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GB491 (lerociclib), is a novel, potent and selective oral bioavailable CDK4/6 inhibitor co-developed by the Company and G1 Therapeutics, a US based company, for use in combination with endocrine therapy/targeted therapies in breast cancer. Based on the data published at the European Society for Medical Oncology 2020 conference, GB491, compared to the currently approved CDK4/6 inhibitor in China, palbociclib, has demonstrated a better safety profile and could be a potentially best-in-class CDK4/6 drug candidate.

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In addition to China, the company is also actively expanding GB491 market development in Asia Pacific (excluding Japan) countries and regions, which would expand the market size beyond China by 150%.

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Patient enrolment of the Phase III trials for both first and second lines has been completed quickly via adaptive and seamless experiment design, scientific reference and data bridging, seamless registration strategy, and excellent execution.

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On 28 March 2023, the NMPA has officially accepted the NDA for GB491 (Lerociclib) in combination with Fluvestran as the treatment of HR+/HER2- locally advanced or metastatic breast cancer patients with disease progression following previous endocrine therapy.

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GB491 (Lerociclib) has garnered international recognition at the 2023 ASCO annual meeting, which was successfully held in Chicago from 2 June to 6 June 2023:

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  • The research results of the LEONARDA-1 study were announced in the poster discussion session of the Metastatic Breast Cancer session with the title “Phase III randomized study of lerociclib plus fulvestrant in patients with HR+/HER2- locally advanced or metastatic breast cancer that has progressed on prior endocrine therapy”.
  • The data from the Phase III clinical study of LEONARDA-1 were selected by ASCO for the ASCO Daily Release, which was published in the ASCO Daily News Column on its website on 25 May 2023 (EST) with the title “Lerociclib/Fulvestrant May Reduce Risk of Disease Progression in Advanced HR-Positive/HER2-Negative Breast Cancer”.
  • The LEONARDA-1 research report and article cited the views of the lead author Prof. Binghe Xu, MD, PhD, the academician of the Chinese Academy of Engineering, the Head of Medical Oncology at Cancer Hospital affiliated with Chinese Academy of Medical Sciences.
  • According to the efficacy and safety data demonstrated in the LEONARDA-1 research, GB491 (Lerociclib) has demonstrated superior efficacy, better safety and tolerability profile to patients with HR+/HER2- advanced breast cancer for whom prior endocrine therapy failed, providing a more reliable clinical option. It could become a preferred option among CDK4/6 inhibitors for refractory patients and patients with suboptimal recovery of myelosuppression after chemotherapy and suboptimal gastrointestinal/hepatic function or patients with poor tolerability.

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GB491 (Lerociclib) will create a new landscape for the treatment of HR+/HER2-advanced breast cancer.

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  • HR+/HER2- is the most common subtype of advanced breast cancer, and its treatment has entered the era of targeted therapy. Combination therapy with CDK4/6 inhibitors has been recommended in multiple guidelines as the preferred regimen for patients with advanced breast cancer following previous failed endocrine therapy.
  • The innovative molecular structure with its unique PK/PD has allowed for continuous oral administration of Lerociclib without the need for treatment breaks. It achieves sustained target inhibition and anti-tumor effects while significantly reducing the common adverse effects of CDK4/6 inhibitors, such as severe myelosuppression and diarrhea.
  • The LEONARDA-1 clinical study demonstrated that the combination therapy of Lerociclib with Fluvestran would significantly reduce the risk of disease progression and death as compared to using Fluvestran as a monotherapy. The investigator-assessed hazard ratio (HR) was 0.451 and the Blinded Independent Central Review (BICR)-assessed HR was 0.353.
  • The median progression free survival (mPFS) (months) assessed by the investigator and BICR were 11.07 vs. 5.49 and 11.93 vs. 5.75, respectively. Furthermore, the results of all predefined subgroups were consistent with the overall efficacy.
  • The LEONARDA-1 clinical study showed that, in comparison with other marketed CDK4/6 inhibitors, Lerociclib had significant comprehensive advantages in terms of safety and tolerance profile. It recorded a low incidence rate of diarrhea at 19.7%, a relatively low percentage of grade III/IV myelosuppression, and only a 5.1% incidence rate of grade IV neutropenia.
  • LEONARDA-1 enrolled a high proportion of refractory patients, including patients with liver metastasis, treated with primary resistance, with 4 or more metastatic organs, received first-line chemotherapy at an advanced stage. The use of Lerociclib substantially improved the progression free survival (PFS) of the refractory patients, indicating a superior efficacy with advantages in terms of safety and tolerance profile and hence fully demonstrating the differentiation advantage of Lerociclib for clinical purposes.

