On August 25, 2020 Sutro Biopharma, Inc. (NASDAQ: STRO), a clinical-stage drug discovery, development and manufacturing company focused on the application of precise protein engineering and rational design to create next-generation oncology therapeutics, reported that it has achieved a clinical supply milestone under its collaboration and license agreement with the healthcare division of Merck KGaA, Darmstadt, Germany and is entitled to receive a milestone payment (Press release, Sutro Biopharma, AUG 25, 2020, View Source [SID1234564023]). The candidate, M1231, was discovered using Sutro’s XpressCF and XpressCF+ drug discovery and manufacturing technologies and includes a proprietary linker-warhead also discovered by Sutro. M1231 is a MUC1-EGFR bispecific antibody drug conjugate (ADC) for the treatment of solid tumors and relies on the strand-exchange engineered domain (SEED) platform from Merck KGaA, Darmstadt, Germany to generate bispecific antibody-like molecules.

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The milestone was achieved with the delivery of GMP clinical trial supply to Merck KGaA, Darmstadt, Germany for the Phase 1 clinical trial testing of M1231 pursuant to a 2014 license agreement. As part of the agreement, Sutro will manufacture M1231 for early clinical supply and is eligible for further milestones and royalties. Merck KGaA, Darmstadt, Germany will be responsible for filling and finishing the drug product, in addition to its clinical development and commercialization.

"Reaching the clinical supply milestone in our collaboration with Merck KGaA, Darmstadt, Germany underscores our continued commitment to deliver novel therapies to patients with cancer," said Bill Newell, Sutro’s Chief Executive Officer. "M1231 bispecific ADC was generated with Sutro’s XpressCF and XpressCF+ drug discovery and manufacturing technologies which enabled the use of iterative optimization through cell-free protein synthesis and site-specific conjugation with the goal of an improved therapeutic window. Through our continued collaboration with Merck KGaA, Darmstadt, Germany, we hope to move closer to bringing new treatment options to cancer patients."

"M1231 is the first bispecific ADC targeting both MUC1 and EGFR. By combining XpressCF+ technology with the SEED antibody platform, Merck KGaA, Darmstadt, Germany and Sutro in collaboration have developed a unique next generation ADC that has the potential to increase the therapeutic window by selectively targeting tumors that co-express two different tumor antigens.," said Trevor Hallam, PhD, Sutro’s Chief Scientific Officer.

"We look forward to working with Merck KGaA, Darmstadt, Germany to apply our proprietary GMP manufacturing platform to supply M1231 for the early clinical studies," said Shabbir Anik, PhD, Sutro’s Chief Technical Officer.

Under the terms of the 2014 license agreement, Sutro and Merck KGaA, Darmstadt, Germany have collaborated to discover and develop ADCs utilizing Sutro’s cell-free protein synthesis and site-specific conjugation platforms, XpressCF and Xpress CF+. Further financial details are not being disclosed.

On August 25, 2020 Sirnaomics, Inc. , a leading biopharmaceutical company in discovery and development of RNAi therapeutics for treatment of cancer and fibrotic diseases, reported that it has published data from a preclinical discovery effort using a novel siRNA-gemcitabine conjugate construct to enhance therapeutic efficacy of the active pharmaceutical ingredient potentially for treatment of multiple types of cancer (Press release, Sirnaomics, AUG 25, 2020, View Source [SID1234564022]). The findings appeared in a manuscript entitled "A novel siRNA–gemcitabine construct as a potential therapeutic for treatment of pancreatic cancer" in the journal Nucleic Acid Research, Cancer. 2020, Vol. 2, No. 3 1.

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SiRNAs are Short Interfering RNA oligos that induce silencing effect of specific targeted genes. Gemcitabine is a nucleotide-based small molecule chemo drug that has been used in the treatment of cancers such as pancreatic cancer, bladder cancer, NSCLC, ovarian cancer, breast cancer, cholangiocarcinoma and others. Gemcitabine replaces the nucleic acid cytidine during DNA replication and can inhibit tumor growth since new nucleosides cannot be attached to this nucleoside mimic, resulting in apoptosis of the cells. While Gemcitabine is the "gold standard" therapeutic for treatment of pancreatic cancer currently, the benefit of gemcitabine treatment in patients with stage IV pancreatic cancer is marginal.

