# PATINA - Precision Administration of Treatment in Neutrophilic severe Asthma

> **NIH NIH UG1** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $482,469

## Abstract

Project Summary
Severe asthma accounts for a disproportionate share of the morbidity associated with asthma.
Multiple biological therapies are now becoming available that target eosinophilic or Type 2-
driven asthma. However, data from SARP indicate that >60% of patients have severe asthma
with a neutrophilic phenotype (SANP), as defined by induced sputum differentials. These
patients experience excess morbidity, and there are currently no therapies that effectively target
neutrophilic inflammation. We recently completed a study wherein we showed that targeting
mast cells with imatinib (an inhibitor of stem-cell factor signaling at KIT) was most effective in
patients with a neutrophilic phenotype. Further, we found that reductions in serum tryptase
could identify patients most likely to respond to this treatment. Additionally, we have shown that
in severe asthma, despite aggressive corticosteroid therapy (which normally reduces
inflammatory eicosanoids) these patients continue to elaborate pro-inflammatory eicosanoids
and low-pro-resolving eicosanoids. This is indicated by our discovery of persistent elevation of
LTB4 (which is a potent neutrophil chemoattractant) in exhaled breath condensate. Lastly, IL-6
has been associated with non-Type 2 asthma, insulin resistance, and TH17 skewing of CD4+
cells. IL6 receptor polymorphisms have been associated with asthma risk, and high IL6 has
been associated with reduced lung function and increased exacerbations, even in a cohort of
severe asthmatics. We posit the following set of primary hypotheses and in each case we list
the severe asthma phenotype and its phenotype marker(s) (PM), our primary candidate
response marker at 2 months (RM) (in parentheses our secondary RMs), and the targeted
intervention (TI). Our hypotheses are that in subjects with : 1) SANP with high serum IL6 (PM),
a fall in—C-reactive protein (TH17 cells, insulin resistance ) (RM), will identify those more likely
to improve after anti-IL6 therapy (TI); 2) SANP with high exhaled LTB4 (PM), a fall in exhaled
LTB4 (urinary cysteinyl leukotrienes) (RM) will identify those more likely to improve with a 5-
lipoxygenase inhibitor (5-LOi) (that blocks production of pro-inflammatory eicosanoids); 3)
Severe asthma with increased sputum neutrophils (PM), a fall in serum tryptase (sputum
supernatant tryptase) (RM) will identify asthmatics more likely to improve after treatment with a
KIT inhibitor (TI). Our adaptive study design and treatment approach will allow us to define the
threshold values of our RM that identify patients with a higher likelihood of response to targeted
therapy. We have a team of seasoned trialists in adult and pediatric asthma, experts in
biomarker development, the mechanisms behind these biomarkers, and adaptive trial design
and integrative analyses, which will add significant strength to a PRECISE network.

## Key facts

- **NIH application ID:** 9979941
- **Project number:** 5UG1HL139124-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Elliot Israel
- **Activity code:** UG1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,469
- **Award type:** 5
- **Project period:** 2017-09-23 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979941

## Citation

> US National Institutes of Health, RePORTER application 9979941, PATINA - Precision Administration of Treatment in Neutrophilic severe Asthma (5UG1HL139124-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979941. Licensed CC0.

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