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Currently, the Company is pushing forward with commercial cooperation in respect of GB491 (Lerociclib). As at 30 June 2023, the Company has presented the phase III research data to various companies, among which several companies have commenced the process of data review. It plans to enter into cooperation agreements in 2023. The transfer of technology for local production of GB491 (Lerociclib) has also been initiated simultaneously.

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GB261 (CD20/CD3, BsAb) is the first T-cell engager with low affinity to bind CD3 and has Fc functions (ADCC and CDC). GB261 (CD20/CD3, BsAb) significantly inhibits rituximabresistant cancer cell proliferation in both in vitro assays and in vivo models; meanwhile with T-cell activation, GB261 (CD20/CD3, BsAb) induces less cytokine release compared with compound in the same class. Thus, GB261 (CD20/CD3, BsAb) is a highly potent bispecific therapeutic antibody for B cell malignancies. It has potential to be a better and safer T-cell engager with competitive advantages over other CD3/CD20 agents.

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More than a dozen of GB261 (CD20/CD3, BsAb) clinical centers have been established in Australia and China. We obtained the preliminary clinical Proof of Concept (“POC”) data in the first-in-human (“FIH”) clinical trial of GB261 in Australia in the process of a dose escalation up to 3mg, which were consistent with the molecular design mechanism of GB261 (CD20/CD3, BsAb), indicating a good safety, pharmacokinetic profile and clinical antitumor activities.

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As at 30 June 2023, the low-medium dose group escalations of the phase I/II GB261 (CD20/ CD3, BsAb) clinical trial were completed. The high dose groups are currently in dose escalation. Preliminary data showed that GB261 (CD20/CD3, BsAb) has demonstrated promising efficacy, while initial efficacy has also been seen in patients who have failed prior CD20/CD3 bi-specific antibodies (mosunetuzumab), CAR-T, and CD3/CD19 bi-specific antibodies therapies.

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Preliminary clinical data showed favourable tolerability, which was favourable for combination therapy. Cytokine release syndrome (CRS) was mild, transient and less frequent compared with other CD20/CD3 bi-specific antibodies products (low incidence: 12.8% (Grade 1: 8.5%; Grade 2: 4.3%); no Grade 3; no anti-IL6 used; no interruption of treatment. No immune effector cellassociated neurotoxicity syndrome (ICANS) was observed.

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In respect of pharmacokinetics (PK), the half-life of GB261 (CD20/CD3, BsAb) was long and supported tri-weekly dosing.

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GB261 (CD20/CD3, BsAb) is scheduled for dose escalations in the second half of 2023.

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Genor Biopharma?participated at the 65th American Society of Hematology (ASH) Annual Meeting held in San Diego, USA on December 9-12, 2023, and shared the poster of the preliminary clinical safety and efficacy results of the phase I/II study of GB261(CD20/CD3).

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GB261, an Fc-Function Enabled and CD3 Affinity De-Tuned CD20/CD3 Bispecifc Antibody, Demonstrated a Highly Advantageous Safety/Efficacy Balance in an Ongoing First-in-Human Dose-Escalation Study in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (Poster Number: 1719)

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Introduction:?GB261 is a novel and highly differentiated CD20/CD3 bispecific T cell engager antibody computationally designed to maintain Fc effector function, i.e., antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to broaden the mechanisms of action (MOA) for tumor cell killing. Furthermore, the “imbalanced” design of GB261 integrates de-tuned CD3 binding to reduce CRS incidence and improve safety features of the Fc effector function. Extensive pre-clinical studies have shown that GB261 has a highly advantageous safety/efficacy balance. Here, we present the preliminary clinical safety and efficacy results of an ongoing phase I/II study for GB261 (NCT04923048).

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Methods:?This is an open-label, multicenter (China and Australia), dose escalation/expansion phase 1/2 study of GB261 to evaluate the safety, tolerability and efficacy in patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma(B-NHL) and Chronic Lymphocytic Leukemia (CLL). Adult patients were eligible when they have CD20+ r/r B-NHL or CLL with no available standard of care treatments, adequate organ function, and no CNS involvement or other CNS disease, infections or other active/serious medical issues that may affect compliance or interpretation of results. GB261 was administered in 21-day cycles, weekly (QW) for the first 6 doses followed by every 3 weeks (Q3W) until disease progression, or other situation defined in protocol. Response assessment was based on Lugano 2014 and LYRIC 2016 criteria.

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Results:?As of June 17, 2023, 47 r/r B-NHL patients (DLBCL:76.6%; FL:23.4%) were enrolled at flat or step-up doses of GB261 ranging from 1mg to 300mg. Median age was 60.0 years (range: 28, 81), 55.3% of patients were male. Median prior lines of therapy were 3 (range: 1, 10). 78.7% of patients were refractory to any anti-CD20 therapy, 70.2% refractory to their last systemic therapy. Median time since last prior therapy to first study treatment was 1.9 months.

