Researchers at the Johns Hopkins University School of Medicine investigated the use of oral everolimus following dilation to treat idiopathic subglottic stenosis (iSGS). The findings may offer a paradigm shift in how rare airway diseases are treated beyond steroid injections or surgical interventions.

The study, published Sep. 26 in JAMA Otolaryngology-Head & Neck Surgery, followed a small cohort of participants to determine if adjuvant oral everolimus, an immunosuppressive medication shown to reduce fibrosis across a range of fibroproliferative disorders, is safe and effective following iSGS standard-of-care excision and dilation. Findings indicate everolimus may lengthen the amount of time between surgical interventions, thereby reducing the cumulative risk of surgical side effects and improving quality of life for those with iSGS.

Idiopathic SGS is a rare disease that affects primarily women in their 40s and 50s. One in 200,000 women in the U.S. are currently have the disease. People with iSGS are primarily of Northern European descent. The disease leads to scar tissue (fibrosis) developing in the subglottis, which is the lowest part of the larynx, located below the vocal cords and just above the trachea. Symptoms include shortness of breath, changes to voice and persistent cough, as increasing scar tissue gradually narrows the throat. Over time, the shortness of breath and wheezing (stridor) can become more severe.

"Individuals are often misdiagnosed with asthma, but asthma medications don’t work for iSGS," says Alexander Hillel, Johns Hopkins professor in the Department of Otolaryngology–Head and Neck Surgery. "The average length of time before individuals with iSGS are diagnosed is two years. Frequently, patients are told the symptoms of not being able to breathe are in their head. The condition is certainly impactful — emotionally and mentally."

In this phase I trial, eight perimenopausal participants took a daily 1.5 milligrams oral dose of everolimus for 42 days following endoscopic excision and dilation surgery. Researchers measured peak expiratory flow up to 180 days after surgery, narrowing of the airway as measured by CT scan and changes in quality of life scores.

Common side effects of everolimus, specifically oral ulcers, and prolonged infections were noted in three participants during the trial. No major adverse effects were reported by the seven people who completed the study. There was measured improvement in peak flow relative to baseline throughout the observation period. Participants sustained post dilation peak expiratory flow (PEF) — the maximum rate a person can exhale air after a full breath in — for the 13-week observation period.

Currently, the only treatment options for iSGS are surgical interventions. The condition recurs despite standard-of-care medical interventions, which are unable to halt the progression of fibrosis long term. Common complications from surgery include tongue numbness, change in taste, and chipped or cracked teeth. More serious complications can include air in the neck (sub-Q air). Risks inherent with surgery, such as airway obstruction that leads to a tracheostomy, are rare. However, such concerns emphasize the need for nonsurgical medical therapy options for iSGS.

Results from this trial suggest that everolimus may be a safe adjuvant therapy that could prolong the dilation interval (time patients have between surgeries). This trial shows how immunosuppressive drug may be repurposed for airway fibrosis and other fibroinflammatory conditions.

Hillel says the next steps for nonsurgical therapeutic advancements for iSGS may include trials that take place over a longer adjuvant course with the same or higher dose. The dose in this phase 1 trial was intentionally kept low to minimize side effects.

"Future trials can build off this study by increasing the scale," says Hillel. "When there are successful results, we can leverage our international airway collaborative to design larger multi-institutional trials to advance care for airway disease."

Other researchers who contributed to this study include Raymond So, Samuel Collins, Sarah Collins, Laura Mafla, Yee Chan-Li, Ioan Lina and Kevin Motz.