The chronic scarring lung disease idiopathic pulmonary fibrosis (IPF) gradually but permanently makes breathing increasingly difficult. While FDA-approved treatments can slow disease progression, none of them can stop or reverse IPF. The first drug designed using generative AI, developed by Insilico Medicine — a Cure Collaboration Residency company — may change that.
Insilico announced encouraging topline results of its phase 2A clinical trial of ISM001-055 in a press release on November 12. Patients who received ISM001-055 — which has the potential to not only be the first-in-class oral agent to treat IPF, but also the best in class — experienced a dose-dependent improvement in respiratory function after just 12 weeks of treatment.
Insilico, a clinical-stage generative AI-driven biotechnology company, developed ISM001-055 in-house to target the TNIK protein. In IPF, TNIK drives the development of fibrosis in the lungs, resulting in a progressive decline in lung function. By inhibiting TNIK, ISM001-055 is designed to halt or reverse fibrotic processes, offering a disease-modifying treatment for people with IPF for the first time.
“I am very impressed by the positive results observed in patients with IPF 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 principal investigator of the clinical trial.
IPF, a relentless rare disease, currently lacks a cure
In people with IPF, lung tissue stiffens and oxygen exchange does not occur efficiently. Patients have a persistent cough and worsening breathing difficulty. About 5 million people around the world have IPF, which carries a poor prognosis. Median survival after diagnosis is only three to four years.
Existing medications do not stop or reverse the disease. They also can have side effects that cause many patients to stop taking them. These include elevated liver enzymes and gastrointestinal issues such as nausea, vomiting, diarrhea and loss of appetite.
The only real cure for IPF is lung transplantation, but that is not an option for everyone. There is therefore a significant unmet medical need for more effective disease-modifying IPF therapies.
Inslicio Medicine's ISM001-055, the first AI-generated drug, completes pivotal clinical trial
The strategic direction for the phase 2A study (NCT05938920) was set at Cure, explained Alex Zhavoronkov, PhD, Founder and CEO of Insilico.
The Insilico team designed the study as a double-blind placebo-controlled clinical trial that enrolled 71 patients with IPF across 21 sites in China. Participants were randomly assigned to receive either placebo, 30 mg of ISM001-055 once daily, 30 mg twice daily or 60 mg once daily for 12 weeks. ISM001-055, a small molecule, is formulated as a tablet.
"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," noted Toby M. Maher, MD, PhD, a leading expert in interstitial lung disease and an investigator in the clinical trial.
Researchers found that:
All dosing groups tolerated ISM001-055 well, with only mild to moderate side effects. Diarrhea and abnormal liver function were the most common side effects (occurring in 14.8 percent of patients).
Therapy with the 60 mg dose of ISM001-055 delivered a 98.4 mL mean improvement from the study start in patients’ forced vital capacity (FVC), a measure of the total volume of air a patient can blow forcefully following a full inhalation of air. In comparison, a mean FVC decline of -62.3 mL occurred in patients in the placebo group.
Similarly, 60 mg therapy of ISM001-055 yielded a dose-dependent trend in percent predicted FVC (ppFVC), a measure of lung function. This dose delivered a 3.05 percent mean ppFVC improvement compared to a mean ppFVC decline of -1.84 percent in the placebo group.
Patients in the 60 mg group also experienced improvements in their quality of life and other functional measures, including a 2-point improvement in the Leicester Cough Questionnaire score.
"There is a lot of hype in AI drug discovery, with many companies making extraordinary statements. And while it is great to have public attention focused on this important area, it is also important to understand that the ultimate objective of AI-driven drug discovery is drug discovery: making drugs cheaper, faster and with a higher probability of success," explained Zhavoronkov.
"We have a clear set of benchmarks: 13 months to preclinical candidate stage on average, and 22 months from zero to being studied in human clinical trials,” he added. “The fact that the first AI-generated drug was discovered in record time and that we completed a phase 2 clinical trial with good safety and unexpected efficacy is a testament that these drugs are of high quality and have a higher probability of success."
Insilico plans next steps for ISM001-055
Insilico will be initiating discussions with regulatory bodies based on these encouraging results. In February 2023, ISM001-055 received Orphan Drug Designation from the FDA for the treatment of patients with IPF.
In addition, complete phase 2A data from this study will be presented at an upcoming medical conference and published in peer-reviewed medical journals. Investigators are now actively recruiting patients for a phase 2A clinical trial in the United States.