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Annual sales of more than $2 billion "lung cancer god medicine" was attacked!Three domestic new drugs compete on the same stage, overcoming drug resistance Zhengda Tianqing big breakthrough
Editor said: A few days ago, Shanghai Ellis Biological independent research and development of domestic third-generation EGFR-TKI targeting drug iflutinib marketing application was accepted by CDE。At present, six EGFR-TKI targeting drugs have been approved for sale in China, and Astrazeneca's "ace" and the only third-generation EGFR-TKI ohitinib sales have grown rapidly。Hausen, Eisen, Ellis 3 domestic class 1 new drugs have been declared for listing, "the same stage competition" who is more amazing？Zhengda clear start, EGFR-TKI targeting drugs are about to enter the fourth generation。
Wonderful content
Recently, the listing application of the domestic third-generation EGFR-TKI targeting drug iflutinib independently developed by Shanghai Ellis Biology was accepted by CDE。At present, six EGFR-TKI targeting drugs have been approved for sale in China, and Astrazeneca's "ace" and the only third-generation EGFR-TKI ohitinib sales have grown rapidly。Hausen, Eisen, Ellis 3 domestic class 1 new drugs have been declared for listing, "the same stage competition" who is more amazing？Zhengda clear start, EGFR-TKI targeting drugs are about to enter the fourth generation。
Of the 6 EGFR-TKI targeting drugs, ohitinib is the only one
According to the latest report released by the National Cancer Center in 2018, there are about 78 new cases of lung cancer in China every year.The incidence and mortality rate are the highest among all diseases, and non-small cell lung cancer (NSCLC) accounts for about 80%-85% of lung cancer。Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are the standard first-line treatment for EGFR-mutated NSCLC and have been widely used in the treatment of lung cancer。
Table 1: EGFR-TKI targeting drugs that have been marketed worldwide
(Source: Mi Intranet database, public information)
After more than 10 years of development, EGFR-TKI targeted drugs currently on the market in the world are divided into three generations: the first-generation representative drugs are Astrazeneca's Gefitinib, Roche's Erlotinib, and Beda's Ectinib。The results of the study showed that the efficacy of the three first-generation EGFR-TKI was comparable, but about 50% of patients developed resistance to EGFR-T790M mutations after 9 to 14 months.The second generation of representative drugs are Boehringer Ingelheim's Afatinib and Pfizer's Dacotinib。The second generation EGFR-TKI has been preliminatively explored to overcome drug resistance, but the side effects are relatively large.The third generation representative drug is Astrazeneca's ohitinib, which can effectively overcome the problem of resistance caused by the T790M mutation。
From the global sales of 6 EGFR-TKI targeted drugs in 2018, ocitinib accounted for 18.$600 million lead。According to Astrazeneca quarterly report data, in the first three quarters of 2019, Ocitinib accounted for 23.Global sales of $0.5 billion became Astrazeneca's number one。
Figure: Sales of EGFR-TKI targeted drugs in Chinese public medical institutions from 2013 to 2018 (unit: 100 million yuan)
(Source: China's public medical institutions terminal competition pattern)
At present, six EGFR-TKI targeting drugs that have been listed in the world have been listed in China，From the terminal sales of China's urban public hospitals, county-level public hospitals, urban community centers and township health centers (referred to as China's public medical institutions) in recent years，Gefitinib and ecotinib were both included in the national health insurance in 2017，Sales increased significantly in 2018;Gefitinib at the end of 2018 has been included in the national collection to achieve a large price reduction，Sales may decline in 2019;Erlotinib has been negotiated to be included in national health care，But sales have fallen in recent years;Afatinib is not yet covered by health insurance，Sales performance is mediocre;Ocitinib is the only third-generation EGFR-TKI targeting drug，Sales grew rapidly after it was launched in China。
Oxitinib is the first choice for T790M-positive NSCLC patients, but the high price makes many patients "prohibitive".。On October 10, 2018, the State Medical Insurance Bureau issued a notice to include 17 anti-cancer drugs in the scope of Class B medical insurance, with an average reduction of 56.7%。Among them, ocitinib decreased by 71%, from 52,800 yuan/box/month to 15,300 yuan/box/month, greatly improving the accessibility of drugs for patients。
The third generation of domestic targeted drugs are emerging, and the three new drugs are more excellent？
Table 2: Domestic third-generation EGFR-TKI targeting drugs that have been applied for marketing
(Source: Mi Intranet database, public information)
With the expansion of indications and the increase of approved areas, the sales of ohitinib are growing rapidly, and in China, the product has successfully entered the medical insurance catalogue through negotiations, greatly improving the accessibility of drugs for patients, and the market is expected to further expand。At present, in addition to ohitinib in the domestic market, the domestic third-generation EGFR-TKI targeted drugs independently developed by domestic pharmaceutical companies have gradually emerged, and Zhejiang Eisen Pharmaceutical's ivetinib, Hausen Pharmaceutical's ometinib, and Shanghai Elis Biological's iflutinib have been declared for listing。
Avitinib, developed by Eisen Pharma, targets EGFR-sensitive mutations (19del, 21L858R) and T790M mutations，It has been supported by the national "Twelfth Five-Year Plan" and "Thirteenth Five-Year Plan" major science and technology projects for the creation of new drugs，It was approved for clinical use in September 2014，Phase I clinical trials were initiated in China and the United States in 2015，Its conditional listing application was accepted by the CDE in June 2018，In August of the same year, it was included in the priority review。At present, a total of 9 clinical trials of avitinib have been registered in China, involving indications including advanced non-small cell lung cancer, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma。
