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Pharmacologic Treatments

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Approved Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis


In October 2014, the Food and Drug Administration (FDA) approved the first two pharmacological (medication) treatments for idiopathic pulmonary fibrosis (IPF). One is pirfenidone (peer-FEH-nih-done), which has the brand name Esbriet®. The other is nintedanib (nin-TED-a-nib), which has the brand name Ofev®.

Pirfenidone and nintedanib have been shown in clinical trials to slow the rate of lung damage for people with IPF. These medications do not cure the disease. They do not reverse lung damage that has already happened. Importantly, they do not improve cough, breathlessness, or fatigue in a meaningful way. People with IPF who take these medications do not usually feel any different. The benefit of these medications is that they increase the chance of a longer time with a slower rate of decline in lung function.1

How Do They Work?

Scar tissue cells (fibrotic cells) in the lungs of patients with IPF have a protein called collagen in them at much higher amounts than is normal. The collagen forms bundles inside the cells (“collagen tendrils”). When cells have many collagen tendrils, they become stiff and hard.

Nintedanib and pirfenidone slow down the formation of scar tissue cells (fibrotic cells) in the lungs. They do this by making it more difficult for collagen to be made. They also slow down the formation of collagen tendrils.1

Nintedanib and pirfenidone are very complex medications. Researchers believe they may slow the disease process in IPF down in several ways. Slowing down the formation of collagen tendrils is one way. Other ways are currently under study. 

One of the ideas that is best supported by research evidence is that both medications slow down scar tissue cells (fibrotic cells) from multiplying.2,3 One scar tissue cell can grow and divide in half to form two new cells. Both of those cells can then grow and divide, making a total of four cells, and so on. If scar tissue cells do this quickly, more and more scar tissue grows around the delicate air sacs of the lungs. By slowing down the growing and dividing of scar tissue cells, lung damage in people with IPF can be slowed down as well.

How Are They Taken?

Pirfenidone is taken by swallowing 3 pills (267 mg each) 3 times every day with food. If a person does well with this after several weeks, there is an option to switch to 1 bigger tablet (801 mg) 3 times every day with food.4

Nintedanib is taken by swallowing 1 pill (150 mg each) 2 times every day with food.5

What Are the Possible Side Effects?

The most common side effects of pirfenidone are rash, upper respiratory tract infection, nausea, stomach pain, diarrhea, indigestion, vomiting, loss of appetite, heartburn, fatigue, headache, dizziness, sinus infection, difficulty sleeping, weight loss, joint pain, and sensitivity to sunlight. An uncommon side effect is liver problems.6

The most common side effects of nintedanib are diarrhea, nausea, stomach pain, vomiting, liver problems, decreased appetite, headache, weight loss, and high blood pressure. Uncommon side effects are an increased risk of bleeding, blood clots in the arteries, tear in the wall of the stomach or intestines (guts), stroke, or heart attack. Nintedanib is dangerous for a fetus or baby, so women who are taking it should not become pregnant or breastfeed.7

The digestive side effects of both medications can be managed by taking them with food or taking other digestive medications that a doctor prescribes. The side effects may become less noticeable over time as the body adjusts. 

It is very important for people with IPF who take these medications to be honest with their doctor about how they are feeling. Side effects can be managed only if a doctor knows about them. Do not stop taking the medications before talking to a doctor.

Clinical Trial Data for Pirfenidone

The clinical trial that led to FDA approval for pirfenidone was called the ASCEND study.8 In the study, 555 patients with IPF were randomly put into one of two groups (a “randomized trial”). The first group of 278 patients took pirfenidone by mouth with a meal three times per day. The dose was 801 mg each time (a total of 2,403 mg every day). The other group of 277 patients took the same number of placebo (sugar pills) of the same color, size, and shape on the same schedule every day. Neither the patients nor the researchers knew which patient was in which group (a “double-blind” trial). Patients took the medication or the placebo pills for 52 weeks. 

Lung damage was measured using spirometry. The key measurement was forced vital capacity (FVC). FVC measures the amount of air a person can exhale with force after inhaling as deeply as possible. The researchers tested the FVC for all patients in the study at the beginning (“baseline”), and at weeks 13, 26, 39, and 52. The measurements showed that treatment with pirfenidone slowed down the average level of lung damage in the group over 52 weeks.

