Advances in drug development
1.The phase III study of cytokinetic myomyosin inhibitor was successful, and Jixing Pharmaceutical has the rights and interests in Greater China
On December 27, Cytokinetics announced positive results from Sequoia-HCM, a pivotal Phase III clinical trial of aficamten in symptomatic obstructive hypertrophic cardiomyopathy (HCM). Aficamten is a cardiac myosin allosteric inhibitor that can improve myocardial diastolic function by inhibiting the overformation of myosin-actin cross bridges, thereby inhibiting myocardial hypercontraction, left ventricular hypertrophy, and decreased compliance, and is currently being developed for the treatment of obstructive hypertrophic cardiomyopathy (OHCM)**, which was granted Breakthrough Designation by the FDA in December 2021. The results of the Sequoia-HCM study showed that aficamten** significantly improved exercise capacity compared with placebo, with an increase in peak oxygen uptake (PVO2) measured by cardiopulmonary exercise testing (CPET) with a least squares mean difference of 174（1.04-2.44）ml/kg/min（95% ci）（p=0.000002), the ** effect of aficamten was consistent across all pre-set subgroups that reflected the baseline characteristics and ** strategy of the patients, including those who received or did not receive the -receptor blocker as a background**. Statistically significant (p<0.) was also observed in all 10 pre-specified secondary endpoints0001) and clinically meaningful improvements, including the Kansas City Cardiomyopathy Questionnaire Clinical Composite Score (KCCQ-CSS) at weeks 12 and 24, the proportion of patients with New York Heart Association (NYHA) functional grade improvement grade 1 at weeks 12 and 24, the change in provocative left ventricular outflow tract pressure gradient (LVOT-G) at weeks 12 and 24 and the proportion of <30mmHg, and indications for surgery for exercise load and ventricular septal volume reduction**. Aficamten was well tolerated in the study, and adverse events were generally comparable to placebo.
2.Henlius obtained FDA Fast Track Designation for HLX42 for EGFR-targeted ADC injection
On December 27, Henlius announced that, based on its collaboration with Yilian Biologics, HLX42 for EGFR-targeted antibody drug conjugate (ADC) injection developed by the company has been granted Fast Track Designation by the U.S. FDA for advanced EGFR-mutated metastatic non-small cell lung cancer (NSCLC) with EGFR mutations that have progressed after third-generation EGFR tyrosine kinase inhibitors. Previously, the IND application of HLX42 for advanced metastatic solid tumors has been approved by China's NMPA and FDA. According to Globocan 2020 data, lung cancer is the second most common malignant tumor with the highest mortality rate in the world. NSCLC accounts for about 80%-85% of all lung cancers, with EGFR mutations occurring in up to 50% in Asian NSCLC patients and about 10% in the Caucasian population. At present, EGFR targeting**, including EGFR tyrosine kinase inhibitors (TKIs), is the standard first-line approach for patients with advanced NSCLC with EGFR mutations**, however, patients with disease progression after ** have limited options in follow-up**, and there is a huge unmet clinical need. According to a press release from Henlius, HLX42 is a novel ADC drug candidate targeting the epidermal growth factor receptor (EGFR) and is one of the first ADC products of Henlius to enter the clinical stage. HLX42 is a novel small-molecule inhibitor of DNA topoisomerase I, which blocks DNA replication by causing DNA double-strand breaks, resulting in apoptosis of tumor cells. After intravenous infusion, the linker-toxin of HLX42 can be specifically lysed and released in the tumor microenvironment, with a strong bystander killing effect, and the unique mechanism of action makes HLX42 have a larger window and enhance the best effect of ADC in solid tumors.
3.Against breast cancer!The sub-journal of Nature published the clinical data of Hengrui Pharmaceutical's pyrotinib combined with **
On December 26, Hengrui Pharmaceutical announced that the data of the open-label, multi-center phase 2 clinical study (PANDORA) of pyrotinib in combination with docetaxel in first-line **HER2-positive metastatic breast cancer developed by the company have been published in Nature Communications, a sub-journal of Nature magazine. The study was led by Professor Xiaojia Wang from the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital). The results of the study showed that the combination of pyrotinib and docetaxel** showed good anti-tumor activity and associated progression-free survival (PFS) benefits. Pyrotinib is an oral HER1, HER2 and HER4 tyrosine kinase inhibitor (TKI) independently developed by Hengrui. The Pandora study is a national multicenter, single-arm trial to explore the efficacy and safety of pyrotinib in combination with docetaxel in first-line**HER2-positive advanced breast cancer. The Pandora study was designed in two phases with SIMon, with objective response rate (ORR) as the primary endpoint and secondary endpoints as PFS, duration of response (DOR), clinical benefit rate (CBR), and safety. In addition, a sequencing panel of 561 genes was used for biomarker analysis to explore correlations with efficacy. The results of the trial showed that pyrotinib in combination with docetaxel showed a good anti-tumor effect in first-line **HER2-positive breast cancer: the confirmed ORR was 79 in the intention-to-treat analysis (ITT) population7% and 81 in the PP population8%；TTR (time from first dose to first PR CR) is 151 months, reflecting the ability of pyrotinib to rapidly shrink tumors and reduce tumor burden;The median PFS was 16At 0 months, the number of people who had previously been treated with trastuzumab was 20At 8 months, 14 were previously trastuzumab-naïve8 months, in line with the Phila research trend.
