Phase 3 IPF Clinical Trials

 
Experimental Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis
Phase 3 Trials

There are two medications that are in phase 3 clinical trials to study their efficacy and safety for patients with idiopathic pulmonary fibrosis (IPF). 

PRM-151/Pentraxin-2

PRM-151 is an experimental medication being developed and tested by Promedior, Inc. PRM-151 is a protein called human pentraxin-2 that is grown and purified in the laboratory. It is given as an intravenous injection.

Pentraxin-2 is normally found at a certain level in the blood of the human body. In healthy people, pentraxin-2 prevents the immune system from making too many fibrotic cells (scar tissue cells) during wound healing. It also works to calm down immune cells so that they do not cause a harmful amount of tissue inflammation during wound healing. Pentraxin-2 slows down the formation of scar tissue and promotes the formation of healthy tissue. 

Studies have shown the average blood level of pentraxin-2 is lower in people with IPF than in people who are healthy.1 Giving pentraxin-2 as a medication should raise the average blood level of pentraxin-2 in people with IPF so that it is similar to that of healthy people. 

PRM-151 is considered a “fast-track” medication by the Food and Drug Administration (FDA). This means that the phase 3 clinical study data will be reviewed quickly to decide if PRM-151 should be approved. 

The phase 3 study is currently screening people with IPF to see if they are eligible to enroll.2 To be eligible, people must be between the ages of 40 and 85 years old. They must also have:

  • A diagnosis of IPF as defined by the 2018 ATS/ERS/JRS/ALAT guidelines.3
  • A high-resolution computed tomography (HRCT) scan result that confirms the IPF diagnosis. 
  • A minimum 6-minute walk distance (6MWD) of 150 meters (164 yards) while using supplemental oxygen of no more than 6 L/min at sea-level or 8 L/min at high altitude and while maintaining oxygen saturation of greater than or equal to 83% during the test.
  • A percent predicted forced vital capacity (FVC) of at least 45%. 
  • A forced expiratory volume in 1 second (FEV1)/FVC ratio of at least 0.70.
  • A percent predicted diffusing capacity for carbon monoxide (DLCO) result of between 30% and 90%. 
  • An expected life expectancy of at least 12 months.

In addition, if the person is receiving pirfenidone or nintedanib treatment for IPF, the person must have been on treatment for at least 3 months. The dose must have been stable for at least 4 weeks prior to screening and must stay stable during screening. If the person took nintedanib or pirfenidone treatment in the past, the person must have discontinued the medications at least 4 weeks prior to screening and during screening.

During the phase 3 study, participants will be randomly assigned to the active group or the placebo group. Those in the active group will receive intravenous (IV) infusions of PRM-151 over 50-70 minutes on days 1, 3 and 5, then will have an additional infusion once every 4 weeks. The study will last 48 weeks (about 12 months). Those in the placebo group will have IV infusions of salt water on the same schedule. Participants will not know which group they are in. The investigators will have participants do FVC, FEV1, and 6MWD tests at the start of the study and at the end to determine if PRM-151 is effective at improving lung function compared with placebo. 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.2

The phase 3 study was allowed to go ahead because earlier phase 2 data about PRM-151 were promising. A recent phase 2 study was done to test PRM-151 in 117 patients with mild-to-moderate IPF.4 The average age was about 69 years. The researchers randomly assigned 77 patients to receive PRM-151 by IV every 4 weeks and 39 patients to receive placebo on the same schedule. After 28 weeks (about 7 months), the average percent predicted FVC decreased (became worse) by 2.5% in the PRM-151 group and by 4.8% in the placebo group. This suggests that PRM-151 slowed the decline in lung function compared with placebo. 

The researchers also tested exercise capacity as measured by the six-minute walk test. After 28 weeks, the average distance walked decreased by half of a meter in the PRM-151 group and by 31.8 meters in the placebo group. This suggests that PRM-151 slowed the decline in exercise capacity compared with placebo.4

PRM-151 was well tolerated. The most common side effects were fatigue, cough, and inflammation of the nasal passages/throat. Two patients out of 77 stopped taking PRM-151 because of intolerable side effects, and 1 patient out of 39 stopped taking placebo because of intolerable side effects.4 

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 average levels of this protein in their blood than healthy people do.5 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. A phase 3 trial is underway, and the investigators are screening people to see if they are eligible to enroll.6 To be eligible to enroll, people must be between 40 and 85 years old. In addition, they must have:

  • A diagnosis of IPF within the past 7 years. IPF must be diagnosed as defined by the 2018 ATS/ERS/JRS/ALAT guidelines.3
  • A high-resolution computed tomography (HRCT) scan done during the screening process that shows with parenchymal fibrosis (scarring) of at least 10% and not more 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 value of more than 45% and less than 95%. 
  • A percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) value of at least 25% and no more than 90%.
  • Not been receiving treatment with pirfenidone or nintedanib.

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 salt water 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.6

The investigators will have participants do FVC and FEV1 tests at the start of the study and at the end to determine if pamrevlumab is effective at improving lung function compared with placebo. 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.6

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.6 

The phase 3 study 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.7 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.

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.7 

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.7

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.7

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.7

What Does This Mean?

These two 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. Dillingh MR, van den Blink B, Moerland M, et al. Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis. Pulm Pharmacol Ther. 2013;26(6):672-676.
  2. ClinicalTrials.gov. A study to evaluate the efficacy and safety of recombinant human pentraxin-2 (rhPTX-2; PRM-151) in participants with idiopathic pulmonary fibrosis. ClinicalTrials.gov Identifier: NCT04552899.
  3. 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. 
  4. Raghu G, van den Blink B, Hamblin MJ, et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: a randomized clinical trial. JAMA. 2018;319(22):2299-2307.
  5. 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. 
  6. ClinicalTrials.gov. Evaluation of efficacy and safety of pamrevlumab in patients with idiopathic pulmonary fibrosis. ClinicalTrials.gov Identifier: NCT03955146.
  7. 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.