Insilico announces positive topline results for IPF treatment

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Developed using generative AI for treatment of Idiopathic Pulmonary Fibrosis, ISM001-055 is safe with ‘encouraging clinical efficacy’.

Insilico Medicine has announced positive topline results from its Phase IIa trial of ISM001-055, a novel drug candidate targeting TNIK (Traf2- and NCK-interacting kinase) for the treatment of idiopathic pulmonary fibrosis (IPF). The trial’s findings indicate that ISM001-055 is safe, well-tolerated, exhibits a favorable pharmacokinetic profile and demonstrates encouraging clinical efficacy, as evidenced by improvements in forced vital capacity (FVC) over a 12-week period; these improvements in lung function metrics offer hope for patients with limited treatment options.

Zuojun Xu, MD, Professor at Peking Union Medical College and the principal investigator of the Phase IIa trial, said: “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.”

Longevity.Technology: 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 [1]. 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.

Generative artificial intelligence (AI), however, is reshaping drug discovery and development, enabling faster, more precise identification of novel drug candidates – particularly for aging-related conditions such as IPF. This technology holds substantial promise for advancing drug therapies in the aging sector, offering new insights and pathways that traditional methods may not readily reveal.

Clinical trial design and key results

The double-blind, placebo-controlled Phase IIa study (NCT05938920) enrolled 71 IPF patients across 21 sites in China. Participants were randomly assigned to receive either a placebo, 30 mg of ISM001-055 once daily (QD), 30 mg twice daily (BID), or 60 mg QD for a 12-week period. The trial’s main goals were to assess the safety, tolerability and pharmacokinetics (PK) of the drug, while also evaluating its effects on lung function through forced vital capacity (FVC) measurements – a critical indicator of disease progression in IPF patients.

The trial data indicate that ISM001-055 was well-tolerated at all doses, with adverse events mainly categorized as mild or moderate; the most common were diarrhea and abnormal liver function, each affecting 14.8% of patients. These results align with findings from prior Phase I studies in healthy participants, which established a PK profile for ISM001-055 characterized by a half-life of 7-12 hours and demonstrated proportional exposure increases at higher doses.

The treatment showed clear benefits, especially at the highest dose (60 mg taken once a day). Patients on this dose had an average improvement of 98.4 mL in their lung capacity (measured by FVC) over 12 weeks. In contrast, those who took a placebo saw their lung capacity decrease by an average of 62.3 mL. Additionally, people on the highest dose saw a 3.05% improvement in their lung function (measured as percent predicted FVC), whereas those on the placebo experienced a drop of 1.84%.

Beyond lung function, quality of life and functional assessments further supported ISM001-055’s potential. Notably, patients on the highest dose exhibited a two-point improvement in the Leicester Cough Questionnaire (LCQ) total score, reflecting better outcomes in cough-related quality of life measures compared with placebo recipients. The two lower doses did not yield significant LCQ improvements, suggesting that higher dosing may be critical to achieving desired patient benefits.

Mechanism of action and implications for future IPF therapies

ISM001-055 is a potentially first-in-class small molecule targeting TNIK, developed using generative AI; its early development was published in a Nature Biotechnology article in March earlier this year [2].

ISM001-055 operates by inhibiting TNIK, a protein implicated in the fibrotic pathways that contribute to IPF’s progression. In the context of IPF, TNIK activation drives fibrosis in lung tissue, leading to reduced lung capacity and function over time. Insilico’s candidate aims to disrupt this pathological cascade, potentially halting or even reversing fibrotic changes – a transformative prospect for IPF patients who currently face limited therapeutic options.

“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,” Xu explained, highlighting the role of advanced technology in the development of ISM001-055 and its relevance for clinical applications.

Insilico plans to build on the success of this trial by initiating pivotal trials and engaging with regulatory authorities to facilitate ISM001-055’s path to market. Additionally, complete Phase IIa data is expected to be shared at upcoming medical conferences, allowing for discussion and validation within the scientific community.

Broader potential of generative AI in drug discovery

Insilico Medicine has pioneered the use of generative AI in the design of novel molecules since 2016, integrating advanced AI techniques such as deep generative models and reinforcement learning into their Pharma.AI platform. This platform now supports a wide range of activities in drug discovery, from target identification to clinical development, and has led to the nomination of 20 preclinical candidates since 2021, with 9 molecules receiving IND approval.

Alex Zhavoronkov, PhD, Founder and CEO of Insilico Medicine, said: “We are thrilled with the positive results from this Phase IIa clinical trial, which underscore the potential of AI to facilitate the development of innovative therapies and improve patient outcomes.” Reflecting the company’s commitment to setting industry benchmarks, Zhavoronkov added: “We aim to set industry benchmarks for drug discovery and development using generative AI and commit to pioneering innovative solutions for complex medical challenges.”

The company’s recent appointment of Carol Satler, MD, PhD, as Vice President of Clinical Development signals a strategic move to reinforce non-oncology programs, including IPF. Satler brings over 20 years of experience in drug discovery and development, a background that will be instrumental in advancing ISM001-055 and other pipeline assets through rigorous clinical validation.