Phase 3 IPF and PF-ILD Clinical Trials

 
Experimental Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis
and Progressive Fibrosing Interstitial Lung Disease
Phase 3 Trials

There are several phase 3 studies underway that are studying the efficacy and safety of new medications for idiopathic pulmonary fibrosis (IPF) and progressive fibrosing ILD (PF-ILD). The following studies are currently active at the ILD Collaborative Partner Centers.

FIBRONEER / BI 1015550 

BI 1015550 is an experimental medication being developed and tested by Boehringer Ingelheim International GmbH as part of a 2-part program called “FIBRONEER.” It is given as an oral tablet.1,2 BI 1015550 is a drug that inhibits an enzyme called phosphodiesterase 4 (PDE4); specifically, it inhibits a subtype (variety) of PDE4 called PDE4B.3

The family of PDE enzymes controls various cellular processes by regulating the way messages are sent within cells.4 Members of the PDE4 subfamily have been shown to promote the process of inflammation, and three inhibitors of PDE4 enzymes have already been approved as treatments for inflammatory diseases of the skin and lung.5

Evidence suggests that inhibiting PDE4 activity also reduces or reverses the formation of scar tissue by cells called fibroblasts. A PDE4 inhibitor called roflumilast (ro-FLOO-mih-last; Daliresp) was tested in rodents that had been exposed to bleomycin (BLEE-oh-MEYE-sin), a drug that is known to cause lung injury. In one study, roflumilast reduced the appearance of molecules that signify scar tissue formation.6 In another study, roflumilast both prevented the formation of new scar tissue and reduced existing scar tissue in the lungs of bleomycin-exposed rodents.7 In a similar animal model, experiments demonstrated that the PDE4 inhibitor cilomilast (si-LOH-mi-LAST) also inhibited scar tissue formation.8

Making these observations relevant to humans, studies of human fibroblasts suggest that PDE4 enzymes help control human fibroblasts and that PDE4 inhibitors inhibit human fibroblast activity and scar tissue formation.3

Therefore, a study has been launched to investigate whether the BI 1015550 improves the forced vital capacity (FVC) in people with IPF. The study is currently recruiting patients.1 To be eligible to enroll, people must be at least 40 years of age. In addition, they must meet criteria that include (but are not limited to) the following:

  • A diagnosis of IPF.
  • Either
    • On stable treatment with either nintedanib (nin-TED-an-ib; Ofev) or pirfenidone (pir-FEN-i-done; Esbriet) (but not both) for at least 12 weeks prior to the first study visit and the intent to remain on that therapy once having begun the study.
    • Not on treatment with nintedanib or pirfenidone for at least 8 weeks prior to the first study visit and no intention to start or restart treatment with either of these drugs.
    • A percent FVC of at least 45%.
    • A percent predicted diffusing capacity of the lung for carbon monoxide (DLCO) corrected for hemoglobin (Hb) of at least 25% and less than 90% at the first study visit.

During this phase 3 study, participants will be randomly assigned to receive either a high dose of BI 1015550, a low dose of BI 1015550, or a placebo (a tablet that looks like a BI 1015550 tablet but that contains no medicine). Throughout the study, all participants will take their assigned tablets twice a day.1

Participants will visit the study site 10 times during the first year of the study. Then, they will visit once every 3 months for the remaining year and a half. FVC tests performed by participants at the beginning and at the end of the study will help investigators determine if BI 1015550 is better than placebo at improving lung function.1

A second component of the FIBRONEER program is investigating whether BI 1015550 improves the FVC in people with progressive fibrosing interstitial lung diseases (PF-ILDs). The phase 3 study is also currently recruiting patients.2 To be eligible to enroll, people must be at least 18 years of age. In addition, they must meet criteria that include (but are not limited to) the following:

  • A diagnosis of a progressive fibrosing ILD other than IPF.
  • Either
    • On stable treatment with either nintedanib for at least 12 weeks prior to the first study visit and the intent to remain on that therapy once having begun the study.
    • Not on treatment with nintedanib for at least 8 weeks prior to the first study visit and no intention to start or restart treatment with that therapy.
    • A percent FVC of at least 45%.
    • A percent predicted DLCO corrected for Hb of at least 25% and less than 90% at the first study visit.
    • If a recipient of prior, permitted immunosuppressive agents, treatment must have been stable for at least 12 weeks prior to the first study visit.

