At #ATS2023, discussions with the biggest names in the field left me feeling engaged and part of the conversations at play.  Big thank you to @JamesChalmers, @NeilAlexis, @AmitGagger, and @PatrickFlume.  Many were vying for their input, but they graciously shared their time and invaluable insight.  Also, kudos to my favorite speakers from the sessions I sat in on, @EnidNeptune, @GeoffryChupp, and @EmilyHenkle. Your talks made a non-pulmonary scientist feel at ease in a new subject.

I went into this meeting with questions surrounding Neutrophil Elastase (NE) and its potential utility in the clinical laboratory space.  If NE Activity testing was available to pulmonary clinics…

  • Which patient populations would NE activity testing be able to best serve in a clinical setting? Bronch?  COPD?  AATD?
  • When would measuring NE levels be most useful? Prior to exacerbations?  Upon diagnosis of a chronic lung disease?  Efficacy of treatment?
  • How would measuring NE activity alter current therapeutic approaches or interventions? Earlier treatment with antibiotics?  Hospital release or treatment cessation?
  • Will future drugs be so targeted that endotyping will improve personalized medicine approaches?

 

I asked all these questions many times.  Here is what I heard.

  • Which patient populations would NE activity testing be able to best serve in a clinical setting? Bronch?  COPD?  AATD?  The overwhelming feedback was favorable towards the use of NE activity testing with bronchiectasis.  The drivers of bronchiectasis disease are extracellular pathogens. Many of the pathogenic subtypes are strongly neutrophilic in nature and there are zero approved therapies in the space.  Unlike cystic fibrosis, bronchiectasis seems to be at the beginning of a journey with pharma and disease characterization.

 

  • When would measuring NE levels be most useful? Prior to exacerbations?  Upon diagnosis of a chronic lung disease?  Efficacy of treatment?  My first thoughts for clinical utility of the NE activity test have been with the potential approval of a DPP1 inhibitor drug.  The mechanism of action of bronchiectasis is neutrophilic, so it would stand to reason that subjects with high NE activity would respond the best to DPP1 inhibitor therapy.  Thus, NE levels could be used to select who should receive the new drug.  On the contrary, the trial for DPP1 inhibitor examined NE levels at enrollment, but the data showed that NE levels did not dictate response to drug.  The drug seemingly benefited all groups.  As the new drug would be first available for bronchiectasis indications, everyone with bronch will likely be eligible for it.

 

Instead, what I heard was measuring NE activity levels to guide treatment could be more useful in the following cases:

  • 1- Disease severity–  Who to treat and when.  Some people have milder disease states than others and exacerbate more frequently.  Other individuals are not at a level of disease progression that requires continuous treatment with antibiotics or other macroglides.  Since these drugs are not always well tolerated, understanding who to treat and when to wait has value.
  • 2- Exacerbation surveillance–  Data supports that NE levels could spike prior to symptoms of exacerbation.  Could a surveillance system provide the ability to start an exacerbation treatment plan before there is a serious episode?
  • 3- Endotyping-  Although NE activity is already important for drug trial population selection and the characterization of disease populations, personalized treatment approaches are not available, such as those seen with subgroups of asthma.  As the understanding of COPD and bronch moves forward, there very well could be a place in a personalized medicine world for measuring NE activity during endotyping.
  • 4- Treatment efficacy–  Decreasing NE activity with preventative therapies likely indicate that the drug is effective and will help to keep exacerbation risk low.  For example, if a patient is in the middle of an exacerbation and NE activity drops below a designated level, such as by > 75% or back to  baseline levels, could indicate that the treatment is working. Treatment decisions could then be made to stop antibiotics or go home while finishing their course.

All of these are interesting thoughts to explore but need much more investment to tease out.

 

  • How would measuring NE activity alter current therapeutic approaches or interventions? Earlier treatment with antibiotics?  Hospital release or treatment cessation?  See #4 above.

 

  • Will future drugs be so targeted that endotyping will improve personalized medicine approaches? I listened to multiple talks about using asthma treatment as a model for understanding mechanisms of disease and developing drug targets for COPD and bronch. Much like IL-5, IL-13, eosinophils, etc, neutrophils and their effectors, NE and PR3, are important for endotype identification and drug targeting in more personalized medicine.

 

Dr. Neil Alexis will be generously providing a free webinar about sputum and neutrophilic biomarkers on July 12, 2023 @ 11 am EST.  Please join us to learn about sputum sampling, processing, nELF and more.

https://us06web.zoom.us/webinar/register/5016886493053/WN_VfRbvGCzRWmk-Apc9_l4Mw