Asandeutertinib

In recent days, the long-standing patent dispute between Pfizer and AZ has finally come to an end. According to Reuters, US District Judge Matthew Kennelly dismissed the jury's decision that AZ's lung cancer drug Tagrisso (osimertinib) had infringed Pfizer's anti-cancer drug Nerlynx (neratinib) patent and should pay $107.5 million in damages. The judge ruled that Pfizer's two patents were invalid.   In the reversal of this patent lawsuit, neratinib, as a human epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), can irreversibly bind to EGFR (HER1), HER2, and HER4, inhibiting the phosphorylation of the receptor and blocking downstream signal transduction, thereby inhibiting the proliferation, survival, and migration of cancer cells and improving the tumor microenvironment.   Pfizer acquired Wyeth for $68 billion in 2009 and included neratinib in its product line. In 2011, Puma Biotechnology obtained a license from Pfizer for neratinib and took full responsibility for the global development and commercialization of the drug. In July 2017, the US Food and Drug Administration (FDA) approved neratinib for reducing the risk of recurrence in early-stage HER2-positive breast cancer. In 2020, the FDA further approved neratinib in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who had received two or more prior therapies. With this indication's approval, neratinib's application range has expanded from early-stage breast cancer patients to patients with advanced or metastatic breast cancer.   Osimertinib is the third-generation EGFR-TKI developed by AstraZeneca, which was approved by the FDA in November 2015 for the treatment of non-small cell lung cancer (NSCLC) patients with the T790M gene mutation as a second-line treatment. Currently, osimertinib has been approved for several indications in the NSCLC field. As the market leader of the third-generation EGFR-TKI, osimertinib's sales have continued to rise, reaching $5.799 billion in 2023 and becoming AstraZeneca's flagship product.   In 2021, Pfizer's subsidiary Wyeth and Puma Biotechnology filed a lawsuit against AstraZeneca, accusing osimertinib of infringing on their two key patents. One of the patents, "Patent 314," involves a method for treating NSCLC patients who are resistant to gefitinib and/or erlotinib with an EGFR inhibitor that covalently binds to cysteine 773 of the protein. The other is Wyeth's "Patent 162," which protects the use of these irreversible inhibitors to treat NSCLC patients who are resistant to gefitinib or erlotinib and carry a specific T790M mutation in the EGFR protein.   In May 2023, a federal jury in Delaware ruled that AstraZeneca had indeed infringed on Pfizer's patent and awarded $107.5 million in damages. Despite AstraZeneca's argument that Pfizer's patent was invalid, the jury did not adopt it. In response to this result, AstraZeneca filed an "additional defense."   In the latest ruling, the judge pointed out that two of Pfizer's patents were invalid because they lacked an effective written description of their invention, and that ordinary scientists in the field could not reproduce them based on these descriptions. Therefore, AstraZeneca has won the patent lawsuit. However, there are still many challenges ahead for Osimertinib.   At present, lung cancer has become the second most common type of cancer globally, according to statistics from the World Health Organization's International Agency for Research on Cancer (IARC), with lung cancer accounting for 11.1% of all cancer cases worldwide in 2020. Among lung cancer patients, non-small cell lung cancer (NSCLC) accounts for 85% of the total, while small cell lung cancer (SCLC) accounts for the remaining 15%. Epidermal growth factor receptor (EGFR) is one of the most important oncogenic driver genes in NSCLC, and studies have shown that the incidence rate of EGFR mutations in metastatic NSCLC patients is about 30%. In China, the proportion of EGFR mutations among NSCLC patients is about 51%.   To date, three generations of EGFR tyrosine kinase inhibitors (EGFR-TKI) have been approved for marketing worldwide. The first and second generation EGFR-TKIs mainly target patients with the EGFR ex19del mutation and the EGFR 21L858R mutation. However, the third-generation drugs are not only effective against these sensitive mutations, but also against the T790M resistance mutation that arises after treatment with the first and second-generation TKIs.   Osimertinib, an EGFR-TKI that is already on the market, has seen consistent sales growth since its launch, becoming an important revenue driver for AstraZeneca. However, despite the huge market potential of the third-generation EGFR-TKIs, the competition is extremely fierce, with seven similar products approved globally and six approved in the domestic market.   Moreover, the compound patent for Osimertinib in China (CN103702990) will expire in July 2032. Given the huge potential of Osimertinib in the domestic market for imported anti-cancer drugs, Jiangsu Wanbangshenghua Pharmaceutical Group has submitted an application for the approval of a biosimilar and successfully obtained approval.   In the field of innovative drugs, Jiangsu Haosen Pharmaceutical's Ametinib and Aileris Pharmaceutical's Fumetinib have been approved for marketing by the National Medical Products Administration (NMPA). Meanwhile, Oseacon's Limertinib, Johnson & Johnson's Lanresertinib, Tongyuan Pharmaceutical's TY-9591, and Aisen Pharmaceutical's Aivetinib have also submitted marketing applications or have entered the III phase clinical trial stage in China. In addition to the competition from similar products, osimertinib is also facing the challenge of dual antibody drugs. Recently, Johnson & Johnson's EGFR/C-MET dual antibody Amivantamab, combined with the third-generation EGFR-TKI Lartruvo (A+L), achieved the primary endpoint of progression-free survival (PFS) in a direct comparison clinical trial with osimertinib monotherapy for the first-line treatment of EGFR-mutated advanced NSCLC. The study results showed that compared with osimertinib, the A+L group significantly reduced the risk of PFS by 30% (HR, 0.70; 95% CI, 0.58-0.85; P<0.001), with a median PFS of 23.7 months (compared with 16.6 months), and an objective response rate (ORR) of 86% (compared with 85%). In terms of overall survival (OS), the median OS for the A+L group could not be estimated (HR, 0.77), while the OS for the osimertinib group was 37.3 months (HR, 0.77). The OS reached a statistically significant endpoint, indicating that A+L may become a new standard for the first-line treatment of EGFR-mutated NSCLC.   Faced with the dual pressure of generic drugs and innovative drugs, AstraZeneca's osimertinib is facing a severe competitive situation. Nevertheless, the victory in the patent lawsuit has saved AstraZeneca up to $107 million in potential compensation.