2024.11.12

Insilico Medicine announces positive topline results of ISM001-055 for the treatment of idiopathic pulmonary fibrosis (IPF) developed using generative AI

ISM001-055 was safe and well-tolerated with a favorable PK profile in IPF patients

Patients who received ISM001-055 showed dose-dependent improvement in the efficacy endpoint, as measured by change in forced vital capacity (FVC) at 12 weeks

CAMBRIDGE, Mass., Nov 12th, 2024 — Insilico Medicine (“Insilico”), a clinical-stage generative artificial intelligence (AI)-driven biotechnology company, today announced positive topline results from the Phase IIa trial of ISM001-055, the novel drug candidate developed in-house using generative AI to target TNIK (Traf2- and NCK- interacting kinase) for the treatment of idiopathic pulmonary fibrosis (IPF). The results demonstrate that ISM001-055 is safe, well-tolerated, exhibits a favorable pharmacokinetics (PK) profile, and has encouraging clinical efficacy as measured by improvement in forced vital capacity (FVC) at 12 weeks.

• Zuojun Xu, M.D.

Professor of Peking Union Medical College and the principal investigator in the Phase IIa trial of ISM001-055 in IPF patients

I am very impressed by the positive results observed in IPF patients treated with ISM001-055, particularly the encouraging improvement in FVC. It not only reflects ISM001-055’s potential to slow disease progression but also suggests its capability to stop or even reverse it. AI, as an advanced technology, is already playing a crucial role in many aspects of medical practice, including drug discovery and clinical research, and we expect to see the real clinical benefits it brings to patients.”

ISM001-055’s Phase IIa study (NCT05938920) was a double-blind, placebo-controlled trial that enrolled 71 patients with IPF across 21 sites in China. Patients were randomized to receive either placebo, 30 mg once daily (QD), 30 mg twice daily (BID), or 60 mg QD for 12 weeks.

Key findings from the ISM001-055 Phase IIa clinical trial topline results include:

• ISM001-055 was well-tolerated across all dosing groups. The majority of the drug-related adverse events were mild or moderate in severity. The most common ISM001-055-related adverse events were diarrhea (14.8%) and abnormal liver function (14.8%).

• The PK profile of ISM001-055 in IPF patients was in line with the results of Phase I studies in healthy subjects with a half-life of 7-12 hours. In addition, a higher proportional exposure was observed at 60 mg QD compared with 30 mg BID.

• Patients who received ISM001-055 demonstrated a dose-dependent improvement in lung function for all doses by the 12 weeks of the trial, with a 98.4 mL mean improvement in forced vital capacity (FVC) from baseline at the highest dose of 60 mg QD as compared to a mean decline in FVC change from baseline of -62.3 mL for patients in the placebo group.

• Patients who received ISM001-055 also showed a similar dose-dependent trend in percent predicted forced vital capacity (ppFVC), with a 3.05% mean improvement in ppFVC from baseline at the highest dose of 60 mg QD as compared to a mean decline in ppFVC of -1.84% for patients in the placebo group.

• Improvement in quality of life (QoL) and functional measures were also evaluated by change in Leicester Cough Questionnaire (LCQ) score from week 0 to week 12, with a meaningful 2-point improvement in LCQ total score in the highest dose of 60 mg QD group compared to the placebo group by week 12. The other two doses (30 mg QD and 30 mg BID) did not show meaningful improvement.

To further progress the program, Insilico Medicine appointed Dr. Carol Satler, MD, PhD, as Vice President of Clinical Development responsible for advancing the development of non-oncology programs. Dr Satler is a seasoned physician executive with over 20 years of experience across drug discovery, development, and lifecycle planning in the industry. In her new role, Dr. Satler will play a pivotal role in the further clinical validation of Insilico’s leading program ISM001-055.

• Dr. Carol Satler, MD, PhD

Vice President of Clinical Development, Insilico Medicine

The results of the Phase IIa study are highly promising. The dose-dependent improvement in FVC in IPF patients treated with ISM001-055 compared to those treated with placebo suggest ISM001-055 may play a role in both the prevention of progression of IPF as well as disease regression, thus highlighting the disease-modifying potential. Future studies will help delineate these benefits further with the hope that ISM001-055 may transform the current treatment paradigm and translate to better overall outcomes for patients with idiopathic pulmonary fibrosis, a progressive fatal debilitating disease.

