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.
As the world's first PD-1 for peripheral T-cell lymphoma (PTCL), Aibining (GB226, Geptanolimab) has been granted priority review by the National Medical Products Administration (NMPA) for its marketing application (NDA).
Relapsed and refractory peripheral T-cell lymphoma (r/r PTCL) represents a highly unmet medical need with a median overall survival (OS) of less than one year for patients who failed first line therapy. Novel combination therapies have been extensively explored to enhance clinical benefit for r/r PTCL patients.
Comparing to existing therapies approved for PTCL, highlights of GB226 are listed below:
- Demonstrated promising efficacy with an Independent Review Committee (IRC) - assessed ORR of 39.4%, which is highly competitive to the other approved drugs in r/r PTCL
- The clinical benefit is very sustainable. As of 30 April 2021, according to IRC assessment, the median Duration of Response (DOR) is over 18 months among those patients with confirmed response, nearly twice that of existing therapies.
- The clinical benefit has been shown in the major PTCL subtypes including the very aggressive subtypes (ALCL ALK-ORR: 53.8%, ENKTL ORR: 64.7%).
- Relapsed or refractory patients who failed Chidamide also obtained the benefit, and the ORR reached 37.5%.
- As a drug with a new MOA, GB226 has a good safety profile with much lower hematological and gastrointestinal toxicities compared with other approved r/r PTCL regimens.
- GB226 is the only drug which has the low overlapped toxicities with the potential combination therapies. Together with the unique Immuno-Oncology (I/O) MOA and the promising clinical activity, GB226 can provide r/r PTCL patients better treatment results via potential combination therapy.
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.
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.
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.
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%.
Based on sufficient clinical data showing that GB491 exhibits no ethnic difference, it was successfully exempted from a combination study with fulvestrant. As such, the product could rapidly enter into a Phase 3 clinical trial almost one year earlier than scheduled. The first-line HR+/HER2- trial proceeded smoothly with the design of a safety lead-in period, which was at least six months faster than expected. With adaptive, seamless study design, scientific-based data, seamless enrollment strategy and excellent execution, the phase 3 trials for both first and second line could be accelerated by approximately 12 months.
The company’s CMC and project management team in cooperation with four CDMOs in China, Europe and America, has solved various CDMO technical and communication problems across countries and regions during the collaboration, ensuring strict compliance with relevant regulations in each country and region. API, clinical supplies of GB491 and placebo have been successfully produced within one year to supply for Phase 3 study, guaranteeing the efficient implementation of projects.
- In March 2021, we obtained investigational new drug (“IND”) and Ethic Committee (“EC”) approvals for the Phase 1b bridging studies: (1) GB491 and Letrozole in first line HR+/ HER2- advanced breast cancer; and (2) GB491 and Fulvestrant in second line HR+/HER2- advanced breast cancer.
- In May 2021, we submitted IND applications for the two Phase 3 clinical studies.
- In June 2021, we received EC approval for the Phase 3 clinical trial of GB491 and Fulvestrant in second line HR+/HER2- advanced breast cancer.
- In July 2021, the Company has received IND approvals from the NMPA for the two Phase 3 clinical studies: (1) GB491 and Letrozole in first line HR+/HER2- advanced breast cancer; and (2) GB491 and Fulvestrant in second line HR+/HER2- advanced breast cancer.
- In August 2021, the Ethic Committee Approval for the phase 3 clinical trial in first line HR+/HER2- advanced breast cancer has been obtained.
- On August 26, 2021, the clinical trial of GB491 combined with flurvestrine in the treatment of second-line HR+/HER2- advanced breast cancer was approved by the Office of Genetics.
- On September 8, 2021, the company achieved the first patient dose of the (CDK4/6) Phase 1b bridging study: GB491 and Letrozole in first-line HR+/HER2- advanced breast cancer.
- On October 28, 2021, the company achieved the first patient dose for GB491 and Fulvestrant in second-line HR+/HER2- advanced breast cancer.
- In January 2022, the first patient has been successfully dosed in a Phase III clinical trial of GB491 (Lerociclib cyclin-dependent kinase 4/6 inhibitor) for first line HR+/HER2- advanced breast cancer.
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.
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.
In the clinical trial of GB492, an innovative FIH trial design was employed combining the dose escalations when GB492 is administered alone and when it is administered with GB226 in one FIH study. It is the first STING agonist combination therapy having obtained clinical trial approval in the country.
- In March 2021, we submitted the IND application for the Phase 1/2 clinical trial of GB492 mono or in combination with GB226 in patients with advanced/treatment-refractory malignancies to the NMPA.
- In May 2021, the IND of GB492 was approved by NMPA, in which an innovative FIH trial design was employed to combine the dose escalations when GB492 is administered alone and when it is administered with GB226 in ONE FIH study.
- In July 2021, the Ethic Committee approval for the Phase 1/2 clinical trial of GB492 in patients with advanced/treatment-refractory malignancies was received in July 2021.
- 16 September 2021, the first patient was dosed in the Phase I/IIa clinical trial of GB492 in China.
In the I/II clinical trial of GB492 as a monotherapy or in combination with GB226 (Aibining?, Geptanolimab) in patients with advanced/treatment-refractory malignancies:
- In January 2022, monotherapy clinical trials finished
- In January 2022, dose escalation up to 400ug completed
- In January 2022, approval from CDE was obtained to directly conduct a dose-escalation study of GB492 in combination with PD-1 in subjects with advanced malignancy, based on the available data on 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 is administered alone and when it is administered with GB226. It is the first STING agonist combination therapy that has obtained clinical trial approval in China.
