On September 25, 2020, Exicure, Inc. and Exicure Operating Company, Exicure’s wholly owned subsidiary (collectively with Exicure, the "Company") reported that it entered into a Credit and Security Agreement (the "Credit Agreement"), with MidCap Financial Trust ("MidCap"), as agent, and the lenders party thereto from time to time (Filing, 8-K, Exicure, SEP 25, 2020, View Source [SID1234567870]).

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The Credit Agreement provides for a secured term loan facility in an aggregate principal amount of up to $25.0 million (the "Credit Facility"). The Company borrowed the first advance of $17.5 million ("Tranche 1") on September 25, 2020 (the "Closing Date"). Under the terms of the Credit Agreement, the second advance of $7.5 million ("Tranche 2") will be available to the Company from April 1, 2021 to September 30, 2021, subject to the Company’s satisfaction of certain conditions described in the Credit Agreement. The proceeds from the Credit Facility are expected to be used for working capital and general corporate purposes.

Tranche 1, and if borrowed Tranche 2, each bear interest at a floating rate equal to 6.25% per annum, plus the greater of (i) 1.50% or (ii) one-month LIBOR. Interest on each loan advance is due and payable monthly in arrears. Principal on each loan advance is payable in 36 equal monthly installments beginning October 1, 2022 until paid in full on October 1, 2025. Prepayments of the loans under the Credit Agreement, in whole or in part, will be subject to early termination fees in an amount equal to 3.0% of principal prepaid if prepayment occurs on or prior to the first anniversary of the Closing Date and 1.0% of principal prepaid if prepayment occurs after the first anniversary of the Closing Date and prior to the maturity date. In connection with execution of the Credit Agreement, the Company paid MidCap a $125,000 origination fee.

Upon termination of the Credit Agreement, the Company is required to pay an exit fee equal to 3.75% of the principal amount of all loans advanced to the Company under the Credit Agreement.

The Company’s obligations under the Credit Agreement are secured by a security interest in substantially all of its assets, excluding intellectual property (which is subject to a negative pledge). Additionally, the Company’s future subsidiaries, if any, may be required to become co-borrowers or guarantors under the Credit Agreement.

The Credit Agreement contains customary affirmative covenants and customary negative covenants limiting the Company’s ability and the ability of the Company’s subsidiaries, if any, to, among other things, dispose of assets, undergo a change in control, merge or consolidate, make acquisitions, incur debt, incur liens, pay dividends, repurchase stock and make investments, in each case subject to certain exceptions.

The Credit Agreement also contains customary events of default relating to, among other things, payment defaults, breaches of covenants, a material adverse change, delisting of the Company’s common stock, bankruptcy and insolvency, cross defaults with certain material indebtedness and certain material contracts, judgments, and inaccuracies of representations and warranties. Upon an event of default, the agent and the lenders may declare all or a portion of the Company’s outstanding obligations to be immediately due and payable and exercise other rights and remedies provided for under the agreement. During the existence of an event of default, interest on the obligations could be increased by 2.0%.

The above description of the Credit Agreement does not purport to be complete and is qualified in its entirety by reference to the full text of the Credit Agreement, a copy of which is filed as Exhibit 10.1 hereto and is incorporated by reference herein.

On September 25, 2020 Shanghai Bangyao Biotechnology Co., Ltd. (BIORAY LABORATORIES Inc. "BIORAY LABORATORIES Inc."), a company focused on gene therapy and cell drug research and development, reported for the first time its cooperation with the First Affiliated Hospital of Zhejiang University School of Medicine The "PD1 knockout non-viral targeted integration of CD19-CART cells for the treatment of relapsed and refractory non-Hodgkin’s lymphoma clinical trials" achieved breakthrough results (Press release, Shanghai Bioray Laboratory, SEP 25, 2020, View Source [SID1234567717]). This is the world’s first use of gene editing technology to achieve targeted integration of CART therapy at the PD1 site, and it is also the world’s first clinical trial of non-viral targeted integration of CART cells to treat lymphoma. At the same time, the latest research results were announced on the preprint platform medRxiv on September 23, 2020, jointly completed by East China Normal University, the First Affiliated Hospital of Zhejiang University School of Medicine, and Shanghai Bangyao Biotechnology.

