Asandeutertinib

On March 9, Synlogic announced that its self-developed drug TY-9591 has successfully outperformed AstraZeneca's renowned lung cancer treatment, Osimertinib, in a pivotal Phase II clinical trial. Founded in 2017, Synlogic is an innovative pharmaceutical company set to go public on the Hong Kong Stock Exchange in August 2024. TY-9591, a deuterated variant of Osimertinib, is the company's lead pipeline candidate. Market reaction to this announcement was swift, interpreting it as a significant challenge to Osimertinib, which is widely regarded as a "miracle drug" for lung cancer. On March 10, Synlogic's stock surged by over 40% in early trading, ultimately closing with a 16.18% increase. In response to this emerging competitor, AstraZeneca stated on March 11 that it could not provide feedback due to the limited information currently available from the study. Osimertinib, the world's first third-generation EGFR-TKI drug, was approved in the U.S. in 2015 and entered the Chinese market in 2017. It has consistently generated robust sales, reaching nearly $5.8 billion globally in 2023. Even with the arrival of domestic third-generation EGFR-TKI drugs, Osimertinib has maintained a dominant position, controlling around 80% of the small molecule targeted lung cancer drug market in China. Notably, Osimertinib's compound patent will not expire until 2032. Synlogic's strategy involves deuterated modifications to Osimertinib. This approach is considered one of the least risky and most straightforward methods to enhance existing drugs. Domestic companies like Zai Lab and HEC Group have also focused on deuterated drugs, with Zai Lab's Donafenib being a notable example that was approved in 2021. In terms of indications, Synlogic is targeting lung cancer with brain metastases, a critical factor affecting the survival of lung cancer patients. The occurrence of brain metastases is significantly higher in patients with EGFR mutations, with risks ranging from 40% to 60%. Osimertinib is recognized for its effectiveness in managing brain metastases, contributing to its success in head-to-head trials. While Synlogic has not disclosed specific Phase II data, it reported that the trial enrolled 224 patients, achieving the primary endpoint of intracranial objective response rate (iORR). More detailed results are expected to be shared at upcoming international or domestic clinical conferences. The announcement has sparked both enthusiasm and skepticism within the industry. Critics have raised questions about Synlogic's choice of objective response rate as the primary endpoint, arguing that it does not align with industry standards and differs from AstraZeneca's original trial design. In a previous instance in September 2024, another company, Kangfang Biopharma, claimed a decisive victory in a head-to-head trial against Merck's Keytruda based on multiple data points, but lacked overall survival data, prompting a cautious response from Merck. Osimertinib's rise to first-line treatment status was largely due to its achievement of significant median progression-free survival (PFS) data. For patients with brain metastases, Osimertinib demonstrated a PFS increase from 9.6 months to 15.2 months, solidifying its reputation as a leading treatment. Although Synlogic has reported an impressive 100% iORR in its single-agent treatment for non-small cell lung cancer with brain metastases, this single data point alone may not be sufficient to sway the medical community, and consensus will depend on comprehensive results. In the competitive landscape, Osimertinib faces challenges not only from Synlogic but also from several other third-generation EGFR-TKI drugs that have recently entered the market. Companies like Betta Pharmaceuticals and Bayer are already exploring fourth-generation TKIs, and Johnson & Johnson's dual-antibody combination has received FDA approval. As Osimertinib stands firm against this growing competition, it is clear that strong clinical data is just one aspect of maintaining its market position. This is a critical factor that Synlogic and other competitors must take into account. On March 11, Synlogic's stock declined nearly 9%, resulting in a market capitalization decrease of over HKD 1 billion.

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.