Trial indicates Ofev slows progression in IPF patients

By Dr Deepu

The interim findings from the INPULSIS-ON extension trial were presented at the European Respiratory Society (ERS) International Congress 2016 in London.

The findings were consistent with those previously reported from the INPULSIS Phase 3 trials (INPULSIS-1 and -2). The interim analysis from the extension trial demonstrated that nintedanib slows disease progression in IPF patients. In addition, long-term treatment with nintedanib  (up to 51 months) was associated with manageable side effects in most patients, with diarrhea being the most frequently reported side effect.

Results from the interim analysis of INPULSIS-ON demonstrated that in terms of forced vital capacity (FVC, a measure of lung function) in IPF patients who continued nintedanib treatment in the extension trial, the change between baseline and week 48 and between weeks 48 and 96 was similar to what was seen in IPF patients who were on active treatment with Ofev in the 52-week INPULSIS clinical trials.

Findings from the trials on the effect of nintedanib on FVC demonstrated that:

In INPULSIS, the mean FVC change from baseline to week 52 was −89mL compared to –203mL for placebo-treated patients;

In INPULSIS-ON, the mean FVC change for patients who continued treatment was −96 mL from baseline to week 48;

In INPULSIS-ON, the mean FVC change for patients who continued treatment was −124mL from week 48 to week 96;

In INPULSIS and INPULSIS-ON, the average exposure to Ofev was around three years (35.7 months).

Two additional sub-group analyses from the trials revealed that treatment with Ofev has a beneficial effect on the annual rate of FVC decline regardless of the patients’ baseline lung impairment, providing additional evidence of the benefits of the drug in slowing disease progression in a range of IPF patients.

nintedanib is a small molecule tyrosine kinase inhibitor, which has been approved and marketed globally for treating IPF in adults. nintedanib blocks multiple signaling pathways that may be involved in the scarring of lung tissue and fibrotic processes, reducing disease progression in IPF and slowing lung function decline.

Antacid therapies may not improve outcomes in patients with IPF

By Dr Deepu

proton pump inhibitors or other antacid therapies” may not “improve outcomes in patients with idiopathic pulmonary fibrosis (IPF), and the treatment may increase infection risk in patients with advanced disease, according to findings from a post-hoc analysis of three large, randomized trials. Patients with IPF from the placebo groups of three trials of pirfenidone (CAPACITY 004, CAPACITY 006, and ASCEND) were included in the analysis. They analysed effects of antacid therapy use from baseline for pulmonary function, exercise tolerance, survival, hospital admission, and adverse events for 52 weeks.
Of 624 patients, 291 (47%) received antacid therapy and 333 (53%) did not. At 52 weeks, there was no significant difference between groups for disease progression. Rates also did not differ for all-cause mortality, IPF-related mortality, absolute FVC decrease, or mean observed change in FVC. The rate of hospital admission was non-significantly higher in the antacid therapy group . When stratified by baseline FVC (<70% or ≥70%), disease progression, mortality, FVC, 6MWD, and hospital admission did not differ between groups. Adverse events were similar between treatment and no treatment groups; 

FDA Grants Fast Track Designation For Idiopathic Pulmonary Fibrosis Drug

By Dr Deepu

Healio (9/11) reports that the Food and Drug Administration gave fast track designation to tipelukast, MediciNova’s experimental drug “for the treatment of patients with idiopathic pulmonary fibrosis.” The drug “demonstrated anti-inflammatory and anti-fibrotic activity in preclinical models through leukotriene receptor antagonism, as well as inhibition of phosphodiesterases and 5-lipoxygenase.” According to a company press release, “5-lipoxygenase/leukotriene pathway is believed to be a pathogenic factor in development of fibrosis, so the inhibitory effects demonstrated by tipelukast may be a novel treatment approach.”

Recent 2015 IPF Guidelines Update Adds New Agents.

By Dr Deepu

I have written this post giving an overview of  the latest IPF guidlines.The update to the 2011 guidelines appeared in the July 15 issue of the American Journal of Respiratory and Critical Care Medicine. At the end I have provided download links for the article and supplements.

  Pirfenidone  and Nintedanib were recommended for use in idiopathic pulmonary fibrosis (IPF) with a moderate level of confidence, in a guideline update from ATS/ERS/JRS/ALAT
      It also mentions that the methods used by guideline panels to appraise the evidence are different than those used by regulatory agencies like FDA when they review applications seeking market approval for the use of pharmacologic agents for treatment of IPF.