During this phase 3 study, participants will be randomly assigned to receive either a high dose of BI 1015550, a low dose of BI 1015550, or a placebo (a tablet that looks like a BI 1015550 tablet but that contains no medicine). Throughout the study, all participants will take their assigned tablets twice a day.2

Participants will visit the study site 10 times during the first year of the study. Then, they will visit once every 3 months for the remaining year and a half. FVC tests performed by participants at the beginning and at the end of the study will help investigators determine if BI 1015550 is better than placebo at improving lung function.2

Because BI 1015550 targets only one PDE4 subtype (PDE4B), the side effects of this drug may be less severe than those caused by a drug that targets multiple subtypes. Specifically, evidence suggests that PDE4D inhibition contributes to the emesis (vomiting) frequently seen with other, less-specific, PDE4 inhibitors.9Therefore, researchers are hopeful that people who take BI 1015550 will experience less emesis and other side effects than people who take other PDE4 inhibitors.3,9

A phase 2 study has already shown that BI 1015550 helped to maintain FVC in patients with IPF. In that study, the most frequent adverse event was diarrhea, and most cases were mild. Researchers reported that the rate of severe adverse events was the same among patients who received BI 1015550 as among patients who received a placebo.10

TETON / Inhaled treprostinil

Treprostinil (Tyvaso) is an experimental medication being developed and tested by United Therapeutics Corp. It is given by oral inhalation. Treprostinil (treh-PROS-tin-il) is an analogue of prostacyclin, which means it has a similar structure to that of prostacyclin, a molecule that is naturally produced by blood vessel cells and that has two effects:

  1. Vasodilation, which means that it widens the blood vessels, lowering blood pressure.
  2. Inhibition of platelet aggregation, which means that it stops platelets from sticking together, as they tend to do when blood vessels are injured.

Because treprostinil is similar in structure to prostacyclin, it behaves similarly in the body, causing vasodilation and inhibiting platelet aggregation. Treprostinil is currently approved for the treatment of pulmonary hypertension (high blood pressure in blood vessels leading from the heart to the lungs) associated with interstitial lung disease (ILD).11

When treprostinil was studied in people with ILD and pulmonary hypertension, this medication significantly increased the distance that patients were able to walk during a six-minute walk test.12 Patients who received treprostinil also experienced an improvement in their forced vital capacity (FVC) and fewer exacerbations of their lung disease.13 Additionally, several preclinical studies (not done in humans) have suggested that treprostinil may inhibit scar tissue formation by preventing cells called fibroblasts from multiplying and/or from producing the material that makes up scar tissue.14 These data support the idea that people with IPF might benefit from taking treprostinil.

Therefore, a study has been launched to investigate whether inhaled treprostinil improves the FVC in people IPF. The study is currently recruiting patients. To be eligible to enroll, people must be at least 40 years of age. In addition, they must meet criteria that include (but are not limited to) the following15:

  • A diagnosis of IPF as defined by the 2018 ATS/ERS/JRS/ALAT guidelines.16
  • A high-resolution computed tomography (HRCT) test that confirms the IPF diagnosis. 
  • A percent predicted FVC of at least 45%.
  • If they are on background pirfenidone (pir-FEN-i-done; Esbriet) or nintedanib (nin-TED-an-ib; Ofev) for IPF, a stable dose for at least 30 days prior to beginning the study.

