On June 26, 2022 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, autoimmune, metabolic, ophthalmology and other major diseases, and Eli Lilly and Company ("Lilly",NYSE: LLY), reported that the National Medical Products Administration (NMPA) of China has approved the supplemental New Drug Application (sNDA) for TYVYT (sintilimab injection) in combination with fluorouracil and platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma (Press release, Innovent Biologics, JUN 26, 2022, View Source [SID1234616257]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This is the sixth NMPA-approved indication of TYVYT. TYVYT is the first domestic PD-1 inhibitor approved for the first-line treatment of gastric cancer and is currently approved for the first-line treatment in five major types of cancers. In China, TYVYT was approved for the treatment of relapsed or refractory classical Hodgkin’s lymphoma in December 2018, first-line treatment of nonsquamous non-small cell lung cancer (NSCLC) in February 2021, first-line treatment of squamous NSCLC, and the first-line treatment of hepatocellular carcinoma in June 2021; and the first-line treatment of esophageal squamous cell carcinoma in June 2022.

The approval in China was based on the results of a randomized, double-blind, multicenter Phase III clinical trial (ORIENT-16, NCT03745170) evaluating sintilimab in combination with chemotherapy (oxaliplatin and capecitabine), compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma. Based on the interim analysis by Independent Data Monitoring Committee (iDMC), sintilimab in combination with chemotherapy demonstrated superior overall survival (OS), compared to placebo plus chemotherapy, with a 34.0% reduction in the risk of death (HR 0.660，95%CI 0.505-0.864，p=0.0023) and a 5.5-month improvement in median OS (mOS 18.4 months vs. 12.9 months) in patients with combined positive score (CPS) ≥5, and 23.4% reduction in the risk of death (HR 0.766, 95%CI 0.626-0.936，p=0.0090）and a 2.9-month improvement in mOS (15.2 months vs. 12.3 months) in all patients regardless of PD-L1 expression. The safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy. The results of ORIENT-16 study were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021[1].

Prof. Jianming Xu, The Fifth Medical Center of People’s Liberation Army General Hospital stated: "Gastric cancer ranks fifth for global cancer incidence and is the third leading cause of cancer mortality worldwide[2]. Nearly half of global gastric cancer incidence cases and mortality cases occur in China annually[2]. The ORIENT-16 study demonstrated that sintilimab in combination with chemotherapy significantly prolonged overall survival of patients with gastric cancer[1]. We are encouraged by the approval of sintilimab, the first domestic anti-PD-1 monoclonal antibody approved for the treatment of gastric cancer, bringing a new and effective treatment option to be provided to patients with gastric cancer in China."

Dr. Yongjun Liu, President of Innovent, stated: "We are grateful for the recognition received from the Chinese regulatory authorities for TYVYT (sintilimab injection). This is the second sNDA approval this year, following the first one of ESCC, and enabling TYVYT (sintilimab injection) to be the domestically first innovative PD-1 inhibitor for the first-line treatment of five major type of cancers. We look forward to bringing TYVYT (sintilimab injection) as a new standard first-line treatment option for patients with advanced gastric cancer, and opening a new chapter of immunotherapy for gastric cancer. Innovent will uphold our mission of ‘to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people’ and make continuous contributions to the ‘Healthy China 2030’ implementation."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "The approval of TYVYT by the NMPA for the treatment of gastric cancer represents an important step forward for Innovent to further expand market coverage and is an important milestone for product development and commercial strategy. Data from the ORIENT-16 study demonstrated significant improvement in overall survival in patients with advanced gastric cancer and safety profile was consistent with that observed in previously reported studies of sintilimab. Survival benefit and reduction in the risk of death were observed, regardless of PD-L1 expression[1]. Gastric cancer is one of the most common malignancies in China and has different disease characteristics when compared with Western population. Innovent will continue to focus on these unmet medical needs and conduct additional clinical trials to untap the potential of our innovative molecules. We hope to bring more safe and efficacious treatment options to cancer patients both in China and worldwide."

Mr. Julio Gay-Ger, President and General Manager of Lilly China, stated, "China is well-known for gastrointestinal cancers[2]. The approval of TYVYT (sintilimab injection) as first-line treatment for gastric cancer marks another milestone. So far, TYVYT has covered major cancer types including lymphoma, lung cancer, liver cancer, esophageal cancer and gastric cancer, benefiting millions of Chinese patients. With our commitment to oncology, Lilly strives for bringing high-quality and affordable innovative drugs to Chinese cancer patients through both independent R&D and local partnerships. We look forward to continually working with our partner Innovent in bringing more innovative anti-tumor drugs to Chinese patients."

