Evaluation of PLN-74809 on Biomarkersfrom Bronchoalveloar Lavage Fluid
Research type
Research Study
Full title
A Continued Evaluation of PLN-74809 on Biomarkers of Transforming Growth Factor Beta (TGF-β) Activation Isolated from Bronchoalveolar Lavage Fluid (BALF)
IRAS ID
294420
Contact name
Stephen Smith
Contact email
Sponsor organisation
Pliant Pharmaceutics Inc
Eudract number
2020-006069-12
Duration of Study in the UK
0 years, 4 months, 29 days
Research summary
Summary of Research
PLN-74809 is being developed for the possible treatment of several conditions of the lungs and gallbladder which are currently difficult to treat. These conditions arise due to chronic inflammation and fibrosis in these parts of the body. These processes occur due to activation of certain growth factors in the body which PLN-74809 is designed to switch off.
Animal models and early indicators from previous human studies suggest that PLN-74809 will have a beneficial effect.
This study aims to determine from collection of fluid from the lung lining (by a bronchoscopy or "lung tube test") whether the expected effects of PLN-74809 are demonstrated in the lung.
The study will also look at safety of PLN-74809 compared to placebo (dummy drug) over 7 days of dosing.
And also provide information on the way that PLN-74809 is handled by the human body.Summary of Results
: RATIONALE BEHIND THE INVESTIGATIONAL STUDY DRUG DEVELOPMENT Pliant Therapeutics Inc. (Pliant) is developing PLN-74809-000 (hereafter referred to as PLN 74809) for the treatment of idiopathic pulmonary fibrosis (IPF) and treatment of primary sclerosing cholangitis (PSC). Pulmonary fibrosis and sclerosing cholangitis are medical conditions involving excessive fibrous tissue formation in the organs. Formation of such fibrous scarring in lungs and gall bladder ducts lead to medical problems. Pliant therapeutics is hoping to develop this study drug into a potential medicine for the treatment of the above fibrotic conditions.
Pliant Therapeutics have previously studied the drug in another study where they measured the effects of the study drug on the process of fibrous tissue formation by monitoring the biomarkers such as Transforming Growth Factor – beta in lung fluid. They have done the same in this study using a dose level that will most likely be taken forward when the study drug moves into the next phase of the clinical development (Phase 2).
OBJECTIVES OF THE STUDY
Primary objective: to measure the biomarkers of fibrosis in lung fluid measured at different time points after dosing of PLN-74809 for 7 days.
Secondary objective:
• to assess the safety of the drug in healthy volunteers who took part in the study. In addition, the blood level of the stud drug concentration was measured to see how well the drug was absorbed into the blood stream.
• to correlate the blood concentration of the study drug PLN-74809 and the effects on the biomarkers of the fibrous tissue formation.
STUDY DESIGN
This was a randomized, double-blind, placebo-controlled study in healthy participants conducted in 2 parts; 48 participants took part in the study.
The participants had to fulfil a range of inclusion/exclusion criteria to be allowed into the study. They were asked to refrain from taking other medications during the conduct of the study.
Healthy participants (18 to 50 years of age) were recruited and remained domiciled in the clinical research unit (CRU) overnight before dosing and 1 day after dosing (Days -1 to 8). Participants received PLN-74809 or matching placebo daily for 7 days from Day 1 through Day 7. Bronchoalveolar fluid (BALF) was collected prior to dosing (Day -1) and at 6 and 24 hours post-dose on Day 7 from the middle lobe or lingula, according to the investigational site’s standard bronchoscopy procedures. Plasma samples for blood concentration analysis were collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 12, and 24 hours post-dose on Days 1 and 7. For participants in Part 2, the Day 7 PK and BALF sampling times were in respect to the morning dose on Day 7; specifically, for 160 mg twice daily, the 24-hour post-dose sample on Day 7 was 12 hours post-dose relative to the afternoon dose on Day 7.
Participants were discharged on Day 8. An outpatient safety follow-up visit (End of Study [EOS] Visit) took place 14 ±3 days after the last dose of study drug (Day 21 ±3).
Treatments AdministeredPart 1
One of the following treatments were offered to the participants in a randomized manner in the ratio of 1:1:1
• 80 mg PLN-74809 once daily
• 160 mg PLN-74809 once daily
• Matching Placebo
Part 2
One of the following treatments were offered to participants in a randomized manner in the ratio of 1:1:1.
• 320 mg PLN-74809 twice daily
• 160 mg PLN-74809 twice daily
• Matching placebo twice dailyAfter the review of the 80 and 160 mg cohorts by the Safety Monitoring Committee, the data had been determined to be safe and well tolerated, thus Part 2 of the study could commence.
STUDY CONCLUSIONS
1. Pharmacodynamics (Effect of the study drug)
• Relative to placebo, administration of PLN-74809 for 7 days reduced the percent change from baseline in biomarkers of fibrosis in lung fluid cells, indicating reduced TGF-β signaling within the alveolar space of the lung. This effect was significant and dose dependent at 24 hours post-dose.2. Pharmacokinetics (Blood concentration of the drug)
• An approximate 4-fold increase in dose (80 to 320 mg) yielded a similar increase in blood concentrations of the drug.3. Relationship between blood concentration of the drug and the treatment effect on fibrosis
There was a trend showing a correlation between reduction in fibrosis biomarkers and the blood concentrations of the PLN-74809 drug.4. Safety of the drug
• Dosing with PLN-74809 for 7 days up to a total daily dose of 320 mg was generally well tolerated. Study participants who took the active drug had a higher percentage of side effects but all events were mild or moderate in severity and no dose-dependent trends were observed. There were no deaths, SAEs, or study drug discontinuations due to an AE. Vital signs like blood pressure, heart rate and ECGs were all normal during the study conduct.REC name
HSC REC B
REC reference
21/NI/0018
Date of REC Opinion
16 Feb 2021
REC opinion
Favourable Opinion