A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial to Evaluate the Tolerability, Safety, Pharmacokinetic Profiles, and Immunogenicity of JS026 and JS026 in Together With JS016 Administered Intravenously to Healthy Chinese Subjects

This is a first-in-human (FIH), randomized, double-blind, placebo-controlled, single-center phase I clinical trial of JS026 and JS026 + JS016 Injection. The objective of the study is to evaluate the safety, tolerability, PK profile and immunogenicity of a single intravenous infusion of JS026 and JS026 + JS016 Injection in healthy subjects.
In this study, the single ascending dose design will be adopted, JS026 will be administered sequentially from low dose group to high dose group, and each subject can only receive an intravenous infusion at one dose level. Five dose groups (30 mg, 100 mg, 300 mg, 600 mg, and 1000 mg) will be set to receive an intravenous infusion of JS026, and two dose groups (300 mg JS026 + 1200 mg JS016, and 600 mg JS026+ 1200 mg JS016) will be set for JS026 + JS016. The investigational product and placebo will be distributed in each dose group in a ratio of 3:1. Four subjects will be enrolled in each of JS026 30 mg and 100 mg groups, and 8 subjects will be enrolled in each of other dose groups, totally 48 subjects.

Start Date16 Dec 2021

Sponsor / Collaborator

Shanghai Junshi Biosciences Co., Ltd.

NCT05205759 / TerminatedPhase 3IIT

Adaptive, Randomized, Non-inferiority Trial to Evaluate the Efficacy of Monoclonal Antibodies in Outpatients With Mild or Moderate COVID-19

Currently, 3 anti-SARS-CoV-2 monoclonal antibody products have received Emergency Use Authorizations from the Italian Medicines Agency (AIFA) for the treatment of mild to moderate COVID-19 in non hospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization (bamlanivimab plus etesevimab, sotrovimab, and casirivimab plus imdevimab). Differently from casirivimab/imdevimab and sotrovimab, the European Medicines Agency (EMA) has never recommended authorising the combination bamlanivimab/etesevimab for treating COVID-19. Moreover, the evidence on sotrovimab relies on the interim analysis results of an ongoing randomised placebo-controlled clinical trial [1], unlike the combinations bamlanivimab/etesevimab and casirivimab/imdevimab, whose results of the randomised placebo-controlled trials were published after having completed the enrolment [2,3]. The study aims at assessing the non-inferiority of bamlanivimab plus etesevimab and sotrovimab vs. casirivimab plus imdevimab on COVID-19 progression in patients aged at least 50 years at an early stage of the disease. The progression of COVID-19 disease (hospitalization, need for supplementary oxygen therapy at home, death) within 14 days of randomisation is the composite outcome variable on which the calculation of the sample size is based. Based on available data regarding the reduction in the number of hospitalisations and medical visits with the use of casirivimab plus imdevimab at an early-stage of COVID-19, a disease progression of 5% has been estimated in the reference arm. 5% delta margin was considered clinically relevant, taking into account both the estimates of disease progression in the study population in absence of early treatment with monoclonal antibodies (20%, based on national data) and the efficacy of the reference standard. Therefore, 1260 participants will be randomly assigned in an equal ratio between the reference standard and each of the other two experimental arms (1:1:1). Randomization will be computer-generated in permuted blocks with a stratification based on site.

Start Date09 Dec 2021

Sponsor / Collaborator

Azienda Ospedaliera Universitaria Integrata Verona

[+2]

NCT04790786 / TerminatedPhase 4IIT

The UPMC OPtimizing Treatment and Impact of Monocolonal antIbodieS Through Evaluation for COVID-19 Trial

Multiple monoclonal antibodies (mABs) have been shown to reduce viral burden and improve clinical outcomes, have been granted FDA Emergency Use Authorization (EUA) for use in select populations, and are routinely used in the UPMC Health System, which has made expanded access a priority. However, the comparative effectiveness of these mABS is unknown. The National Academies of Sciences, Engineering, and Medicine has called for expanded access and clinical use of mABs, noting it is "critical to collect data and evaluate whether they are working as predicted". This pragmatic evaluation will determine the relative effects of the EUA-governed mABs versus each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mABs will accordingly change.