4.The FDA suspended the clinical trial of Iovance's Til**LN-145
On December 27, Iovance Biotherapeutics announced that the FDA recently (December 22) suspended a clinical trial codenamed IOV-LUN-202 in response to recently reported grade 5 (fatal) serious adverse events that may be related to a nonmyeloablative lymphodepletion conditioning regimen. The IOV-LUN-202 study is designed to evaluate the efficacy of TIL**LN-145 in patients with advanced (unresectable or metastatic) non-small cell lung cancer (NSCLC) who have progressed on prior chemotherapy and PD-1** without EGFR, ROS, or ALK genomic mutations and who have received at least one FDA-approved target** if they have other tumor mutations. Iovance said the clinical hold of the IOV-LUN-202 study has no impact on any other clinical trials of the company and is independent of another Til**lifileucel under review by the FDA, which has a PDUFA date of Feb. 24, 2024, for advanced melanoma. Iovance said it will pause the enrollment of new patients and the conduct of LN-145** in the IOV-LUN-202 trial. Patients who previously received LN-145** in the IOV-LUN-202 trial will continue to be monitored and followed according to the trial protocol. Patients who have already undergone tumor resection will continue to receive the LN-145** regimen with additional precautions to reduce risk. Iovance Biotherapeutics aims to be a global leader in the innovation, development and delivery of tumor-infiltrating lymphocytes (TILs)** for cancer patients. The company pioneered a way to revolutionize cancer** by harnessing the human immune system's ability to recognize and destroy different cancer cells in each patient's body. The Company's lead late-stage TIL product candidate, lifileucel, is on track to be the first approved single-use solid tumor cancer cell** in metastatic melanoma.
5.Boan Biotech has independently developed two claudin182. Targeted drugs were granted FDA orphan drug designation
On December 27, Boan Biotech announced its self-developed two targeting claudin182. The innovative antibody BA1105 and the innovative antibody drug conjugate (ADC) BA1301 have been granted orphan drug designation by the US FDA for the indication of pancreatic cancer. Pancreatic cancer is regarded as one of the deadliest cancers and is a major problem in clinical diagnosis and treatment. Due to the insidious early symptoms of the disease, most patients are in the middle and advanced stages of the disease once discovered. The prognosis of advanced pancreatic cancer is extremely poor, and palliative chemotherapy is the mainstay, and the overall efficacy and prognosis are extremely unsatisfactory. claudin 18.2 protein is a transmembrane protein involved in the regulation of tight junctions between cells, which can be continuously and stably highly expressed in digestive tract tumors. The study found that claudin182 It is expressed in 70% of gastric cancer patients, 50% of pancreatic cancer patients and 30% of esophageal cancer patients, which makes it a molecular target with great potential for antitumor drugs. According to a press release from Boan Biotech, BA1105 is a recombinant anti-Claudin182. Fully human IgG1 monoclonal antibody for **Claudin182. Positively expressed advanced solid tumors. The product uses antibody-dependent cell-mediated cytotoxicity (ADCC) enhancement technology, which gives it enhanced potency potential. BA1301 is Boan Biotech's first clinical stage ADC product and is currently in Phase 1 clinical trial in China. BA1301 uses site-specific conjugation technology to bind a small molecule cytotoxin to target Claudin 182. The monoclonal antibody conjugation guides the small molecule toxin to reach the tumor site through the targeting of the antibody, which can play a role in killing the tumor while reducing the toxicity of the small molecule toxin and improving the window.
6.Tianguangshi CD3 GPRC5D BCMA triclonal antibody was approved for clinical trial
On December 28, the official website of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration of China announced that Tianguangshi's Class 1 new drug MBS314 injection was approved for clinical trial, and it is planned to develop *** refractory multiple myeloma (R r mm). According to public information, MBS314 injection is a CD3 BCMA GPRC5D trispecific antibody. According to public information, BCMA is mainly expressed in mature B lymphocytes and plasma cells, and one of its biggest characteristics is that it is expressed in all multiple myeloma cells, which is an ideal antigen target for multiple myeloma. GPRC5D is a novel multiple myeloma target that is highly expressed on the surface of multiple myeloma cells and non-malignant plasma cells, as well as some healthy tissues such as ** and lingual epithelial cells. According to Tianguangshi's earlier press release, MBS314 has a differentiated CD3-binding epitope, which can achieve a very low affinity for T cells but a long-lasting activation and killing effect, giving the product a better safety profile. MBS314 can bind to BCMA and GPRC5D with high affinity at the same time, which can overcome the heterogeneity of BCMA and GPRC5D expression of tumor cells in patients, and more completely and effectively kill and remove tumor lesions. Previously, Tianguangshi announced the latest preclinical research data of MBS314 at the 2023 American Association for Cancer Research Annual Meeting (AACR), and the ex vivo killing of primary tumor cells of patients and in vivo tumor growth experiments in mice showed that MBS314 has a better tumor killing effect than bispecific antibodies targeting CD3 BCMA and CD3 GPRC5D.