Dr. Li Wang, Senior Vice President of Lilly China and Head of Lilly China Drug Development and Medical Affairs Center, stated, "The ORIENT-16 study, led by Chinese investigators, is the first randomized, double-blind Phase III clinical study in China to demonstrate the significant benefit of immunotherapy combined with chemotherapy for the first-line treatment of advanced gastric cancer[1]. It provided strong evidence for the treatment of advanced gastric cancer in China. The approval of TYVYT (sintilimab injection) as first-line treatment for gastric cancer has provided a new option and fresh perspective for existing treatment, and will further benefit more and more Chinese gastric patients"

About the ORIENT-16 Study

ORIENT-16 is a randomized, double-blind, multi-center Phase 3 clinical study evaluating sintilimab or placebo, in combination with chemotherapy (oxaliplatin and capecitabine), for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ClinicalTrials.gov, NCT03745170). The primary endpoint was overall survival, in PD-L1 positive (CPS>5) and all randomized patients[1].

As of the cutoff date for the interim analysis, a total of 650 patients were enrolled and randomly assigned with a 1:1 ratio to receive sintilimab or placebo in combination with chemotherapy until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. The study met both primary endpoints and the safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy. The results were published at the ESMO (Free ESMO Whitepaper) Congress 2021.

About Gastric Cancer

Gastric cancer is one of the most common malignant tumor types worldwide. According to GLOBOCAN estimates, there were approximately one million new cases in 2020 and 769,000 new deaths of gastric cancer each year, making it the fifth most common cancer and third leading cause of cancer death globally[2],[3]. About half of all gastric cancer cases occurred in East Asia, mainly in China[2]. The first-line treatment of advanced gastric cancer is still limited. Currently, the 5-year survival rate of advanced or metastatic gastric cancer ranges from 5 to 20 percent. The median survival was about 1 year for patients who received chemotherapy only[4],[5].

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody jointly developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells[6]. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for six indications as below, with the first four included in the National Reimbursement Drug List (NRDL), including:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy;
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of non-squamous non-small cell lung cancer lacking EGFR or ALK driver mutations;
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer;
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of unresectable or advanced hepatocellular carcinoma;
In combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil for the first-line treatment of esophageal squamous cell carcinoma;
In combination with fluorouracil and platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma.
Innovent currently has the regulatory submission for sintilimab in combination with bevacizumab biosimilar and chemotherapy for EGFR-mutated non-squamous NSCLC following EGFR-TKI treatment under review in the China’s NMPA.

Additionally, two clinical studies of sintilimab have met their primary endpoints:

Phase 2 study as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.

On June 25, 2022 Dragon Boat reported that its IND application of the innovative anti-CLDN 18.2/CD47 bi-specific antibody (bsAb) injection (R&D code: BC007) was officially accepted by National Medical Products Administration (NMPA) under the acceptance number CXSL2200267 (Press release, Dragonboat Biopharmaceutical, JUN 25, 2022, View Source [SID1234616258]). This drug is the first domestic clinical filing of the CLDN 18.2/ CD47 bsAb, which is intended for the treatment of late stage solid tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

BC007 is a innovative bsAb targeting CLDN 18.2 and CD47 and the early-stage development was completed collaboratively by Sanyou and Dragon Boat. Validation results of the in vivo efficacy showed that BC007 exhibited dose-dependent anti-tumor effects against CLDN18.2 overexpressing CDX mouse models of human gastric cancer, human pancreatic cancer and human colon cancer, and was significantly better than the selected comparator antibody. In the safety studies, hematological toxicity is one of the common challenges of CD47 targeting antibodies. But in the cynomolgus monkey toxicity study, multiple doses of BC007 was administered for 5 weeks without animal death, and the hematological toxicity was mild and well tolerated by the animals.

In March this year, the IND application of anti-CLDN 18.2 antibody injection (BC008) developed by Dragon Boat has been approved by National Medical Products Administration. In the future, Dragon Boat will bring greater clinical benefits to the patients by exploring more treatment options.

Dr. Guojun Lang, CEO of Sanyou, said "We sincerely congratulate Dragon Boat on the NMPA acceptance of IND application with the CLDN 18.2/CD47 bsAb, which is another milestone after the clinical approval of the anti-CLDN 18.2 nanoantibody co-developed by Sanyou and Dragon Boat in March. This project further proves the outstanding competency of Dragon Boat in the field of innovative biopharmaceutical research and development. This project is also another successful case of Sanyou’s Cooperative Project Organization (CPO) business model. We wish the clinical studies will proceed successfully and benefit the patients as soon as possible".

