August 28, 2024 Genor Biopharma reported its interim results for 2024, sharing the company’s business progress, financial data, highlights during the period, and future development prospects (Press release, Genor Biopharma, AUG 28, 2024, View Source [SID1234647167]).
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!
Dr. GUO Feng, Chairman of the Board and Chief Executive Officer, Genor Biopharma, said: "Highly focused on accelerating the development of its core pipeline, the Group has further optimized its structure and adopted various flexible modes of external cooperation during the Reporting Period, successfully achieving the transformation into an enterprise adopting the assetlight model. As the Company reduces its costs and increases its efficiency, the Company continues to develop in technology, research and development, processes, management and other areas."
GB261(CD3/CD20) goes global
On 2 August 2024, the Group has entered into the License Agreement and the Stock Purchase Agreement with the Licensee, a company co-founded by Two River, LLC and Third Rock Ventures in Delaware, the United States of America. Under the License Agreement, the Group has agreed, among others, to grant the Licensee an exclusive worldwide license to develop, use, manufacture, commercialize and otherwise exploit GB261, excluding mainland China, Hong Kong, Macau and Taiwan. The collaboration between both parties will mainly focus on exploring the potential of GB261 (CD20/CD3, BsAb) in autoimmune diseases.
As a consideration of the License, the Group shall receive (1) a significant equity participation in the Licensee; (2) a double digit million US dollars upfront payment; (3) up to 443 million US dollars in milestone payments; and (4) tiered single to ouble digits royalty payments on net sales.
GB261 (CD20/CD3, BsAb) is the first TCE with low affinity to bind CD3 and has Fc functions (ADCC and CDC). GB261 (CD20/CD3, BsAb) significantly inhibits rituximab-resistant 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 TCE with competitive advantages over other CD3/CD20 agents.
A number of clinical centres for GB261 (CD20/CD3, BsAb) have been opened in Australia and China. We obtained the preliminary clinical Proof of Concept (POC) data in the first-in-human clinical trial of GB261 (CD20/CD3, BsAb) in Australia in the process of a dose escalation up to 3 mg, which were consistent with the molecular design mechanism of GB261 (CD20/CD3, BsAb), indicating a good safety, pharmacokinetic profile and clinical antitumor activities. As at October 2023, the dose-escalation was completed in the phase I/II clinical trial of GB261, which demonstrated promising efficacy and a favorable safety profile.
In accordance with the preliminary clinical safety and efficacy results of phase I/II study of GB261 (CD20/CD3, BsAb) led by Beijing Cancer Hospital, which was presented at the annual meeting of the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) in the poster discussion session:
GB261 is a novel and highly differentiated CD20/CD3 bispecific antibody and is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated BNHL patients, GB261 showed a highly advantageous safety/efficacy balance. The safety profile of GB261 is excellent especially for the CRS which is very mild, transient and less frequent as compared with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. Additionally, clinical benefit is still seen in other CD20/CD3 failed patients, which provides clinical support to the unique and differentiated mechanism of action of GB261.
The CSR of phase I/II clinical trial of GB261 (CD20/CD3, BsAb) for lymphoma is about to be completed.
GB491 (Lerociclib) 1L&2L NDA are progressing efficiently and smoothly
GB491 (Lerociclib), is a novel, potent, selective oral bioavailable CDK4/6 inhibitor co-developed by the Group and G1 Therapeutics for use in combination with endocrine therapy in advanced breast cancer.
The NMPA has previously officially accepted the NDA of GB491 (Lerociclib) in combination with Fluvestran for use in the treatment of HR+/HER2- locally advanced or metastatic breast cancer patients with disease progression following previous endocrine therapy in March last year and the Company has successfully completed the clinical inspection in August last year. In March 2024, the Company has submitted the supplementary materials for the NDA of GB491 (Lerociclib), and subsequently completed the drug testing at the National Institutes for Food and Drug Control in May 2024.
The Company has completed its patient enrolment for the advanced first-line phase III clinical study of GB491 (Lerociclib) and its interim analysis has reached the primary endpoint. The Company submitted the NDA to the NMPA officially on 28 February 2024, which was officially accepted on 13 March 2024.