About 17% of patients (almost 1 in 5) in the pirfenidone group had a worsening in their FVC measurement by 10 percentage points or more (or they died) by week 52. In the placebo group, 32% of patients had a worsening in their FVC measurement by 10 percentage points or more (or they died) by week 52. The FVC measurement stayed the same across the 52 weeks for 23% of the people in the pirfenidone group but only 9% of people in the placebo group. 

It is important to point out that the researchers asked patients about breathlessness during the study. Patients scored their own breathlessness using the University of California San Diego Shortness of Breath Questionnaire. The medication did not improve breathlessness during the study when compared to placebo. 

Not all patients got the same level of benefit from pirfenidone in the ASCEND study. Some patients’ lung function stayed the same across 52 weeks. Other patients’ lung function became a little bit worse. Other patients’ lung function became much worse. This study looked at average lung function for all the patients in each of the two groups. On average, pirfenidone slowed down how fast lung function became worse. It did not help every patient who took it.

A long-term follow-up study was done that looked to see if patients whose lung function got worse while taking pirfenidone would benefit if they continued to take it for another year. That study found that there was benefit to taking pirfenidone for a second year, because the FVC measurement got worse more slowly than would be expected for a person with moderate or severe IPF who did not take pirfenidone.9 

Clinical Trial Data for Nintedanib

Two randomized, double-blind clinical trials were done that led to FDA approval of nintedanib: INPULSIS-1 and INPULSIS-2.10 The total number of patients in these trials was 1,066. Of those, 638 patients were randomly assigned to the nintedanib group. They took 150 mg of nintedanib two times a day. The other 423 patients were randomly assigned to the placebo (sugar pill) group. They took sugar pills of the same color, size, and shape two times a day. The trial lasted 52 weeks. The measurement used for lung function was FVC, the same as in the ASCEND trial. 

In INPULSIS-1, the average FVC declined less over 52 weeks in the nintedanib group than in the placebo group. About 29% of patients (almost 1 in 3) in the nintedanib group had a worsening in their FVC measurement by more than 10 percentage points (or they died) by week 52. In the placebo group, 43% of patients (about 4 in 10) had a worsening in their FVC measurement by more than 10 percentage points (or they died) by week 52. In INPULSIS-2, there was no difference between the groups in average FVC by the end of the study. 

The researchers also looked at health-related quality of life. This was measured using the St. George's Respiratory Questionnaire. The questionnaire asks about the frequency and severity of breathlessness. It also asks about activities that caused by or are limited by breathlessness and about social functioning and mood. In INPULSIS-1, there was no difference between the groups in the scores for this questionnaire during the study. This means that nintedanib did not improve breathlessness, social functioning, or mood. These symptoms continued to worsen during the study in both groups.

In INPULSIS-2, there was a slight improvement in the average score on the St. George’s Respiratory Questionnaire during the study for the nintedanib group as compared with the placebo group. The difference was not very big. This means that symptoms for the nintedanib group got worse over the 52 weeks, but not quite as bad as the symptoms in the placebo group. 

Do Patients in the Clinical Trials Represent Real-World IPF Patients?

The clinical trials do not completely represent real-world IPF patients.

First, the clinical trials included mostly white, male patients in their late 60s. In the ASCEND study8, nearly 8 out of 10 of patients were male (about 75%). The average age was about 68 years old. In the IMPULSIS-1 and IMPULSIS-2 studies10, about 8 out of 10 patients were male (about 80%). The average age was about 67 years old, and about 9 out of 10 were white (about 90%). More trials in a diverse group of patients are needed to mimic the real world experience of IPF.

Second, the clinical trials included only patients with mild-to-moderate IPF at the start of the trial. Patients with severe disease were not included. At the beginning of the ASCEND study, the average FVC was about 68% of what would be normally expected for healthy person of the same age and gender.8 At the beginning of the IMPULSIS-1 and IMPULSIS-2 studies, the average FVC at the beginning of the study was about 80% of what would be normally expected for a healthy person of the same age and gender.10

A few, small studies have been done in patients who have severe IPF at the beginning of the study. Severe IPF is defined by an FVC of 50% or less of what would be normally expected for a healthy person of the same age and gender. These studies found mixed results. Some studies found that the medications slowed down lung function decline in patients with severe IPF. Other studies found that there the medications did not.11-14

There have not been any large, placebo-controlled clinical trials that have enrolled patients with severe IPF at the start of the trial. These studies will be needed to fully answer the question of whether the medications give benefit to patients with severe disease who have never taken an IPF medication before.