This study has less restrictive inclusion criteria than do some other studies, because the researchers want to evaluate inhaled treprostinil in conditions that mimic real life. Specifically, there is no upper age limit and no upper FVC limit, and people are allowed to enroll even if they are on the lung transplant list or are taking pirfenidone or nintedanib (though taking both is not permitted).14

During this phase 3 study, participants will be randomly assigned to receive either inhaled treprostinil or a placebo over the course 6 treatment visits, at weeks 4, 8, 16, 28, 40, and 52. At the beginning of the study, patients will receive their assigned treatment at a dosage of 3 breaths, 4 times daily. The dosage will be gradually increased to the maximally tolerated dose, or no more than 12 breaths, 4 times daily.15

FVC tests performed by participants at the beginning and at the end of the study will help investigators determine if inhaled treprostinil is better than placebo at improving lung function. Participants will also fill out a questionnaire to determine if inhaled treprostinil is better than the placebo at improving patients’ quality of life with respect to chest symptoms, breathlessness, and psychological effects of disease.15

After completing week 52 of the study, patients may be eligible to enroll in an open-label extension study. In the open-label study, all participants will receive inhaled treprostinil. This will allow investigators to evaluate how well patients tolerate the drug over an extended period of time.15

The safety of inhaled treprostinil has already been evaluated in an earlier study of patients with ILD. In that study, the most common side effects of the drug were mild or moderate cough, headache, dyspnea (labored breathing), dizziness, nausea, and fatigue. No serious side effects were caused significantly more often by the drug than by the placebo.12

BMS-986278

BMS-986278 is a novel, orally administered drug being developed and tested by Bristol Myers Squibb.17 BMS-986278 binds to a cell-surface molecule called lysophosphatidic acid receptor 1 (LPA1) and thus prevents cells from sensing the presence of lysophosphatidic acid (LPA), a signaling molecule.17

Normally, LPA contributes to wound healing. However, LPA has been shown to be present at increased levels in a mouse model of pulmonary fibrosis, and when LPA signaling is reduced in experimental mice, lung fibrosis is also reduced. LPA has also been shown to be elevated in humans with idiopathic pulmonary fibrosis (IPF).18This suggests that LPA signaling is important in the formation of fibrotic (scar) tissue in the lungs.

Experiments with human cells have affirmed this role for LPA in humans. The results of these experiments show that LPA can trigger the production of cellular growth factors and promote cellular changes associated with fibrosis.19

A phase 3 study is underway to investigate safety and efficacy of BMS-986278 in treating people with IPF and people with other forms of progressive pulmonary fibrosis (PPF).20,21

To participate in the IPF component of this study, persons with IPF must: 

  • Be at least 40 years of age.
  • Have been diagnosed with IPF within 7 years, with the diagnosis confirmed at screening by high-resolution computed tomography (HRCT) and verification of usual interstitial pneumonia.
  • If female, use highly effective contraception and provide a negative pregnancy test.

People with IPF who have been on a stable dose of pirfenidone or nintedanib for at least 90 days prior to screening can continue to take their stable dose. Otherwise, these medications must not have been taken within 28 days prior to screening.

Participants in the IPF component of the study must not have symptoms of heart failure or have experienced stroke or ischemic attack within 3 months or malignancy within 5 years prior to screening, excepting cured nonmetastatic squamous cell skin carcinoma, basal cell skin carcinoma, or cervical carcinoma in situ.

To participate in the PPF component of this study, persons with PPF must:

  • Be at least 21 years of age.
  • Have been diagnosed with progressive interstitial lung disease within 2 years, with ≥10% fibrosis as assessed by HRCT.
  • If female, use highly effective contraception and provide a negative pregnancy test.

People with PPF who have been on a stable dose of pirfenidone, nintedanib, mycophenolate mofetil, mycophenolic acid, azathioprine, tacrolimus, traditional disease-modifying antirheumatic drugs (DMARDs) (e.g., methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine), biologic DMARDs (e.g., TNF blockers or IL-1 inhibitors), or Janus kinase inhibitors (e.g., tofacitinib or upadacitinib) for at least 90 days prior to screening can continue to take their stable dose. Otherwise, these medications must not have been taken within 28 days prior to screening. Systemic corticosteroids equivalent to prednisone >15 mg/day must not have been taken within 4 weeks prior to screening.