Following its preclinical candidate nomination, ISM001-055 was tested in multiple preclinical animal models of lung, kidney, and skin fibrosis. ISM001-055 exhibited favorable safety, favorable toxicity, and robust efficacy across all tested models, justifying in-human clinical testing beginning in 2021. After completing these investigational new drug-enabling studies, Insilico Medicine carried out a Phase 0 microdose trial and two independent Phase 1 clinical trials in New Zealand and China to translate these studies into humans. Indeed, ISM001-055 was found to be safe and well-tolerated by healthy volunteers across all 3 trials. Investigators observed no significant accumulation after 7 days, and ISM001_055 exhibited a favorable pharmacokinetic profile. In March 2024, this collective body of work from target identification to Phase 0/1 clinical trial completion was peer-reviewed and published in Nature Biotechnology as ISM001-055 progressed into Phase 2 clinical testing.

The US Clinical Study is Actively Enrolling

• Toby M. Maher, MD, PhD

Leading expert in interstitial lung disease and the leading investigator of the ISM001-055 US clinical trial

These results are very encouraging, particularly the dose-dependent response in FVC. IPF is a devastating disease, and seeing improvements in lung function over just 12 weeks of treatment is a promising indication that ISM001-055 may provide a new therapeutic option for patients. Our Phase IIa in the U.S. is actively recruiting patients.

Program Background and Peer-Reviewed Published Materials

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, scarring lung disease characterized by a progressive and irreversible decline in lung function. Affecting approximately 5 million people worldwide, IPF carries a poor prognosis, with a median survival of 3 to 4 years. Current approved treatments, including antifibrotic drugs, can slow disease progression but do not stop or reverse it, leaving a significant unmet need for more effective, disease-modifying therapies.

ISM001-055 is a potentially first-in-class small molecule targeting TNIK developed utilizing generative AI. In IPF, the activation of TNIK drives pathological fibrosis in the lungs, contributing to the progressive decline in lung function. By inhibiting TNIK, ISM001-055 aims to halt or reverse fibrotic processes, offering a disease-modifying treatment for patients with IPF. The history of discovery, design and development including target discovery, generative chemistry, multiple in-vitro and in-vivo experiments as well as the results of Phase I clinical studies in human volunteers were published in a Nature Biotechnology article in March 2024. The medicinal chemistry portion of ISM001-055’s discovery was published in the Journal of Medicinal Chemistry in October 2024. Potential additional roles of TNIK in age-related diseases were published in Cell Trends in Pharmacological Sciences in June 2024.

Insilico will be initiating discussions with regulatory bodies based on these encouraging results and will be pursuing a pivotal trial of ISM001-055 in IPF patients. In addition, complete Phase IIa data from this study will be presented at an upcoming medical conference and published in reputable medical journals.

• Alex Zhavoronkov, PhD

Founder and CEO of Insilico Medicine

We are thrilled with the positive results from this Phase IIa clinical trial, which underscore the potential of generative AI and robotics to facilitate the discovery, design, and development of innovative therapies and improve patient outcomes. We aim to set industry benchmarks for drug discovery and development using generative AI and execute on the promise to make effective therapies faster, cheaper, with higher probability of success, and with higher quality, reproducibility, and academic integrity compared with traditional biotechnology approaches.

In 2016, Insilico first describedthe concept of using generative AI for the design of novel molecules in a peer-reviewed journal, which laid the foundation for the commercially availablePharma.AI platform. In 2018, Insilico applied for patents covering generative biology approachespublished in 2020 andgranted in 2022, demonstrating the ability to generate molecules for the desired expression patterns. In 2019, it demonstrated the potential and experimental validation of itsGenerative Tensorial Reinforcement Learning (GENTRL)approach to small molecule drug design. Since then, Insilico has continued to integrate technical breakthroughs into the Pharma.AI platform, which is currently a generative AI-powered solution spanning biology, chemistry and clinical development. Powered by Pharma.AI, Insilico hasnominated 20 preclinical candidates in its comprehensive portfolio of over 30 assets since 2021 and has received IND approval for 9 molecules. AI software platforms used to discover TNIK and design ISM001-055,Biology42: PandaOmics and Chemistry42: Generative Chemistry are commercially available as part of Pharma.AI.