OptiNose (Norway)

The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) play important and interrelated roles in modulating mammalian social behaviour. While the OT system has received considerable research attention for its potential to treat psychiatric symptoms, comparatively little is known about the role of the AVP system in human social behaviour. To better understand the intraindividual stability of basal AVP, the present study assessed the reproducibility of basal plasma AVP concentrations. Basal plasma AVP was assessed at four sampling points separated by 8 days, on average, in 16 healthy adult males. Only one out of six comparisons revealed strong evidence for reproducibility of basal AVP concentrations (visit 2 vs. visit 4: r=0.8, p0.1). The concordance correlation coefficient [0.15, 95% CI (-0.55, 0.73)] also revealed poor overall reproducibility. Poor reliability of basal AVP concentrations suggests future work covarying AVP with trait markers should proceed with careful consideration of intraindividual fluctuations.

ObjectiveThe 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.BackgroundIn phases 2 and 3, randomized, placebo-controlled trials, AVP-825 provided early and sustained relief of moderate or severe migraine headache in adults, with a low incidence of triptan-related adverse effects.MethodsThis was a randomized, active-comparator, double-dummy, cross-over, multi-attack study (COMPASS; NCT01667679) with two ≤12-week double-blind periods. Subjects experiencing 2-8 migraines/month in the past year were randomized 1:1 using computer-generated sequences to AVP-825 plus oral placebo tablet or an identical placebo delivery system plus 100 mg oral sumatriptan tablet for the first period; patients switched treatment for the second period in this controlled comparative design. Subjects treated ≤5 qualifying migraines per period within 1 hour of onset, even if pain was mild. The primary end-point was the mean value of the summed pain intensity differences through 30 minutes post-dose (SPID-30) using Headache Severity scores. Secondary outcomes included pain relief, pain freedom, pain reduction, consistency of response across multiple migraines, migraine-associated symptoms, and atypical sensations. Safety was also assessed.ResultsA total of 275 adults were randomized, 174 (63.3%) completed the study (ie, completed the second treatment period), and 185 (67.3%) treated at least one migraine in both periods (1531 migraines assessed). There was significantly greater reduction in migraine pain intensity with AVP-825 vs oral sumatriptan in the first 30 minutes post-dose (least squares mean SPID-30 = 10.80 vs 7.41, adjusted mean difference 3.39 [95% confidence interval 1.76, 5.01]; P < .001). At each time point measured between 15 and 90 minutes, significantly greater rates of pain relief and pain freedom occurred with AVP-825 treatment compared with oral sumatriptan. At 2 hours, rates of pain relief and pain freedom became comparable; rates of sustained pain relief and sustained pain freedom from 2 to 48 hours remained comparable. Nasal discomfort and abnormal taste were more common with AVP-825 vs oral sumatriptan (16% vs 1% and 26% vs 4%, respectively), but ∼90% were mild, leading to only one discontinuation. Atypical sensation rates were significantly lower with AVP-825 than with conventional higher dose 100 mg oral sumatriptan.ConclusionsAVP-825 (containing 22 mg sumatriptan nasal powder) provided statistically significantly greater reduction of migraine pain intensity over the first 30 minutes following treatment, and greater rates of pain relief and pain freedom within 15 minutes, compared with 100 mg oral sumatriptan. Sustained pain relief and pain freedom through 24 and 48 hours was achieved in a similar percentage of attacks for both treatments, despite substantially lower total systemic drug exposure with AVP-825. Treatment was well tolerated, with statistically significantly fewer atypical sensations with AVP-825.