Participants in the PPF component of the study must not have IPF with usual interstitial pneumonia nor may they have symptoms of heart failure or have experienced stroke or ischemic attack within 3 months or malignancy within 5 years prior to screening, excepting cured nonmetastatic squamous cell skin carcinoma, basal cell skin carcinoma, or cervical carcinoma in situ.

In an initial part of this trial, a preliminary, small group of participants (Cohort 1) was randomly assigned to receive a placebo, a 60-mg dosage of BMS-986278, or a 120-mg dosage of BMS-986278. Data from this part of the trial will be used to assess the safety of the 120-mg dose of BMS-986278 with respect to spontaneous syncopal events (fainting) at approximately 4 weeks. Depending on the results of Cohort 1, eligible participants will be randomly assigned to either a) receive placebo, a 60-mg dosage of BMS-986278, or 120-mg dosage of BMS-986278, or b) receive only placebo or a 60-mg dosage of BMS-986278 in Cohort 2. Randomization in Cohort 2 will begin late spring of 2024. 

For participants in Cohort 2, forced vital capacity (FVC) and percent predicted FVC will be assessed at the beginning of the study and at 52 weeks. Members of this cohort will also be assessed for disease progression for up to 4 years (with “progression” defined as a decline of percent predicted FVC of at least 10%, acute exacerbation of pulmonary fibrosis, respiratory-related hospitalization, and all-cause mortality). Additionally, the following parameters will be measured for members of Cohort 2:

  • Living with Pulmonary Fibrosis Questionnaire (L-PF) cough domain score (at baseline, week 52, and up to approximately 3 years)
  • L-PF dyspnea domain score (at baseline, week 52, and up to approximately 4 years)
  • Walking distance measured in a 6-minute walk test (at baseline and week 52)
  • L-PF fatigue domain score (at baseline, week 52, and up to approximately 3 years)
  • L-PF impacts module score (at baseline, week 52, and up to approximately 3 years)
  • Cough numeric rating scale (at baseline, week 52, and up to approximately 3 years)
  • EuroQol 5 Dimension 5 Level (EQ-5D-5L) health utility index score (at baseline and week 52)
  • EQ-5D-5L visual analog scale score (at baseline and week 52)
  • Single-breath diffusing capacity of the lung for carbon monoxide (DLco) (corrected for hemoglobin) (mL/min/mm Hg) (at baseline and week 52)
  • Percent predicted single-breath DLco (corrected for hemoglobin) (at baseline and week 52)
  • Quantitative lung fibrosis score as assessed by HRCT (at baseline and week 52)

In a phase 2 clinical study, BMS-986278 was well tolerated and produced adverse events at a rate similar to that of placebo. Among the most frequently reported adverse events were diarrhea, cough, and dyspnea.17,22,23

What Does This Mean?

These medications show promise for the treatment of IPF or PF-ILD / PPF. However, it is not completely sure that phase 3 trials will show that they are safe and effective. Not all medications that seem promising in phase 2 trials are actually effective and safe in phase 3 trials. Not all medications that are tested in phase 3 trials become approved for use. It usually takes several years from the time of trial initiation before the results of the phase 3 trials are available. Other possible medications are also being developed for IPF and PF-ILD/PPF. These are being tested for safety and dosing in phase 1 and phase 2 trials now. 

Some patients with IPF or PF-ILD / PPF are interested in enrolling in clinical trials. If you are interested, you can talk to your doctor about whether that is appropriate for you.

