First COVID-19 Drug Generated By AI Approved For Human Use

Today Insilico Medicine announced that the China National Medical Products Administration has approved an Investigational New Drug application for a new drug called ISM3312. This orally available 3CLpro inhibitor was generated and designed using Chemistry42 for the treatment of COVID-19. Chemistry42 is Insilico Medicine's generative chemistry platform. In preclinical studies, ISM3312 significantly reduced viral load in lung tissue and decreased lung inflammation. It also demonstrated broad spectrum anti-coronavirus activities, not only for SARS-CoV-2 and its popular variants, but also for other types of coronaviruses. This is the first time that a COVID-19 drug designed by generative AI has been approved for human use.

Insilico initially trained its generative AI platform based on viral structures and knowledge discovered during the SARS pandemic. The company narrowed and identified 3CL protease as the target in early 2020 powered by its target discovery platform PandaOmics, then published its first set of novel compound structures designed using its generative chemistry platform Chemistry42 in February 2020 and filed a related patent application in April 2020.

“Generative AI is transforming every area of human development. The invention of ChatGPT has consumerized generative AI, however, generative AI is not new and our company has been working in the field since the publication of our first peer-reviewed papers in this space in 2016. We’re extremely happy to announce that our second small molecule therapeutic generated using generative AI is now entering human clinical trials and there is a very clear timeline to demonstrate the discovery and development cycle.” 

Alex Zhavoronkov, PhD, Founder and CEO, Insilico Medicine

Highlights

• ISM3312 is a highly selective 3CLpro inhibitor with a novel molecular structure optimized from compounds designed by Chemistry42, Insilico’s generative chemistry AI platform.
• ISM3312 has a novel molecular structure that provides broader anti-coronavirus activity, excellent single agent oral bioavailability, and potential drug-resistant mutations.
• The clinical trial of ISM3312 will explore the tolerability, safety, and PK profile of the drug in humans, as well as its efficacy and safety in different subgroups of patients with COVID-19.

ISM3312 is a highly selective small molecule inhibitor with a novel molecular structure optimized from compounds which were generated and designed by Chemistry42 based on the structure of 3CL protease. It binds to the target protein in a unique, irreversible, covalent binding mode, providing a broader spectrum of anti-coronavirus activities, excellent single agent oral bioavailability, and potentially drug-resistant mutations.

Non-clinical pharmacokinetic studies show that ISM3312 has promising oral absorbability, permeability, and bioavailability. Compared to existing 3CLpro inhibitors (e.g., Nirmatrelvir and Ensitrelvir), it retains a favorable in vivo efficacy at low doses and expected clinical efficacy is independent of co-administration with CYP3A and P-gp inhibitors (e.g., Ritonavir),  which is expected to further reduce the drug-drug interaction (DDI) issue and side effects.

"Insilico fully utilized its unique features in this internal COVID R&D program by leveraging AI capabilities with the R&D expertise to design an innovative 3CLpro inhibitor with novel structure and molecular backbone. ISM3312 has significant differences and distinct advantages from exciting 3CL protease inhibitors. We are committed to accelerating clinical trials through fast-tracking development policy of the treatment for COVID-19 to benefit patients worldwide."

Feng Ren, PhD., Co-CEO and Chief Scientific Officer, Insilico Medicine

It is possible that drug resistant strains may emerge with use of Paxlovid™ and similar approved drugs given the highly mutable nature of coronavirus. ISM3312 has the potential ability to overcome clinical resistance which may provide a solution to the problem of resistant strains caused by the widespread use of single drugs in current clinical treatment.

As a small molecule drug generated and designed by a generative chemistry AI platform, ISM3312 can be efficiently prepared with a two-step synthesis from simple commercially available starting materials, which may be suitable for chemistry manufacturing and control to ensure accessibility worldwide. Insilico will soon initiate clinical trials of ISM3312 in China to explore the tolerability, safety, and pharmacokinetic profile of the drug in humans, as well as its efficacy and safety in different subgroups of patients with COVID-19, thus providing an alternative option for health management in the post-pandemic era.

“There  remains  an urgent need for conducting well-designed clinical trials for scientific evaluation of potential COVID-19 therapies such as ISM3312. We are committed  to exploring  ongoing  unmet medical need to include  subgroups underrepresented in COVID-19 trials as well as in patients who may have variants that are more resistant to antiviral drugs.”

Sujata Rao, M.D., SVP, Head of Clinical Development, Insilico Medicine

Insilico Medicine is an AI-driven biotech company pioneering the application of generative AI to drug discovery and development in 2014. Since 2021, Insilico has delivered 10 preclinical compound candidates discovered and designed by the generative AI platform Pharma.AI, covering the disease areas of fibrosis, oncology, and immunology. The most advanced is Insilico’s anti-fibrosis program. The Company is conducting a global multi-center Phase II clinical trial, which was also granted FDA orphan drug designation in February 2023.

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Copyright © 2023 Margaretta Colangelo. All Rights Reserved.

This article was written by Margaretta Colangelo.  Margaretta is a leading AI analyst consulting at Insilico Medicine. She serves on the advisory board of the AI Precision Health Institute at the University of Hawaiʻi Cancer Center. Twitter @realmargaretta