Phase 2 IPF and PF-ILD Clinical Trials

 
Experimental Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis
and Progressive Fibrotic Interstitial Lung Disease
Phase 2 Trials

There are several phase 2 studies underway that are studying the efficacy and safety of new medications for idiopathic pulmonary fibrosis (IPF) and progressive fibrotic ILD (PF-ILD). The following studies are currently active at the ILD Collaborative Partner Centers.

BMS-986278

BMS-986278 is an experimental medication being developed and tested by Bristol-Myers Squibb. This medication blocks the ability of cells to sense a molecule called lysophosphatidic acid (LPA). BMS-9862278 blocks the ability of lung cells to sense LPA by binding to and inactivating those cells’ LPA receptors (called a “receptor antagonist”). 

In healthy people, LPA is made in response to injury. It promotes wound healing in multiple tissues, including lung tissue. In people with IPF, LPA levels in the lungs are higher than those seen in healthy people.1 It may be that the high levels of LPA encourage the formation of too much fibrotic (scar) tissue. By blocking the ability of lung cells to sense the higher levels of LPA, BMS-986278 may protect against the creation of fibrotic (scar) tissue in the lungs. 

A phase 2 study of BMS-986278 is currently screening people with IPF or with progressive fibrotic interstitial lung disease (PF-ILD) to see if they are eligible to enroll in the study.2 To be eligible, people with IPF must:

  • Have a diagnosis of IPF within 7 years.
  • Be at least 40 years of age.
  • Must not smoke.

People with PF-ILD must:

  • Have evidence of progressive ILD within the 24 months before screening.
  • Be at least 21 years of age.
  • Must not smoke.

People who enroll in the study are allowed to remain on a stable dose of pirfenidone or nintedanib if they were taking one of these medications before entering the study.2

During the study, participants will be randomly assigned to one of three groups. The first group and second groups will receive 30 mg and 60 mg, respectively, of BMS-986278 taken by mouth twice daily. The third group will receive a placebo pill to take by mouth twice daily. Participants will not know which group they are in. The study will last 26 weeks.2

The investigators will have participants do FVC, FEV1, DLCO, and 6MWD tests at the start of the study and at the end to determine if BMS-986278 is effective at improving lung function compared with placebo, and if there are differences between the two dose groups of BMS-986278. Participants will also undergo an electrocardiogram (ECG) at the beginning and end of the study to ensure that the medication does not negatively affect heart function.2

Once they have finished the 26-week period of the phase 2 study, participants may be able to enter an optional “open-label” period of the trial. In the open-label period, they will receive BMS-986278 at the dose that seems safest and most effective, no matter which group they were in during the initial study. The ending time of the open-label period depends on many factors, including the timing of a possible phase 3 study.2

The phase 2 study design was based on information that investigators learned during the earlier phase 1 study that provided guidance on safe dosing levels.3 The phase 1 study investigated BMS-986278 at doses of 3, 10, 30, 100, 150, or 250 mg in healthy participants. Based on side effects at the higher doses, the study was revised to test BMS-986278 at doses of 10 or 30 mg once daily or doses of 30, 60, 90, or 125 mg twice daily for 14 days. There was a placebo group included. A total of 112 healthy participants were enrolled. The medication was well tolerated. Headache was the most commonly reported side effect, and some reversible reductions in blood pressure were seen at higher doses. The 30 mg and 60 mg twice daily doses were selected for testing in the phase 2 study.

PLN-74809

PLN-74809 an oral medication (taken by mouth) that blocks the action of two molecules called αvβ6 integrin and αvβ1 integrin. These two types of integrins are found on the surface of some types of lung cells. They allow lung cells to grow and divide properly in healthy people. People with IPF have much higher levels of these two integrins, which may lead to increased cell growth and too much collagen production, and eventually may lead to fibrosis (scarring) in the lungs.4 By blocking the action of the excess αvβ6 and αvβ1 integrins, PLN-74809 may slow and potentially halt the progression of fibrosis (scarring) in people with IPF. 

A phase 2 study of PLN-74809 is currently screening people with IPF to see if they are eligible to enroll in the study.5 To be eligible, people with IPF must be at least 40 years old and also must have:

  • A diagnosis of IPF based upon the 2018 Fleischner Society guidelines6 within 3 years, or based on the 2018 ATS/ERS/JRS/ALAT guidelines7 within 5 years.
  • A percent predicted FVC of at least 45%.
  • A percent predicted DLCO of at least 30%.

Participants are allowed to take nintedanib or pirfenidone if they have been on a stable dose of either medication for at least 3 months prior to enrolling in the study. Participants must not smoke.5

This is a three part study:

  • Part A: A four-week treatment period evaluating two lower PLN-74809 dose cohorts or matching placebo.
  • Part B: A 12-week treatment period evaluating one PLN-74809 dose cohort or matching placebo.
  • Part C: A 12-week treatment period evaluating one or two higher PLN-74809 dose cohorts or matching placebo.