Targeted therapies have been actively sought to potentiate the efficacy of gemcitabine in killing tumor cells and therefore allow a reduction of the dose required for therapeutic efficacy. The publication describes the ability to attach gemcitabine moieties directly to a siRNA and examines the efficacy and potency improvements associated with inserting gemcitabine at various locations throughout the siRNA sequence. By modifying an siRNA against targets that augment the activity of gemcitabine (CHK1 or RAD17), Sirnaomics believes that it has demonstrated synergism in reducing cell viability across a number of pancreatic tumor cells upon transfection of the siRNAs into the cells. This synergism resulted in a product that can kill pancreatic tumor cells at a 5-100 fold lower dose than gemcitabine alone.

In the optimal construct, the gemcitabine is attached to the Sense strand of the siRNA. When administered to tumor cells, the antisense strand is separated from the sense strand as it binds to the RISC complex. The antisense strand induces silencing of the targeted gene while the sense strand is degraded in the cytoplasm – releasing the gemcitabine moieties to augment the activity from the reduction in gene expression. This siRNA-Chemo-Oligo Nucleotide (SICON) construct provides a novel therapeutic modality for advancing RNAi Cancer Therapeutics.

David Evans, PhD, Chief Scientific Officer of Sirnaomics and the senior author of the publication, stated, "Sirnaomics can deliver this SICON construct into tumor cells and tumor microenvironment, using our proprietary polypeptide nanoparticle formulation (PNP) that protects the siRNA in the plasma and minimizes toxicity of gemcitabine outside tumor tissue. The SICON construct is a single agent that provides a dual mechanism of action – making it easier for regulatory approval than using 2 separate agents. The construct will also alleviate the requirement to infuse free gemcitabine into patients at a high dose required to get delivery to the tumor tissue. Silencing the right gene target associated with gemcitabine drug resistance and tumorigenicity can further enhance the potency of our RNAi cancer drug candidates."

Patrick Lu, PhD, President and CEO of Sirnaomics, added, "This publication illustrates the Company’s continuing effort to enhance our RNAi cancer therapeutic platform, in addition to advancing our delivery technologies, large scale CMC process and clinical studies to treat various types of cancer. With advancements of our local and systemic delivery formulations, plus this unique SICON drug modality, we envision expanding the potential of RNAi cancer therapeutics."

On August 25, 2020 AstraZeneca PLC (NYSE:AZN) reported $6 billion bet on an antibody-drug conjugate (ADC) called DS-1062 from Japanese developers Daiichirecently Sankyo (Press release, AstraZeneca, AUG 25, 2020, https://www.prnewswire.com/news-releases/billions-pouring-into-drugs-that-could-treat-cancer-patients-with-high-trop2-expressions-301117474.html [SID1234564021]). The move signalled AZ’s confidence that this solid tumor drug could hit the same target as another approved ADC, known as Trodelvy from Immunomedics, Inc. (NASDAQ:IMMU). That target is trophoblast cell-surface antigen 2 (TROP2), a transmembrane protein overexpressed by tumors of the lung, breast, pancreas and other organs. Given the level of investment AstraZeneca has now committed to, a highlight is being shone on a segment of biotech companies tackling these forms of cancer through new drugs and drug combinations, including Oncolytics Biotech Inc. (NASDAQ:ONCY) (TSX:ONC), Merck & Co., Inc. (NYSE:MRK) and Pfizer Inc. (NYSE:PFE).

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The potential for breakthroughs in these fields has Wall Street quite bullish. An example of a consensus on the sentiment comes when looking at Oncolytics Biotech Inc. (NASDAQ:ONCY) (TSX:ONC), which has earned an average rating from Wall Street analysts of Buy (3 Buy, 1 Hold, and no Sell ratings), and a significantly increased price projection over the next 12 months.

Optimism directed at the company is being credited to the milestones being met by its flagship platform, pelareorep, which promotes an anti-cancer response by inducing innate and adaptive immune responses creating a cancer immunotherapy that actively turns "COLD" tumors "HOT".

Much like Daiichi Sankyo’s DS-1062, pelareorep is also being tested in combination with KEYTRUDA made by Merck & Co., Inc. (NYSE:MRK). However, the DS-1062/KEYTRUDA trial is for treating NCLC, while the pelareorep/KEYTRUDA is in Phase II of study to treat pancreatic cancer.

As well, both DS-1062 and pelareorep are being studied for treating triple-negative breast cancer (TNBC). This is significant, since high TROP2 expression has been reported in up to 80% of patients with TNBC.

Oncolytics recently kicked off its TNBC study, sponsored by New Jersey-based Rutgers Cancer Insitute (RCI), through a Phase 2 clinical trial to investigate the use of pelareorep and retifanlinmab, an anti-PD-1 checkpoint inhibitor. RCI will manage this clinical trial in patients with unsectable metastatic or locally advanced TNBC.

