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

Zephyrus II / Pamrevlumab

Pamrevlumab (also called FG-3019) is an experimental medication being developed and tested by FibroGen, Inc. Pamrevlumab (pam-REHV-loo-mab) is an antibody that binds to a protein called “connective tissue growth factor”. When pamrevlumab antibody binds to a molecule of connective tissue growth factor protein, that molecule can no longer have any function in the body. The connective tissue growth factor molecule becomes inactivated.

Some amount of connective tissue growth factor protein occurs naturally in a healthy person. It helps the body heal wounds by prompting the growth of fibrotic (scar tissue) cells. However, people with IPF have much higher-than-average levels of this protein in their blood than do healthy people.17 They make too many fibrotic (scar tissue) cells. By inactivating some connective tissue growth factor protein, pamrevlumab may help slow down the growth of scar tissue cells that cause the lung damage of IPF.

Pamrevlumab has been designated as a “fast-track” medication by the FDA. One phase 3 trial (Zephyrus I) has finished recruiting people and is underway.18 A second phase 3 trial (Zephyrus II) has begun, and the investigators are screening people to see if they are eligible to enroll. To be eligible to enroll, people must be at least 40 years of age and no more than 85 years of age. In addition, they must meet the following criteria19:

  • A diagnosis of IPF within the past 7 years. IPF must be diagnosed as defined by the 2018 ATS/ERS/JRS/ALAT guidelines.16
  • A high-resolution computed tomography (HRCT) scan done during the screening process that shows parenchymal fibrosis (scarring) of at least 10% and less than 50% of lung tissue. The scan also must show that less than 25% of lung tissue is affected by honeycombing.
  • A percent predicted forced vital capacity (FVC) value of more than 45% and less than 95% at the beginning of the study. 
  • A percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin (Hb) of at least 25% and no more than 90%.
  • Not currently receiving treatment with pirfenidone or nintedanib or willing to consider discontinuation of the therapy after discussing this option with the Investigator.

These are the same criteria that were used to enroll people for the Zephyrus I trial.18

Participants who enroll in the phase 3 study will be randomly assigned to the active group or the placebo group. Those in the active group will receive pamrevlumab by IV infusion once every 3 weeks. Those in the placebo group will receive sterile injection solution that contains no medicine by IV infusion once every 3 weeks. There will be a total of 17 infusions over 48 weeks. Participants will not know if they are in the active or placebo group.19

FVC and FEV1 tests performed by participants at the beginning and at the end of the study will help investigators determine if pamrevlumab is better than placebo at improving lung function. They will also have participants fill out questionnaires about their symptoms periodically to determine if the medication is effective at reducing symptoms compared with placebo.19

Once they have received the 17 infusions in the initial period of the phase 3 study, participants may be able to enter an optional “open-label” period of the trial. In the open-label period, they will receive pamrevlumab by IV every 3 weeks, no matter which group they were in during the initial study. The open-label period could last 48 weeks or longer. The ending time of the open-label period depends on whether the medication is approved or not approved by the FDA.19 

The phase 3 study of pamrevlumab is based on encouraging data from a recent phase 2 trial that was done to test pamrevlumab versus placebo for patients with IPF. The phase 2 trial, called PRAISE, enrolled 103 patients with mild-to-moderate IPF. The average age was 68 years old. Of those 103 patients, 50 patients were randomly assigned to receive pamrevlumab (30 mg/kg as an intravenous infusion) every 3 weeks, and 53 patients were assigned to receive a placebo infusion every three weeks. Treatment occurred over 45 weeks for a total of 16 infusions.20

Lung function was measured by percent predicted FVC at the beginning of the study and at weeks 12, 24, 36, and 48. At week 48, the average decrease in the percent predicted FVC was 2.9% for the pamrevlumab group and 7.2% for the placebo group. This suggests that pamrevlumab treatment slowed the decline in lung function over 48 weeks by 60.3% compared with placebo.20 

The researchers also looked at disease progression, which was defined as a decrease in percent predicted FVC of 10% or more, or death, for any individual patient when counting from the start of the study. Over 48 weeks, 10% of people in the pamrevlumab group experienced disease progression, compared to 31.4% of people in the placebo group. This means that pamrevlumab treatment lowers the risk of a rapid worsening in lung disease, or death.20

The study also checked lung fibrosis (scarring) at weeks 24 and 48 using an imaging technique called quantitative high-resolution computed tomography (qHRCT). On qHRCT, the average amount of fibrosis that could be seen in the lungs of the patients in the pamrevlumab group increased by 75.4 mL between the start of the study and week 48. In contrast, the average amount of fibrosis in the placebo group increased by 151.5 mL between the start of the study and week 48. This finding suggests that pamrevlumab treatment slowed the accumulation of fibrotic (scar) tissue over 48 weeks.20

The most common side effects were cough, fatigue, breathlessness, upper respiratory tract infection, bronchitis, and headache. Three patients on pamrevlumab and seven patients on placebo stopped participating the study because of side effects.20

What Does This Mean?

These medications show promise for the treatment of IPF. 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 will be several years before the results of the phase 3 trials are available. Other possible medications are also being developed for IPF. These are in phase 1 and phase 2 trials now. 

Some patients with IPF 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. Kono M, Nakamura Y, Suda T, et al. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin Chim Acta. 2011;412(23-24):2211-2215. 
  18. ClinicalTrials.gov. Zephyrus I: evaluation of efficacy and safety of pamrevlumab in participants with idiopathic pulmonary fibrosis (IPF) ClinicalTrials.gov Identifier: NCT03955146
  19. ClinicalTrials.gov. Zephyrus II: efficacy and safety study of pamrevlumab in participants with idiopathic pulmonary fibrosis (IPF). ClinicalTrials.gov Identifier: NCT04419558.
  20. Richeldi L, Fernández Pérez ER, Costabel U, et al. Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2020;8(1):25-33.