The Independent Data Monitoring Committee ("IDMC") has conducted efficacy and safety data monitoring over the interim analysis of the advanced first-line phase III clinical trial of Lerociclib in combination with letrozole. The IDMC recommended that this clinical trial had met the prespecified requirement of statistical significance in efficacy for the interim analysis with positive safety and tolerance. The interim analysis results are as follows:
Progression-free survival ("PFS") based on the investigator assessment: hazard-ratio (95% CI) and p-value, 0.464 (0.293, 0.733), p=0.0004.
PFS based on the Independent Review Committee’s (IRC) assessment: hazard-ratio (95% CI) and p-value, 0.457 (0.274, 0.761), p=0.0011.
The results of the interim analysis were presented in the poster discussion session at the ASCO (Free ASCO Whitepaper) annual meeting in June 2024.
The superior efficacy and safety profile of GB491 (Lerociclib) will provide a better treatment option for patients with HR+/HER2-advanced breast cancer:
HR+/HER2- is the most common subtype of advanced breast cancer, and its treatment has entered the era of targeted therapy. The combination therapy with CDK4/6 inhibitors has been recommended in multiple guidelines as the preferred regimen for patients with advanced breast cancer following previously-failed endocrine therapy.
The innovative molecular structure, targeting specificity and high efficacy, with its unique pharmacokinetics/pharmacodynamics (PK/PD), has allowed for continuous oral administration of Lerociclib without the need for treatment breaks. It achieves sustained target inhibition and antitumor effects while significantly reduces the common adverse effects of CDK4/6 inhibitors, such as severe myelosuppression and diarrhea.
The LEONARDA-1 clinical study has demonstrated that the combination therapy of Lerociclib with Fluvestran could 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%, which was a relatively low percentage of grade 3/4 myelosuppression, and only a 5.1% incidence rate of grade 4 neutropenia.
The LEONARDA-1 clinical study enrolled a high proportion of refractory patients, including patients with liver metastasis, treated with primary resistance, with four or more metastatic organs, and received first-line chemotherapy at an advanced stage. The use of Lerociclib substantially improved the 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.
The LEONARDA-2 clinical study also demonstrated superior efficacy and safety profile in combination with letrozole for the treatment of HR+/HER2- locally advanced or metastatic breast cancer patients who had not received prior systemic antitumor therapy.
The interim analysis showed that Lerociclib significantly reduced the risk of disease progression in patients by more than 50%, based on investigator-assessed PFS: hazard ratio (95% CI) and p-value of 0.464 (0.293, 0.733), p=0.0004, respectively; mPFS was in the Lerociclib group. PFS based on IRC assessment: hazard ratio (95% CI) and p-value of 0.457 (0.274, 0.761), p=0.0011, respectively.
The safety advantage was reaffirmed: the overall incidence rate of gastrointestinal adverse events ("AEs") was low and mild, with grade 3 diarrhea occurred in only one patient (0.7%). No grade ≥3 nausea or vomiting has occurred, and grade 4 neutropenia occurred in only 5.1% of the patients.
Currently, the Company is actively pushing forward the commercial cooperation in respect of GB491 (Lerociclib). As at 30 June 2024, the Company has received several term sheets on sales cooperation from various local pharmaceutical companies.
The transfer of technology for local production of GB491 (Lerociclib) has been initiated.
The latest research data of GB263T (EGFR/cMET/cMET, TsAb) has been internationally recognized
GB263T (EGFR/cMET/cMET, TsAb) is 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 profile. 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.
In pre-clinical studies, GB263T (EGFR/cMET/cMET, TsAb) effectively thwarted ligand-induced phosphorylation of EGFR and cMET 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.
As of 31 December 2023, a total of 15 patients had received at least one GB263T treatment. All patients had received previous third-generation EGFR-TKI and platinum-based chemotherapy and the median number of prior lines of systemic therapy was 3.
GB263T has shown promising efficacy at the therapeutic dose range (1,260-1,680 mg).
