Novartis Secures Chinese Clinical Approval for Three Novel Biologics Targeting PD-1, TGF-β, and TIM-3 for Myelofibrosis

Source | Medical Perspective

On September 17, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration released its latest public notice, indicating that three Class 1 biologic new drugs from Novartis have received implicit approval for clinical trials. These include the TGF-β inhibitor NIS793, the PD-1 inhibitor PDR001, and the monoclonal antibody MBG453 targeting the TIM-3 receptor. According to the CDE website, the proposed indications for these three newly approved clinical trials in China are: treatment of myelofibrosis with MBG453 and NIS793 as monotherapies or in combination with PDR001.

Screenshot source: CDE official website

According to the Novartis website, the three-drug combination therapy for myelofibrosis is currently undergoing Phase 1 clinical trials. In this study, novel combination therapies, including those with immunotherapeutic agents, will focus on identifying promising regimens that offer acceptable safety and efficacy profiles beyond JAK inhibitors. Notably, the immunotherapy combination of MBG453 and NIS793 may hold potential for targeting myelofibrosis across its genetic heterogeneity.

(1) TGF-β Inhibitor: NIS793

NIS793 is a transforming growth factor-beta 1 (TGF-β) inhibitor. The TGF-β signaling pathway primarily participates in mediating biological processes such as normal tissue and organ growth and development, as well as the body’s immune response, by regulating cellular processes including growth, proliferation, differentiation, migration, and apoptosis. Studies have shown that TGF-β1 affects the apoptosis of fibroblasts and myofibroblasts and is directly associated with T-cell exhaustion and the upregulation of PD-L1 and CTLA-4 within the tumor microenvironment. These findings suggest that NIS793 holds broad application potential in various fibrotic and oncologic diseases.

According to the ClinicalTrials.gov website, Novartis has currently registered three clinical trials involving NIS793. These are: a Phase 1/1b study of NIS793 in combination with PDR001 in patients with advanced malignant tumors; a Phase 2 study of NIS793 (with or without PDR001) combined with standard-of-care (SOC) chemotherapy as first-line treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC); and a Phase 1 study of NIS793 in combination with MBG453 and PDR001 for adult myelofibrosis.

(2) PD-1 Inhibitor: PDR001 Concentrated Solution for Injection

PDR001 is a PD-1 inhibitor developed by Novartis, also known as spartalizumab. Currently, Novartis is conducting clinical trials of PDR001 as monotherapy or in combination with other drugs for various types of cancer. Among these, the fastest has progressed to Phase 3 clinical trials, which involves the use of PDR001 in combination with the B-Raf inhibitor dabrafenib and the MEK inhibitor trametinib for treating patients with metastatic melanoma carrying BRAF V600 mutations. Preliminary efficacy results have been achieved, with an objective response rate of 78% and a complete response rate of 42%.

▲Introduction to Sparta-DabTram Therapy (Image source: Reference [2])

PDR001 has received clinical trial approval in China, with the proposed indication being its use in combination with drugs such as MBG453 and NIS793 for the treatment of myelofibrosis. According to the official website of the Center for Drug Evaluation (CDE), PDR001 had previously obtained implicit approval for more than 10 clinical trials in China. These include its use in combination with the MET inhibitor INC280 for previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) that is EGFR wild-type and ALK rearrangement-negative; as well as the use of the SHP2 inhibitor TNO155 in combination with the CDK4/6 inhibitor LEE011, or in combination with PDR001, for the treatment of specific advanced malignancies.

Furthermore, according to the Drug Clinical Trial Registration and Information Publicity Platform, patient enrollment has been completed for the Phase 2 clinical study of PDR001 monotherapy in patients with advanced nasopharyngeal carcinoma, as well as for the Phase 1b/2 study of PDR001 alone or in combination with INC280 for advanced hepatocellular carcinoma. A Phase 1 study of TNO155 in combination with LEE011 or PDR001 for specific advanced malignancies is also ongoing, covering cancer types including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, gastrointestinal stromal tumors, and colorectal cancer.

Screenshot source: chinadrugtrials

(3) TIM-3 antibody: MBG453

MBG453 is a monoclonal antibody targeting the TIM-3 receptor. The TIM-3 receptor is an inhibitory receptor expressed on the surface of immune cells and myeloid leukemia cells. Its expression level correlates with the severity of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). By inhibiting the function of the TIM-3 receptor, MBG453 can simultaneously target myeloid leukemia cells and immune cells, thereby not only killing cancer cells but also potentially enhancing the activity of immune cells.

▲ Therapeutic Strategies Targeting the TIM-3 Receptor (Image source: Reference [2])

Previously, MBG453 demonstrated favorable safety and anticancer activity in Phase I clinical trials involving patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Reportedly, Novartis has high hopes for this innovative therapy, believing it could become a cornerstone in the treatment of various myeloid disorders.

Currently, MBG453 is undergoing multiple clinical trials, with indications including AML, MDS, and advanced malignancies. According to the Novartis website, the fastest-progressing investigational project for MBG453 has reached Phase 3 clinical trials, targeting high-risk myelodysplastic syndromes (HR-MDS).

In July this year, MBG453 received implicit approval for clinical trials in China for the first time. The intended indication is to be developed for use in combination with azacitidine for the treatment of patients with intermediate-, high-, or very-high-risk myelodysplastic syndromes (MDS) according to the IPSS-R stratification, or chronic myelomonocytic leukemia-2 (CMML-2). According to the Drug Clinical Trial Registration and Information Publicity Platform, this is a randomized, double-blind, placebo-controlled Phase III international multicenter study, which is currently ongoing.

Screenshot source: chinadrugtrials

Novartis is committed to enhancing the accessibility of innovative medicines, enabling more patients to benefit from breakthroughs as quickly as possible. Since 1987, Novartis has had more than 60 new drugs approved in China, covering therapeutic areas such as cardiovascular disease, diabetes, ophthalmology, immunology and dermatology, central nervous system disorders, respiratory diseases, and transplantation. According to the Novartis website, the company expects to submit nearly 30 applications for approval of new products and indications in China between 2020 and 2024.

References:

[1] Official Website of China’s National Medical Products Administration and Center for Drug Evaluation. Retrieved Sep 17, 2020, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21#

[2]Novartis R&D Day. Retrieved December 5, 2019, from https://www.novartis.com/sites/www.novartis.com/files/2019-12-05-novartis-r-d-day-investor-presentation.pdf

[3] Novartis Official Website and Public Information

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