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Asthma is a chronic disease marked by bronchoconstriction, inflammation and airways hyperresponsiveness (AHR). Inhaled corticosteroids remain the anti-inflammatory drug of choice, and short (SABA) and long-acting beta agonists (LABA) provide relief from bronchoconstrictoin. However, AHR is hypothesized as an independent measure of severity, and studies have shown that treatment with LABA may exacerbate underlying severity, so that breakthrough, when it occurs, may be severe and even-life-threatening. AHR has been the target of studies with INV102, with potential to restore the safety of LABA while maintaining the efficacy of SABA.
Currently in Phase II, Inverseon is developing INV102 (nadolol) as a follow-on indication for the long-term treatment of asthma. The drug is presently administered orally and is being developed for dosing by inhalation, either alone or in combination with other anti-inflammatory medications. INV102 will complement low-dose inhaled corticosteroids and improve the efficacy and safety of long acting beta agonists.
In coordination with independent investigators, Inverseon is utilizing government grants while the Company pursues the initial indication for smoking cessation with funding raised from private sources. Investigators have filed for over $8 million in government grant requests to support continuing clinical trials in patients with asthma.
Key Preclinical Findings
Effects of chronic nadolol in murine asthma model
- 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
*Also seen in human trials in asthma.
Proof-of-Concept Trials
INV102 has achieved clinical proof-of-concept in two open-label trials of patients with mild, steroid-naive asthma (mean FEV1 of 90%) who were given incremental doses of nadolol up to 40 mg for =9 weeks in chronic dosing protocols. As previously seen with the benefits associated with carvedilol, protocols sought to maximize the dose of INV102 that each subject received. No subject required acute rescue medication after a dose increase, although there were occasional asymptomatic reductions in lung function ( FEV1 ) with the first dose or dose increase. Importantly, airway hyper-responsiveness (AHR) to methacholine challenge significantly improved with chronic nadolol dosing. This key finding demonstrated that chronic nadolol dosing resulted in a doubling-dilution shift in AHR comparable to results achieved with inhaled corticosteroids for several weeks.
Longer term independent clinical trials, under the Company's IND are in planning with NIH (NIAID and NHLBI).
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