The objective response rate (ORR) of patients with EGFR-sensitive mutations and resistance to the third-generation TKI treatment at the therapeutic dose range was about 30%;
An apparent benefit was observed in three patients who have developed drugresistant cMET changes after a third-generation TKI treatment.
At the same time, an advantage of safety profile was also demonstrated.
The infusion reaction rate was relatively low and mild;
The incidence rates of nail groove and rash were mild (grade 1/2) with only grade 1 diarrhea;
No MET target-related peripheral edema toxicity has been reported.
These updated research data have been accepted by the ESMO (Free ESMO Whitepaper) Congress 2024 and will be published on 14 September 2024.
Focused on developing targets and projects with FIC potential.
As at 30 June 2024, five PCC molecules have been developed, all of which are the FIC/BIC bi-specific/multi-specific antibody projects;
GB268 (TsAb) has entered the investigational new drug ("IND") enabling stage. Certain CMC developments and PK/ADA and 4-week pre-toxicological experiments in cynomolgus monkeys have been completed. The preliminary results suggest that the tri-specific molecule has a good drug developability and stability, and no significant drug-related toxicity has been observed in the high, medium and low dose groups.
Abstracts of two TsAb molecule projects have been accepted for publication at the 2024 Annual Meeting of the AACR (Free AACR Whitepaper).
Topic of "Single Target and Bispecific Antibodies", Number: PO.IM01.06
Title: "Development of GB268, a tri-specific antibody targeting PD-1/CTLA-4/VEGF, with enhanced efficacy and reduced toxicity in pre-clinical studies"
Abstract:
Research background:
Immunotherapy using immune checkpoint modulators such as anti-PD1/PD-L1 have been widely used in cancer therapy. Combination use of anti-PD1 and anti-CTLA4 inhibitors may improve therapeutic efficacy but is also accompanied by severe immune related adverse events (irAEs) which limited their clinical use. Bi-specific antibody targeting PD-1/CTLA-4 such as cadonilimab has shown improved clinical benefits with reduced irAEs in cervical cancer. Vascular endothelial growth factor ("VEGF") is over expressed in various solid tumors and anti-VEGF agents inhibit neovascularization. Combined application of bevacizumab and PD-1/PD-L1 blockade displays durable and significant antitumor effects. GB268 is a tri-specific molecule that specifically targets PD-1, CTLA-4 and VEGF. The pre-clinical results show the combined effect of triple targets and good safety.
Methods:
GB268 is a hexavalent antibody with symmetrical structure, composed of anti-PD-1 VHH antibody, anti-CTLA-4 VHH antibody, and anti-VEGF conventional antibody. The design of molecule and the activity of each arm have been adjusted and explored based on the biological characteristics in order to achieve functional balance. L234A/L235A mutations have been introduced to the FC part.
Results:
GB268 specifically bound to PD-1, VEGF, and CTLA-4 effectively blocked PD-1 and VEGF pathways. To reduce the CTLA4 inhibition-induced AEs, the CTLA-4 arm only partially blocked the interaction of CTLA4 to its ligands CD80/CD86, and furthermore, the combination of CTLA-4 arm was highly dependent on PD-1 arm. GB268 displayed robust antitumor efficacy with attenuated toxicity in murine models. In multiple PBMC-humanized models including A375 melanoma model, HT29 colorectal cancer model, and NCI-H460 NSCLC model, etc., GB268 exhibited better antitumor efficacy, compared to PD-1/CTLA-4 bsAb and PD-1/VEGF bsAb, or in the combination of the three monoclonal antibodies, namely PD-1, CTLA-4 and VEGF. In arthritis induction model using hPD1/hCTLA4 KI mice, GB268 had improved tolerance than cadonilimab and at least 20-fold better safety profile than ipilimumab combined with OPDIVO.
Conclusions:
GB268 is a FIC anti-PD-1/CTLA-4/VEGF tri-specific antibody with innovative
design. Preclinical data demonstrated the efficient antitumor responses of GB268. At the meantime, immune-related AEs is alleviated. Thus, GB268 may emerge as a promising novel therapeutics for cancer treatment.
