On September 27, 2020 InventisBio, a clinical stage biotech company dedicated to the research and development of innovative small molecule drugs, reported the recent completion of a $147 million series D financing which has attracted participation of many top biopharmaceutical and healthcare venture capital funds (Press release, InventisBio, SEP 27, 2020, View Source [SID1234567637]). This round of investment was led by Hillhouse affiliate GL Ventures, followed by Qiming Venture Partners, Janchor, AIHC Capital, Matrix Partner China, Dyee Capital, E Fund Capital and other investors. The existing shareholders including Lilly Asia Venture, OrbiMed Asia, Pudong Innotek, AdvanTech Capital, and CMB International continued their support. China Renaissance was the exclusive financial advisor of this transaction.

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Currently InventisBio has three drug products in the mid- to late-stage clinical development, and one new product just entered global phase I clinical study. Among them, D-0502 is an oral selective estrogen receptor degrader (SERD), which also acts as an estrogen receptor antagonist, with therapeutic potential for the treatment of hormone receptor positive breast cancer. Compared with other oral SERDs under clinical development worldwide, D-0502 has shown promising anti-tumor activity during phase 1 study with excellent bioavailability and tolerable safety profile. In addition, the company has independently developed a third-generation EGFR-T790M tyrosine kinase inhibitor BPI-D0316 and out-licensed China right to Betta Pharma. This product is currently in registration trials of first- and second-line treatment of EGFR-mutated non-small cell lung cancer patients and the trials are progressing smoothly.

Dr. Yaolin Wang, Chairman and CEO of InventisBio, said: "InventisBio is committed to developing first- and best-in-class innovative drugs for cancer and other major diseases. We are grateful and honored to have Hillhouse’s GL Ventures led this series D round and thankful to other top investment funds, as well as the continued support from the existing investors. This investment demonstrated the recognition of our strong pipeline and fully integrated innovative R&D platform by top healthcare investors. It also shows our strategic investors’ confidence in the future success of our company as a key player in the global pharmaceutical market."

Funds raised in this round will be mainly used to support the company’s current products into phase II clinical studies in China and the United States, including D-0502 trials in hormone receptor positive breast cancer and D-0120 trials in gout. This round will also support the company’s global clinical development of other new drugs, enable further expansion of the company’s product pipeline and team.

Michael Yi, co-chief investment officer of Hillhouse Capital and head of biomedicine and medical devices of Hillhouse’s GL Ventures, said: "As a small molecule innovative drug research and development company, InventisBio has an in-depth knowledge of small molecules’ structure activity relationship and integrated understanding and experience in the efficient and successful development of novel molecules. The founding members have more than 20 years of experience in drug discovery and development, thorough understanding of drug’s mechanism of action and selection of lead candidate for development. Since its establishment, InventisBio has balanced innovation and druggability, and has effectively developed multiple assets for diseases with unmet clinical needs. With four drug candidates in various clinical stages and two clinical registration trials ongoing, InventisBio has established its pipeline in two major therapeutic areas of oncology and metabolic diseases. In addition, the company has maintained a leading position in the drug development of similar products in China. We look forward to developing deep collaboration with InventisBio, advancing its drug discovery and clinical development to bring innovative drugs to the market faster to benefit more patients."

On September 27, 2020 Radius Health, Inc. ("Radius" or the "Company") (Nasdaq: RDUS ) and Menarini Group reported an update on Elacestrant Phase 3 EMERALD Study known (Press release, Radius, SEP 27, 2020, View Source [SID1234567636]).

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The target enrollment milestone has been reached in the Phase 3 EMERALD clinical trial of elacestrant. Elacestrant is an oral Selective Estrogen Receptor Degrader (SERD) that is being studied in postmenopausal women and men with ER+/HER2- advanced or metastatic breast cancer. The study reached its enrollment goal of 466 patients overall, including 220 (47%) with tumors harboring an ESR1 mutation as detected in circulating tumor DNA by the Guardant Health Guardant360 liquid biopsy test.

Patients will be followed until the required number of events to assess progression-free survival – the primary endpoint of the study – is reached at which time the primary analysis will be performed. It is anticipated that this analysis will take place in the second half of 2021.