While also being in Phase 1 clinical development for treating non-small cell lung cancer (NSCLC), in July Daiichi Sankyo expanded its Phase 1 study for DS-1062 to include patients with advanced/unresectable or metastatic TNBC.

Should Daiichi (and now AstraZeneca) succeed with DS-1062, it won’t be the first drug targeting TROP2 to win FDA approval.

Immunomedics, Inc. (NASDAQ:IMMU) won that distinction in April, when the FDA authorized its lead ADC Trodelvy (sacituzumab govitecan-hziy) as a treatment for adults with metastatic TNBC who had at least received two prior therapies for metastatic disease. Trodelvy officially became the first ADC approved by the FDA specifically for relapsed or refractory metastatic TNBC, and is also the first FDA-approved anti-Trop-2 ADC.

The company recently reported encouraging early adoption of Trodelvy in the US, with $20.1 million in net sales during the first two months of launch.

BIG BETS BEING MADE

AstraZeneca’s (NYSE:AZN) recent deal with Daiichi Sankyo will have the pharma giant paying out $1 billion to co-develop an ADC called DS-1062 outside of Japan. The deal also features a further $5 billion in milestones, with the bet being made that it can hit the same target as Trodelvy.

Now the market’s hope is that platforms such as DS-1062 and others such as pelareorep can capitalize on similar successes as Trodelvy. It was results such as 33.3% of all patients that received Trodelvy experiencing a certain amount of shrinkage of their tumors that led to the drug’s approval.

Immunomedics, Inc. also recently announced that the FDA also approved Samsung Biologics to produce commercial-scale hRS7, the antibody used in Trodelvy, at its manufacturing facilities in Incheon, South Korea. The approval is said to enhance Immunomedics’ long-term supply of Trodelvy.

Previously, pharma giant Pfizer Inc. (NYSE:PFE) had also taken an anti-TROP2 ADC into the clinic but (according to Fierce Biotech) scrapped the trial after seeing early data, which left Trodelvy and DS-1062 as the front-runners. However, in late July, a partner of Pfizer announced that "very good progress" was being made on its own TNBC trial for a compound called ZEN-3694.

At the end of July, Merck & Co., Inc. announced two US regulatory milestones for its drug KEYTRUDA (pembrolizumab) in TNBC. First off the FDA granted priority review to KEYTRUDA’s Supplemental Biologics License Application (sBLA) when combined with chemotherapy for the treatment of certain patients with metastatic TNBC based on the Phase 3 KEYNOTE-355 trial. The FDA also accepted an sBLA for KEYTRUDA for the treatment of patients with high-risk early-stage TNBC based on the Phase 3 KEYNOTE-522 trial.

CURRENT PELAREOREP STUDIES

Back in June of 2019, Pfizer had signed a co-development agreement with both Oncolytics Biotech Inc. and Merck KGaA for what’s known as the BRACELET-1 study—(BReast cAnCEr with the Oncolytic Reovirus PeLareorEp in CombinaTion with anti- PD-L1 and Paclitaxel).

Though the BRACELET-1 study pertains to HR+ breast cancer, and not TNBC, there is much anticipation over its potential. Oncolytics has already announced that it has advanced its lead breast cancer program with the dosing of the first patient in the BRACELET-1 study.

The study will take place at 20 trial sites and enroll 45 patients randomized into three cohorts: one with just paclitaxel; one with paclitaxel + pelareorep; and a third with paclitaxel + pelareorep + avelumab (Merck and Pfizer’s shared immuno-oncology drug Bavencio).

As stated above, pelareorep is also being studied for its potential in treating TNBC through a study dubbed "IRENE". According to the available preclinical data, the drug shows potential in addressing the unmet needs in TNBC.

Clinical trial data suggests that the systematic administration of pelareorep shows promising outcomes in patients suffering from tumors in their breasts—helping to improve the patient count responding to what are known as checkpoint inhibitors.

Checkpoint investigators are used to target interactions between PD-1 and PD-L1. Commercially proven checkpoint investigators only achieve 20% success in patients with TNBC because of an ITM (immunosuppressive tumor microenvironment).

Throughout this study, RCI’s investigators will evaluate the efficacy and safety of pelareorep in TNBC patients in an anti-PD-1 combination cure. It will study the changes in the PD-L1 expression in this trial, along with peripheral T-Cell Clonality and correlations between the treatments’ outcomes.

The IRENE study is an open-label, single-arm, Phase 2 clinical trial investigating the use of INCMGA00012 and pelareorep to treat Metastatic TNBC or unresectable LA (locally advanced) TNBC. The drug combination is administered intravenously to the patients on the first, second, fifteen, and sixteenth day of the 28-day treatment program. Approximately 25 patients are enrolled for this clinical study at RCI.