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The CD19-CART integrated by PD1 is a CART product obtained by Bangyao Biologics using the Quikin CART platform technology of independent intellectual property rights without using viral vectors. This product combines PD1 immune checkpoint suppression and CART tumor killing functions into one, which has the effect of combined application of PD1 immunotherapy and CART therapy.

2 patients in complete remission after 3 months of treatment

The clinical research plan enrolled 15 patients. The 4 patients that have been evaluated have achieved partial remission (PR) at 1 month, and 2 patients who have reached the evaluation time of 3 months have achieved complete remission (CR). ).

The first patient who achieved complete remission was diagnosed with diffuse large B lymphoma stage IVBE in 2018. After multiple radiotherapy and chemotherapy, the condition has not been effectively controlled. Before enrollment, imaging showed that the size of the mesangial space of the left lower abdominal small intestine was 3.6*3.5cm, and the radioactive uptake was abnormally increased. In May 2020, he was enrolled in the group for PD1 knockout non-viral targeted integration of CD19-CART cells for reinfusion therapy. PET-CT imaging showed that FDG metabolism was significantly lower than before 28 days after treatment, reaching PR. PET-CT after 90 days of treatment Imaging revealed that all the lesions disappeared, and FDG metabolism did not increase, reaching CR.

During the entire CART treatment process, no adverse events above grade 3 occurred, including cytokine storm and neurotoxicity. After reinfusion, CART expanded well in the body and lasted for a long time. The d90 flow cytometry showed that the CART cells in the peripheral blood remained at a certain proportion. At present, 2 patients have recovered and been discharged and are still undergoing long-term follow-up.

Comparison of imaging examinations before and after treatment

The principal investigator (PI) of the clinical study (PI), Dean of Huanghe, the First Affiliated Hospital of Zhejiang University School of Medicine, said : "Diffuse large B-cell lymphoma is the most common type of non-Hodgkin’s lymphoma. Lack of effective treatment. This year we began to explore the clinical research of non-viral targeted integrated CART based on gene editing technology. We are very pleased to see that patients quickly achieve complete remission after treatment. We expect this new CART technology will be difficult Treating relapsed patients will bring more convenient, safe and accurate long-term treatment effects."

Bangyao Bio-CART is upgraded to version 2.0, which is more effective and safer!

Bangyao Biotech’s non-viral targeted integration CART technology (Quikin CART) can use CRISPR/Cas9 gene editing technology to insert CAR elements into specific locations in the genome without using viral vectors, achieving gene knockout in one step Stable integration with CAR is a pipeline product of Bangyao Biology 2.0 version of CART.

PD-L1/PD1 is an important immune checkpoint for inhibiting T cell function. At present, PD-L1/PD1 inhibitors have achieved good efficacy in many types of malignant tumors, and many studies have reported PD1 knockout Can effectively enhance the function of CART cells. Non-Hodgkin’s lymphoma is a hematological malignant tumor that originates in the lymphatic tissues, accounting for 80%-90% of all lymphomas. Although the disease is relieved after the initial treatment, the patient often relapses afterwards. Although CART products have been approved for the clinical treatment of relapsed and refractory non-Hodgkin’s lymphoma, the overall efficacy is still limited, and studies have suggested that inhibiting the PD1 pathway may bring better clinical results.

Therefore, Bangyao Biosciences developed non-viral PD1 targeted integration of CD19-CART cells using Quikin CART platform to carry out clinical treatment of relapsed and refractory non-Hodgkin’s lymphoma. This product has the two major advantages of uniform and stable expression of CAR and PD1 gene knockout, which is equivalent to the combination of PD1 inhibitor and CART cells. In many clinical trials that have been carried out so far, the CART product has demonstrated excellent safety and effectiveness.

