Merck's c-Met inhibitor is declared for listing in China, Jiangsu Hansoh, Haihe Pharmaceutical are multi-enterprise layout, is there any chance for latecomers?

Source: Yaodu Written by: Xiaoguang Editor: Amphetamine On March 30, the Center for Drug Evaluation (CDE) of the State Food and Drug Administration of China announced that the marketing application of tepotinib hydrochloride by Merck KGaA of Germany was accepted
.

Figure 1.
The marketing application of tepotinib hydrochloride was accepted, source: CDE official website Tepotinib (tepotinib, trade name Tepmetko) is an oral c-MET inhibitor that has been approved for marketing in Japan and the United States for the treatment of Non-small cell lung cancer (NSCLC) patients with MET exon 14 (MET ex14) skipping
.

1c-MET and cancer mesenchymal-epithelial transition factor (c-Mesenchymal-epithelial transition factor, c-Met) is a kind of receptor tyrosine kinase, which encodes a synthetic protein c-Met that can interact with hepatocyte growth factor ( HGF)-binding receptor tyrosine kinase
.

When the c-MET pathway is normally expressed, it promotes tissue differentiation and repair, and when it is abnormally regulated, it promotes the proliferation and metastasis of tumor cells
.

Abnormal activation of the MET pathway occurs in many solid tumors, including brain, breast, colorectal, gastric, head and neck, lung, liver, skin, prostate, and soft tissue cancers.
Sexual mechanisms occur, mainly including MET exon 14 skipping mutation, MET amplification, rearrangement, and MET protein overexpression
.

 Figure 1.
Schematic diagram of c-Met-related signaling pathways (Reference 2) c-MET has become one of the hot research targets in the current cancer field
.

At present, small molecule c-Met inhibitors are divided into single-target or multi-target c-Met inhibitors
.

Single-target c-Met inhibitors can anchor the unique hinge region of Met and inhibit Met kinase with high selectivity; while multi-target c-Met inhibitors can target multiple kinases, and their VEGFR activity is much higher than Met activity , for targeting Met oncogenic mutations is more reluctant, such as Crizotinib (crizotinib) and so on
.

Therefore, we mainly understand the single-target c-Met inhibitors below
.

2c-Met inhibitor represents the world's first approved c-Met inhibitor - Tepotinib Tepotinib is the world's first approved c-Met inhibitor, first obtained on March 25, 2020 Approved by the Japanese Ministry of Health, Labour and Welfare and listed in Japan
.

On August 26, 2020, the FDA granted priority review to tepotinib for the treatment of patients with metastatic NSCLC with MET ex14 mutations
.

Previously, tepotinib was awarded the title of breakthrough therapy by the FDA, and was awarded the title of innovative drug and orphan drug by the Japanese Ministry of Health, Labour and Welfare, which can be said to be highly acclaimed
.

Figure 2.
Tepotinib Knowledge Graph, Source: Yaodu Data The pivotal clinical trial of tepotinib approved in Japan and the United States is a single-arm, multicenter, open-label phase II clinical study called VISION
.

A total of 152 patients with advanced or metastatic NSCLC harboring a MET ex14 mutation received tepotinib monotherapy
.

They do not carry EGFR or ALK gene mutations
.

The results showed that tepotinib achieved an overall response rate of 43% in both treatment-naive and treatment-experienced patients
.

The median duration of response (DOR) in treatment-naïve and treatment-experienced patients was 10.
8 months (95% CI, 6.
9-NE) and 11.
1 months (95% CI, 9.
5-18.
5), respectively
.

67% of treatment-naïve patients and 75% of treatment-experienced patients had responses lasting more than 6 months, and 30% of treatment-naïve patients and 50% of treatment-experienced patients had responses lasting more than 9 months
.

The first FDA-approved c-Met inhibitor - Capmatinib (Capmatinib, trade name Tabrecta) is the first FDA-approved c-Met inhibitor
.

Developed by Novartis, on May 6, 2020, the FDA approved capmatinib for the treatment of patients with MET ex14-mutated NSCLC
.

Figure 3.
Capmatinib knowledge map, source: Yaodu data This approval is based on the phase II GEOMETRY mono-1 trial of capmatinib, which is a multi-center, non-randomized, multi-cohort phase II clinical trial , enrolled 97 patients with advanced or metastatic NSCLC with MET ex14 mutations
.

The main evaluation indicators were objective response rate (ORR) and DOR
.

The results of the study showed that among the 28 treatment-naïve patients, the ORR was 68% (4% of which were complete responses and 64% were partial responses), and the DOR was 12.
6 months; among the 69 treatment-experienced patients, the ORR was 41% ( 41% were partial responses) with a DOR of 9.
7 months
.

The first domestically approved c-Met inhibitor, Savolitinib (trade name Volitinib), was developed by Chi-Med Pharmaceuticals and was approved by the NMPA on June 22, 2021 for the treatment of MET Patients with locally advanced or metastatic NSCLC with ex14 mutations
.

