Several other mechanisms have failed to show meaningful activity along the neutrophil activation pathway, including those targeting neutrophil elastase, CXCR2, and LTB4 -- would targeting DPP1 be expected to have broader anti-inflammatory effects compared to these other approaches?

How could differences in GSK's DPP1 inhibitor's half life (1.5 hours) and irreversible binding contribute to observed differences in activity compared to INSM (26-34 hr half life, reversible binding)? Would these differences be sufficient to expect a different outcome from the underlying mechanism?

Is INSM providing sufficient on-target suppression of DPP1 to be active? (NE activity reduction of 30-50% in blood and 86-91% in sputum)? Why are sputum reductions in NSPs higher than in blood?

Do macrolides provide validation for NE reduction in bronchiectasis or could broader anti-inflammatory/anti-bacterial properties be a more likely explanation?

How well validated is DPP1 inhibition in bronchiectasis as a potential therapeutic target? Would this MOA be expected to have activity across all bronchiectasis endotypes or only in patients with high NE levels?

Are high NE levels being associated with increased exacerbation risk a case of correlation not equating to causation? I.e., NE levels are elevated due to an underlying viral/bacterial infection that drives exacerbation risk, but NE levels not being the driver of the exacerbation? 

How important are other non-neutrophil associated inflammatory pathways in driving exacerbation risk (i.e., eosiniophils, etc., that would not be targeted by DPP1)

Could DPP1 inhibition increase exacerbation or infection risk due to impairment of the immune response? How big of a risk is that for the ongoing phase 3 clinical trial?

Do PLS and Haim Munk syndrome's provide validation of the MOA in bronchiectasis? Does a PLS patient born with congenital bronchiectasis refute the DPP1 MOA?

How could an imbalance in background macrolide use influence the trial outcome? What's your most likely explanation for the inverse dose response in the WILLOW phase 2?