About CLDN 18.2

Tight junction protein claudin-18 isoform 2 (CLDN18.2) is a member of the claudin family, which includes tight junction proteins that establish paracellular barriers to control the molecular passage and motions among cells. Normally, CLDN 18.2 is expressed only on the surface of differentiated epithelial cells of the gastric mucosa. However, after the development of malignant tumors, tight junction proteins are disrupted, exposing the CLDN 18.2 epitope on the surface of tumor cells. Studies have shown high CLDN 18.2 expression in the tumor cells of 50%-80% of gastric cancer patients and 60% of pancreatic cancer patients.

About CD47

CD47 is a glycosylated transmembrane protein, a key member of the immunosuppressive signaling pathway, which inhibits macrophage phagocytosis and mediates the immune escape mechanism of various malignant tumors, mainly by interacting with the inhibitory receptor signal-regulatory protein alpha (SIRPα), which is widely recognized as a "don’t eat me" signal. Numerous studies have shown that CD47 is overexpressed in different types of tumors, including myeloma, smooth muscle sarcoma, acute lymphoblastic leukemia, and non-Hodgkin’s lymphoma.

On June 24, 2022 (the "Closing Date"), G1 Therapeutics, Inc. (the "Company"), as borrower, and Hercules Capital, Inc. and certain of its affiliates (collectively, the "Lender") reported that entered into a third amendment (the "Third Amendment") to amend that certain loan and security agreement, dated as of May 29, 2020, as amended by the First Amendment to Loan and Security Agreement, dated as of March 31, 2021 (the "First Amendment") and the Second Amendment to Loan and Security Agreement, dated as of November 1, 2021 (the "Second Amendment"); the loan and security agreement, as amended by the First Amendment, the Second Amendment and the Third Amendment, the "Loan and Security Agreement"), under which the Lender has agreed to lend the Company up to $150.0 million, to be made available in a series of tranches, subject to specified conditions (Filing, 8-K, G1 Therapeutics, JUN 24, 2022, View Source [SID1234616242]). The total loan amount outstanding is $75.0 million. The Third Amendment extends the time for drawing the Tranche 1D Advance (as defined in the Loan and Security Agreement) of up to $25.0 million from September 15, 2022 to December 31, 2022.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Third Amendment adds a minimum cash covenant whereby the Company must maintain unrestricted cash equal to at least 50% of the outstanding debt, and such percentage shall decrease upon the Company achieving specified net product revenue of COSELA. The Third Amendment further provides for a minimum revenue covenant that, beginning August 15, 2022, with the reporting of the financial results for the second fiscal quarter ended June 30, 2022, and tested monthly, the Company must have achieved net product revenue of COSELA of at least 80% of the amounts projected in the Company’s forecast. Testing of the minimum revenue covenant shall be waived at any time in which either (a) the Company’s market capitalization exceeds $750.0 million and the Company maintains unrestricted cash equal to at least 50% of the total amounts funded, or (b) the Company maintains unrestricted cash equal to at least 100% of the total amounts funded.

The foregoing description is only a summary of certain provisions of the Third Amendment and is qualified in its entirety by reference to the Third Amendment, a copy of which will be filed as an exhibit to the Company’s Quarterly Report on Form 10-Q for the quarter ending June 30, 2022 and will be incorporated by reference herein.

On June 24, 2022 Chimeric Therapeutics Ltd (ASX:CHM) reported the first ever trial studying NK cells in combination with IL-2 and Vactosertib, using Chimeric’s CORE NK platform cells (Press release, Chimeric Therapeutics, JUN 24, 2022, View Source [SID1234616225]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Phase 1B investigator-initiated trial has been approved by the US Food and Drug Administration (FDA) and will enrol 12 patients at UH Seidman Cancer Center in Ohio, with either locally advanced or metastatic colorectal cancer or relapsed/refractory blood cancers.

Chimeric’s CORE NK platform is a novel NK cell therapy platform of ex-vivo expanded non-HLA*-matched universal donor NK cells.

Safety and early efficacy demonstrated
The CORE NK platform was studied in a Phase 1A clinical trial demonstrating safety and an early efficacy signal in patients with metastatic colorectal cancer and refractory haematological malignancies.

The new study seeks to build upon responses observed during the initial CORE NK clinical trial, by co-administering the CORE NK cells with subcutaneous IL-2 and oral Vactosertib.

Study looks at combination
IL-2 is known to activate NK cells by stimulating proliferation and enhancing function.

Vactosertib is an oral TGF-β receptor inhibitor that can potentially disrupt the TGF-β signalling pathway, which has been shown to limit the effectiveness of immune therapies like NK cells.

"Vactosertib has never been used in combination with NK cells in the clinic, but it has been used in humans in other clinical trials," said UH Seidman oncologist Dr J Eva Selfridge, assistant professor at Case Western Reserve University School of Medicine in Ohio, who will lead the upcoming trial.