An independent data monitoring committee (IDMC) has been continuously monitoring the safety and efficacy of patients enrolled in the EMERALD trial. After enrollment of 70% of planned patients, the committee formally reviewed results of a futility analysis. In completing their review, the IDMC recommended that the trial continues to advance in an unmodified manner.

"We are thrilled about the continued progress for the program. Elacestrant continues to be the most advanced oral SERD in Phase 3 development and given that, we aim on being first to deliver Phase 3 data in the class, and upon clinical success, a regulatory submission," said Elcin Barker Ergun, Chief Executive Officer of the Menarini Group.

Commenting further, Barker Ergun added that "the Menarini/Radius partnership has been a tremendous success to date and the completion of patient enrollment in the EMERALD trial brings us one step closer to bringing an oral SERD to women and men with advanced breast cancer."

Dr. Maureen Conlan, Oncology Therapeutic Area Head for Radius, commented "Completing the enrollment of the EMERALD trial, despite the challenges of the COVID-19 pandemic, has been a great achievement. I am grateful to our team as well as the study investigators and patients for their efforts to date in supporting and participating in this trial."

In summarizing on recent progress, Dr. Charles Morris, Chief Medical Officer for Radius added "This is an exciting milestone for Radius and our partner, the Menarini Group, with regard to the elacestrant program. We look forward to seeing additional advancement of the program including activities related to various life cycle management opportunities for the compound."

On September 25, 2020 Nirogy Therapeutics Inc. reported that it was awarded a $2M NIH/NCI SBIR grant to develop dual monocarboxylate transport inhibitors (dMCTi) for Triple Negative Breast Cancer (TNBC) (Press release, Nirogy Therapeutics, SEP 25, 2020, View Source [SID1234576776]).

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"We are delighted to receive this highly competitive award from NIH/NCI under small business innovation research grant program. We are appreciative of the continued support from NCI for our breast cancer program. I believe that this award attests the validity of our science strategy to target the untapped class of solute carrier transporters (SLCT) family of proteins for cancer, and the progress we have made so far in this breast cancer program. This fund allows us to rapidly move through the initial stages of commercialization activities and execute part of the IND enabling studies for the pre-clinical development candidate compound" stated Dr. Vincent Sandanayaka, Founder, President & CEO of Nirogy Therapeutics.

Worldwide, approximately 1 million women are diagnosed with breast cancer each year. TNBC is the deadliest sub-type of breast cancer, accounting for ~15% of the breast cancer diagnoses and ~25% of breast cancer-related deaths. Median survival for 30% of the patients with TNBC is just one year. TNBC has poor clinical outcomes due to its high metastatic rate, resistance to chemotherapy, and lack of effective treatment options. The lactate-rich tumor microenvironment (TME) of TNBC has been shown to be highly immunosuppressive, promoting tumor growth and progression. Lactate metabolite produced from glucose metabolism via glycolysis is increasingly recognized as a strong immune suppressor in many tumors.

Cancer cells transport lactate across the cell membrane to the extracellular matrix via monocarboxylate transporters, MCT1 and MCT4. We have discovered that dMCTi block lactate excretion to the TME, thereby directly killing cancer cells and simultaneously activating local immunity in the TME. In our preliminary studies, we have shown that dMCTi are potent compounds against multiple TNBC cell lines. Also, we have shown that in both mouse xenograft models (MDA-MB-231, TNBC), and syngeneic mouse models (SM1, BRAFV600E, melanoma; and 4T1, TNBC), dMCTi exert significant anti-tumor efficacy. In 4T1 and SM1 syngeneic models, we observed a decrease in expression of multiple immunosuppressive molecules such as B7H family proteins, M2 macrophages, and MDSCs while increase in CD8+ population in treated tumors compared to the control tumors. Furthermore, the profiling of cytokines in these tumors indicated an increase in pro-inflammatory IFNγ, TNFα, IL-1β and decrease in tumor promoting TGFβ, IL-10 compared to the control tumors, confirming that the anti-tumor effect of dMCTi is in part due to the enhanced immune function.

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.