An Insilico Medicine drug candidate spawned by the company’s artificial intelligence technology now has clinical data showing breathing improvement in patients who have a debilitating lung disorder. While these preliminary results are encouraging for the company and for an AI drug discovery field that has weathered setbacks, there’s little detail to evaluate the Insilico drug on its own merits, let alone see how it matches up to competitors that includes one molecule some industry observers view as potentially best in class.
The disease is idiopathic pulmonary fibrosis (IPF), a chronic disorder that causes scarring in the lungs and an irreversible decline in the organ’s function. IPF is a prevalent disease, affecting an estimated 5 million people worldwide, mainly older adults. Once diagnosed, patients survive a median of three to four years. The cause of IPF is unknown; standard therapies are older drugs that slow its progression but do not alter the course of the disease.
Insilico’s drug, ISM001-055, targets and inhibits Traf2- and Nck-interacting kinase (TNIK), an enzyme that plays a role in signaling pathways associated with disease. While TNIK inhibition has been studied as a way to treat cancer, Insilico’s technology identified this target as a promising one for fibrosis, the formation of scar tissue characteristic of IPF. The company then used generative AI to design the small molecule that is now its IPF drug candidate. Details about this development process were published in March in Nature Biotechnology. Included in the paper were preclinical data and results from Phase 0 (small doses of drug tested in low numbers of people) and Phase 1 studies.
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The results announced last week are from a placebo-controlled Phase 2a study that enrolled 71 IPF patients in China. Patients were randomly assigned to receive a 30 mg dose of the drug once daily, a 30 mg dose twice daily, a 60 mg dose once daily, or a placebo. The main goal of the 12-week study is assessing the ISM001-055’s safety and tolerability across all dose levels. Measuring improvement in forced vital capacity (FVC), which is how much air a person can exhale, is a secondary endpoint.
Without disclosing any figures, Insilico said ISM001-055 met the primary endpoint of safety and posted positive results on the secondary efficacy endpoint. The company added that these results show a dose-dependent improvement in FVC, with the largest improvement observed in the cohort that received the 60 mg dose once daily. Insilico said more details about the preliminary data will be released at an upcoming medical conference and the trial results will be submitted for publication in a peer-reviewed journal. A parallel Phase 2 study in the U.S. is actively enrolling patients.
Following the positive results from this mid-stage study, Insilico said it will discuss with regulatory authorities the design of a Phase 2b study that will explore extended treatment durations and larger groups of patients. Meanwhile, the clinical trial results so far keep Insilico in the mix of drug developers pursuing IPF, though it still trails those rivals.
On Sept. 16, Boehringer Ingelheim announced its IPF drug candidate hit the main goal of its pivotal studies, paving the way for regulatory submissions to the FDA and other health authorities around the world. The Boehringer drug, nerandomilast, is a small molecule designed to inhibit phosphodiesterase 4B (PDE4B), an enzyme whose roles include regulating inflammation.
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Boehringer studied its twice-daily pill in two placebo-controlled Phase 3 studies, one in IPF and the other in progressive pulmonary fibrosis (PPF), a progressive and fibrotic disease that shares characteristics with IPF. The main goal of both studies was to show the absolute change in FVC measured at 52 weeks. Without releasing details, Boehringer said preliminary results show nerandomilast met this goal. The company added that full efficacy and safety data will be presented in the first half of next year. The company did not specify a timeline for the expected regulatory submissions for the drug.
Pliant Therapeutics’ contender is bexotegrast, a small molecule inhibitor of TGF-beta. This signaling protein contributes to IPF by sparking high levels of collagen, which in turn leads to a progressive loss of elasticity and function in the lungs. During the recent European Respiratory Society (ERS) meeting, Pliant presented Phase 2 results showing its drug led to a reduction in collagen after 12 weeks of treatment. Study participants who received a placebo experienced an increase in collagen. The reduction in treated patients correlates with improvement in lung function, specifically FVC and cough severity, Pliant said.
In a note sent to investors this after the ERS meeting, Leerink Partners analyst Faisal Khurshid said bexotegrast’s collagen data provide “compelling proof of disease modification.” He added that the safety analyses continue to suggest the Pliant drug has a clean profile. Khurshid said bexotegrast has potential to become a best-in-class treatment option in IPF and the collagen data give incremental confidence ahead of Phase 2b data expected in mid-2026.
PureTech Health’s approach to IPF is to improve on pirfenidone, brand name Esbriet, an old IPF drug whose gastrointestinal and skin side effects lead many patients to stop taking the medication. Despite those limitations, Leerink Partners’ Khurshid noted in a research note that branded Esbriet generated $1.3 billion in peak sales before going generic. PureTech’s IPF drug, LYT-100, is pirfenidone with chemical modifications to improve its tolerability.
“We have a favorable view on LYT-100 as it improves on a known anti-fibrotic drug in a manner that should diminish well-recognized safety liabilities,” Khurshid said. “While this is an improvement on an existing molecule, we see it as a real opportunity in an area of high unmet need.”
A Phase 2b test of LYT-100 is currently evaluating two doses of the drug compared to pirfenidone and a placebo. With the lower dose, the study aims to show whether the PureTech drug improves on the safety profile of pirfenidone. Evaluating the higher dose is meant to assess whether higher exposure of the drug offers even better efficacy while still retaining acceptable safety. Khurshid said there is less evidence to support the latter hypothesis, but Leerink sees it as an intriguing upside opportunity.
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