• Allist Chief Chemistry Officer Dr. Luo Huibing: “Precision R&D” with Artistic Elegance
    2021/09/22

    Introduction:

    In the eyes of all Allist staff, Furmonertinib is a "fortune medicine" indeed. It saved Allist in deep trouble and helped it go public on the Science and Technology Innovation Board of the Shanghai Stock Exchange. Furthermore, non-small cell lung cancer (NSCLC) patients with brain metastases, who had been given the notice of critical illness, miraculously turned from a state of unconsciousness to being able to talk and walk in just a few days. Now, Furmonertinib sets sail and go global, bringing hope for more lung cancer patients...

    How did this Class I innovative drug in China, which brought great changes to the fate of Allist and patients, break through the ground and become a miracle when the company’s future was still uncertain at that time?


    Mission appointed at the time of crisis

    In 2012, Dr. Guo Jianhui, co-founder of Allist in charge of R&D, unfortunately passed away due to illness. This is when the core product of Allist, the first national Class I anti-hypertension drug Allisartan Isoproxil, has just been transferred. How does the company survive? Allist now stands at a crossroads.

    With his discernment and acumen and decades of experience in business, Chairman Du Jinhao decided to devote all available capital and human resources to solving the huge pain spot in clinical oncology — lung cancer. Dr. Luo Huibing was appointed to lead the R&D team on the expedition to develop the company’s first innovative cancer drug. Dr. Luo has rich R&D experience and an outstanding innovative spirit. He once was a researcher guided by Academician Xie Yuyuan of Shanghai Institute of Materia Medica of Chinese Academy of Sciences.

    To achieve what others cannot

    Lung cancer is a malignant tumor with an extremely high fatality rate. According to the latest data in 2020, both the morbidity and mortality rate in China rank the first in the world. NSCLC patients account for 85% of all lung cancer patients; about 50% of lung cancer patients in Asia develop EGFR mutation, and EGFR mutation is the most common in Asian NSCLC patients.

    Dr. Luo Huibing found that T790M mutation’s resistance of the first and second generation of EGFR-targeting drugs had been an unsolved clinical pain spot for nearly a decade since the release of EGFR-targeting drugs in 2005. He decided to lead his team to solve the clinical enigma of EGFR-targeting drugs. "At that time, the R&D resources of Allist were scarce, and the team was short of hands. Nonetheless, we enjoy a space of independence and innovation to explore, inspire, and try things differently," Dr. Luo recalled.

    Furmonertinib, the fourth compound synthesized by Luo’s team, proved to show excellent activity in vitro cell activity test. However, when the team performed in vivo pharmacokinetic (PK) tests of the compound on animals, the blood concentration and drug exposure of Furmonertinib were very low. According to the research procedure of large pharmaceutical companies, if the compound’s PK properties were not good, it would be abandoned and subsequent R&D would be terminated. As the scientific architect who designed Furmonertinib, Dr. Luo had firm belief in his own judgment and insisted on taking the compound to the next stage of its in vivo efficacy test. Then came the "miracle" moment. The final results of animal trials showed that the drug functioned perfectly in vivo. It is a counterintuitive phenomenon that "very low drug exposure in animals can produce a good in vivo effect".

    After further studies, it was found that after entering the animal, Furmonertinib would get rapidly distributed into the body tissues, mostly in lungs. As a result, only a very small amount of Furmonertinib could be detected in the plasma. This is the "ideal state" of tissue distribution of drug molecules, precisely targeting of the lesion tissue, which is both effective and safe.

    "The innate entrepreneurial spirit and the scientific innovative spirit of Allist staff have always been inspiring us to make the impossible possible! To achieve what others cannot!" This is the creed that Du Jinhao, chairman of the board, often mentioned, encouraging the team to adhere to the faith, feel no fear of adversity, and have the courage to break the routine.

    Unique ideas and precision R&D

    In the face of facts that defy conventional logic, what makes Dr. Luo so convinced and steadfast? And what led the team to develop Furmonertinib with unique molecular structure? Dr. Luo attributes this to Allist-style "precision R&D".

    Before the research on Furmonertinib was officially launched, the team led by Dr. Luo had been developing concepts for more than two months. Based on a thorough understanding of the structure of EGFR target proteins, as well as continuous careful conceptualization and scientific verification, Dr. Luo set two "precise" design goals for the third generation of EGFR inhibitors right from the start: 1. Pure EGFR family inhibitors; 2. Additional hydrophobic cavities in the EGFR structure need to be utilized to improve activity and kinase selectivity.

    Dr. Luo innovatively proposed the scientific idea that by placing trifluoroethoxyl in a hydrophobic pocket and binding it to the unexplored binding pocket of EGFR target protein, the activity of drug molecules to EGFR (including EGFR T790M) can be improved, and that trifluoroethoxyl also improves kinase selectivity and metabolic stability. The unique trifluoroethoxypyridine structure of Furmonertinib blocks the production of non-selective metabolites and improves the selectivity of EGFR wild-type. The steric hindrance effect of the structure can also improve the selectivity of the kinase spectrum and reduce the off-target effect, thus improving the overall safety.

    Artistic elegance of "one flower, one world"

    For large multinational pharmaceutical companies, it usually takes a huge amount of capital and human resources to conduct trial-and-error screening to find a good candidate among thousands of compounds. However, this approach was impossible for Allist, which was short of money and manpower. Therefore, Dr. Luo boldly created the model of "precision R&D", which contributes to the successful selection of Furmonertinib after screening only more than 30 compounds, minimizing the time and capital costs for the company.

    Dr. Luo Huibing, who is honored as the "father of Furmonertinib" by his colleagues, still firmly believes that"the development of new drugs is actually an 'art'. It needs the irrigation of inspiration and the imagination of the wildest kind. It should not be constrained by any rules. It sometimes even requires lonely perseverance." In Dr. Luo's view, once the molecular structure is fully understood, it is possible to see another mysterious world, just like "one flower, one world". This is one of the inspiration sources of his unique research ideas.

    "Fortune medicine" maximizes benefit for patients

    Shortly after its launch on March 3, 2021, Furmonertinib has been written into The Chinese Treatment Guidelines for Stage IV Primary Lung Cancer (2021 edition) and The Chinese Treatment Guidelines for Lung Cancer Brain Metastasis (2021 edition) respectively. Also in March, Furmonertinib-based clinical study was published in The Lancet Respiratory Medicine, a leading international academic journal.

    The results show sound efficacy and safety of Furmonertinib. It is also effective in patients with central nervous system (CNS) metastases. Since its launch, more and more patients with brain metastases from NSCLC have achieved positive treatment progress after receiving Furmonertinib treatment. "Fortune medicine" maximizes the benefit for patients’ survival.

    In order to meet more clinical needs, Allist has fully launched clinical trials for new indications of Furmonertinib, actively exploring the potential of Furmonertinib in the treatment of NSCLC with different EGFR target mutations, so that "fortune medicine" can benefit more patients in China and even around the world in the near future.


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