A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine.

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Technology Evaluation

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Overview of the market

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How the technology works

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Clinical findings with AVP-825

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Conclusion

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Expert opinion

A novel intranasal breathpowered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine Roger Cady Headache Care Center, Springfield, MO, USA

Introduction: AVP-825, formerly ‘OptiNose Sumatriptan,’ is an investigational Breath-PoweredTM Bi-DirectionalTM intranasal delivery system containing low-dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology. Areas covered: This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies. Expert opinion: AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP-825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability. Keywords: AVP-825, intranasal, migraine, sumatriptan Expert Opin. Drug Deliv. [Early Online]

1.

Overview of the market

Impact of migraine and available treatments Migraine is a disabling condition that affects approximately 12% of the US population, with more women affected than men [1]. Globally, migraine is the third most common disease in both men and women, and the seventh leading cause of disability [2,3]. Despite its prevalence, migraine is underdiagnosed and undertreated [4,5]. Over-the-counter analgesics such as aspirin or other NSAIDs are the most commonly used treatments for migraine and are typical first-line 1.1

10.1517/17425247.2015.1060959 © 2015 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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Triptans are a valuable therapy choice for acute treatment of migraine, though inconsistent treatment response and patient dissatisfaction have impacted their clinical utility. Patients report dissatisfaction with the speed of effect, degree of relief and tolerability of their acute migraine medication, and most patients are willing to try a new therapy. Migraines are often accompanied by decreased gastric motility, and many patients experience nausea and/or vomiting. Reduced GI function can interfere with the use and effectiveness of oral migraine treatment; therefore, medication formulations beyond the commonly used oral tablets are particularly relevant for migraine patients. Some acute migraine medications are available as a liquid nasal spray formulation, but these have not achieved widespread use. AVP-825 (intranasal delivery system containing 22 mg sumatriptan powder) employs a unique approach to intranasal drug delivery, using breath-powered technology to deliver a low dose of sumatriptan to the upper posterior nasal regions beyond the narrow nasal valve, which is an area of richly vascular mucosa conducive to drug absorption directly into the systemic circulation. Advantages of this technology relative to oral sumatriptan tablet or traditional liquid sumatriptan nasal spray include the potential for faster absorption, which may increase the speed of migraine relief, reduced drug swallowing and first-pass hepatic metabolism, and lower drug exposure, which may improve tolerability. In principle, local activity at intranasal structures implicated in migraine pathogenesis may also be enabled. Phase II and III, randomized, double-blind, placebocontrolled trials of AVP-825 in acute treatment of migraine showed early and sustained efficacy with a low rate of triptan-related adverse effects. A Phase III comparative efficacy trial with 100 mg oral sumatriptan showed that AVP-825 produced superior efficacy at early time points up to 90 min, similar sustained efficacy to 48 h, as well as fewer triptan-related adverse effects.

This box summarizes key points contained in the article.

abortive therapies for migraines of mild or moderate severity [6]. Triptans, which act on serotonin receptors, are considered first-line abortive treatments for attacks of moderate to severe migraine, for mild migraines that have not responded well to over-the-counter analgesics, or for migraines in more advanced stages [6,7]. Sumatriptan was the first triptan developed and remains the most commonly prescribed medication for the acute treatment of migraine [8,9]. Several formulations of sumatriptan are available in the United States by prescription, including oral tablets, needle and needle-free subcutaneous injection, traditional liquid nasal spray, an iontophoretic sumatriptan transdermal patch, and a combination tablet containing sumatriptan and naproxen sodium [8,10-12]. Sumatriptan suppositories 2

are available in other countries, and orally disintegrating sumatriptan tablets are currently under development [13]. Subcutaneous injection of sumatriptan is the most rapid and effective self-administered treatment for migraine [8], though it is also associated with a higher rate of adverse events than other formulations. In addition to sumatriptan, other triptans are available in the United States as conventional oral tablets (naratriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan) and some in additional formulations, including orally disintegrating tablets (rizatriptan and zolmitriptan) and traditional liquid nasal sprays (zolmitriptan) [14]. Multiple NSAIDs and combination analgesics are also available. In addition, several drugs with non-triptan mechanisms, such as calcitonin gene-related peptide antagonists, a dual-action therapy targeting 5-HT1B/1D receptors and neuronal nitric oxide synthase, and a metered-dose inhaler that delivers oral dihydroergotamine, are also under investigation [15,16].

Unmet needs Despite the numerous available treatment options, many patients remain unsatisfied with the specific migraine treatment they are prescribed, the formulation they are being provided, or the lack of education on how and when to use the medication properly. Observational studies consistently show low persistence with triptan therapy and frequent switching due to a number of factors, including formulary restrictions, adverse events, perceived lack of efficacy and cost [17-20]. Patients report dissatisfaction with the speed of effect, degree of relief, and tolerability of their acute migraine medication, and most patients (80%) are willing to try a new therapy [21]. Response to treatment may be inconsistent across multiple migraine attacks, and approximately two-thirds of migraine attacks do not achieve pain freedom with sumatriptan oral tablets or traditional liquid nasal spray [8]. In addition, triptan-related adverse effects (e.g., atypical sensations such as tingling, and chest, jaw, or neck tightness) may be problematic for some patients. Although oral administration is seen as the most convenient and is the most commonly prescribed route of delivery, medication absorption and onset of effect after oral delivery of treatment may be delayed compared to other routes of administration due to decreased gastric motility in patients with migraine [9]. Yet, nonoral routes of administration are rarely prescribed even though they can be a useful alternative for the many patients with migraine-associated nausea and/or vomiting [22], for those who have migraine-associated aversion to swallowing oral fluids or pills, and for patients with unrecognized gastric dysmotility. The focus of this review is AVP-825 (Avanir Pharmaceuticals, Inc.), a product using a novel intranasal delivery system for low-dose, dry-powder sumatriptan that is currently under investigation for the acute treatment of migraine. 1.2