When Should Medication Treatment Start?

Ideally, medication treatment should begin as early as possible. All of the clinical trials that led to FDA approval for both medications enrolled mostly patients with mild-to-moderate IPF. 

Doctors do not always agree that people with severe IPF should receive medication therapy. Some say that any slowing in lung damage is a positive outcome, and that side effects are often manageable.15 Others say that the side effects are not worth any slowing in lung damage for these patients because it is not sure that the medication will be beneficial.16

This is decision that the patient, family, and health care team should make together. The pros and cons of medication in severe disease should be discussed carefully.

Do These Medications Increase Life Expectancy?

Some meta-analysis studies have looked at this question.17,18 A meta-analysis is a type of study that takes data from many earlier clinical studies and uses statistics to look at the data all together as one group. One recent meta-analysis15 found that pirfenidone reduces the risk of dying in the first year of treatment by about 50%. Nintedanib did not seem to reduce the risk of dying in the first year of treatment. 

Longer-term studies are needed to help answer the question of whether the medications improve survival time.

Is One Better Than the Other?

No clinical studies have directly compared pirfenidone with nintedanib, so it is impossible to say. Both medications had similar benefits compared with placebo in clinical trials. 

References

  1. Knüppel, L.D., Ishikawa, Y., Aichler, M., et al. A novel antifibrotic mechanism of nintedanib and pirfenidone. inhibition of collagen fibril assembly. Am J Respir Cell Mol Biol. 2017;57(1):77-90.
  2. Barratt SL, Flower VA, Pauling JD, Millar AB. VEGF (Vascular Endothelial Growth Factor) and fibrotic lung disease. Int J Mol Sci. 2018;19(5):1269.
  3. Ballester B, Milara J, Cortijo J. Idiopathic pulmonary fibrosis and lung cancer: mechanisms and molecular targets. Int J Mol Sci. 2019 Jan 30;20(3):E593.
  4. Genentech USA, Inc. How to take Esbriet. 2019. 
  5. Boehringer Ingelheim Pharmaceuticals, Inc. How to take Ofev. 2019. 
  6. Genentech USA, Inc. Managing certain Esbriet side effects. 2019.
  7. Boehringer Ingelheim Pharmaceuticals, Inc. What to talk to your doctor about and what are the possible side effects of OFEV? 2019. 
  8. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92.
  9. Costabel U, Albera C, Glassberg MK, et al. Effect of pirfenidone in patients with more advanced idiopathic pulmonary fibrosis. Respir Res. 2019;20(1):55.
  10. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82.
  11. Tzouvelekis A, Ntolios P, Karampitsakos T, et al. Safety and efficacy of pirfenidone in severe idiopathic pulmonary fibrosis: A real-world observational study. Pulm Pharmacol Ther. 2017;46:48-53.
  12. Harari S, Caminati A, Albera C, et al. Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study. Respir Med. 2015;109(7):904-13.
  13. Yoon HY, Park S, Kim DS, Song JW. Efficacy and safety of nintedanib in advanced idiopathic pulmonary fibrosis. Respir Res. 2018;19(1):203.
  14. Caminati A, Cassandro R, Torre O, Harari S. Severe idiopathic pulmonary fibrosis: what can be done? Eur Respir Rev. 2017;26(145).
  15. King, Christopher S. POINT: Should all patients with idiopathic pulmonary fibrosis, even those with more than moderate impairment, be treated with nintedanib or pirfenidone? Yes. Chest. 2016;150(2):273-75.
  16. Brown KK. COUNTERPOINT: Should all patients with idiopathic pulmonary fibrosis, even those with more than moderate impairment, be treated with nintedanib or pirfenidone? No. Chest. 2016;150(2):276-8.
  17. Nathan SD, Albera C, Bradford WZ, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med. 2017;5(1):33-41.
  18. Fleetwood K, McCool R, Glanville J, et al. Systematic review and network meta-analysis of idiopathic pulmonary fibrosis treatments. J Manag Care Spec Pharm. 2017;23(3-b Suppl):S5-S16.