This is the first c-Met inhibitor to be declared for marketing in China, and also the world's first new drug marketing application for savatinib
.

Figure 4.
Knowledge map of sivotinib, source: Yaodu data.
Its approval was based on an open-label, phase II study that enrolled 70 patients with MET ex14-mutant NSCLC from 32 centers in China, with a median follow-up of 17.
6 The results showed that among the 61 patients evaluable for efficacy, the ORR was 49.
2%, the disease control rate (DCR) was 93.
4%, the median time to response was 1.
4 months, and the DOR was 8.
3 months
.

In addition, Chi-Med is also developing indications for gastric and colorectal cancer of savatinib, both of which have reached Phase II
.

3.
Current status of research and development of small molecule c-Met inhibitors in China Haihe Drug - Gumetinib Gumetinib is a small molecule c-Met inhibitor jointly developed by Shanghai Haihe Drug and Shanghai Institute of Materia Medica, Chinese Academy of Sciences
.

Preclinical studies have shown that gumetinib potently and specifically targets MET kinase activity
.

Preliminary clinical research results show that glumetinib has excellent pharmacokinetic properties, good safety and tolerability, long drug half-life and high steady-state trough concentration in humans, which is conducive to the continuous inhibition of the target
.

Gumetinib showed preliminary efficacy in MET ex14-mutated NSCLC
.

Figure 5.
Gumetinib knowledge map, source: Yaodu data In September 2021, Gumetinib was included in the breakthrough therapy category by CDE; in January 2022, Gumetinib was also granted orphan drug status by the US FDA , for the treatment of NSCLC patients with MET gene variants
.

Purana Bio-Beritinib Beritinib was independently developed by Beijing Purana Biotechnology Co.
,
Ltd.

In 2020, the results of the Phase I clinical trial of Britinib in the treatment of advanced NSCLC with abnormal c-Met were presented at the AACR Annual Meeting
.

Figure 6.
Britinib knowledge map, source: Yaodu data The study was conducted in 37 patients with locally advanced or metastatic advanced NSCLC who had not received c-Met inhibitors or HGF-targeted therapy.
The results showed that : Among all 36 patients evaluable for efficacy, the ORR of britinib was 30.
6% and the DCR was 94.
4%
.

In subgroup analyses, among patients with c-Met overexpression, amplification, or ex14 skipping mutations, ORRs were 30.
6%, 41.
2%, and 66.
7%, respectively
.

Currently, beritinib is planned to be included in the breakthrough therapy category by CDE for the treatment of NSCLC patients with MET ex14 mutations
.

In addition, the drug is also intended to be developed for the treatment of glioma, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC)
.

In addition, HS-10241 of Jiangsu Haosen is undergoing clinical trials in China, and the indication is MET ex14-mutated NSCLC, and the indications for liver cancer and gastric cancer are also under clinical research
.

4 Market prospects for small molecule c-Met inhibitors In non-small cell lung cancer, 3% to 5% of patients will have MET gene amplification or exon 14 mutation.
Immunotherapy was not sensitive
.

There are more than 800,000 new cases of lung cancer in China every year, of which non-small cell lung cancer accounts for about 80%-85%.
Under this huge patient base, the mutation frequency of 3%-5% also corresponds to a large number of patients.
Patients urgently need new targeted drugs with low toxicity and high efficiency
.

In addition, about 50% of patients who develop resistance to EGFR-TKI therapy have T790M mutations, and about 20% have c-Met amplification
.

For these patients, c-Met inhibitors have become a good medicine
.

At present, most of the domestic companies that deploy small molecule c-Met inhibitors are in the early stage of research and development, and because MET gene mutations are related to various cancers, it is conducive to differentiated distribution in indications and avoid homogenous competition
.

In short, the domestic market for c-Met inhibitors is sufficient
.

However, since c-Met has become one of the popular targets for researchers to develop targeted drugs for cancer (especially non-small cell lung cancer), in addition to single-target inhibitors, there are also multi-target inhibitors for c-Met, There are more than ten c-Met targeted drugs entering the clinical stage in China, such as double antibodies and antibody-conjugated drugs (ADCs)
.

References: 1.
CDE official website 2.
Puccini, A.
, et al.
(2019).
Safety and Tolerability of c-MET Inhibitors in Cancer.
DrugSafety.
doi: 10.
1007/s40264-018-0780-x; 3.
Comoglio PM , Trusolino L, Boccaccio C.
Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy.
doi: 10.
1038/s41568-018-0002-y.
4.
Pharmacodia https://data.
pharmacodia.
com The columnist has a background in biochemistry and molecular biology.
He has been engaged in the molecular typing of esophageal squamous cell carcinoma, and is familiar with the pathogenesis and drug regimens of various solid tumors
.

Now I take the discovery and dissemination of knowledge as a means of making a living, and I have no end to learn.
I hope that I will always maintain a humble attitude and plasticity, and welcome the golden age of the medical field with my colleagues
.

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