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In efficacy evaluable patients (n=22) from 3mg to 100mg, with at least 75% dose exposure before the first radiographic assessment, the median duration of study follow-up was 4.5 months (95%CI: 4.0, 7.4). The overall response rate (ORR) was 73% (16/22), and complete response rate (CRR) was 45.5% (10/22). ORR and CRR were 100% and 100% in 3mg, 56% and 22% in 10mg, 67% and 33% in 30mg. At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient). Median time to response (TTR) was 1.3 months (95%CI: 1.2, 1.5), the same as median time to CR. Median duration of response (DOR) was not reached.

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In safety evaluable patients (n=47), the median duration of study follow-up was 4.1 months (95%CI: 2.9, 5.3). Treatment-emergent adverse events (TEAEs) were 95.7%, treatment-related adverse events were 85.1%. The most common TEAEs were COVID-19 infection (40.4%; grade 1 or 2: 27.6%; grade >=3: 12.8%) and neutropenia (31.9%; grade 1or 2: 14.9%; grade >=3: 17.0%). AE related treatment discontinuation and death were reported in 2 patients, which were all due to COVID-19 pneumonia. CRS occurred in 12.8% (6/47) patients, was mild and transient. CRS in 100mg were 14.3% (2/14). All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab. The median duration of CRS was 7 hours. No ICANS were reported.

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The PK profile of GB261 appeared to be linear across dose ranges tested (1mg -100mg). Effective half-life appeared to be 2-3 weeks which supports every 3-4 weeks dosing.

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Conclusion:?GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. At the 100mg dose level, 80% of patients achieved CR and with favorable safety. Additionally, clinical benefit seen in other CD20/CD3 bispecific antibody failed patients provides clinical support to the unique and differentiated MOA of GB261.

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Click here to download the full content of the poster.

GB263T (EGFR/cMET/cMET, TsAb) was the first tri-specific antibody of EGFR/cMET/cMET in the world, targeting EGFR and two different cMET epitopes, so designed to enhance its safety and efficacy. With highly differentiated design, GB263T (EGFR/cMET/cMET, TsAb) exhibits multiple mechanisms of action to inhibit primary and secondary EGFR mutations and cMET signaling pathway simultaneously.

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In pre-clinical studies, GB263T (EGFR/cMET/cMET, TsAb) effectively thwarted ligand-induced phosphorylation of EGFR and c-MET compared to its Amivantamab (JNJ-372) analogue, and demonstrated better dual inhibition of EGFR and cMET signaling pathways. Meanwhile, GB263T (EGFR/cMET/cMET, TsAb) effectively induced the endocytosis of EGFR and cMET, and significantly reduced the protein expression levels of EGFR and cMET. GB263T (EGFR/cMET/ cMET, TsAb) played a significant dosage-dependent role in tumor suppression in several different tumor models including EGFR exon 20 insertions, EGFR exon 19 deletions, C797S mutations and various cMET expression abnormalities. In toxicology studies in cynomolgus monkeys, no significant toxic side effects were observed after 4 weeks of observation, even in the highly-dosed group.

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As at 30 June 2023, the phase I/II clinical trial of GB263T (EGFR/cMET/cMET, TsAb) completed DLT (dose-limiting toxicity) observation in the low-medium dose groups, and high dose escalations are in progress currently. Currently, preliminary clinical efficacy has been observed, which validated that the mechanism of action of GB263T (EGFR/cMET/cMET, TsAb) effectively inhibited the dual targets of EGFR and CMET. Patients with EGFR-sensitive mutated NSCLC who failed multi-line therapies including the third generation TKI and platinum-based chemotherapy responded to GB263T; and the PR exceeded 24 weeks.

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Preliminary clinical data demonstrated that GB263T (EGFR/cMET/cMET, TsAb) is safe and well tolerated, with an infusion reaction rate (IRR) of 35.7%, significantly lower than that of competitor (66%), and both were mildly graded 1/2. No MET target-related peripheral edema toxicity was observed.

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The Company is expecting the validation of the clinical POC data to be completed in 2023

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Genor Biopharma has published preliminary dose escalation results from a phase I/II study of GB263T in the December 1, 2023 issue of Molecular Cancer Therapeutics, an AACR journal

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Abstract C114: Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)

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Background: GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes, in which a conformational change induced by the first VHH binding exposes the second epitope for the second VHH to bind. Sequential binding of the two VHH antibodies to cMET increases tumor specificity, which results in widening of the safety window. In vitro studies show that GB263T induces better antigen-antibody molecular endocytosis, more completely blocks the signal transduction pathway, and has better ADCC activity compared to a benchmark. In addition, GB263T has demonstrated promising pre-clinical activity in models with various EGFR/cMET alterations, including those with high medical need. Here, we report updated dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574).