Start Date10 Mar 2021

Sponsor / Collaborator

University of Pittsburgh Medical Center

[+1]

100 Clinical Results associated with Etesevimab

100 Translational Medicine associated with Etesevimab

100 Patents (Medical) associated with Etesevimab

162

Literatures (Medical) associated with Etesevimab

01 Dec 2023·Computers in biology and medicine

Impact of BA.1, BA.2, and BA.4/BA.5 Omicron mutations on therapeutic monoclonal antibodies

Article

Author: Podgornik, Rudolf ; Ching, Wai-Yim ; Adhikari, Puja ; Jawad, Bahaa

The emergence of Omicron SARS-CoV-2 subvariants (BA.1, BA.2, BA.4, and BA.5), with an unprecedented number of mutations in their receptor-binding domain (RBD) of the spike-protein, has fueled a resurgence of COVID-19 infections, posing a major challenge to the efficacy of existing vaccines and monoclonal antibody (mAb) therapeutics. We conducted a systematic molecular dynamics (MD) simulation to investigate how the RBD mutations of these subvariants affect the interactions with broad mAbs including AstraZeneca (COV2-2196 and COV2-2130), Brii Biosciences (BRII-196), Celltrion (CT-P59), Eli Lilly (LY-CoV555 and LY-CoV016), Regeneron (REGN10933 and REGN10987), Vir Biotechnology (S309), and S2X259. Our results show a complete loss of binding for COV2-2196, BRII-196, CT-P59, and LY-CoV555 with all Omicron RBDs. Additionally, REGN10987 totally loses its binding with BA.1, but retains a partial binding with BA.2 and BA.4/5. The binding reduction is significant for LY-CoV016 and REGN10933 but moderate for COV2-2130. S309 and S2X259 retain their binding with BA.1 but exhibit decreased binding with other subvariants. We introduce a mutational escape map for each mAb to identify the key RBD sites and the corresponding critical mutations. Overall, our findings suggest that the majority of therapeutic mAbs have diminished or missing activity against Omicron subvariants, indicating the urgent need for a new therapeutic mAb with a better design.

01 Dec 2023·Journal, genetic engineering & biotechnology

Insights on the interaction of SARS-CoV-2 variant B.1.617.2 with antibody CR3022 and analysis of antibody resistance

Article

Author: Ks, Sandhya ; Nair, Achuthsankar S

Background:

The existence of mutated Delta (B.1.617.2) variants of SARS-CoV-2 causes rapid transmissibility, increase in virulence, and decrease in the effectiveness of public health. Majority of mutations are seen in the surface spike, and they are considered as antigenicity and immunogenicity of the virus. Hence, finding suitable cross antibody or natural antibody and understanding its biomolecular recognition for neutralizing surface spike are crucial for developing many clinically approved COVID-19 vaccines. Here, we aim to design SARS-CoV-2 variant and hence, to understand its mechanism, binding affinity and neutralization potential with several antibodies.

Results:

In this study, we modelled six feasible spike protein (S1) configurations for Delta SARS-CoV-2 (B.1.617.2) and identified the best structure to interact with human antibodies. Initially, the impact of mutations at the receptor-binding domain (RBD) of B.1.617.2 was tested, and it is found that all mutations increase the stability of proteins (ΔΔG) and decrease the entropies. An exceptional case is noted for the mutation of G614D variant for which the vibration entropy change is found to be within the range of 0.133–0.004 kcal/mol/K. Temperature-dependent free energy change values (ΔG) for wild type is found to be − 0.1 kcal/mol, whereas all other cases exhibit values within the range of − 5.1 to − 5.5 kcal/mol. Mutation on spike increases the interaction with the glycoprotein antibody CR3022 and the binding affinity (CLUSpro energy = − 99.7 kcal/mol). The docked Delta variant with the following antibodies, etesevimab, bebtelovimab, BD-368–2, imdevimab, bamlanivimab, and casirivimab, exhibit a substantially decreased docking score (− 61.7 to − 112.0 kcal/mol) and the disappearance of several hydrogen bond interactions.

Conclusion:

Characterization of antibody resistance for Delta variant with respect to the wild type gives understanding regarding why Delta variant endures the resistance boosted through several trademark vaccines. Several interactions with CR3022 have appeared compared to Wild for Delta variant, and hence, it is suggested that modification on the CR3022 antibody could further improve for the prevention of viral spread. Antibody resistance decreased significantly due to numerous hydrogen bond interactions which clearly indicate that these marketed/launched vaccines (etesevimab) will be effective for Delta variants.

Graphical Abstract:

01 Nov 2023·Journal of virological methods

Low BAU/ml values with 4 of 5 SARS CoV-2 spike-specific monoclonal antibodies in the Roche Elecsys antibody assay

Article

Author: Biemann, Ronald ; Hönemann, Mario ; Jassoy, Christian

BACKGROUND:

The Abbott SARS-CoV-2 IgG Quant II assay and the Roche Elecsys double antigen sandwich (DAgS) immunoassay measure SARS-CoV-2 receptor binding domain (RBD)-specific antibodies in serum samples in different ways. The IgG Quant II assay uses an antigen in combination with a secondary antibody and the DAgS assay uses two antigens. The aim of the study was to investigate whether the assays give comparable results with monoclonal antibodies.

MATERIAL AND METHODS:

The immunoassays were tested with the RBD-specific human monoclonal antibodies (mAbs) casirivimab. imdevimab, CR3022, etesevimab and sotrovimab. The mAbs were tested at various concentrations in µg/ml, alone or in combination and the relative light units (RLU) and binding antibody units (BAU)/ml were determined.