During the study, participants will be randomly assigned to a dose group of PLN-74809 or placebo, and they will not know which group they are in. The study will last 4 weeks for those in part A, and 12 weeks for those in parts B and C. There is no open-label extension period for this study.5

The investigators will have participants do blood tests, FVC tests, and HRCT scans at the beginning and end of the study to see how much medication is in the blood at various doses and to determine if PLN-74809 can slow or stop the progression of lung disease compared with placebo. The investigators will also have participants fill out a questionnaire about cough and possibly other symptoms to see if the medication improves symptoms compared with placebo.5

The design of the phase 2 study was based on data from an earlier phase 1 studies.8 In the first phase 1 study, 71 healthy volunteers received single doses of PLN-74809 ranging from 15 mg to 75 mg to test for blood levels of medication and for side effects. They then received doses ranging from 10 mg to 40 mg each day for 14 days to further assess for safety. In the second phase 1 study, bronchoalveolar lavage (BAL) was done on 13 healthy volunteers before receiving any medication and then again at 3 hours and 12 hours, or 6 hours and 24 hours, after receiving PLN-74809 at 20 mg or 40 mg each day for 7 days. The cells were examined to see if PLN-74809 blocked αvβ6 integrin and αvβ1 integrin as expected, and there appeared to be at least a 50% reduction in activity. PLN-74809 was well tolerated in both studies with few side effects. The most frequent side effect was mild constipation. 

ND-L02-s0201

ND-L02-s0201 is a medication that is delivered by intravenous (IV) infusion. This new type of drug is a lipid nanoparticle (tiny bead of fat) with small inhibitory RNAs (siRNAs) inside. These siRNAs are short pieces of double-stranded RNA molecules that interfere with the ability of cells to make a protein called heat shock protein 47 (HSP47). HSP47 is a protein that assists in the formation of collagen, which is a key part of fibrotic (scar) tissue. Previous studies have shown that people with IPF have higher levels of HSP47 than healthy people do.9 By “dialing down” the amount of HSP47 that is made, ND-L02-s0201 may reduce the amount of collagen made in the lung tissue. Having less collagen in lung tissue may help slow or stop the scarring process in the lungs of people with IPF.  

Currently, investigators are screening people to see if they are eligible to enroll in a phase 2 study of ND-L02-s0201.10 To be eligible, people with IPF must be 40 to 80 years old. They also must have: 

  • A precent predicted FVC of at least 45%.
  • A percent predicated DLCO of at least 30%.
  • A ratio of FEV1 to FVC of at least 0.70.

Participants are allowed to take nintedanib or pirfenidone if they have been on a stable dose of either medication for at least 3 months prior to enrolling in the study.10

Participants in the study will be randomly assigned to receive ND-L02-s0201 IV infusions every 2 weeks at two different doses, or placebo (salt water) infusions every 2 weeks. The study will last 24 weeks. There is no open-label extension period for this study. Participants will have blood tests, FVC tests, and HRCT scans at the beginning and end of the study to see how much medication is in the blood at various doses and to determine if ND-L02-s0201 can slow or stop the progression of lung disease compared with placebo.10

ND-L02-s0201 was tested in an earlier phase 1 safety study in which 20 healthy volunteers received 90 mg of ND-L02-s0201 or placebo by IV every week for 3 weeks. The most common side effects were phlebitis (inflammation of the vein), burning sensation, and headache. There were no serious side effects.11

References

1. Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leakNat Med. 2008;14(1):45-54.
2. ClinicalTrials.gov. A study measuring the effectiveness, safety, and tolerability of BMS-986278 in participants with lung fibrosis. ClinicalTrials.gov Identifier: NCT04308681.
3. Tirucherai GS, Yu D, Revankar G, et al. BMS-986278, A lysophosphatidic acid 1 (LPA1) receptor antagonist, in healthy participants: a single/multiple ascending dose (SAD/MAD) and Japanese MAD (JMAD) phase 1 studyAm J Respir Crit Care Med. 2020;201:A1492.
4. Teoh CM, Tan SS, Tran T. Integrins as therapeutic targets for respiratory diseasesCurr Mol Med. 2015;15(8):714-734.
5. ClinicalTrials.gov. Evaluation of efficacy and safety of PLN-74809 in patients with idiopathic pulmonary fibrosis. ClinicalTrials.gov Identifier: NCT04396756.
6. Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White PaperLancet Respir Med. 2018;6(2):138-153.
7. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice GuidelineAm J Respir Crit Care Med. 2018;198(5):e44-e68.
8. Gorina E, Decaris M, Turner S, et al. PLN-74809, a Dual αVβ6/αVβ1, oral, selective integrin inhibitor, is well tolerated and reduces lung TGF-β activity in healthy volunteersAm J Respir Crit Care Med. 2020;201:A4554.
9. Liu Y, Liu J, Quimbo A, et al. Anti-HSP47 siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis in preclinical rat modelsERJ Open Res. 2021;7(2):00733-2020.
10. ClinicalTrials.gov. JUNIPER: A phase 2 study to evaluate the safety, biological activity, and PK of ND-L02-s0201 in subjects with IPF. ClinicalTrials.gov Identifier: NCT03538301.
11. Soulé B, Tirucherai G, Kavita U, et al. Safety, tolerability, and pharmacokinetics of BMS-986263/ND-L02-s0201, a novel targeted lipid nanoparticle delivering HSP47 siRNA, in healthy participants: A randomised, placebo-controlled, double-blind, phase 1 study. J Hepatol. 2018;68(suppl 1): S112.