AI-based drug developer Insilico Medicine said it plans to advance its lead candidate ISM001-055 into a potentially pivotal study, after generating positive topline results in a Phase IIa trial showing encouraging clinical efficacy against idiopathic pulmonary fibrosis (IPF).
The topline data showed ISM001-055 to have improved the forced vital capacity (FVC) of IPF patients studied 12 weeks after dosing. The drug was also shown to be safe and well-tolerated, with a favorable pharmacokinetics (PK) profile.
According to Insilico, patients randomized to ISM001-055 showed dose-dependent improvement in lung function for all doses during the trial’s 12 weeks. While all doses of the drug showed FVC improvement, the best results were seen in the 98.4 mL mean FVC improvement from baseline reported for the highest dose of 60 mg QD. Placebo patients showed a negative 62.3 mL mean decline in FVC change from baseline.
ISM001-055 patients 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, compared to a negative 1.84% mean decline in ppFVC for patients randomized to placebo.
Complete data from the study, Insilico said, will be presented at an upcoming medical conference and published in medical journals.
“Insilico will very soon be initiating discussions with regulatory bodies based on these encouraging results and will be pursuing a potentially pivotal trial of ISM001-055 in IPF patients,” Insilico founder and co-CEO Alex Zhavoronkov, PhD, told GEN Edge.
The pivotal trial would be a global Phase IIb study that is now envisioned to enroll 90 patients in each of three arms—approximately 270 total—and assess ISM001-055 through longer treatment periods than the Phase IIa study. The company will not confirm exact numbers until after the discussions with regulators.
The potentially pivotal global Phase IIb could be started by the second half of 2025, Zhavoronkov said.
New vp to oversee ‘055
Continuing the advancement of ISM001-055 through the clinic will be the role of a newly appointed vice president at Insilico.
The company has named Carol Satler, MD, PhD, as vice president of clinical development and responsible for advancing the development of non-oncology programs. A physician executive with more than 20 years of successful clinical development, Salter was most recently chief medical officer at Respira Therapeutics, with a focus on pulmonary-targeted therapeutics that is closely related to ISM-001-055.
Previously, Salter held positions at Pfizer, Sanofi, Bayer, Takeda/Millennium, Puretech Health, and Gilead. Satler played key roles in launching and commercializing numerous blockbuster drugs that have generated $1 billion or more in annual revenues, including Plavix® (clopidogrel), Lipitor® (atorvastatin calcium), Lovenox® (enoxaparin sodium), Norvasc® (amlodipine), Velcade® (bortezomib), Avapro®/Avalide® (irbesartan), and Letairis® (ambrisentan).
“With her leadership, we will aim to expand our non-oncology pipeline in the clinical stage and can also fast-track the development of novel drugs, and revolutionize the treatment landscape by leveraging AI for more efficient and effective outcomes,” Zhavoronkov said.
The data released came from a Phase IIa trial of ISM001-055 that Insilico conducted across 21 sites in China (NCT05938920). “The Phase IIa study was assessed in China due to the large IPF patient population in the country and the extremely efficient patient enrollment process,” Zhavoronkov said.
The double-blind, placebo-controlled trial enrolled 71 IPF patients who were randomized to receive either placebo, 30 mg once daily (QD), 30 mg twice daily (BID), or 60 mg QD for 12 weeks.
The Phase IIa trial also showed improvement in quality of life (QoL) and functional measures for patients at the high dose, as evaluated by a change in Leicester Cough Questionnaire (LCQ) score from week 0 to week 12. Patients randomized to 60 mg QD showed a meaningful two-point improvement in LCQ total score compared to the placebo group by week 12.
Patients receiving the other two doses (30 mg QD and 30 mg BID) did not show meaningful improvement, Insilico added.
“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,” said Zuojun Xu, MD, professor of Peking Union Medical College and the Phase IIa trial’s principal investigator.
U.S. trial recruiting patients
In addition to the Phase IIa study in China, Insilico is also studying ISM001-055 in a U.S. Phase IIa trial (NCT05975983) that is now enrolling patients. The study is estimated to be enrolling a total of 60 patients and achieve primary completion in February 2026.
“Enrollment in the U.S. has the likely potential to speed up with these positive Phase IIa China results,” Zhavoronkov said.
ISM001-055 is an internally developed drug candidate developed using generative AI. The drug is designed to treat IPF by targeting Traf2- and NCK- interacting kinase (TNIK), a serine/threonine kinase whose activation plays a crucial role in cellular processes that include signal transduction pathways essential for fibrosis development.
In a paper published in March in Nature Biotechnology, a team of 30 researchers led by Zhavoronkov detailed how they used generative AI to discover INS018_055, with a novel target discovered by Insilico’s target identification engine, PandaOmics, and a novel molecular structure designed by its generative chemistry engine, Chemistry42. Both are specific-function platforms within the company’s AI platform, Pharma.AI.
ISM001-055 is Insilico’s first wholly-owned program in which AI was used to identify a novel target and generate novel small molecules through Pharma.AI. Insilico won the FDA’s first Orphan Drug Designation for an AI drug last year.
Research published by Zhavoronkov and colleagues has shown evidence that TNIK regulates major signaling pathways known to be causal for the development of IPF and other fibrotic conditions—including through activation of the profibrotic c-JUN pathway, regulation of cell spreading as a RAP2 effector, and mediation of the WNT signaling axis by direct interaction with the LCF–LF complex and TCF in gut epithelial cells. TNIK has also been identified as tightly connected with genes associated with IPF, including TGFB1, FGF, FLT1, KDR, and others.
“This causal relationship has been underscored by our interactome community transparency analysis, which revealed that TNIK inhibition is connected to multiple biological processes important for fibrosis progression, such as focal adhesion signaling, myofibroblast differentiation, and mesenchymal cell migration,” Zhavaronkov said.
In June, Zhavoronkov and colleagues published a study in Trends in Pharmacological Sciences detailing how TNIK inhibition could also treat age-related diseases that included forms of cancer, metabolic disorders, and neuronal function.
“TNIK signaling appears to converge on four critical hallmarks of aging: cellular senescence, deregulated nutrient sensing, chronic inflammation, and altered intercellular communication. TNIK’s contribution to these processes implicate it as a possible contributor to aging-related pathology,” Zhavoronkov and colleagues concluded. “An interesting hypothesis would be whether TNIK dysregulation contributes to the aging process itself or is a consequence of it.”
Insilico is now conducting preclinical IND-enabling studies for TNIK in kidney fibrosis, as well as for an inhalable formulation of INS001-055 in IPF, Zhavoronkov said. However, the company is keeping confidential for now its studies of TNIK in fighting cancer and metabolic disease.