RESULTS:

With 1 µg/ml of casirivimab, imdevimab, CR3022 and etesevimab the Abbott IgG II Quant assay yielded between 65 and 158 BAU/ml and the Elecsys assay < 0.4 - 7.1 BAU/ml. In the DAgS assay, the addition of a second and a third mAb increased the BAU/ml values synergistically. With increasing concentrations of the mAb combinations in µg/ml the Abbott IgG Quant II assay showed proportionate and the Elecsys DAgS assay disproportionate increases in BAU/ml. With 1 µg/ml sotrovimab the Abbott assay gave 39 and the Elecsys assay 136 BAU/ml. The DAgS assay showed a high dose hook effect in the µg/ml range.

CONCLUSIONS:

The secondary antibody-based and the DAgS-based SARS CoV-2 antibody assays gave very different results with 4 of 5 mAbs. This suggests that the two assays measure different binding characteristics. The ability of antibodies to cross-link multiple antigen-antibody complexes may contribute to the measurement signal in the DAgS assay.

139

News (Medical) associated with Etesevimab

25 Jun 2024

·www.biospace.com

Junshi Biosciences Announces Approval of the sNDA for Toripalimab for the 1st-Line Treatment of Advanced TNBC

SHANGHAI, June 25, 2024 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (Junshi Biosciences, HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies, announced that the National Medical Products Administration (NMPA) has approved the supplemental new drug application (sNDA) for toripalimab (product code: JS001) in combination with paclitaxel for injection (albumin-bound) for the first-line treatment of recurrent or metastatic triple-negative breast cancer (TNBC). According to the GLOBOCAN 2020 statistics, breast cancer became the most common cancer in the world, with 2.31 million new cases and 0.67 million deaths. In China, there were 0.36 million new cases and 0.07 million deaths due to breast cancer, accounting for 15.5% and 11.2% of global cases. Amongst these, TNBC accounts for about 10% to 15% of all breast cancer cases, making TNBC a more aggressive type of cancer with a higher risk of recurrence and poor prognosis. Advanced TNBC is not responsive to targeted or endocrine therapies and lacks specific treatment methods. Chemotherapy remains the standard treatment for advanced TNBC in China, but both mono-chemotherapy and combined chemotherapy have poor efficacy, with a median survival time of about 9 to 12 months and a 5-year survival rate of less than 30%. The supplemental NDA approval is based on the TORCHLIGHT study (NCT04085276), a randomized, double-blind, placebo-controlled, multi-center Phase III clinical study jointly conducted in 56 centers across the country. Professor Zefei JIANG, Vice President and Secretary General of the Chinese Society of Clinical Oncology (CSCO) and from the Department of Oncology of the Chinese People’s Liberation Army General Hospital, served as the principal investigator. In February 2023, the Independent Data Monitoring Committee (IDMC) determined in an interim analysis that the primary endpoint of the TORCHLIGHT study had met the pre-defined efficacy boundary. TORCHLIGHT is the first registered domestic Phase III study to achieve positive results in the field of advanced TNBC immunotherapy. In January 2024, Nature Medicine (Impact Factor: 58.7) published the interim results of the TORCHLIGHT study. The findings showed that, compared with paclitaxel alone, toripalimab in combination with paclitaxel in patients with an initial diagnosis of stage IV or recurrent metastatic TNBC can significantly prolong the progression-free survival (PFS) of PD-L1-positive patients. The overall survival (OS) also showed a positive trend, achieving a breakthrough in immunotherapy for advanced TNBC in China. The median PFS in the toripalimab group was 8.4 months, and the risk of disease progression or death was reduced by 35% (P=0.0102). The median OS in the toripalimab group was extended by 13.3 months (32.8 months vs 19.5 months), and the risk of death was reduced by 38% (P=0.0148). The safety pro toripalimab remained consistent with the established safety profile, with no new safety signals identified. “Immunotherapy has become the most important treatment for TNBC,” said Principal investigator Professor Zefei JIANG from the Department of Oncology of the Chinese People’s Liberation Army General Hospital. “The TORCHLIGHT study introduces immune checkpoint inhibitors in addition to traditional chemotherapy, which not only significantly prolongs the mPFS for patients with advanced TNBC, but also demonstrates notable benefits to overall survival, increasing the total survival time for TNBC patients to more than 30 months. As the very first approved immunotherapy for TNBC in China, toripalimab will set a new standard for the first-line treatment of TNBC.” “For a long time, effective treatments for advanced TNBC have been lacking,” said Dr. Jianjun ZOU, General Manager and CEO of Junshi Biosciences. “The approval of this new indication is another milestone success, and it offers new hope to Chinese patients with advanced TNBC. As of now, toripalimab has 10 approved indications in China. Moving forward, we will remain dedicated to patient care, collaborate with Chinese experts and scholars, and address the long-standing unmet clinical needs of many more patients.” About Toripalimab Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promotes the immune system’s ability to attack and kill tumor cells. More than forty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally by Junshi Biosciences, including in China, the United States, Southeast Asia, and Europe. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types, including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin. In the Chinese mainland, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI®). Currently, there are ten approved indications for toripalimab in the Chinese mainland: unresectable or metastatic melanoma after failure of standard systemic therapy; recurrent or metastatic nasopharyngeal carcinoma (NPC) after failure of at least two lines of prior systemic therapy; locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy; in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC; in combination with paclitaxel and cisplatin in first-line treatment of patients with unresectable locally advanced/recurrent or distant metastatic esophageal squamous cell carcinoma (ESCC); in combination with pemetrexed and platinum as the first-line treatment in EGFR mutation-negative and ALK mutation-negative, unresectable, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC); in combination with chemotherapy as perioperative treatment and subsequently with monotherapy as adjuvant therapy for the treatment of adult patients with resectable stage IIIA-IIIB NSCLC; in combination with axitinib for the first-line treatment of patients with medium to high risk unresectable or metastatic renal cell carcinoma (RCC); in combination with etoposide plus platinum for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC); in combination with paclitaxel for injection (albumin-bound) for the first-line treatment of recurrent or metastatic triple-negative breast cancer (TNBC). The first six indications have been included in the National Reimbursement Drug List (NRDL) (2023 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for the treatment of melanoma. In April 2024, the Drug Office at the Department of Health in the Government of the Hong Kong Special Administration Region (DO) accepted the NDA for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy. In the United States, the US FDA has approved the Biologics License Application for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy in October 2023. The FDA has granted toripalimab 2 Breakthrough Therapy designations for the treatment of NPC, 1 Fast Track designation for the treatment of mucosal melanoma, and 5 Orphan Drug designations for the treatment of esophageal cancer, NPC, mucosal melanoma, soft tissue sarcoma, and small cell lung cancer (SCLC). In Europe, marketing authorization applications (MAA) were accepted by the European Medicines Agency (EMA) and the MHRA for 1) toripalimab combined with cisplatin and gemcitabine for the first-line treatment of patients with locally recurrent or metastatic NPC and 2) toripalimab combined with paclitaxel and cisplatin for the first-line treatment of patients with unresectable locally advanced/recurrent or metastatic ESCC, in December 2022 and February 2023. In Australia, the new chemical entity (NCE) application was accepted by the Australia Therapeutic Goods Administration (TGA) in November 2023. The TGA has also granted toripalimab an Orphan Drug designation for the treatment of NPC. In Singapore, the NDA application was accepted by the Singapore Health Sciences Authority (HSA) in January 2024. The HSA has also granted priority review designation for the NDA. About Junshi Biosciences Founded in December 2012, Junshi Biosciences (HKEX: 1877; SSE: 688180) is an innovation-driven biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapeutics. The company has established a diversified R&D pipeline comprising over 50 drug candidates, with five therapeutic focus areas covering cancer, autoimmune, metabolic, neurological, and infectious diseases. Four of the company’s innovations have already reached the Chinese or international markets, one of which is toripalimab, China’s first domestically produced and independently developed anti-PD-1 monoclonal antibody, approved in China and the US. Additionally, more than 30 drugs are currently in clinical development. During the COVID-19 pandemic, Junshi Biosciences actively shouldered the social responsibilities of a Chinese pharmaceutical company through its involvement in developing etesevimab, MINDEWEI®, and other novel therapies for the prevention and treatment of COVID-19. With a mission of “providing patients with world-class, trustworthy, affordable, and innovative drugs,” Junshi Biosciences is “In China, For Global.” At present, the company boasts approximately 3,000 employees in the United States (San Francisco and Maryland) and China (Shanghai, Suzhou, Beijing, Guangzhou, etc.). For more information, please visit: Junshi Biosciences Contact Information IR Team: Junshi Biosciences info@junshipharma.com + 86 021-6105 8800 PR Team: Junshi Biosciences Zhi Li zhi_li@junshipharma.com + 86 021-6105 8800

Orphan DrugBreakthrough TherapyPhase 3Drug ApprovalClinical Result

18 Jun 2024

·www.biospace.com

Junshi Biosciences Announces Approval of the sNDA for Toripalimab for the 1st-Line Treatment of Small Cell Lung Cancer

