, and the most common adverse events were anemia, hypophosphatemia, diarrhea, and lymphopenia.

On November 18, 2020 AC Immune SA (NASDAQ: ACIU), a Swiss-based, clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, reported that Prof. Johannes R. Streffer, an authority on neurology and psychiatry, was hired as the Company’s Chief Medical Officer, and he is expected to join the Company in January 2021 (Press release, AC Immune, NOV 18, 2020, View Source [SID1234571322]).

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Prof. Streffer joins AC Immune from UCB Biopharma SPRL where he currently holds the position of Vice President, Head of Translational Medicine Neuroscience. His expertise will further accelerate AC Immune’s progress in advancing its pipeline of therapies targeting neurodegenerative diseases.

Prof. Andrea Pfeifer, CEO of AC Immune SA, commented: "We welcome Prof. Streffer’s timely appointment, as his understanding of biomarkers and experience of clinical study design in Alzheimer’s disease (AD), and particularly preclinical AD, will positively impact AC Immune’s discovery efforts. His appointment is a further affirmation of our scientific leadership in the neurodegenerative disease field. Prof. Streffer’s significant expertise and standing in the scientific and medical community will be an invaluable asset as we work to develop innovative treatments for neurodegenerative diseases using our proprietary technology platforms."

Prof. Streffer commented: "I am humbled and proud to be invited to join AC Immune, an established pioneer at the forefront of discovering and developing treatments for neurodegenerative diseases. It is tremendously exciting to be involved at the cutting edge of research addressing an area with such a high unmet medical need and where my work on clinical studies and understanding early biomarkers in Alzheimer’s could play a critically important role. The existing and developing pipeline of AC Immune is very impressive. I look forward to working with the outstanding team at AC Immune and hope my own expertise will contribute to their continued success."

At UCB Prof. Streffer led the development of a translational space in neuroscience, integrating clinical and biomarker sciences. Prior to this he was a member of the Alzheimer Disease Area Leadership Team at Janssen, Pharmaceutical Companies of Johnson & Johnson. Here he gained experience in early experimental AD trials, including biomolecular modalities such as positron emission tomography (PET), volumetric and functional MRI, genetics, cognition and cerebrospinal fluid markers. As a member of the Experimental Medicine group and as leader of the Janssen

BACE inhibitor (BACEi) program targeting Alzheimer’s Disease he initiated a number of methodological and biomarker studies focusing on early diagnosis and translation. Prof. Streffer was also the industrial lead for European Medical Information Framework (EMIF)-AD. In the Innovative Medicines Initiative (IMI)-EMIF program researchers from 14 countries combined in a EUR 56 million project to integrate a wide variety of AD data cohorts to foster understanding of early biomarkers and change in the predementia AD spectrum.

Prof. Streffer is a graduate of the University of Tübingen, Germany, where he received his medical degree. He also completed graduate studies on neuro-oncology and is Board certified in psychiatry and neurology. He has published more than 70 manuscripts and is a visiting Professor in the Department of Biomedical Sciences at the University of Antwerp.