Expert Opin. Drug Deliv. (2015) 12(9)

A novel intranasal breath-powered delivery system for sumatriptan

Intranasal drug delivery and its relevance to migraine


1.3

Intranasal drug delivery offers a number of compelling clinical advantages beyond the basic patient need for nonoral options [23,24]. The nose is an ideal route for noninvasive and convenient drug delivery. It offers many of the same potential advantages of systemic delivery via injection, including better bioavailability, faster drug absorption, fewer treatment-related gastrointestinal (GI) adverse events, and avoidance of first-pass metabolism in the liver [23,24]. This is particularly important during a migraine attack where autonomic dysfunction slows gastric emptying, which can delay and/or reduce intestinal absorption of orally administered drugs [25,26]. In addition to being an effective method of systemic drug delivery, intranasal delivery of medication into the most vascular and highly innervated nasal regions may allow for local effects at nasal structures implicated in the pathophysiology of migraine. Triptans exert their effect on 5-HT1B receptors, to reduce vasoconstriction, and 5-HT1D receptors, to block neurogenic inflammation and interfere with the afferent return of nociceptive signals to the trigeminal nucleus caudalis [27,28]. Results from animal studies have identified 5-HT1D receptors on trigeminal neurons that innervate the nasal mucosa, suggesting a potential local target of intranasally delivered drugs for the acute treatment of migraine [29]. In addition, the first and second branches of the trigeminal nerve and the parasympathetic synapses to the sphenopalatine ganglion are implicated in the pathophysiology of both migraine and cluster headache [30]. Despite the potential advantages of intranasal delivery, challenges do exist -- most notably, how to achieve drug deposition to the posterior regions beyond the narrow nasal valve that are most conducive to rapid absorption into the systemic circulation and where therapeutically relevant nasal nerve structures reside. When considering nasal delivery devices and mechanisms, it is important to keep in mind that a primary purpose of the nasal airway is to protect the lungs from hazardous exposures, not to serve as a delivery route for drugs [31]. One important obstacle to achieve efficient nasal drug delivery is the nasal valve, which is the narrowest point in the entire respiratory tract acting as a physical barrier separating the ‘external from the internal nose.’ In addition, nasal drug absorption is impacted by the location of four types of epithelia within the nasal cavity, including squamous, transitional, respiratory and olfactory, each with different properties suited to a particular function [24,32]. Since the anterior nasal cavity is designed to afford high resistance against potentially toxic environmental substances, this area is lined with nonciliated squamous and transitional epithelium, cell types that are less conducive to absorption of environmental substances or drugs. In contrast, the upper and posterior nasal regions beyond the narrow nasal valve contain primarily ciliated respiratory epithelium that is richly vascular and

therefore is more favorable to rapid drug absorption into the systemic circulation. The distinctive properties of different regions of the nasal mucosa underscore the importance of the specific site of drug deposition in the nasal passages as it relates to systemic absorption of drugs [23,33]. It is therefore necessary to consider the complexity of nasal anatomy and physiology to successfully achieve systemic drug delivery through the nose. Given the importance to patients of achieving rapid migraine relief, efforts have been directed to develop therapies for the acute treatment of migraine that avoid the challenges of oral delivery by capitalizing on the potential benefits of nonoral drug delivery. Intranasal liquid spray formulations of sumatriptan and zolmitriptan have shown superior migraine relief relative to placebo [34,35], with an earlier observed effect than their respective oral tablets [34]. However, no marked increase in total bioavailability of either of these intranasal drugs relative to their oral counterpart has been shown [36,37]. Both of these migraine treatments utilize a conventional liquid nasal delivery system, which is a spray device that emits a circular fan of liquid into the nasal cavity [23,31]. It has been shown that with this type of nasal delivery, a limited fraction of the spray penetrates beyond the nasal valve to reach the target sites for efficient absorption. Because a large portion of the liquid spray volume remains in the anterior nasal canal where it is subject to poor absorption, much of the delivered dose may be lost if it drips out of the nostril. Further, both imaging and pharmacokinetic (PK) evidence suggest that much of the dose delivered by liquid nasal spray remains on the floor of the nasal cavity [33,36-38], where it is prone to be swallowed and thus becomes an orally administered medication. This is consistent with the bimodal absorption pattern observed following use of conventional liquid triptan nasal sprays, with a smaller, early peak presumably representing absorption across the nasal mucosa and a later, larger peak representing GI absorption of the drug that was swallowed [33,36-38]. A more ideal intranasal product, particularly for the migraine patient, would minimize the amount of drug swallowed or dripped out of the nose and maximize the amount bypassing the nasal valve to reach the large posterior and superiorly located mucosal surface that is favorable to drug absorption directly into the systemic circulation. Toward this end, AVP-825 (formerly ‘OptiNose Sumatriptan’) is a novel intranasal delivery system currently under investigation for the acute treatment of migraine. AVP-825 takes advantage of multiple features of nasal anatomy in an effort to avoid the limitations of other types of intranasal migraine products. 2.

How the technology works

AVP-825: a breath-powered intranasal delivery system for sumatriptan

2.1

AVP-825 is a multiuse delivery system that includes: i) the reusable body; and ii) two disposable nosepieces, each


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1. Disposable unit-dose with drug is inserted into reusable body 2. