Idiopathic Pulmonary Fibrosis Treatment
27 May, 2022 | DelveInsight
- PLN-74809 is an oral small-molecule dual-selective inhibitor of αvβ6 and αvβ1 integrins in development for the treatment of IPF, with Fast Track and Orphan Drug designation granted by the US FDA.
- PLN-74809 reduces the activity of the Transforming Growth Factor-β (TGF-β), a key mediator of the fibrosis pathway, in the lungs.
- Pliant received up to USD 100 million of non-dilutive capital from Oxford Finance LLC that will support the continued clinical development of PLN-74809 in IPF treatment.
Pliant Therapeutics is focused on discovering and developing novel therapeutics for the treatment of fibrosis. The Company presented five scientific posters as part of the American Thoracic Society (ATS) International Conference 2022 held from 13th May to 18th May in San Francisco, California.
The company's oral and poster presentations in the session reflect some of the findings that support the development of PLN-74809 as a potential novel treatment for Idiopathic Pulmonary Fibrosis (IPF). PLN-74809 is an oral small-molecule dual-selective inhibitor of αvβ6 and αvβ1 integrins in development for the treatment of IPF, with Fast Track and Orphan Drug designation granted by the US FDA. These integrins are increased in the lungs of IPF patients, where they activate TGF- β, a critical driver of the fibrotic process. By inhibiting these integrins, TGF activation is inhibited, potentially preventing the formation of scar tissue.
Day 5 Session C22: Influence of Systems and Society on Healthcare and Healthcare Delivery
As per the data presented in Poster 419, in seven completed Phase I studies, PLN-74809 was well tolerated by 283 healthy adults who received single doses of up to 640 mg or repeated doses of up to 320 mg once a day for up to 14 days. Headache and constipation were the most commonly reported drug-related adverse events, with no drug-related severe adverse events observed. More recently, PLN-74809 has been given to approximately 450 people, including healthy people and people with IPF, primary sclerosing cholangitis, and acute respiratory distress syndrome, with no safety issues.
Day 6 Session D30: The Injured Lung: Mechanisms and Therapeutic Targets
In Poster 710, the company presented data from an ongoing Phase II (NCT04072315/PLN-74809-IPF-201) study evaluating PLN-74809 on αvβ6 receptor occupancy using [18F] FP-R01-MG-F2 PET/CT imaging in participants with IPF. Four people were given a single dose of 60 mg, 120 mg, 240 mg, or 320 mg PLN-74809 in this interim analysis; two of the participants were given additional doses of 240 mg and 320 mg, respectively. The study's preliminary findings showed that target engagement was dosage and plasma concentration-dependent, with all individuals reaching >50% αvβ6 target engagement. At the two highest doses of 240 mg and 320 mg, αvβ6 target engagement achieved saturation (>90%) in two subjects. There were no severe or significant side effects noted. In this first interventional study measuring αvβ6 receptor occupancy using PET imaging, PLN-74809 exhibited dose-dependent target engagement of up to 98% in the lungs of patients with IPF, suggesting a necessary step for inhibiting the activation of TGF-β, a key driver of fibrotic disease progression.
Further, in Poster 707, results from the Phase Ib (PLN-74809-109) proof-of-mechanism trial in healthy subjects were presented. The company evaluated the effect of PLN-74809 on TGF-signaling in alveolar macrophages obtained by bronchoalveolar lavage (BAL) from healthy subjects after 7 days of dosage to better characterize PLN-74809 pharmacokinetic/pharmacodynamics features. The ratio of phosphorylated Smad2 (pSmad2) to Smad2 in BAL cells was measured using an electrochemiluminescence assay. Dosing with PLN-74809 reduced pSmad2 levels by 41.2% and 36.6% at 6 and 24-hours post-dose (80 mg), respectively, and by 57.8% and 53.2% (160 mg), respectively, compared to baseline, with unbound plasma concentrations of PLN-74809 exceeding IC50 for αvβ6 inhibition over 24-hours (160 mg).
Following dosing with placebo, pSmad2 levels declined by 17.7% and increased by 74.3% (6 and 24 hours post-dose, respectively). On Day 7, at the two highest dosages examined, PLN-74809 revealed inhibition levels of up to 92% and 76% at 6 and 24 hours after dosing, respectively. PLN-74809 was well tolerated in general, with few drug-related side effects and no severe side effects noted.
To conclude, as there are currently only two existing FDA-approved therapies for IPF, the medical need remains high. These data of all posters mentioned above that were presented in the ATS support the continued Phase II evaluation of PLN-74809 in participants with IPF in the ongoing multinational INTEGRIS-IPF (NCT04396756/ PLN-74809-IPF-202) study. Also recently, Pliant entered into a loan facility agreement with Oxford Finance LLC for up to USD 100 million of non-dilutive financing. This facility will also support the continued clinical development of PLN-74809 in IPF treatment.
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