GB261 is a highly differentiated CD20/CD3 bi-specific antibody developed in-house. GB261 is the first T-cell engager with very low CD3 binding affinity and maintaining Fc effector functions (ADCC and CDC). With similar binding affinity to CD20 as rituximab, GB261 significantly inhibits rituximab-resistant cancer cell proliferation by in vitro assays and in vivo models.
More importantly, GB261 induces low levels of cytokine production by hPBMC and in monkeys, indicating low occurrences of CRS. Thus, GB261 is a highly promising bispecific therapeutic antibody for B cell malignancies. It may ultimately provide a concept shift to better and safer T-cell engager antibody drugs for various cancers.
With CMC fully compliant with NMPA and US FDA standard, we plan to conduct global multi-center clinical trials across Australia, China and the US. Dual IND fillings with the NMPA in China and FDA in the US are in progress. Benefiting from the strong CMC development platform, it only took about twelve months from sequence determination of GB261 to providing clinical materials with high purity to clinical study centers.
The Genor team has received both EC and CTN approvals for the GB261’s FIH trial in Australia, in which an optimized trial design was employed to achieve a good balance of patient safety and trial acceleration. Leveraging the differentiated product features, the starting dose of GB261 clinical trial was selected to be higher than other compounds in the same class, still ensuring safety and meanwhile minimizing patients’ exposure to ineffective doses. As such, the effectiveness of dose escalation was improved significantly.
- 19 October 2021, the first patient was dosed in the First in Human (FIH) clinical trial of GB261 (CD20/CD3, BsAb) for the treatment of B-cell non-Hodgkin Lymphoma (B-NHL) in Australia Peninsula & South Eastern Haematology & Oncology Group Center.
- The trial of first dose group was completed in November 2021, and data showed that T1/2 of this product exceeded one week. GB261 was very safe in the first dose level with no CRS and which is in line with the product’s designed differentiated features.
- As at August 2022, we are in the process of a dose escalation up to 10mg in the clinical trial of GB261 for the treatment of B-cell non-Hodgkin Lymphoma (B-NHL) in Australia. We have obtained preliminary clinical Proof of Concept (POC) data and observed objective responses, which were consistent with the molecular design mechanism of GB261, indicating a good safety and pharmacokinetic profile.
- On 18 March 2022, the NMPA accepted GB261’s IND application, and made an approval for its phase I/II clinical trial on 23 May. On 8 September 2022, GB261(CD20/CD3, bispecific antibody) has achieved the first patient dose in a Phase I/II clinical trial in China.
GB263T has been designed as a tri-specific antibody targeting EGFR and two different cMet epitopes. The tri-specific antibody has two Fabs to bind EGFR. Its Fc fragment has been mutated to enhance Fc functions. Thus, GB263T with highly differentiated design, exhibits multiple mechanisms of action to inhibit primary and secondary EGFR mutations and cMet signaling pathway simultaneously. The significant anti-tumor activities have been demonstrated by in vitro studies and in vivo animal models.
GB263T potently blocks ligand-induced phosphorylation of EGFR and c-Met, and demonstrated better dual inhibition of EGFR and cMet signaling pathways compared to JNJ analogue. GB263T effectively induced internalization of EGFR and cMet, and downregulated the expression levels of both EGFR and cMet. GB263T strongly inhibited cell growth of Ba/F3 cells harboring EGFRexon20ins mutation, and resulted in dose-dependent inhibition of tumor growth in in vivo studies. GB263T showed remarkable ADCC effects to kill cancer cells harboring resistance mutations of EGFR or cMet alterations. In addition, GB263T did not show any major toxicities in monkeys, even at a high dose of 100mg/kg given weekly for 4 weeks in a pre-tox study.
The research and development of GB263T fully demonstrated the advantage of cross-team collaboration and helped expand the organization’s international capabilities and outreach. Closely working with globally renowned KOLs, the clinical trial protocol was rapidly finalized the day that toxicology data was obtained, substantially speeding up the submission to the EC.
Benefiting from the effective and fast-moving execution ability of the Group’s CMC, the process technology development, toxicology study, clinical drug manufacturing, medical and regulatory preparation, as well as clinical trial application of GB263T, were all completed within only twelve months in compliance with the international standards and much faster than the industry average. Moreover, the product quality is ensured with high expression level of 5-6g/L and high purity of 99.5%.
- The FIH clinical trial application of GB263T to the Bellberry Human Research Ethics Committee (HREC) was submitted in Australia on 20 December 2021.
- The new drug clinical trial application of GB263 in China was formally accepted by the NMPA on 28 March 2022, the phase I/II clinical trials of which was approved on 2 June 2022.
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.
- In February 2022，GB242 (Jiayoujian?, Infliximab Biosimilar) received approval for the treatment of Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriasis, Adult Ulcerative Colitis, Adult and Pediatric Crohn's Disease and Fistulizing Crohn’s Disease.
- By August 2022. GB242 (Jiayoujian?, Infliximab Biosimilar) has passed the consistency evaluation of the quality and efficacy of generic drugs and online procurement in Yunna, Shandong, Hainan, Guangzhou of Guangdong province, Hebei, Anhui, Shanghai, Tianjin and other 20+ provinces.
GB242 (Jiayoujian?, Infliximab Biosimilar) will be commercialized through cooperation with a focus on the development of gastrointestinal indications, such as ulcerative colitis. By doing so, we are able to create a differentiation advantage from other competing products in the market and maximize the value of this Inflixmab Biosimilar.