At the ASCO Annual meeting in 2019, Avitinib demonstrated the clinical results of its treatment of EGFR-T790M mutation-positive non-small cell lung cancer patients in China: Among more than 200 subjects, 90% of the target lesions were clearly reduced, and the objective tumor response rate (ORR) was 52.The disease control rate (DCR) was 88.The median duration of disease response (DOR) was 7.64个月。Safety data showed that the majority of adverse events reported by subjects treated with avitinib were grade 1 or grade 2, with major adverse events similar to those of approved EGFR-TKI。The results of this clinical study show that the efficacy of the subjects receiving avitinib treatment is clear, safe and well tolerated。
Ometinib (HS-10296), independently developed by Hausen Pharmaceutical, can irreversibly and highly selectively inhibit EGFR sensitive mutations and EGFR T790M drug-resistant mutations, avoiding the production of non-selective metabolites and easily breaking the blood-brain barrier。In April 2019, Hausen Pharmaceutical submitted the conditional listing application for ometinib and was accepted by CDE, and was included in the priority review in June of the same year。At present, a total of 8 clinical trials of HS-10296 have been registered in China, involving indications including advanced non-small cell lung cancer with EGFR mutation, locally advanced or metastatic non-small cell lung cancer。
The 2019WCLC Congress presented the results of a Phase II study of ometinib in second-line treatment of EGFR T790M mutation-positive locally advanced or metastatic non-small cell lung cancer。Of 244 patients enrolled in the trial, 182 completed treatment, with an overall median treatment time of 9.The median follow-up time was 4 months.After 7 months, the results of the independent evaluation Committee showed that the ORR was 68.4%, with a DCR of 93.4%。In terms of safety, the incidence of treatment-related AES of grade 3 and above was 20.The incidence of drug-related severe AE was 10%.2%。This clinical data was compared with the phase II clinical results of AURA17 of ocittinib. The ORR and DCR of ometinib were comparable to that of ocittinib, but the control ability of brain metastases was inferior to that of ocittinib, and the incidence of grade 3 and above adverse reactions was also higher than that of ocittinib。
Eflutinib, independently developed by Shanghai Iris Biology, is a new third-generation irreversible and selective EGFR-TKI targeting drug。The product was approved for clinical use in September 2016, its listing application was accepted by CDE on December 10, 2019, and it was intended to be included in the priority review on December 17。At present, a total of 9 clinical trials of iflutinib have been registered in China, involving indications including advanced non-small cell lung cancer, locally advanced or metastatic non-small cell lung cancer。
At the 2019ESMO Annual meeting, data from the latest Phase 1/2 clinical study of iflutinib was announced，The trial included 130 patients with locally advanced or metastatic T790M mutation-positive NSCLC who progressed after first - or second-generation EGFR-TKI treatment (14 patients in the dose-climbing group;Dose extension group 116 cases)。Results evaluated by an independent review committee showed that 116 patients in the dose extension group had an ORR of 76.7%, with a DCR of 88.1%, DOR has not yet been reached。
The weather is clear and the fourth generation EGFR-TKI is here
The third generation EGFR-TKI targeting drug ocitinib, which specifically targets T790M mutation resistance, solves about 50% of the EGFR inhibitor resistance problem，But the tumor cells continue to mutate under the pressure of the drug，New drug resistance problems arise，Currently in patients taking ocitinib，20%-40% will produce a triple mutation of either 19Del, T790M, C797S, or L858R, T790M, or C797S。
What a surprise，The fourth generation EGFR-TKI targeted drug (TQB3804) of Zhengda Tianqing took the lead in entering phase I clinical treatment in China，This means，Once the product is successfully approved for marketing，The plight of patients with advanced NSCLC with EGFR mutation who are resistant to third generation targeted drugs will be improved。
Mi Intranet data show，The clinical application of Zhengda Tianqing TQB3804 tablets was accepted by CDE in April 2019，Subsequently received implicit approval for clinical trials;November of the same year，The Phase I clinical trial of TQB3804 was successfully registered，Registration number CTR20192284，The clinical trial is currently in an "ongoing (recruiting)" state。
It is reported that TQB3804 can not only overcome the two common categories of triple mutations produced after the third generation of EGFR-TKI targeted drug resistance, but also inhibit EGFR wild mutations and T790M mutations caused by the previous second generation of targeted drugs。It took a full four years from drug discovery to IND review, and it is expected to become the fourth generation of EGFR targeted inhibitors to crack C797S resistant mutations。
In preclinical trials，TQB3804 tablets had zero IC50 (the concentration of the drug needed to kill half of the cancer cells) for 19del/T790M/C797S, L858R/T790M/C797S, d746-750/T790M, and L858R/T790M.46nM、0.13nM、0.26nM and 0.19nM, suggesting that TQB3804 has a good inhibitory ability on tumor cells with EGFR triple and double mutations after first-generation to third-generation EGFR-TKI targeted drug resistance。
Source: Mi Intranet database, public information
Note: Data statistics as of December 20, if there are omissions, welcome to correct! | 
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