John Messina

The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview

The intricate pathophysiology of brain disorders, difficult access to the brain, and the complexity and high risks and costs of drug development represent major hurdles for improving therapies. Nose-to-brain drug transport offers an attractive alternative or addition to formulation-only strategies attempting to enhance drug penetration into the CNS. Although still a matter of controversy, many studies in animals claim direct nose-to-brain transport along the olfactory and trigeminal nerves, circumventing the traditional barriers to CNS entry. Some clinical trials in man also suggest nose-to-brain drug delivery, although definitive proof in man is lacking. This review focuses on new nasal delivery technologies designed to overcome inherent anatomical and physiological challenges and facilitate more efficient and targeted drug delivery for CNS disorders.

Improved Pharmacokinetics of Sumatriptan With Breath Powered™ Nasal Delivery of Sumatriptan Powder

The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22‐mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20‐mg sumatriptan liquid nasal spray, a 100‐mg oral tablet, and a 6‐mg subcutaneous injection.

AVP‐825 Breath‐Powered Intranasal Delivery System Containing 22 mg Sumatriptan Powder vs 100 mg Oral Sumatriptan in the Acute Treatment of Migraines (The COMPASS Study): A Comparative Randomized Clinical Trial Across Multiple Attacks

The objective of this study was to compare the efficacy, tolerability, and safety of AVP‐825, an investigational bi‐directional breath‐powered intranasal delivery system containing low‐dose (22 mg) sumatriptan powder, vs 100 mg oral sumatriptan for acute treatment of migraine in a double‐dummy, randomized comparative efficacy clinical trial allowing treatment across multiple migraine attacks.

Breath Powered Nasal Delivery: A New Route to Rapid Headache Relief

The nose offers an attractive noninvasive alternative for drug delivery. Nasal anatomy, with a large mucosal surface area and high vascularity, allows for rapid systemic absorption and other potential benefits. However, the complex nasal geometry, including the narrow anterior valve, poses a serious challenge to efficient drug delivery. This barrier, plus the inherent limitations of traditional nasal delivery mechanisms, has precluded achievement of the full potential of nasal delivery. Breath Powered bi‐directional delivery, a simple but novel nasal delivery mechanism, overcomes these barriers. This innovative mechanism has now been applied to the delivery of sumatriptan. Multiple studies of drug deposition, including comparisons of traditional nasal sprays to Breath Powered delivery, demonstrate significantly improved deposition to superior and posterior intranasal target sites beyond the nasal valve. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposition of sumatriptan translates into improved absorption and pharmacokinetics. Importantly, the absorption profile is shifted toward a more pronounced early peak, representing nasal absorption, with a reduced late peak, representing predominantly gastrointestinal (GI) absorption. The flattening and “spreading out” of the GI peak appears more pronounced in migraine sufferers than healthy volunteers, likely reflecting impaired GI absorption described in migraineurs. In replicated clinical trials, Breath Powered delivery of low‐dose sumatriptan was well accepted and well tolerated by patients, and onset of pain relief was faster than generally reported in previous trials with noninjectable triptans. Interestingly, Breath Powered delivery also allows for the potential of headache‐targeted medications to be better delivered to the trigeminal nerve and the sphenopalatine ganglion, potentially improving treatment of various types of headache. In brief, Breath Powered bi‐directional intranasal delivery offers a new and more efficient mechanism for nasal drug delivery, providing an attractive option for improved treatment of headaches by enabling or enhancing the benefits of current and future headache therapies.

EXHANCE-12: 1-year study of the exhalation delivery system with fluticasone (EDS-FLU) in chronic rhinosinusitis: EDS-FLU in chronic rhinosinusitis

Inadequate efficacy of current intranasal steroids in chronic rhinosinusitis (CRS) is attributable to ineffective and/or inconsistent drug delivery to target anatomic sites. A new exhalation delivery system with fluticasone (EDS‐FLU) may improve outcomes by significantly increasing superior/posterior corticosteroid delivery. A study was conducted to assess the long‐term efficacy and safety outcomes of EDS‐FLU in individuals with CRS.

NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis

Background: Chronic rhinosinusitis is common and sometimes complicated by nasal polyps (NPs). Corticosteroid nasal sprays are often unsatisfactory because they are ineffective at delivering medication to high/deep sites of inflammation. Objective: We sought to assess whether an exhalation delivery system with fluticasone (EDS‐FLU) capable of high/deep drug deposition improves outcomes. Methods: Patients (n = 323) 18 years and older with moderate‐to‐severe congestion and NPs were randomized to twice‐daily EDS‐FLU (93, 186, or 372 &mgr;g) or exhalation delivery system (EDS)–placebo for 24 weeks (16 double‐blind plus 8 open‐label when all received 372 &mgr;g). Coprimary end points were change in nasal congestion/obstruction at 4 weeks and summed bilateral polyp grade at 16 weeks. Secondary end points included symptoms, polyp elimination, and functioning. Results: EDS‐FLU was superior on both coprimary end points (P < .001 vs EDS‐placebo, all doses). Mean polyp grade improved continuously through week 24 (P < .009, all comparisons), with polyps eliminated on at least 1 side in approximately 25% of patients at week 24 versus 8.7% with EDS‐placebo (P ≤ .014, all comparisons). Sino‐Nasal Outcomes Test scores also improved significantly versus those in patients receiving EDS‐placebo (−21.1 to −21.4 vs −11.7 at week 16, P < .05 all doses). At the end of the double‐blind period, EDS‐FLU (all doses) significantly improved all 4 defining disease symptoms. In most patients (68%), those receiving EDS‐FLU reported “much” or “very much” improvement. The number of patients eligible for surgery decreased by 62%‐67%. The safety profile was similar to that reported in prior trials evaluating conventional corticosteroid nasal sprays in comparable populations. Conclusion: EDS‐FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with chronic rhinosinusitis with NPs.