Monday, May 19, 2014

Clinical trial results for pirfenidone, nintedanib, and NAC for IPF

There have been some exciting developments recently. On Sunday, May 18, 2014, The New England Journal of Medicine published the results of three clinical trials that studied three different treatments for idiopathic pulmonary fibrosis (IPF): pirfenidone, nintedanib, and N-acetylcysteine (NAC).

Before I get into the details, you should know that I have a financial relationship with Intermune, the sponsor of one of the clinical trials. I was a member of Intermune's steering committee for the ASCEND clinical trial of pirfenidone. This means that I have given advice to Intermune about the clinical trial and they've paid me consulting fees in return. Not a lot of money (less than 5% of my annual personal income), but enough that you should know about this financial relationship before you read what I have to say about these clinical trials.

I will discuss the results of the pirfenidone and nintedanib trials below. I will write about the NAC trial shortly.

Background: Pirfenidone is an experimental drug in the United States. It has not been approved by the Food and Drug Administration (FDA) for any medical condition at all. It is, however, approved and available to treat IPF in other parts of the world, including Europe, Canada, and Japan. No one is exactly sure what pirfenidone does inside the lung, but it seems to block the effect of important proteins that tell the lung to make scar tissue. Pirfenidone is taken by mouth.

Previous studies: There have been previous clinical trials of pirfenidone to treat IPF based largely in the United States and in Japan (here and here). I could write pages about the results of these clinical trials, but I won't. Instead, I'll just say that most of these studies suggested that pirfenidone "worked" (I'll define "worked" in a bit), but one of the studies done in the U.S. suggested that pirfenidone may not have worked. The FDA reviewed the results of these trials in 2010 and decided not to approve pirfenidone because of insufficient evidence that it "worked." Intermune then sponsored the ASCEND trial of pirfenidone to treat IPF. The results of the ASCEND trial were published online on May 18, 2014.

ASCEND trial results: The ASCEND trial enrolled 555 adults with IPF. About half were told to take 801mg of pirfenidone three times daily for one year. The other half were told to take a "placebo" three times daily for one year. Here is what they found:
  1. About two out of 7 people taking the placebo had progression of their disease during the study. Only 1 out of 7 had progression while taking pirfenidone. So, pirfenidone slowed down the progression of IPF for some people. 
  2. Pirfenidone also appears to have reduced the risk of dying. For every 32 people who took pirfenidone, 1 person's life was saved.
  3. Pirfenidone caused side effects in some people: About 1 out of 5 people had nausea or rash due to pirfenidone. Some people also had vomiting, heartburn, or other side effects.
Background: Nintedanib is an experimental drug and is not approved in the United States (or elsewhere to my knowledge) for any medical condition. Nintedanib is a drug that blocks the effect of important proteins (called "tyrosine kinases") that tell the lung to make scar tissue.

Previous study: Nintedanib was previously studied in a small ("phase 2") clinical trial to treat IPF called the TOMORROW trial. In this trial, nintedanib (then called "BIBF 1120") seemed to slow progression of IPF and reduce the risk of a sudden worsening of IPF (called an "acute exacerbation"). Boehringer-Ingelheim, the sponsor of the TOMORROW trial, then performed two large ("phase 3") clinical trials of nintedanib to treat IPF called the INPULSIS trials. The results of the INPULSIS trials were published online on May 18, 2014.

INPULSIS trial results: The INPULSIS trials enrolled 1,066 adults with IPF. About 60% were told to take 150mg of nintedanib twice daily for one year. The other 40% were told to take a "placebo" twice daily for one year. Here is what they found:
  1. About 4 out of 10 people taking the placebo had progression of their disease during the study. Only 3 out of 10 had progression while taking ninetanib. So, nintedanib slowed down the progression of IPF for some people. 
  2. Nintedanib may have improved the quality-of-life of some people with IPF and also might have reduced the risk of IPF becoming much worse all of a sudden, but these findings were only seen in one of the two INPULSIS studies. It is not clear yet how we should think about these findings.
  3. Nintedanib caused side effects in some people. About 40% of people developed diarrhea attributable to nintedanib. Some people had nausea, vomiting, and other side effects.
I will get around to writing about NAC shortly -- bottom line was that NAC did not seem to have any meaningful effect at all. If you are taking NAC, please discuss the results of this trial with your doctor before making any changes to the medications you take.


  1. Thanks for breaking the stats down into understandable information.

  2. Thanks Doc!
    This is awesome

  3. Thank you for all that you do to help keep us up-to-date on such a difficult condition to treat and understand.

  4. Your posts are a lifeline, as you are "the horse's mouth", a professional, on whom we can rely.

    Hope is on the horizon!

  5. Thanks, good post

  6. Really helpful to have INPULSIS and ASCEND trial results broken down like this. One minor language gripe. 'Patients were told to take a placebo'?!? Surely in a double-blinded trial neither the patients nor their HCPs knew whether they were receiving the drug or the placebo. Sorry to be a pedant but there is so much anti-science sentiment floating around these days I think it's important people understand clearly how a scientific trial works. Many thanks.

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  8. My husband has Idiopathic PF. He also has RA for many years, and is currently on Humera for it.
    His Pulmonologist wants to put him on Pirfenidone, as his lung function is slowly deteriorating. However he is reluctant to combine the two meds, as they both target the immune system. Both he and the Rheumatologist have no experience with the administration of both drugs together. So far they have had no guidance from the respective drug makers. They are still deciding on a plan of care.
    My question to you, is has anyone had experience with administering both these drugs together? Any info would be appreciated.

    1. Hi Laurel. Thanks for reaching out to me. It is unlikely that there is much experience using Humira and pirfenidone together. Pirfenidone is indicated for the treatment of idiopathic pulmonary fibrosis. The combination of rheumatoid arthritis and pulmonary fibrosis usually means that the pulmonary fibrosis is a result of the same immune system abnormalities that led to rheumatoid arthritis, and is therefore not "idiopathic" (which means "of unknown cause"). I suggest that you and your husband discuss the risks and benefits of both therapies in your husband's individual case. You can also consider an evaluation at a Pulmonary Fibrosis Foundation Care Center. You can find one at:

    2. I was told by his pulmonologist that the PF is idiopathic. per the biopsy report from the Mayo Clinic, a wedge biopsy showed Usual interstitial Pneumonia with mild lymphoid hyperplasia.. He has many possible triggers for the disease. Has RA for 25 yrs, was a firefighter for 30 yrs in Newark, and was on methotrexate for 15 yrs. His RA is pretty stable on Humera. Just trying to wrap my head around this complicated dilemma. I assume the best course of treatment would be to replace the Humera with another drug, and hope that he remains fairly stable on it. If the pulmonary drug benefits him, that would be the best choice.Thank you for hearing me out, I appreciate any insight you may have about this problem. We are actively involved with both docs and are confident in their abilities. But we need all the information we can amass to deal with this problem.

  9. A CT scan in August of 2009 verified that I had Idiopathic Pulmonary Fibrosis. My first symptoms were cough and shortness of breath. I was on prednisone and inhalers. My blood oxygen level was 50 and i was extremely short of breath, i was barely able to breath. I went through cardio pulmonary rehab, It helped but not too long before all the severe symptoms returned. December last year, a family friend told us about Rich Herbs Foundation and their successful lungs disease treatments, we visited their website and ordered their IPF herbal treatment, i am happy to report this treatment effectively reversed my Idiopathic pulmonary fibrosis and symptoms. I am back on my feet, i walk daily now and has made me able to walk my two dogs again without shortness of breath or sudden loss of energy. My activity level is up again.

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