References

  1. ClinicalTrials.gov. A study to find out whether BI 1015550 improves lung function in people with idiopathic pulmonary fibrosis (IPF). ClinicalTrials.gov identifier: NCT05321069
  2. ClinicalTrials.gov. A study to find out whether BI 1015550 improves lung function in people with progressive fibrosing interstitial lung diseases (PF-ILDs). ClinicalTrials.gov identifier: NCT05321082
  3. Herrmann FE, Hesslinger C, Wollin L, Nickolaus P. BI 1015550 is a PDE4B inhibitor and a clinical drug candidate for the oral treatment of idiopathic pulmonary fibrosis. Front Pharmacol. 2022;13:838449. doi:10.3389/fphar.2022.838449
  4. Azevedo MF, Faucz FR, Bimpaki E, et al. Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev. 2014;35(2):195-233. doi:10.1210/er.2013-1053
  5. Sakkas LI, Mavropoulos A, Bogdanos DP. Phosphodiesterase 4 inhibitors in immune-mediated diseases: mode of action, clinical applications, current and future perspectives. Curr Med Chem. 2017;24(28):3054-3067. doi:10.2174/0929867324666170530093902
  6. Milara J, Morcillo E, Monleon D, Tenor H, Cortijo J. Roflumilast prevents the metabolic effects of bleomycin-induced fibrosis in a murine model. PLoS One. 2015;10(7):e0133453. doi:10.1371/journal.pone.0133453
  7. Cortijo J, Iranzo A, Milara X, et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br J Pharmacol. 2009;156(3):534-544. doi:10.1111/j.1476-5381.2008.00041.x
  8. Udalov S, Dumitrascu R, Pullamsetti SS, et al. Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice. BMC Pulm Med. 2010;10:26. Published correction appears in BMC Pulm Med. 2022;22(1):113. doi:10.1186/1471-2466-10-26
  9. Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol. 2018;9:1048. doi:10.3389/fphar.2018.01048
  10. Richeldi L, Azuma A, Cottin V, et al. Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N Engl J Med. 2022;386(23):2178-2187. doi:10.1056/NEJMoa2201737
  11. Treprostinil. Prescribing information. Sandoz Inc.; 2015. Accessed March 24, 2023. Treprostinil prescribing information
  12. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325-334. doi:10.1056/NEJMoa2008470
  13. Nathan SD, Waxman A, Rajagopal S, et al. Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study. Lancet Respir Med. 2021;9(11):1266-1274. doi:10.1016/S2213-2600(21)00165-X
  14. Nathan SD, Behr J, Cottin V, et al. Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis. BMJ Open Respir Res. 2022;9(1):e001310. doi:10.1136/bmjresp-2022-001310
  15. ClinicalTrials.gov Study of efficacy and safety of inhaled treprostinil in subjects with idiopathic pulmonary fibrosis (TETON) ClinicalTrials.gov identifier: NCT04708782
  16. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68.
  17. Bristol Myers Squibb. Bristol Myers Squibb’s investigational LPA1 antagonist reduces rate of lung function decline in progressive pulmonary fibrosis cohort of phase 2 study. September 9, 2023. Accessed April 16, 2024.
  18. 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 leak.  Nat Med. 2008;14(1):45-54. doi:10.1038/nm1685
  19. Nathan S, Zhang H, Andreoli M, Leopold PL, Crystal RG. CREB-dependent LPA-induced signaling initiates a pro-fibrotic feedback loop between small airway basal cells and fibroblasts. Respir Res. 2021;22(1):97. doi:10.1186/s12931-021-01677-0
  20. ClinicalTrials.gov A study to evaluate the efficacy, safety, and tolerability of BMS-986278 in participants with idiopathic pulmonary fibrosis.ClinicalTrials.gov identifier: NCT06003426
  21. ClinicalTrials.gov A study to evaluate the efficacy, safety, and tolerability of BMS-986278 in participants with progressive pulmonary fibrosis.ClinicalTrials.gov identifier: NCT06025578
  22. Corte TJ, Cottin V, Glassberg MK, et al. BMS-986278, an oral lysophosphatidic acid receptor 1 (LPA1) antagonist, for patients with idiopathic pulmonary fibrosis: results from a phase 2 randomized trial. Am J Respir Crit Care Med.