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Methods: This multicenter (China and Australia), phase I/II study was conducted using an accelerated titration method followed by a traditional 3+3 design for dose escalation. Pts with EGFRm NSCLC with prior EGFR-TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg (5 dose cohorts) IV weekly for the first two 28-day cycles and biweekly thereafter. Objectives were to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), assess the pharmacokinetics, immunogenicity, and preliminary efficacy of GB263T.

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Results:?As of July 5, 2023, 13 pts were treated: 140mg (n=1), 420mg (n=1), 840mg (n=3), 1260mg (n=3), 1680mg (n=5). The enrolment of the 1680mg cohort is ongoing. All pts had received previous third-generation EGFR-TKI and platinum-based chemotherapy. Median number of prior lines of systemic therapy was 3 (range 1-7). One patient at 1680mg experienced DLT (grade 3 oral mucositis, which has resolved after symptomatic treatment). The most common treatment-related adverse events (TRAEs) were rash (61.5%), infusion related reaction (38.5%), fatigue (30.8%) and myalgia (23.1%), and all are mild (grade 1/2). Only one patient developed ≥grade 3 TRAE (grade 3 oral mucositis). There were no treatment-related discontinuations. Among 10 response-evaluable pts, two achieved partial response (PR) and four achieved stable disease (SD) with tumor shrinkage observed in 3/4 SD pts. The disease control rate (DCR) is 60%. The objective response rate (ORR) at the therapeutic dose range (1260-1680mg) is 40% (2/5). Two PR pts and 2/4 SD pts remained on treatment at data cutoff.

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Conclusions:?Results to date demonstrate a good safety profile with promising efficacy at the therapeutic dose range (1260-1680mg). Continued dose escalation and clinical investigation of GB263T is ongoing.

GB226 is an investigational, humanized, IgG4 mAb targeting the programmed cell death-1 receptor (PD-1) on immune cells. It selectively blocks dual ligands (PD-L1 and PD-L2), and restores the ability of the immune system to recognize and kill tumor cells.

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We will continue to explore approval for geptanolimab (GB226) in other indications as well as novel combination therapy potential, including combination therapy with our STING agonist (GB492), to benefit more patients in China with unmet medical needs.

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In January 2022, Gxplore-008, a phase II pivotal clinical study evaluating GB226 in recurrent or metastatic cervical cancer patients with PD-L1 positive status having failed in platinum-based chemotherapy, completed the last subject enrollment.

GB492 (IMSA101, STimulator of interferon genes, STING) is the major mediator of innate immune sensing of cancerous cells, which the Group exclusively licensed from ImmuneSensor Therapeutic in June 2020.

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STING agonist, as an immune stimulatory therapy, may further increase the response of immune checkpoint inhibitors for patients. Multiple studies have shown that STING agonists can activate the cGAS-STING signaling and significantly enhance the efficacy of cancer immunity cycle when using in combo with other immune checkpoint inhibitors (ICI), which may become a potential first-in-class therapy.

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In Phase I/II clinical trials of GB492 (IMSA101) ?as a monotherapy or in combination with GB226 (Aibining?艾比寧?, Geptanolimab) in patients with advanced/treatment-refractory malignancies, monotherapy clinical trials were finished and a dose escalation up to 400ug was completed in January 2022.

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In January 2022, approval was obtained from the CDE to directly conduct a dose-escalating study of GB492 (IMSA101) in combination with PD-1 in patients with advanced malignancy, based on the available data on the 400ug dose group in the monotherapy study in China and all data of the monotherapy dose-escalation study in the United States. In this clinical trial, an innovative FIH trial design was employed to combine the dose escalations when GB492 (IMSA101) was administered alone and when it was administered with GB226 (Aibining?艾比寧?, Geptanolimab). It is the first STING agonist combination therapy that has obtained clinical trial approval in China.

GB242 is potentially one of the first three infliximab (Remicade) biosimilar?products to the markets in China, and our clinical trial has the largest patient?enrollment. Remicade has the most extensive indications approved in China among?TNF--targeting drugs, including RA, AS, PsA, CD and UC, which gives GB242 a?premium access to sizeable markets for autoimmune diseases in China.

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On February 23, 2022, the NMPA granted marketing approval for Jiayoujian 佳佑健? (GB242, Infliximab) which is used for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriasis, adult ulcerative colitis, adult and pediatric (aged above 6 years old) Crohn’s disease and fistulizing Crohn’s disease. Genor Biopharma commercialized its first product. By the end of June 2023, Jiayoujian 佳佑健? (GB242, Infliximab) is available for online procurement in 26 provinces and cities across the country.

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