OBJECTIVE: COMPASS (NCT01667679) evaluated comparative efficacy, safety and tolerability of AVP-825 (22mg sumatriptan powder) and 100mg oral sumatriptan in adults with migraines. BACKGROUND: AVP-825 is an investigational Breath Powered™ Bi-Directional™ device that delivers low-dose sumatriptan powder (15-16mg on average) deep into the nasal cavity where it is rapidly absorbed. DESIGN/METHODS: Multicenter, double-dummy, crossover, multi-attack study with two 12-week double-blind periods. Migraineurs (2-8 attacks/month) were randomized 1:1 to AVP-825 plus oral placebo or an identical placebo device plus 100mg oral sumatriptan for period-1; treatment switched for period-2. Patients treated ≤5 qualifying migraines/period (<1 hour from onset, even if mild). The primary endpoint, SPID-30, assessed summed pain intensity differences in headache severity scores through 30 minutes. Key secondary endpoints included pain relief and pain freedom at each time point. RESULTS: 275 migraineurs were randomized; 185 treated migraines in both periods (full analysis set; 1531 migraines assessed). Significantly greater benefit over the first 30 minutes post-dose was observed with AVP-825 vs oral sumatriptan (SPID-30: 10.80 vs 7.41 P<.001). At time points between 15-90 minutes, significantly greater rates of pain relief and pain freedom were achieved with AVP-825 (30 minutes: 53.8[percnt] vs 38.7[percnt] P<.0001 and 18.2[percnt] vs 10.8[percnt] P=.0003, respectively). Pain relief/freedom were comparable at 120 minutes, 24 and 48 hours. No serious adverse events (AEs) occurred; ≤2[percnt] of patients discontinued due to AEs. Nasal discomfort and abnormal taste were more common with AVP-825 (16[percnt] vs 1[percnt]; 26[percnt] vs 4[percnt]) but ~90[percnt] were mild and led to only one discontinuation. Atypical sensation rates were lower with AVP-825 (2[percnt] vs 5[percnt], P=.02). CONCLUSIONS: AVP-825 confers faster pain relief compared with 100mg of oral sumatriptan, relief is sustained through 48 hours, and treatment is well tolerated. If approved, AVP-825 will constitute an important treatment option for migraineurs. Support: Avanir Pharmaceuticals, Inc.

OBJECTIVE: Evaluate relief of migraine disability and associated functional improvement with AVP-825 (22mg sumatriptan powder) using key secondary outcomes from the Phase 3 TARGET study (NCT01462812) in adults with episodic migraines. BACKGROUND: AVP-825 is a first-in-class treatment for migraine, using a novel closed-palate Breath Powered™ device that delivers low-dose sumatriptan powder deep into the nasal cavity. In the randomized, double-blind, placebo-controlled TARGET study, 42[percnt] (AVP-825) vs 27[percnt] (placebo) of patients reported headache relief by 30 minutes (P=.03), with 68[percnt] vs 45[percnt] reporting headache relief at 2 hours (P=.0016; primary outcome). DESIGN/METHODS: Patients treated the first migraine following randomization when intensity reached moderate to severe. Efficacy assessments were made pre-dose and at multiple timepoints up to 2 hours post-dose. Headache Impact Test (HIT-6; a measure of disability) was assessed at baseline. Results reported here include meaningful pain relief over time and change in clinical disability score. RESULTS: A total of 212 patients (n=108 AVP-825, n=104 placebo) experienced a qualifying migraine headache and comprised the efficacy analysis set. Baseline values for the HIT-6 demonstrate substantial headache-associated disability within the study population. Median time to meaningful pain relief was 47.5 minutes for AVP-825, and was not achieved within 120 minutes for placebo (P<.01). Mean clinical disability scores showed progressive improvement, with between-group differences reaching significance by 45 minutes. At 2 hours post-dose, 42[percnt] (AVP-825) vs 27[percnt] (placebo) reported a clinical disability score of “0” (no disability); baseline values were 2[percnt] and 4[percnt], respectively. The percentage of patients reporting moderate to severe disability at baseline, 57[percnt] (AVP-825) vs 55[percnt] (placebo), was reduced to 19[percnt] (AVP-825) vs 35[percnt] (placebo; P<.05). CONCLUSIONS: Low-dose sumatriptan powder delivered through the innovative AVP-825 device offers potential for rapid headache relief as well as significant reduction in migraine-associated clinical disability and improved function. Support: Avanir Pharmaceuticals, Inc.; OptiNose Inc. Disclosure: Dr. McAllister has received personal compensation for activities with Allergan, Inc. Dr. Cady has received personal compensation for activities with Avanir Pharmaceuticals, Inc., and OptiNose US Inc. as a consultant, investigator and/or advisory board member. Dr. Spierings has received personal compensation for activities with Capnia as an employee, and Abbott Laboratories as a scientific advisory board participant. Dr. Messina has received personal compensation for activities with OptiNose US Inc. as an employee. Dr. Djupesland has received personal compensation for activities with OptiNose AS. Dr. Siffert has received personal compensation for activities with Avanir Pharmaceuticals as an employee. Dr. Siegert has received personal compensation for activities with Avanir Pharmaceuticals. Dr. Mahmoud has received personal compensation for activities with OptiNose US Inc. as an employee.

Abstract Objectives The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. Methods The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. Key findings Following intranasal delivery, median tmax was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean ± SD values for Cmax were 96 ± 25, 11 ± 7 and 16 ± 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. Conclusions Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.