NK cells can "actually make it into the tumours"
"The goal of using it in this trial is to disrupt the TGF-β signaling pathway that is so strong in colorectal cancer and cells. We want to shut down that TGF-β signaling pathway so that the NK cells can actually make it into the tumours. Once they’re there, they have a chance of being active instead of just being silenced right away."

Dr. Selfridge says she is hopeful this new clinical trial at UH Seidman Cancer Center will present patients with more and better options for treatment and care: "T cell-directed immunotherapy is only available for 5% or less of cancer patients, but immunotherapy is really the only way we have to cure people with metastatic disease," she said.

"We’re just beginning our study, but ultimately the goal is to find immune therapies that work long-term."

Busy clinical pipeline
The study adds to CHM’s busy clinical pipeline, with now four clinical trials in progress or planned within 9 months.

"With the initial positive results seen in the Phase 1A clinical trial with our CORE NK Platform cells, we have been eager to accelerate the development opportunities for it," said Chimeric CEO Jennifer Chow.

"This study looks to combine novel therapeutics to overcome the challenges that are commonly thought to limit disease responses to NK cells.

"We hope that this combination will allow us to see more complete responses in patients with difficult to treat diseases, like the one seen in the Phase 1A study that has resulted in complete tumour eradication for more than 15 months now."

On June 24, 2022 Green3Bio, a subsidiary of Greenfire Bio, reported a publication in the Journal of Clinical Investigation1 led by researchers at The University of Texas MD Anderson Cancer Center demonstrating that SIK2 inhibitors, including GRN-300 sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors (Press release, Greenfire, JUN 24, 2022, View Source [SID1234616243]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Zhen Lu, M.D., and Robert Bast, M.D., and colleagues demonstrated that a combination of PARPi and SIKi provides a novel therapeutic approach to enhance PARPi sensitivity in ovarian cancers that initially respond to PARPi and eventually develop drug resistance.

The major findings from the preclinical research study include:

GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity
The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300
GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis
Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC.
These findings provide strong preclinical evidence supporting future clinical trials to determine whether the combination will benefit patients with ovarian and triple negative breast cancers. Animal studies, particularly those with olaparib and GRN-300, did not show significant toxicity based on weight loss. Pre-clinical toxicology studies in rodents and dogs showed no hematologic toxicity, which is particularly important for combination with PARPi.

"Patients with ovarian and triple-negative breast cancers are in great need for more effective treatments due to the high prevalence of acquired resistance to standard therapies that involve PARP inhibition," said Steve Morris, MD (Chairperson, Scientific Advisory Board of Greenfire Bio). He added, "The GRN-300 preclinical data published in The Journal of Clinical Investigation shows the potential of GRN-300 and its unique mechanism of action through SIK2/3 inhibition to help change the combination treatment paradigm in gynecologic and breast cancers, irrespective of BRCA mutation status."

Ajit Gill, CEO and founder of Greenfire Bio, commented that "This publication provides further support for the development of our clinical asset GRN-300. We believe this agent has the potential to improve treatment of ovarian and other cancers – both as a single agent and in combination with existing therapies such as the PARP inhibitor olaparib that is indicated for the treatment of ovarian and breast cancers under the tradename Lynparza."

These data further support the preclinical proof-of-concept for SIK2 inhibitors as potential cancer therapeutics in combination with carboplatin for hard-to-treat ovarian cancer, recently published in Cancers, and they support the continued efforts in our first-in-human clinical trial ongoing at MD Anderson.

About Ovarian Cancer

According to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women. They estimate that in 2022 there will be about 19,880 new cases of ovarian cancer diagnosed in the United States and that about 12,810 will die of the disease. According to the World Cancer Research Fund International, there were about 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early, more treatable stage; therefore, the current lack of salvage treatment for women, who experience a recurrence, results in a 5-year survival rate of less than 30%.

About GRN-300

GRN-300 (previously ARN3261) is an orally bioavailable first-in-class novel, small molecule, dual inhibitor of the salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance based on its mechanism of action (MOA) and synergistic effects with standard of care including paclitaxel, carboplatin, PARP inhibitors, and immune checkpoint inhibitors (ICIs). SIK2 is overexpressed in 30% of ovarian cancer specimens suggesting a multifunctional role of SIK2/3 in tumorigenesis. SIK2 and SIK3 are known to play [an] oncogenic role in other tumor types, including prostate cancer, breast cancer, diffuse large B-cell lymphoma, and melanoma. Higher levels of expression of SIK2 have been shown to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth & inhibition in several preclinical xenograft ovarian cancer models as a single agent and in combination with paclitaxel. The clinical activity of GRN-300 as a single agent and in combination with paclitaxel is currently being evaluated in a Phase 1a/1b Clinical Study in subjects with Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers (ClinicalTrials.gov Identifier: NCT04711161).