Asthma, like chronic bronchitis, is a chronic inflammatory disease of the air passageways of the lungs. Asthma causes the bronchial tubes to be overly sensitive, or “hyper-responsive”, to many different stimuli, causing them to swell and produce mucus and making it difficult for air to pass freely in and out of the lungs. For many people with asthma symptoms come and go, but their susceptibility to developing bronchial narrowing persists. A major goal of modern asthma treatment is reducing bronchial sensitivity to as close to normal as possible.
Some of the triggers of asthma that cause narrowing of the bronchial tubes can also promote a persistent low-level of bronchial tube inflammation. Examples include inhalation of cigarette smoke, dust mites, and pollen. Removal of these “triggers” can lead to improvement in symptoms, so a change in the home or work environment, for example, can result in fewer symptoms and less need for medications to treat asthma. As the bronchial tubes become gradually less inflamed, their hyper-responsiveness to various triggers lessens.
Inflammation of the bronchial tubes is also managed by the use of medications. Treatments for asthma are divided primarily into ‘relievers’, ‘preventers’ and ‘symptom controllers’.
Bronchodilator medicines (SABAs and LABAs) help to relax the muscles around the airways in the lungs, however studies have shown that treatment with LABAs may exacerbate underlying disease severity. Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur, potentially leading to death, and LABAs now contain “black box” warnings from the FDA.
Invion is developing INV102 as a follow-on indication for the long-term treatment of asthma. The drug has been administered orally in two proof-of-concept phase IIa clinical trials and is being developed for dosing by inhalation, either alone or in combination with other anti-inflammatory medications. INV102 is targeted to complement low-dose inhaled corticosteroids and improve the efficacy and safety of LABAs by reducing airway hyper-responsiveness.
Rationale: Beta-blockers are currently contraindicated in asthma because their acute administration may be associated with worsening bronchospasm. However, their effects and safety with chronic administration are not well evaluated. The rationale for investigating INV102 in asthma is based on the paradigm shift that was observed with the use of beta blockers in congestive heart failure. Once contraindicated because of their acute detrimental effects, beta blockers have now been shown to reduce mortality with chronic use. It is hypothesized that certain beta blockers may also be safe and useful in chronic asthma therapy.
In proof-of-concept studies, the safety and effects of escalating doses of nadolol (INV102) was evaluated over nine weeks in 10 subjects with mild asthma. Dose escalation was performed on a weekly basis based on pre-determined safety, lung function, asthma control and hemodynamic parameters. The primary objective was to evaluate safety and secondary objectives were to evaluate effects on airway hyperresponsiveness, and indices of respiratory function. The escalating administration of nadolol was well tolerated. In eight out of the 10 patients, nine weeks of nadolol treatment produced a significant, dose-dependent increase in PC20 that reached 2.1 doubling doses at 40 mg (P<0.0042). However, there was also a dose-independent 5% reduction in mean FEV1 over the study period (P<0.01).
The findings demonstrated that chronic nadolol dosing resulted in a doubling-dilution shift in AHR comparable to results achieved with inhaled corticosteroids for several weeks. A larger phase II study in asthma patients is currently underway. This study is funded by the US National Institutes of Health (NIH).
Key Preclinical Findings
- Reduced airway hyper-responsiveness to methacholine
- Increased β2-adrenergic receptor density in lungs
- Decreased total inflammatory cells and eosinophils in the lungs
- Decreased mucous metaplasia
- Decreased mucin production
- Decreased cytokines (interleukins 5, 10, and 13, and TGF β1)
- Decreased expression of airway constricting enzymes: Phospholipase C-β1 and Phosphodiesterase 4D