TNIK

iStock/ Mihaela Rosu Clinical trial results shared by Boehringer Ingelheim and Insilico Medicine showed improvement in idiopathic pulmonary fibrosis, an intractable lung disease for which current treatment options fail to stop progression, but the data were limited, leaving experts wanting. Patients with idiopathic pulmonary fibrosis got a double helping of good news in the clinical trials arena last week as Boehringer Ingelheim and Insilico Medicine each reported positive data from their respective trials. The results indicate that both companies’ idiopathic pulmonary fibrosis (IPF) drug candidates might be able to stop or reverse decline in lung function—something no current treatments can offer. But experts cautioned that the data drops were light on the details and that more information is needed before either asset can be accurately evaluated. A progressive interstitial lung disease disproportionately affecting older adults, IPF is characterized by lung scarring, inflammation, fatigue and shortness of breath. It ultimately leads to respiratory failure and death within 3–5 years of diagnosis. As its name suggests, the origin of IPF is unknown. “IPF is a very complex, multifactorial and very idiopathic process,” Insilico co-CEO Alex Zhavoronkov told BioSpace . There is no cure for IPF and current treatment is designed to minimize symptoms, maintain quality-of-life and slow progression, Allison Reiss, an associate professor at NYU Grossman Long Island School of Medicine, told BioSpace in an email. She added that “mainstay treatment” consists of Boehringer’s Ofev (nintedanib) and Roche’s Esbriet (pirfenidone), both antifibrotic drugs, along with pulmonary rehabilitation. However, Zhavoronkov said, “neither of these drugs are extremely well tolerated,” and they only slow down decline in forced vital capacity (FVC), a key measure of lung function in IPF. “Usually, you see the decline on the standard of care.” Insilico, Boehringer See Improvements in Key IPF Indicator On Sept. 16, Boehringer reported that its IPF drug candidate nerandomilast elicited a significant improvement in FVC at 52 weeks versus placebo in the Phase III FIBRONEER-IPF trial of 1,177 patients. FIBRONEER-IPF “is the first IPF Phase III trial in a decade to meet its primary endpoint,” Ioannis Sapountzis, Boehringer’s head of global therapeutic areas, said in a statement. Reiss said she would like further specifics in regard to that endpoint. “[Boehringer Ingelheim] said [the study] met the endpoint, which means that those on the drug performed better on the forced vital capacity test, but on both doses or one of the doses? And how much better?” Trial participants were given either 9 mg or 18 mg of nerandomilast twice a day or a placebo for at least 52 weeks. Additionally, Reiss is seeking more information on the secondary endpoints: time to an IPF exacerbation, first hospitalization for respiratory cause, or death. She noted, however, that nerandomilast’s mechanism of action is promising. By preferentially blocking the phosphodiesterase 4B enzyme, she explained, “PDE4B inhibitors interfere with the function of a very specific form of the phosphodiesterase enzyme so that this class of drugs may be able to reduce inflammation and fibrosis in IPF with less side effects than a drug that would inhibit multiple forms of the enzyme.” In an emailed statement, a Boehringer spokesperson told BioSpace the company has a strong focus on IPF, given the high unmet need. The company plans to present full data and analyses from FIBRONEER-IPF in the first half of 2025. Insilico, meanwhile, reported similarly positive results on its much smaller Phase IIa trial of 60 patients with IPF. Specifically, the company released results the day after Boehringer showing that its ISM001-055 met the primary endpoint of safety and secondary efficacy endpoints, demonstrating a dose-dependent improvement in FVC over 12 weeks. Zhavoronkov acknowledged that the study is “not powered enough for me to go out and make super big claims . . . but when you see the chart, it’s very clear that you see that the drug is working.” Insilico is currently awaiting the results of a second, parallel Phase IIa trial. Next, Zhavoronkov said the company expects to run a Phase IIb study but added that the team wants to meet with regulators to understand the regulatory pathway. He suggested there could be potential for the candidate to be fast-tracked. “If you see the improvements in forced vital capacity, and it’s strong enough evidence to convince the regulators, maybe patients should be on the drug right now,” he told BioSpace . ISM001-055—which was wholly designed using Insilico’s generative AI engine referencing millions of data including patents, research publications, grants and clinical trial databases—targets Traf2- and NCK- interacting kinase (TNIK). Zhavoronkov explained that, due to the prevalence of IPF in people 65 years and older, Insilico was looking for targets that were also “very strongly implicated” in aging, Zhavoronkov said. “We were looking for a dual-purpose target.” TNIK scored high in six hallmarks of aging, and there was significant overlap in hallmarks of IPF, he said. However, Reiss said she is “pretty skeptical” about the approach. She noted that while TNIK is present in the lungs and “does regulate transforming growth factor-β signaling, which is important in IPF,” it is mostly found in the gastrointestinal system. Reiss added that the duration of the study was too short and the number of subjects was too small to draw any conclusions about ISM001-055’s efficacy. “[We’ll] have to wait and see,” she said.

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. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health 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. Sponsored Post Get Ready for HLTH 2024: A Preview Guide HLTH 2024, scheduled for October 20-23 at the Venetian Expo Center in Las Vegas, will highlight new programming, a physicians roundtable, generative AI, the shifting landscapes of telemedicine, retail health, women's health, and lots more. By Stephanie Baum 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.

Insilico Medicine, a biotech company with offices in both China and the US, announced this week that its lead candidate drug had met its primary endpoint of safety and its secondary efficacy endpoints. INS018_055 (also known as ISM001-055) is a small molecule drug candidate targeting TRAF2- and NCK-interacting kinase (TNIK). TNIK inhibitors are being investigated ​ for potential anticancer properties, but are also thought to have anti-fibrotic properties that could be effective for treating lung diseases such as idiopathic pulmonary fibrosis (IPF). The phase 2a trial of INS018_055/ISM001-055 enrolled 71 patients in China with IPF who were randomly assigned to receive: placebo, 30mg once daily, 30mg twice daily, or 60mg once daily for 12 weeks. A similar phase 2a trial is currently recruiting in the US. In a statement released this week, the company reported that its candidate therapy had met its primary endpoint of safety and tolerability at all doses. It also said secondary efficacy endpoints were also met, with the highest improvement in forced vital capacity (FVC) seen with the highest dose of 60mg once daily. The company will now design a phase 2b trial in consultation with regulators. Notably, Insilico has not yet released full data from the trial, making it difficult to judge the degree of efficacy of the candidate therapy. In a press statement it said that complete topline data would be released at an upcoming medical conference and that the clinical trial results would be submitted for publication in a peer-reviewed journal. googletag.cmd.push(function () { googletag.display('text-ad1'); }); "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," said Toby Maher, an expert in interstitial lung disease who is involved with the Insilico clinical trials program for this drug candidate, in the company press statement. Insilico is not the only company targeting IPF, Boehringer Ingelheim reported positive phase 3 results ​ for its new IPF candidate earlier this week and Vicore Pharma, Bridge Therapeutics and Pliant Therapeutics all have candidates that have reached phase 2. Whether Insilico’s candidate is effective enough to compete with others in the space remains to be seen. AI-based drug design ​ Insilico specializes in using generative artificial intelligence (AI) to look for new drug targets and speed up the early stages of drug-discovery before the potential therapies enter clinical trials. It was one of the first company’s in the space to propose and apply the use of generative AI to drug development, publishing a paper ​ on the topic in 2016. Since 2021, the company has announced 12 different preclinical therapeutic candidates in development for treatment of conditions such as cancer, Covid-19, inflammatory bowel disease, and kidney fibrosis and advanced three of them to clinical trials. Its lead candidate and indication targets IPF and INS018_055 was the first drug designed with generative AI to enter phase 2 trials ​ in 2023. “This study result represents a critical milestone in AI-powered drug discovery and in my life to date,” said Alex Zhavoronkov, co-CEO of Insilico Medicine. “While we expected the drug to be safe, we did not expect to see such a clear dose-dependent efficacy signal after such a short dosing period. IPF is a very diverse disease, and it is very rare to see improvement in FVC.”