Topic of "Late-Breaking Research: Immunology 2", Number: LBPO.IM02
Title: "GBD218 – A tri-specific T cell engager (TCE) targeting BCMA and GPRC5D for treatment of multiple myeloma"
Abstract
Research background:
Multiple myeloma ("MM") accounts for 10% of all hematologic cancers. Recent advances in MM therapy have greatly increased the overall response and survival rate. However, most of the patients eventually relapse. The prognosis still remains poor. Although CAR-T and T cell engager ("TCE") targeting BCMA or GPRC5D have been highly efficacious in treating MM patients, resistance still occurs. Since the expression of BCMA and GPRC5D in MM are heterogeneous, to further improve the verall response and survival, the Company has generated a tri-specific TCE, GBD218, targeting both BCMA and GPRC5D.
Methods:
Anti-BCMA and GPRC5D nanobodies were screened from alpaca immune libraries. The format of the tri-specific antibodies was optimized by multiple rounds of in vitro activity and drug physicochemical properties evaluation. The in vivo tumor growth inhibition effects were evaluated in PBMC-humanized xenograft mouse models.
Results:
GBD218 is able to potently bind hBCMA (KD=0.4nM) and hGPRC5D (cell binding EC50 ~ 2nM). To reduce CRS and other potential AEs associated with TCEs, anti-CD3 with relatively low affinity was used. In cell-based functional assays, GBD218 showed efficient killing effect against single and double positive MM cell lines with various expression levels of BCMA and GPRC5D. Cell activation and cytokine release are nicely balanced for great killing efficacy and the low risk of CRS. The vitro results showed that GBD218 exhibited superior in vitro killing activity compared to benchmarks, including teclistamab, talquetamab, the combination of teclistamab and talquetamab, suggesting a synergistic effect of GBD218 by targeting both BCMA and GPRC5D. In xenograft models, GBD218 showed excellent antitumor activity, indicating potential for GBD218 as a promising therapeutics for MM.
Conclusions:
GBD218 is a tri-specific antibody that showed potent in vitro and in vivo antitumor activity. GBD218 efficiently kills both BCMA and/or GPRC5D expressing MM cells, which may hold promise to increase response rate and improve survival in MM patients in clinic.
Efficient operation, and continuous promotion
After successfully realizing the enterprise’s transformation into asset-light model and with regards to concentration and optimization, we will continuously seek to accelerate the clinical advancement and diversification of market expansion, so as to obtain the NDA approval 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, and GB491 (Lerociclib) combined with Letrozole for the treatment of HR+/HER2- patients with advanced breast cancer who have not previously undergone systemic antitumor therapy. The Group will also enter into agreements with local pharmaceutical companies for the sales of GB491 (Lerociclib), with a view to introducing safe, effective and well-tolerated novel therapies to address the treatment needs of the large number of patients with breast cancer in China and around the world. The transfer of technology for local production of GB491 (Lerociclib) has also been initiated simultaneously. It is expected that pharmaceutic preparation local production of GB491 (Lerociclib) will commence in 2027.
Through the close collaboration with partners, the Group will promote the clinical development of GB261 in the field of autoimmune diseases, and push forward the research and development of GB268 and multi-specific TCE at the pre-clinical stage. On the basis of the global clinical concept validation data for GB263T EGFR/cMET/cMET, TsAb), the Group will actively expand external partnership in its clinical programs.
FINANCIAL HIGHLIGHTS
Total revenue was approximately RMB14.5 million for the Reporting Period, mainly attributable to the provision of research and manufacturing services to our customers under fee-for-service contracts.
Research and development expenses were approximately RMB109.7 million for the Reporting Period, as compared with approximately RMB224.8 million for the six months ended 30 June 2023. The decrease was mainly attributable to (i) the decrease in employee benefits expenses for research and development personnel; and (ii) the decrease in our new drugs development fee and clinical trial expenses.
Total comprehensive loss was approximately RMB132.3 million for the Reporting Period, as compared with approximately RMB276.4 million for the six months ended 30 June 2023. The decrease was primary due to the decrease in expenses.
As of the end of June 2024, the cash balance of 1.03billion RMB is enough to support the operation of the company in the next 5