PharmaSources/CaicaiApril 03, 2019
Tag: NSCLC , Osimertinib , EGFR-TKI
Third-generation EGFR-TKI becoming a R&D hotspot
Sales of Osimertinib Approaching RMB 2 Billion in China in 2018
BPI-7711 of Beta Pharma into Phase III Clinical Trial.
Beta Pharma has recently started the Phase III clinical trial of BPI-7711 as a first-line therapy of non-small cell lung cancer (NSCLC), which has enrolled 294 participants, with gefitinib as the comparator.
BPI-7711 is a third-generation EGFR-TKI, making Beta Pharma the fourth Chinese pharmaceutical enterprises and hospital medical supply companies that enter the Phase III clinical trial of the variety following ACEA, Hansoh, and Allist.
Third-generation EGFR-TKI becoming a R&D hotspot
EGFR-TKI stands for epidermal growth factor receptor-tyrosine kinase inhibitor which is a targeted drug produced accompanying the cancer molecular typing and molecular biology development, and inhibits the whole pathway transduction and tumor growth by inhibiting nodes in intracellular signaling pathways, wherein, EGFR-TKI has become the drug of first choice recommended by NCCN for the big cancer type: EGFR-positive NSCLC (accounting for about 30% of lung cancers) owing to its prominent clinical efficacy. After over a decade of R&D, the EGFR-TKIs currently in the market are mainly divided into three generations:
Generation | Representative drug | Mechanism of action | Efficacy |
First-generation EGFR-TKI
| Gefitinib, erlotinib, icotinib (Chinese-produced) | Reversibly binding drug that binds to EGFR kinase domain through competing with ATP, to inhibit the activation thereof | Clinical effects significantly better than chemotherapy, with drug resistance situation |
Second-generation EGFR-TKI | Afatinib | Irreversibly binding drug that forms covalent attachments to the EGFR kinase domain, with the binding using covalent bond being more stable than the first-generation TKI, to thus improve the efficacy | Irreversible binding, with clinical effects better than the first-generation TKI, with drug resistance situation and big side effects |
Third-generation EGFR-TKI | Osimertinib | Binding to the small T790M mutation domain through a smaller binding region, to reach the treatment effect | The only effective drug for patients who have developed T790M mutation after treatment, with the clinical effects better than first-generation TKI, but with no effectiveness against rare resistance mutations |
(Organized according to public data)
The third-generation EGFR-TKI mainly targets patients with T790M resistance mutation. T790M gene mutation is the major mutation type (accounting for about 50%) of resistance after using EGFR-TKI. The first-generation and second-generation EGFR-TKIs are ineffective against T790M because the latter has a small domain, which is difficult for conventional drugs to bind to. As a result, the third generation has become the R&D hotspot of the giants.
Sales of Osimertinib Approaching RMB 2 Billion in China in 2018
Avitinib, the first Chinese-produced third-generation EGFR-TKI, to be marketed soon
As the first third-generation EGFR-TKI independently developed by ACEA, avitinib maleate can inhibit EGFR L858R, Exon19del, and T790M mutation, and is used to treat NSCLC with EGFR mutation or resistance mutation. As an original new drug supported by China’s National S&T Major Project for Major New Drug Invention during the 12th Five-year Plan period, the drug has a global compound patent, and will be marketed soon. ACEA is now preparing for the marketing, and has determined the trade name to be Aoweikai, with the application process as follows:
Sep. 2014 | Received clinical approvals of CFDA and FDA |
2015 | Started Phase I clinical study separately in China and the U.S., to become the first independent innovative drug conducted clinical studies in China and the U.S. at the same time |
June 2016 | Filed the Phase II/III clinical application to CFDA |
June 2018 | Filed the marketing application to CFDA, and accepted by CDE |
Aug. 2018 | Appeared in the 31st batch of registration applications of pharmaceutical products to be included in the priority review procedure of CDE |
The only fly in the ointment is that the penetration of the blood-brain barrier (BBB) by avitinib is far lower than that by osimertinib; the drug still could achieve good efficacy in patients with brain metastases and partly damaged BBB, however, meningeal metastases differ greatly from brain parenchyma metastases.
Hansoh, Allist, Beta Pharma, and Betta following closely
Besides ACEA, the third-generation EGFR-TKIs of Hansoh, Allist, and Beta Pharma have all entered Phase III clinical trials.
Pharmaceutical product name | Company | Indication | R&D stage | Date of first publicity of information |
HS-10296 | Hansoh | Locally advanced or metastatic NSCLC | Phase III clinical trial | Nov. 14, 2018 |
Alflutinib | Allist | Locally advanced or metastatic NSCLC | Phase III clinical trial | Jan. 7, 2019 |
BPI-7711 | Beta Pharma | Advanced or metastatic NSCLC | Phase III clinical trial | Mar. 7, 2019 |
BPI-15086 | Betta | Advanced NSCLC | Phase I clinical trial | Sep. 20, 2016 |
(Organized according to open data)
The next 5 years will be the harvest period of the third-generation EGFR-TKIs as the drugs have successively entered Phase III clinical trials.
Caicai, a Master of Pharmacy from Shanghai Jiaotong University, used to work in the Institute of Science and Technical Information. Currently as a practitioner in the drug surveillance system, she is good at interpreting industry regulations, pharmaceutical research developments, etc.
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