The preparation of traditional CART products mainly uses viral vectors, which puts forward high requirements on the virus preparation process, which greatly increases the manufacturing cost and difficulty of CART cells, and hinders the large-scale clinical application of CART treatment; and the price is very expensive, as currently For CART products on the market, Novartis’ Kymriah is priced at US$475,000, and Kite’s Yescarta is priced at US$373,000. In addition, because the virus uses random insertion to integrate CAR elements into the cell genome, it may change the expression of normal genes. The safety hazards of cancer. Quikin CART technology does not require the use of viral vectors for cell preparation, which greatly reduces the production cost of CART products and avoids the risk of cancer by random insertion.

Quikin CART technology can simultaneously realize the regulation of T cell endogenous genes and the continuous expression of CAR in one step. Compared with other CART technology, it has the advantages of simple process, fewer production links, short preparation time, and high product uniformity. This technology platform can be used for the preparation of multiple immune checkpoint knockout enhanced CART cells, rapid production of universal CART cells, and the development of dynamically regulated safe CART products, etc., providing a strong foundation for the diversified transformation of CART cells in the future. Strong technical support.

Professor Liu Mingyao, Chief Scientist of Bangyao Biosciences , East China Normal University, said : "Compared with traditional autologous CART technology, Quikin CART technology can achieve the targeted integration of CAR elements in the genome in one step without the use of viruses. Regulation and intervention of endogenous genes in T cells. This means that the preparation process, production links, and preparation time of CART cells will be greatly simplified and shortened, thus greatly reducing the production cost of CART cells and reducing tumorigenicity caused by random insertion of viruses Risks have also improved the uniformity of CART products. The current results show that the non-viral PD1 site-specific integration of CD19-CART cells prepared by us has great therapeutic potential and has shown good safety and remission rates in clinical trials."

Dr. Zhang Jiqin, the main person in charge of the project, the first author of the paper, the R&D director of Bangyao Bio-Innovation CART, and the associate researcher of the School of Life Sciences of East China Normal University, said: "In recent years, the continuous maturity and development of CRISPR/Cas9 gene editing technology has given us birth. Applying it to the idea of ​​CART therapy. Through an in-depth analysis of the existing CART technology problems, we realized that the use of gene editing technology to prepare non-viral targeted integration of CART cells is a very promising direction. Through a large number of methods to try and After exploring the conditions, we have established a mature Quikin CART technology platform. This technology does not require the use of any virus, and can produce CART cells in one step. It has many advantages that cannot be compared with the existing CART technology. Looking forward to using this technology platform in the future We can develop more successful CART products and make greater breakthroughs in clinical treatment."

It is reported that in addition to the ongoing non-viral PD1 targeted integration of CD19-CART clinical research, Bangyao Biosciences is also deploying other non-viral targeted integration of CART products for solid tumors in order to achieve greater breakthroughs in CART therapy.

On September 25, 2020 Accord Healthcare reported that it has launched Zercepac (trastuzumab), a biosimilar of Roche’s Herceptin, in the UK after winning approval from the European Commission in July (Press release, Accord Healthcare, SEP 25, 2020, View Source [SID1234567633]).

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The biosimilar is indicated for use as a treatment of certain patients with HER2-positive early and metastatic breast cancer, as well as previously untreated HER2-positive metastatic gastric cancer.

The European Commission approval of Zercepac was based on a number of clinical studies including comparative quality studies, preclinical and clinical studies. The results confirmed the biosimilarity between the products, demonstrating comparable efficacy and safety to Herceptin.

"We are proud to launch Zercepac in the UK and offer healthcare professionals an additional option of this vital oncology medicine," said Anup Sidhu, speciality brands director at Accord.

"This is the launch of our first monoclonal antibody, reinforcing our commitment to ensuring improved patient access whilst also helping to alleviate some of the pressures on overstretched health systems," he added.

Zercepac is the fourth biosimilar to be launched in Europe by Accord, among a 30-strong portfolio of oncology treatments.

On September 25, 2020 M2GEN reported that it has entered into an agreement with Discovery Life Sciences, a global leader in biospecimen solutions, genomic, cell, and immunohistochemistry (IHC) services, to provide M2GEN’s recently launched oncology-focused bioinformatics support services (Press release, M2Gen, SEP 25, 2020, View Source [SID1234567625]).

