Phase III IPF Clinical Trials
Experimental Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis: Phase 3 Trials
There are a number of pharmacologic (medication) treatments for idiopathic pulmonary fibrosis (IPF) that are still in stages of testing. These treatments are not approved to give to patients except as part of clinical trials. A clinical trial is a way for researchers to test a new medication or treatment in a small group of patients. Patients are watched carefully for side effects to make sure they do not suffer harm. If they do, the medication or treatment being tested is stopped.
There are three stages of clinical trials that a treatment must pass before it is approved to be prescribed by all doctors in regular offices, clinics, or hospitals.
- Phase 1: The new treatment is tested in 20 to 80 healthy volunteers, or sometimes in people with the condition to be treated. These trials are closely monitored and gather information about how a treatment affects the human body. The goal is to figure out how much of a medication the body can handle and what the side effects are. Researchers also might look at whether the medication seems to be helping, if the study is done in people with the condition. If the medication seems safe and tolerable, it can move to phase 2 trials.
- Phase 2: The new treatment is tested in up to several hundred people with the condition to be treated. Phase 2 studies provide researchers with additional safety data. Early data about whether the drug helps or not is also gathered. Researchers use these data to decide whether a medication should move on to phase 3 studies. Only about one-third of medications that are tested in a phase 2 trial will ever move on to phase 3.
- Phase 3: The new treatment is tested in 300-3,000 people with the condition to be treated, and the study lasts for one to four years. Researchers design Phase 3 studies to show whether or not a medication helps the people to be treated. These studies are known as “pivotal studies” because approval from the United States Food and Drug Administration (FDA) “pivots” on a successful study. Phase 3 studies also gather a lot of safety data, particularly about side effects that are rarer or may only be seen after taking a medication for months or years.
After a medication or treatment passes phase 3 studies by showing it is helpful and safe, the company can apply for it to become FDA approved. Only about 13% (13 out of 100) of all medications or treatments that start in phase 1 clinical trials eventually become approved.
More information about clinical trials from the FDA can be found here.
Phase 3 Studies for IPF Medications
There are several medications that are in, or entering phase 3 clinical trials to study their efficacy and safety for patients with IPF.
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.
A recent phase 2 study was done to test PRM-151 in 117 patients with mild-to-moderate IPF.2 The average age was about 69 years. The researchers randomly assigned 77 patients to receive PRM-151 (10 mg/kg intravenous injection every 4 weeks), and 39 patients to receive placebo. The study lasted 28 weeks.
Lung function was measured at the beginning of the study and every 4 weeks throughout the study. Lung function was measured using forced vital capacity (FVC), which is the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. The results were reported as “percent predicted FVC”. A person with a percent predicted FVC of 100% has all of the lung function that would be predicted for a person of their age and height. A person with a percent predicted FVC of 70% has only 70% of the lung function that would be predicted for a person of their age and height. Lower numbers indicate worse lung function.
After 28 weeks, 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.
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.
PRM-151 is considered a “fast-track” medication by the Food and Drug Administration (FDA). This means that future clinical study data will be reviewed quickly to decide if PRM-151 should be approved. The next step is a phase 3 trial, which may begin enrolling patients as early as the second half of 2019.
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. 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.
PRAISE is the name of a recent phase 2 trial that was done to test pamrevlumab versus placebo for patients with IPF. The study enrolled 103 patients with mild-to-moderate IPF.3 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 2.85% for the pamrevlumab group and 7.17% for the placebo group. This suggests that pamrevlumab treatment slowed the decline in lung function over 48 weeks.
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.
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.
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.
Pamrevlumab has also been designated as a “fast-track” medication by the FDA. A phase 3 trial is currently being designed.
GLPG1960 is an experimental medication being developed and tested by Galapagos, NV. This medication is a protein inhibitor. A protein inhibitor is a small molecule that can attach to a protein and make it inactive. GLPG1960 inhibits a protein called autotaxin.
Autotaxin naturally occurs in the human body. It can be found in biological fluids, such as blood, bronchoalveolar lavage fluid (BALF), blister fluid, and urine. It helps regulate how much cells grow and divide. Studies have shown that people with IPF have higher than average levels of autotaxin within the lungs. Researchers believe that too much autotaxin may prompt fibrotic (scar tissue) cells to grow and divide too fast. Therefore, they hope that inhibiting some of the autotaxin in people with IPF will slow the growth of fibrotic (scar) tissue in the lungs.
A recent phase 2 trial called FLORA tested the use of GLPG1960 in mild-to-moderate IPF.4 The median age of the patients was 66 years. Of the 23 patients who were enrolled, 17 were randomly assigned to take a GLPG1960 600 mg pill by mouth once a day and 6 were randomly assigned to take a placebo pill once a day. The study lasted for 12 weeks.
Lung function was measured using FVC at the beginning of the study and at weeks 4, 8, and 12. The average change in FVC from the beginning of the study to week 12 was an increase (improvement) of 25 mL in the GLPG1690 group and a decrease (decline) by 70 mL in the placebo group. This suggests that GLPG1690 may stabilize or possibly even improve lung function over 12 weeks when compared with placebo.
The most common side effects were respiratory tract infections, cough, upset stomach, and diarrhea. Two patients, one from the GLPG1690 group and one from the placebo group, dropped out of the study because of intolerable side effects. One patient in the GLPG1690 group withdrew from the study for personal reasons.
Two phase 3 trials, called ISABELA 1 (NCT03711162) and ISABELA 2 (NCT03733444) are underway. The studies will enroll a total of 1,500 patients aged 40 years or older who were diagnosed in the previous 5 years. Patients will be allowed to continue to take a stable dose of pirfenidone or nintedanib if they were taking them in the 2 months before beginning the study.
What Does This Mean?
These three 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.
- 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.
- 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.
- 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. 2019 Sep 27.
- Maher TM, van der Aar EM, Van de Steen O, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med. 2018;6(8):627-635.