Image Shows Comparison of 2015 and 2011 guidelines. Image published in AJRCCM

 
  The guidline doesnot provide recommendations for one treatment regimen over another.  The guideline does not provide suggestions for or against combination regimens or sequential therapies.
     
The updated guidline has given strong recommendation against using prednisone with azathioprine and N-acetylcysteine,The update also included strong recommendations against use of warfarin or other anticoagulants due to signals for harm in randomized trials in both cases. Both previously had been suggested as not appropriate for most patients but perhaps reasonable for some.
   
 Imatinib and ambrisentan, not previously addressed in the guidelines, got strong recommendations against use in IPF patients. Sildenafil is included in the guidelines, and got a conditional recommendation against use.

     The guidelines also updates on the dual endothelin receptor antagonists macitentan and bosentan , it has changed from a strong to a conditional recommendation against use.

   The Lung transplantation which was not addressed in 2011 was also included but formulation of recommendation for single vs bilateral lung transplantation was deffered.

   There is no change in the recommendation for anatacid therapy and N acetyl cysteine monotherapy which remains as conditional recommendation for use and conditional recommendation against use respectively.

     Adverse effects were common with nintedanib therapy, particularly diarrhea, although serious adverse events were not increased and relatively few patients discontinued the drug due to adverse effects. 
      Pooled results from the pirfenidone trials showed more risk of photosensitivity, fatigue, stomach discomfort, and anorexia with the drug.
 I have Provide the links to Download article from ATS.. Happy reading :)

1.http://www.atsjournals.org/doi/suppl/10.1164/rccm.201506-1063ST/suppl_file/executive_summary.pdf
2.http://www.atsjournals.org/doi/suppl/10.1164/rccm.201506-1063ST/suppl_file/raghu_data_supplement.pdf
3.http://www.atsjournals.org/doi/suppl/10.1164/rccm.201506-1063ST/suppl_file/raghu_data_supplement+2.pdf

IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis is a disease characterized by diffuse interstitial fibrosis of unknown etiology and frequently occurs between the ages of 50-70.

Clinical Picture

• Patients present with dry cough and shortness of breath and sometimes with fever, arthralgias and Raynaud's phenomenon.
• Clubbing (40-70%) tachypnea and persistent coarse basal crackles are encountered on physical exam. Often they are using accessory muscles of inspiration for tidal breathing.
• CXR: Normal to reticulonodular to honeycombing. HRCT may show ground glass appearance or honeycomb cysts.  In Desquamative interstitial pneumonitis alveolar features can be recognized..
• PFT shows a restrictive and diffusion defects. Patients are hypoxic and desaturate significantly with exercise.
• In 25-45%, serum cryoglobulins, RF and ANA are present.
• BAL: Predominance of neutrophils.

Pathology

Desquamative Interstitial pneumonitis(DIP), Usual Interstitial Pneumonitis(UIP), Lymphocytic Interstitial Pneumonitis( LIP) are various subgroups, probably of the same disease process.

a.      Early IPF: Desquamation predominates where alveolar macrophages fill alveolar spaces (desquamative interstitial pneumonitis or DIP).

b.     Late IPF: Inflammation of alveolar walls continues and fibroblast proliferation with collagen formation occurs (usual interstitial pneumonitis or UIP).

Diagnosis

•  By exclusion, it will be necessary to rule out other known causes for fibrosis like Silicosis or drugs. A long list of conditions can give rise to interstitial fibrosis 
• Transbronchial lung biopsy  can identify interstitial fibrosis. Usually need open lung biopsy to confirm.

Treatment

• Therapy is useful in acute stages when there is significant inflammatory process.
• Once the fibrosis is chronic or if the chest X-ray has been stable for years or if there is honeycombing, therapy is of no benefit.
• Corticosteroids + immunosupressants (cyclophosphamide or azathioprine); anecdotal reports describing colchicine or methotrexate or cyclosporine.
• Oxygen is often prescribed for these patients, probably not influencing pulmonary hypertension.
• In some cases  Plasmapheresis and Lung Transplant are considerations.
• Transplantation: 50% two year survival with single lung.

Prognosis

• In the acute progressive form "Hamman-Rich Syndrome" the prognosis is poor.
• In the chronic form patients can live long with disability.