On August 25, 2020 CARISMA Therapeutics Inc., a biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported it has entered into a scientific research and licensing agreement with Nathaniel R. Landau, PhD and NYU Langone Health through which CARISMA will attain exclusive rights to develop and commercialize their Vpx lentiviral vector globally for all indications (Press release, Carisma Therapeutics, AUG 25, 2020, View Source [SID1234564020]). The Vpx lentiviral and CARISMA’s Ad5f35 vectors are the only two vectors known to be effective in engineering macrophages, a pivotal aspect of CARISMA’s approach.

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The Vpx lentiviral vector, which is proven to be highly effective at transducing human monocytes, macrophages and dendritic cells, will broaden the utility of the CARISMA-engineered monocyte and macrophage platforms by enabling integration of transgenes for long-term, durable expression.

"CARISMA is committed to pursuing science and partnerships that will build upon and enhance our macrophage technology," said Steven Kelly, President and Chief Executive Officer at CARISMA Therapeutics. "This exciting collaboration with NYU Langone Health and Dr. Landau advances CARISMA’s position as the leader in the engineered macrophage space and equips us with additional tools to further unlock the power and potential of the macrophage."

The announcement follows the recent U.S. Food and Drug Administration clearance of an investigational new drug (IND) application for CARISMA’s lead product candidate, CT-0508, an anti-human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M). Under this IND, CARISMA intends to initiate its Phase 1, first-in-human, multi-center study in patients with recurrent or metastatic HER2 overexpressing solid tumors after failure of approved HER2 targeted agents later this year.

"We are excited to collaborate with CARISMA on this project. We believe that that the Company’s commitment to immunotherapy and its achievements to date in macrophage engineering will bring important advances in the treatment of cancer," said Dr. Landau, a Professor in the Department of Microbiology at the NYU Grossman School of Medicine and the inventor of the Vpx lentiviral vector. "The collaboration will advance the field of cancer immunotherapy and bring new understanding of how to engineer macrophages for therapeutic purposes."

On August 25, 2020 M2GEN reported the launch of its oncology-focused Bioinformatics Support Services (Press release, M2Gen, AUG 25, 2020, View Source [SID1234564019]). Leveraging the results and knowledge gained from the ORIEN Avatar Program, an extensive, unique and ever-growing oncology clinico-genomics dataset, the M2GEN Bioinformatics team provides bioinformatics support services adhering to best-in-class standards.

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M2GEN offers the following bioinformatics services: Paired Tumor and Germline Whole Exome Sequencing (WES) analysis with Panel of Normals (PoN) filtering, Tumor-Only Whole Exome Sequencing (WES) analysis with Virtual Normal (VN) somatic mutation classification, and Tumor-Only RNA Sequencing (RNA-Seq) analysis. Pipeline analysis is WES and RNA-Seq capture kit agnostic, and uses the most up to date human genome reference (GRCh38/hg38) and gene build (Gencode V32). All bioinformatics services are performed in HIPAA compliant and HI Trust certified cloud solutions.

M2GEN Bioinformatics Support Services utilize one of the largest Panel of Normals (PoN) available for high-quality somatic mutation calling. Over 20,000 germline samples from cancer patients inform the segregation of somatic and germline variants, and identify recurrent sequencing artifacts. In addition, the Avatar germline sequencing data is leveraged as a Virtual Normal (VN) cohort during Tumor-Only analysis, allowing for superior somatic mutation classification when patients’ matched normal biospecimens are unavailable.

M2GEN’s Bioinformatics Support Services are led by an experienced team of bioinformatics and computational biology experts trained at world-renowned scientific institutions such as Baylor College of Medicine Human Genome Sequencing Center, Memorial Sloan Kettering Cancer Center, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Sanger Institute and Columbia University.

"M2GEN now provides next generation sequencing analysis pipelines to customers in academia and biopharma industry. Our end-to-end bioinformatics solutions and pipelines are tuned for large-scale oncology multi-omics studies that allow our customers to dedicate more time to results interpretation and discovery," said Oliver Hampton PhD, Vice President of Bioinformatics & Biostatistics at M2GEN.

"M2GEN continues to expand its portfolio of data solutions, services, and technologies to be the best partner possible for its clients as we transform cancer care together and make precision medicine a reality," said Helge Bastian, PhD, President & CEO of M2GEN. "M2GEN’s bioinformatics services enable researchers in academic and pharmaceutical research worldwide to gain the most meaningful molecular insights in oncology. These molecular insights will accelerate the development of novel and more effective patient specific therapies, turning cancer into a manageable condition, or better still a curable disease."