Industry information
1.Over $1.7 billion!Astellas and Elpiscience have entered into a partnership
On December 28, Elpiscience announced that it has entered into a collaborative development and licensing agreement with Astellas for the new BIME (bispecific antibody macrophage engagger) platform and drug candidate ES019 and another molecule program. The two companies will collaborate on the development of the two projects, and Elpiscience will also grant Astellas the co-development rights to two additional products. If Astellas exercises its rights, Elpiscience will grant it an exclusive right to further research, develop, manufacture and commercialize the related products. Elpiscience will receive an upfront payment of $37 million and an exercise fee from Astellas. In addition, Elpiscience will receive additional R&D funding from Astellas to advance the project. Following the exercise of all of Astellas' interests, Elpiscience will be eligible for potential development, registration and commercialization milestone payments totaling more than $1.7 billion. Elpiscience will also receive single-digit to double-digit percentage royalties on net global sales of licensed products. BIME is a bispecific antibody platform based on tumor-associated antigen (TAA) and inhibitory receptor (SIRP) on macrophages, BIME molecules bind to TAA to specifically direct tumor-associated macrophages (TAMs) to tumor cells, and then activate the "eat me" signal on macrophages and block the CD47-SIRP "don't eat me" signaling pathway, thereby efficiently causing the specific killing effect of macrophages on tumor cells. The ES019 project is based on the PD-L1 SIRP bispecific antibody molecule generated by the BIME platform. TAMs are one of the most abundant immune cells in a variety of tumor microenvironments and are associated with poor prognosis and immune checkpoint inhibitor resistance. As a novel technology, BIME is expected to change the immunosuppressive state in the tumor microenvironment by activating macrophages and reprogramming TAMs, thereby providing a new option for cancer patients who are immune to existing tumors.
2.Innovent Biologics and Xuanzhu Biologics have entered into a collaboration to explore the potential of sintilimab in combination with a new ADC drug** for advanced solid tumors
Rockville, USA and Suzhou, China, December 28 – Innovent Biologics Group (HKEX***01801), a biopharmaceutical company dedicated to the research and development, production and sales of innovative drugs in the fields of oncology, autoimmunity, metabolism, ophthalmology and other major diseases, and Xuanzhu Biotechnology Co., Ltd. (hereinafter referred to as "Xuanzhu Biotech"), jointly announced that they have entered into a clinical research and drug supply cooperation agreement to discuss the cooperation agreement for sinlidicumab injection (PD-1 inhibitor, trade name: Tyvyt ) and Xuanzhu Biotech's novel bispecific antibody drug conjugate KM-501 (targeting HER2-HER2 biepitope antigen ADC) to carry out clinical research cooperation in combination therapy. Under the terms of the agreement, Innovent will provide investigational use of sintilimab, and Xuanzhu will conduct a Phase Ib clinical study in China to evaluate the safety, tolerability and preliminary efficacy of sintilizumab in combination with KM-501 in patients with multiple solid tumors. Jointly developed by Innovent Biologics and Eli Lilly, Tyvyt (sintilimab injection) has been approved for seven indications, covering non-squamous non-small cell lung cancer, squamous non-small cell lung cancer, EGFR mutant lung cancer, liver cancer, gastric cancer, esophageal cancer, and Hodgkin lymphoma, all of which are included in the National Medical Insurance List, and is the only PD-1 inhibitor that has included all five first-line high-incidence tumor types** in the National Medical Insurance Catalog. KM501 is designed by Xuanzhu Biopharma through the MEBS-Ig (antibody-edited bispecific antibody) platform with independent intellectual property rights, targeting two different domains of HER2 bispecific antibody ADC, suitable for locally advanced metastatic solid tumors with HER2-positive expression, amplification or mutation, including related advanced tumors with low HER2 expression. The drug candidate was approved by the National Medical Products Administration of China for clinical trials in March this year and is currently in the phase I clinical phase of single-agent ramp-up. Preclinical studies have shown that KM-501 is superior to DS-8201 and Herceptin in terms of intracellular endocytosis rate, internalization rate and in vitro inhibitory activityKM501 has better antitumor activity than DS-8201 in tumor models with high and low HER2 expression.