Chinese-Produced Anticancer Drugs Granted Designations by the FDA

As we wave goodbye to 2020 and embrace the arrival of 2021, it’s time for us to review, sum-up, and outlook. In recent years, more and more Chinese-produced innovative drugs have gone global and received Fast Track designations from the FDA. Receiving the fast track designations means that the new drugs have shown potential to meet unmet medical needs in early trials, and the pharmaceutical companies can have more opportunities to communicate with the FDA to speed up the entire R&D process. Then, which are the Chinese innovative oncology drugs that have granted Breakthrough Therapy designations or Fast Track designations in 2020?

Pharmaceutical product: Sintilimab

Target: PD-1

Company: Innovent

The FDA granted an Orphan Drug designation to sintilimab (TYVYT) on Apr. 14, 2020, for the treatment of esophagus cancer, which was the third Orphan Drug designation obtained by TYVYT, followed by being granted the designation for peripheral T-cell lymphoma by the EMA and the designation for T-cell lymphoma by the FDA.

As an anti-PD-1 monoclonal antibody co-developed by Innovent and Eli Lilly and Company, sintilimab was approved for marketing in China in Dec. 2018 for the treatment of relapsed/refractory classical Hodgkin's lymphoma (r/r cHL) and has been included in the National Reimbursement Drug List of China. Furthermore, two new indication applications for the products: first-line treatment for non-squamous non-small cell lung cancer (NSCLC) and first-line treatment for non-squamous NSCLC in combination with gemcitabine have been accepted by the NMPA.

Pharmaceutical product: Sugemalimab (CS1001)

Target: PD-L1

Company: CStone Pharmaceuticals

CStone Pharmaceuticals announced in Oct. 2020 that sugemalimab received a Breakthrough Therapy designation from the U.S. FDA for the treatment of adult patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL).

As a fully human, full-length anti-PD-L1 monoclonal antibody, sugemalimab mirrors the natural G-type immunoglobulin 4 (IgG4) human antibody, which may reduce the risk of immunogenicity and toxicities in patients, showing a potentially unique advantage over similar drugs. According to the data presented at the 2020 annual meeting of the Chinese Society of Clinical Oncology (CSCO), the objective response rate (ORR) of 38 evaluable patients with ENKTL was 44.7%, with a complete response (CR) rate of 31.6%; the median duration of response (mDoR) was 16.8 months. The median overall survival (mOS) of the 43 patients who received study drug treatment was 19.7 months, and the 1-year OS rate was 55.5%.

Bio pharmaceutical products: KN026

Target: HER2

Company: Alphamab

Pharmaceutical product: KN046

Target: PD-L1/CTLA-4

Company: Alphamab

Alphamab Oncology announced on Dec. 23, 2020, that the combination therapy of the bispecific antibodies KN026 (anti-HER2 bispecific antibody) and KN046 (anti-PD-L1/CTLA-4 bispecific single domain antibody) independently developed by the company received an Orphan Drug designation from the FDA for the treatment of HER2-positive or low expressing gastric or gastroesophageal junction cancer.

This is the third Orphan Drug designation granted to Alphamab. According to early trial data, the objective response rate of KN046 in combination with KN026 in HER2-positive tumors was 64.3%, and the disease control rate 92.9%. Its phase Ⅱ pivotal clinical study (SEARCH-01) is in planning. Let’s look forward to the new approach that KN046 plus KN026 will provide to address the unmet medical need in near future.

Pharmaceutical product: Disitamab vedotin (RC48)

Target: HER2

Company: RemeGen

The U.S. FDA granted a Breakthrough Therapy designation to disitamab vedotin in Sept. 2020 for the indication of second-line treatment of HER2-expressing (IHC 2+ or IHC 3+) locally advanced or metastatic urothelial cancer (UC). In Nov. 2020, disitamab vedotin received approval in the U.S. for the clinical trial of treating advanced or metastatic gastric cancer and gastroesophageal junction adenocarcinoma,  and a Fast Track designation from the U.S. FDA for the treatment of gastric cancer. According to public data, RemeGen plans to initiate clinical studies of disitamab vedotin for the treatment of UC and gastric cancer in the U.S. in 2021.

Disitamab vedotin is a humanized anti-HER2 ADC conjugated with monomethyl auristatin E (MMAE) via a cathepsin cleavable linker, with an optimized drug-to-antibody ratio (DAR). It is the first independently developed ADC applied for production in China, with the marketing application included by the CDE in the priority review.

Pharmaceutical product: Toripalimab (JS001)

Target: PD-1

Company: Junshi Biosciences

Junshi Biosciences announced on Sept. 11, 2020, that toripalimab received the FDA’s Breakthrough Therapy designation for the treatment of nasopharyngeal carcinoma, making it the first Chinese-produced anti-PD-1 monoclonal antibody that receives the FDA’s Breakthrough Therapy designation. It was another registration development of toripalimab, followed by its receipt of the FDA’s Orphan Drug designation in May 2020.