SHANGHAI, June 18, 2024 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (Junshi Biosciences, HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies, announced that the National Medical Products Administration (NMPA) has approved the supplemental new drug application (sNDA) for toripalimab (product code: JS001) in combination with etoposide plus platinum for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Lung cancer is currently the most prevalent malignant tumor with the highest mortality rate in China. Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, accounting for approximately 15%-20% of all lung cancer cases with characteristics including rapid progression, early metastasis and poor prognosis. SCLC is divided into limited-stage small cell lung cancer (LS-SCLC) and ES-SCLC. For patients with LS-SCLC, an objective response rate of approximately 90% and a five-year survival rate of approximately 25% could be achieved through standard chemotherapy and radiotherapy. However, most patients have already been diagnosed with ES-SCLC when seeking medical treatment, with a median survival time of less than one year and a two-year survival rate of less than 10%, and thus ES-SCLC remains a major unmet clinical problem. The approval of the supplemental new drug application is mainly based on data from the EXTENTORCH study (NCT04012606), a randomized, double-blind, placebo-controlled, multi-center Phase 3 clinical study, aiming to compare the efficacy and safety of toripalimab or placebo in combination with etoposide plus platinum for the first-line treatment of ES-SCLC. Led by principal investigator Professor Ying CHENG from Jilin Cancer Hospital, the study was conducted across 51 clinical centers nationwide. In May 2023, the primary endpoints of EXTENTORCH met their pre-defined efficacy boundary, and toripalimab thus became the first PD-1 inhibitor in the world to meet the primary endpoints of both overall survival (OS) and progression-free survival (PFS) in a Phase 3 study for the first-line treatment of ES-SCLC. At the European Society for Medical Oncology (ESMO) Congress held in October 2023, the EXTENTORCH data was released in the form of an oral presentation for the first time. The study results showed that, compared to chemotherapy alone, toripalimab in combination with chemotherapy could significantly prolong the PFS and OS of patients and demonstrated a favorable safety profile. This suggests that toripalimab may be an optimal immunotherapy for ES-SCLC. In particular, the median PFS of the toripalimab group reached 5.8 months, and the risk of disease progression or death was reduced by 33.3% (P=0.0002). The one-year PFS was nearly four times higher in the toripalimab group compared with the chemotherapy group (18.1% vs. 4.9%). The median OS of the toripalimab group reached 14.6 months, the risk of death was reduced by 20.2% (P=0.0327), and the one-year OS reached 63.1%. “SCLC is highly invasive, mestastasizes early, and has a poor prognosis. For a long time, the standard treatment of ES-SCLC has been platinum-based chemotherapy. Although patients are responsive to the initial stage of treatment, they are prone to drug resistance. Immunotherapy, however, has opened a new chapter,” said Professor Ying CHENG from Jilin Cancer Hospital. “The double primary endpoint design of PFS and OS in EXTENTORCH followed a higher statistical standard and achieved positive results for both endpoints. This means that compared to mono-chemotherapy, toripalimab combined with chemotherapy can significantly improve patients’ PFS and OS. The approval of toripalimab’s new indication for the first-line treatment of ES-SCLC will provide a new, effective, safe and affordable treatment option for SCLC patients in China!” “With the highest number of new cases and deaths, lung cancer has always been the archenemy of tumor treatment,” said Dr. Jianjun ZOU, General Manager and CEO of Junshi Biosciences. “Junshi Biosciences has continuously invested in the research and development of new drugs for lung cancer. To date, three indications have been successfully approved, covering the main subtypes of non-small cell lung cancer and SCLC, as well as patients at all stages from early to advanced. More products and indications are currently in development, and we look forward to bringing better treatment options to lung cancer patients!” About Toripalimab Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promotes the immune system’s ability to attack and kill tumor cells. More than forty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally by Junshi Biosciences, including in China, the United States, Southeast Asia, and Europe. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types, including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin. In Chinese mainland, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI®). Currently, there are nine approved indications for toripalimab in Chinese mainland: unresectable or metastatic melanoma after failure of standard systemic therapy; recurrent or metastatic nasopharyngeal carcinoma (NPC) after failure of at least two lines of prior systemic therapy; locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy; in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC; in combination with paclitaxel and cisplatin in first-line treatment of patients with unresectable locally advanced/recurrent or distant metastatic esophageal squamous cell carcinoma (ESCC); in combination with pemetrexed and platinum as the first-line treatment in EGFR mutation-negative and ALK mutation-negative, unresectable, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC); in combination with chemotherapy as perioperative treatment and subsequently with monotherapy as adjuvant therapy for the treatment of adult patients with resectable stage IIIA-IIIB NSCLC; in combination with axitinib for the first-line treatment of patients with medium to high risk unresectable or metastatic renal cell carcinoma (RCC); in combination with etoposide plus platinum for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). The first six indications have been included in the National Reimbursement Drug List (NRDL) (2023 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for the treatment of melanoma. In April 2024, the Drug Office at the Department of Health in the Government of the Hong Kong Special Administration Region (DO) accepted the NDA for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy. In the United States, the US FDA has approved the Biologics License Application for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy in October 2023. The FDA has granted toripalimab 2 Breakthrough Therapy designations for the treatment of NPC, 1 Fast Track designation for the treatment of mucosal melanoma, and 5 Orphan Drug designations for the treatment of esophageal cancer, NPC, mucosal melanoma, soft tissue sarcoma, and small cell lung cancer (SCLC). In Europe, marketing authorization applications (MAA) were accepted by the European Medicines Agency (EMA) and the MHRA for 1) toripalimab combined with cisplatin and gemcitabine for the first-line treatment of patients with locally recurrent or metastatic NPC and 2) toripalimab combined with paclitaxel and cisplatin for the first-line treatment of patients with unresectable locally advanced/recurrent or metastatic ESCC, in December 2022 and February 2023. In Australia, the new chemical entity (NCE) application was accepted by the Australia Therapeutic Goods Administration (TGA) in November 2023. The TGA has also granted toripalimab an Orphan Drug designation for the treatment of NPC. In Singapore, the NDA application was accepted by the Singapore Health Sciences Authority (HSA) in January 2024. The HSA has also granted priority review designation for the NDA. About Junshi Biosciences Founded in December 2012, Junshi Biosciences (HKEX: 1877; SSE: 688180) is an innovation-driven biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapeutics. The company has established a diversified R&D pipeline comprising over 50 drug candidates, with five therapeutic focus areas covering cancer, autoimmune, metabolic, neurological, and infectious diseases. Four of the company’s innovations have already reached the Chinese or international markets, one of which is toripalimab, China’s first domestically produced and independently developed anti-PD-1 monoclonal antibody, approved in China and the US. Additionally, more than 30 drugs are currently in clinical development. During the COVID-19 pandemic, Junshi Biosciences actively shouldered the social responsibilities of a Chinese pharmaceutical company through its involvement in developing etesevimab, MINDEWEI®, and other novel therapies for the prevention and treatment of COVID-19. With a mission of “providing patients with world-class, trustworthy, affordable, and innovative drugs”, Junshi Biosciences is “In China, For Global.” At present, the company boasts approximately 3,000 employees in the United States (San Francisco and Maryland) and China (Shanghai, Suzhou, Beijing, Guangzhou, etc.). For more information, please visit: Junshi Biosciences Contact Information IR Team: Junshi Biosciences info@junshipharma.com + 86 021-6105 8800 PR Team: Junshi Biosciences Zhi Li zhi_li@junshipharma.com + 86 021-6105 8800