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Under the agreement, M2GEN will provide pipeline analyses for paired tumor/normal and tumor-only somatic mutation identification from Whole Exome Sequencing (WES), and gene expression and fusion detection from tumor RNA Sequencing (RNA-Seq).

M2GEN’s bioinformatics analysis pipelines leverage results and interpretation gained from its cancer knowledge base including, ORIEN AVATAR, a comprehensive ever-expanding clinico-genomic database. M2GEN’s Bioinfomatics Support Services key differentiators include applying one of the largest Panel of Normals (PoN) available for high-quality somatic mutation calling. Over 20,000 germline samples from cancer patients with a wide range of oncology diagnoses inform the segregation of somatic and germline variants, and identify recurrent sequencing artifacts. In addition, germline data from ORIEN AVATAR patients are leveraged as a Virtual Normal (VN) cohort during tumor-only analysis, allowing for superior somatic mutation classification when patients’ matched normal biospecimens are unavailable.

Over the last four years, M2GEN and Discovery Life Sciences have collaborated to establish a standardized workflow combining preanalytical and sequencing solutions to analyze precious clinical liquid and solid biospecimens. Discovery Life Sciences has sequenced tens of thousands samples from oncology patients using its harmonized Whole Exome and RNA-Seq platforms. This effort significantly contributed to building M2GEN’s ORIEN AVATAR database which has recently been launched to the global pharma, biopharma and molecular and companion diagnostic industry to enhance oncology research, improve protocol design for and support patient identification and enrollment to clinical trials, thus, accelerating the discovery and development of new diagnostics, medicines and targeted therapies for cancer patients.

"M2GEN’s best in class bioinformatics services, combined with the ability to annotate data against M2GEN’s longitudinal clinical and molecular databases, perfectly complement the suite of genomic sequencing services offered by HudsonAlpha Discovery ," said Shawn Levy, PhD, Chief Scientific Officer at HudsonAlpha Discovery.

"We are excited to expand our long-standing successful collaboration with Discovery Life Sciences by providing our oncology focused bioinformatics services and solutions to Discovery," said Oliver Hampton PhD, Vice President of Bioinformatics & Biostatistics at M2GEN. "This agreement demonstrates the power of our multi-disciplinary expertise to access, curate, harmonize and interpret complex clinical and molecular data sets and to leverage our high-depth database for the benefit of interpreting and adding value to information generated by third parties", adds Helge Bastian, PhD, M2GEN’s President & CEO.

On September 25, 2020 Rakuten Medical Inc. reported that its wholly owned subsidiary Rakuten Medical Japan K.K. has received marketing approval in Japan from the Ministry of Health, Labour and Welfare for Akalux IV Infusion 250mg (cetuximab saratolacan sodium) to treat unresectable locally advanced or recurrent head and neck cancer. BioBlade Laser System, the medical device used in the combination with Akalux, was also approved on September 2nd. This combination was developed under the Rakuten Medical Illuminox platform. Akalux received Sakigake Designation in April 2019, and application for approval under the Conditional Early Approval System was made in March 2020. Outside of Japan, Rakuten Medical does not have approval of its investigational therapies and is currently running a global Phase 3 trial.

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Hiroshi Mikitani, Representative Director and Chairman of Rakuten Medical Japan K.K. commented, "In my search for a treatment for my father who was diagnosed with cancer, I encountered a treatment developed by a Japanese researcher. Now, we are moving forth to deliver this treatment to patients fighting with cancer, as soon as possible. Today, we are deeply moved to receive approval in Japan ahead of the world. However, this is just the beginning of Rakuten Medical’s mission. We are dedicated to contribute to cancer treatment and improving the quality of life of as many patients as possible around the world. By bringing everyone together, we will continue to aspire to achieve our corporate mission ‘to conquer cancer.’" (Press release, Rakuten Medical, SEP 25, 2020, View Source [SID1234567624])