The approval was based on a Phase II open-label pivotal study involving 190 patients with advanced cases who have failed systemic treatment. The drug met the primary endpoint on the overall response rate. Furthermore, the patient enrollment for the phase III clinical study JUPITER-02 of toripalimab injection in combination with chemotherapy as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) has completed.

Pharmaceutical product: Plinabulin

Target: GEF-H1

Company: BeyondSpring

BeyondSpring announced in Sept. 2020 that the U.S. FDA granted a Breakthrough Therapy designation to plinabulin concentrated solution for injection in patients with non-myeloid malignancies for the prevention of chemotherapy-induced neutropenia (CIN).
As a guanine nucleotide exchange factor (GEF)-H1 activator, plinabulin achieves early protection of white blood cells in the bone marrow by reversing a chemotherapy-induced-block in the bone marrow, and maintaining the normal levels of neutrophils, and reduces the occurrence of early CIN by a mechanism of action different from that of G-CSF (granulocyte colony-stimulating factor).

Pharmaceutical product: Zanubrutinib

Target: BTK

Company: BeiGene

As a Chinese-produced innovative drug, zanubrutinib is a highly selective BTK inhibitor independently developed by BeiGene. It received the FDA’s accelerated approval in Nov. 2019 as a second-line treatment of mantle cell lymphoma (MCL) in adults who have received at least one prior therapy.

Zanubrutinib was officially approved for marketing by the U.S. FDA in Dec. 2019 for the treatment of R/R MCL in adults who have received at least one prior therapy, making it the first new anticancer drug developed in China and approved for marketing by the FDA based on clinical studies in Chinese patients.

Zanubrutinib was approved in June 2020 in China through priority review for MCL in adults who have received at least one prior therapy and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in adults who have received at least one prior therapy. Furthermore, the marketing applications of zanubrutinib have been accepted in Europe and Israel.

Pharmaceutical product: Sulfatinib

Target: VEGFR, FGFR, CSF-1R

Company: Hutchison MediPharma

The U.S. FDA granted two Fast Track designations to sulfatinib in Apr. 2020 for the treatment of both advanced and progressive pancreatic neuroendocrine tumors (“NET”) and extra-pancreatic (non-pancreatic) NET in patients who are not amenable to surgery.
Surufatinib is a small molecule oral tyrosine kinase inhibitor, and the mechanism of action is to block tumor angiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), inhibit colony-stimulating factor-1 receptor (CSF-1R)  and promote the body’s immune response against tumor cells by regulating tumor-associated macrophages. The dual mechanism of action of tumor angiogenesis blocking and immunoregulation may make it very suitable for possible combinations with other immunotherapies. According to the data from the SANET-ep phase III clinical study, surufatinib reduced the progression of relevant disease or mortality by 67% and was generally well tolerated.

Pharmaceutical product: Fruquintinib

Target: VEGFR

Company: Hutchison MediPharma

Fruquintinib received a Fast Track designation from the U.S. FDA in Jun. 2020 for the treatment of metastatic colorectal cancer (mCRC). A Phase III study of fruquintinib for the treatment of patients with mCRC, FRESCO-2, has been registered and initiated in the U.S., Europe, and Japan, with patient enrollment planned at approximately 130 study centers in 10 countries.

Pharmaceutical product: Penpulimab (AK105)

Target: PD-1

Company: Akeso/Chiatai Tianqing

On Oct. 27, Chiatai Tianqing, an enterprise of Sino Biopharmaceutical, and Akeso announced the joint development and commercialization of the anti-PD-1 monoclonal antibody penpulimab for the third-line treatment of metastatic nasopharyngeal carcinoma, which has received a Fast Track designation from the U.S. FDA.

Penpulimab’s Fc receptor and complement-mediated effector are completely removed by mutations of Fc region; it also has a slower antigen-binding off rate. These features have made penpulimab more effective in blocking the activity of the PD-1 pathway and maintain stronger T-cell anti-tumor activity, therefore it has the potential to become an anti-PD-1 drug that can achieve better clinical efficacy.

References:

1. Shi YK, Su H, Song YP, et al. Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial. Lancet Haematol, 2019,6: e12–19.

2. Xu JM, Li Y, Fan QX, et al. Sintilimab in patients with advanced esophageal squamous cell carcinoma refractory to previous chemotherapy: A randomized, open-label phase II trial (ORIENT-2). 2020 ASCO, 4511.

3. Yang H, Liu H, Chen YP, et al. Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. J Clin Oncol, 2018,36(27):2796-2803.

4. http://www.cstonepharma.com/html/news/2736.html.

5. Recombinant Humanized Anti-PD-1 Monoclonal Antibody Toripalimab (JS001) in patients with refractory/metastatic nasopharyngeal carcinoma: Interim results of a phase II clinical study POLARIS-02. 2019 ASCO, abs6017.

6. JAMA Oncol. Published online September 24, 2020. doi:10.1001/jamaoncol.2020.4429.

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