Orphan DrugNDAPhase 3Clinical ResultBreakthrough Therapy

12 Jun 2024

·www.globenewswire.com

Junshi Biosciences Announces Phase 3 Study of Toripalimab Combined with Bevacizumab for the First-line Treatment of Advanced Hepatocellular Carcinoma Meets Primary Endpoint

SHANGHAI, June 11, 2024 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (“Junshi Biosciences”, HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies, announced that the primary endpoints of progression-free survival (“PFS,” based on independent radiographic review) and overall survival (“OS”) of a multi-center, randomized, open-label, active-controlled phase III clinical study (the “HEPATORCH study,” NCT04723004) of the company’s product, toripalimab (trade name: TUOYI®, product code: JS001), in combination with bevacizumab for the first-line treatment of advanced hepatocellular carcinoma (“HCC”) has met the pre-defined efficacy boundary. Junshi Biosciences plans to submit a supplemental new drug application (“NDA”) for this indication to the regulatory authorities in the near future. Liver cancer is a common malignant tumor of the digestive system worldwide, and the predominant pathological type is HCC (accounting for about 90%). According to the GLOBOCAN Report for 2022, there were 866,000 new cases and 759,000 deaths from liver cancer globally that year. China in particular suffers greatly from liver cancer. The number of new liver cancer cases reached 368,000 (accounting for 42.4% of global cases) in 2022, ranking fourth in new cases among domestic malignant tumors; the numbr of deaths reached 317,000 (accounting for 41.7% of global cases), ranking second among domestic malignant tumors. Due to its insidious onset, about 70%-80% of liver cancer patients in China are already at the intermediate or advanced stage upon first diagnosis, with a median OS of approximately only 10 months and a 5-year survival rate of approximately 12%. In recent years, with the continuous emergence of the combination therapies based on the immunotherapeutic drugs, the treatment pattern of advanced liver cancer has changed, and radical cure after down-stage transformation is gradually becoming a possibility. The HEPATORCH study is a multi-center, randomized, open-label, active-controlled phase 3 clinical study, aiming to evaluate the efficacy and safety of toripalimab in combination with bevacizumab for the first-line treatment of unresectable or metastatic HCC compared to the standard treatment of sorafenib. According to the analysis results of this study, toripalimab in combination with bevacizumab for the first-line treatment of patients with advanced HCC could significantly prolong the PFS and OS of the patients compared with sorafenib while improving the secondary endpoints such as objective response rate and time to progression. The safety profile of toripalimab was consistent with the known risks, and no new safety signals were identified. Further details will be presented at a subsequent international academic conference. Principal investigator Professor Jia FAN, Academician of Chinese Academy of Sciences and President of Zhongshan Hospital, said, “Currently, the combination of immune checkpoint inhibitors and anti-angiogenesis targeted therapies has become a vital first-line treatment for advanced liver cancer. The HEPATORCH phase 3 clinical study evaluating toripalimab combined with bevacizumab achieved its primary endpoint, potentially offering a new treatment option with better survival benefits for advanced liver cancer patients. Toripalimab has already been approved for marketing in the US. As the first innovative biological drug independently developed and produced in China to receive FDA approval, toripalimab has received international recognition for its quality. We look forward to a day when more advanced liver cancer patients can benefit from domestically developed innovative drugs!” Dr. Jianjun ZOU, General Manager and CEO of Junshi Biosciences, said “The incidence and mortality rates of hepatocellular carcinoma in China have remained consistently high, posing a serious threat to public health. Junshi Biosciences is committed to putting patients first, with the mission of ‘providing patients with world-class, trustworthy, and affordable and innovative drugs’. In this study, toripalimab demonstrated its powerful synergy as a cornerstone of immuno-oncology, significantly improving survival rates for patients with advanced HCC. Moving forward, we will actively communicate with regulatory authorities to expedite the approval of relevant indications, and we hope our efforts will benefit more patients with advanced liver cancer.” About Toripalimab Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promotes the immune system’s ability to attack and kill tumor cells. More than forty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally by Junshi Biosciences, including in China, the United States, Southeast Asia, and Europe. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types, including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin. In mainland China, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI®). Currently, there are eight approved indications for toripalimab in mainland China: unresectable or metastatic melanoma after failure of standard systemic therapy;recurrent or metastatic nasopharyngeal carcinoma (“NPC”) after failure of at least two lines of prior systemic therapy;locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy;in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC;in combination with paclitaxel and cisplatin in first-line treatment of patients with unresectable locally advanced/recurrent or distant metastatic esophageal squamous cell carcinoma (“ESCC”);in combination with pemetrexed and platinum as the first-line treatment in EGFR mutation-negative and ALK mutation-negative, unresectable, locally advanced or metastatic non-squamous non-small cell lung cancer (“NSCLC”);in combination with chemotherapy as perioperative treatment and subsequently with monotherapy as adjuvant therapy for the treatment of adult patients with resectable stage IIIA-IIIB NSCLC;in combination with axitinib for the first-line treatment of patients with medium to high risk unresectable or metastatic renal cell carcinoma (RCC). The first six indications have been included in the National Reimbursement Drug List (NRDL) (2023 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for the treatment of melanoma. In April 2024, the Drug Office at the Department of Health in the Government of the Hong Kong Special Administration Region (DO) accepted the NDA for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy. In the United States, the US FDA has approved the Biologics License Application for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy in October 2023. The FDA has granted toripalimab 2 Breakthrough Therapy designations for the treatment of NPC, 1 Fast Track designation for the treatment of mucosal melanoma, and 5 Orphan Drug designations for the treatment of esophageal cancer, NPC, mucosal melanoma, soft tissue sarcoma, and small cell lung cancer (SCLC). In Europe, marketing authorization applications (MAA) were accepted by the European Medicines Agency (EMA) and the MHRA for 1) toripalimab combined with cisplatin and gemcitabine for the first-line treatment of patients with locally recurrent or metastatic NPC and 2) toripalimab combined with paclitaxel and cisplatin for the first-line treatment of patients with unresectable locally advanced/recurrent or metastatic ESCC, in December 2022 and February 2023. In Australia, the new chemical entity (NCE) application was accepted by the Australia Therapeutic Goods Administration (“TGA”) in November 2023. The TGA has also granted toripalimab an Orphan Drug designation for the treatment of NPC. In Singapore, the NDA application was accepted by the Singapore Health Sciences Authority (“HSA") in January 2024. The HSA has also granted priority review designation for the NDA. About Junshi Biosciences Founded in December 2012, Junshi Biosciences (HKEX: 1877; SSE: 688180) is an innovation-driven biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapeutics. The company has established a diversified R&D pipeline comprising over 50 drug candidates, with five therapeutic focus areas covering cancer, autoimmune, metabolic, neurological, and infectious diseases. Four of the company’s innovations have already reached the Chinese or international markets, one of which is toripalimab, China’s first domestically produced and independently developed anti-PD-1 monoclonal antibody, approved in China and the US. Additionally, more than 30 drugs are currently in clinical development. During the COVID-19 pandemic, Junshi Biosciences actively shouldered the social responsibilities of a Chinese pharmaceutical company through its involvement in developing etesevimab, MINDEWEI®, and other novel therapies for the prevention and treatment of COVID-19. With a mission of “providing patients with world-class, trustworthy, affordable, and innovative drugs”, Junshi Biosciences is “In China, For Global.” At present, the company boasts approximately 3,000 employees in the United States (San Francisco and Maryland) and China (Shanghai, Suzhou, Beijing, Guangzhou, etc.). For more information, please visit: http://junshipharma.com. Junshi Biosciences Contact InformationIR Team:Junshi Biosciencesinfo@junshipharma.com+ 86 021-6105 8800 PR Team:Junshi BiosciencesZhi Lizhi_li@junshipharma.com+ 86 021-6105 8800

Orphan DrugPhase 3Breakthrough TherapyNDADrug Approval

100 Deals associated with Etesevimab

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KEGG	Wiki	ATC	Drug Bank
D11944	-	-	DB15897

R&D Status

Approved

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Indication	Country/Location	Organization	Date
COVID-19	US	Eli Lilly & Co.	09 Feb 2021

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Indication	Highest Phase	Country/Location	Organization	Date
Severe Acute Respiratory Syndrome	Phase 2	CN	Shanghai Junshi Biosciences Co., Ltd.	30 Oct 2020

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04931238 (Pubmed \| Antimicrob Agents Chemother) Manual	Phase 2/3	COVID-19	197	standard care+Etesevimab	ugtwyjrtqu(fnzlbhkyqq) = lpblifylif wukswnzetw (jqhohswbpw )	Negative	22 Feb 2022
				standard care	ugtwyjrtqu(fnzlbhkyqq) = sjhubvymqv wukswnzetw (jqhohswbpw )
NCT04497987 (CTgov)	Phase 3	COVID-19	1,180	Placebo (Placebo)	kzxcpeyegs(yomvfgxqxj) = tjfshuduji ztisfzrxql (cnmguspibm, ufbirmfpye - qtkbicynoa) View more	-	04 Feb 2022
				Bamlanivimab (4200mg Bamlanivimab)	kzxcpeyegs(yomvfgxqxj) = nkxpaifxzu ztisfzrxql (cnmguspibm, nkatacacbl - dbevoshtwy) View more
NCT04441931 (CTgov)	Phase 1	-	26	Placebo (Pooled Placebo)	ugydmyuoyq(yncjmyyqcd) = nzxmgfklyc nfwyyveosf (rovgnpayps, commgtemye - uobumrgaoh)	-	06 Dec 2021
				LY3832479 (700 mg LY3832479 IV)	ugydmyuoyq(yncjmyyqcd) = ovsapzxhqk nfwyyveosf (rovgnpayps, weltwqdgiu - wcreczuwgp) View more
NCT04427501 (BLAZE-1, Pubmed \| Br Dent J) Manual	Phase 2/3	COVID-19	1,035	bamlanivimab+etesevimab	cemkdtmrbh(wmujfcuyzu) = flgbqggqfe zryualrtwg (iajalhlpyn ) View more	Positive	07 Oct 2021
				Placebo	cemkdtmrbh(wmujfcuyzu) = zuqerebksk zryualrtwg (iajalhlpyn ) View more
NCT04441918 (Pubmed) Manual	Phase 1	COVID-19	40	Etesevimab	-	Positive	16 Jul 2021
				Placebo
NCT04427501 (BLAZE-1, FDA) Manual	Phase 2	COVID-19	369	Bamlanivimab 2800mg+Etesevimab 2800mg	bngcbvhkwu(ahrloqpjie) = Most subjects, including those receiving placebo, effectively cleared virus by Day 11. kieyvbunpz (tardumsilj ) View more	Positive	09 Feb 2021
				Bamlanivimab 700 mg
NCT04634409 (BLAZE-4, FDA) Manual	Phase 2	COVID-19	483	Bamlanivimab 700mg+Etesevimab 1400mg	vvpmvsjtts(pofwlvhvbg) = ohlnegtefp nnzcjjutub (rvzkydfvqx )	Positive	09 Feb 2021
				Bamlanivimab 2800mg+Etesevimab 2800mg	vvpmvsjtts(pofwlvhvbg) = hwpbfktckf nnzcjjutub (rvzkydfvqx )
NCT04427501 (BLAZE-1, FDA) Manual	Phase 3	COVID-19	1,035	Bamlanivimab 2800mg+Etesevimab 2800mg	xyhwoctmtj(pminazlotm) = dwxutwmigs zwvttnzaev (liqfwisoyb ) View more	Positive	09 Feb 2021
				Placebo	xyhwoctmtj(pminazlotm) = gfeozcuuvi zwvttnzaev (liqfwisoyb ) View more
NCT04427501 (BLAZE-1, GlobeNewswire) Manual	Phase 2	COVID-19	268	Etesevimab+Bamlanivimab	tqoabxgnpu(nxpicopjxp): P-Value = 0.011 View more	Positive	07 Oct 2020
				Placebo

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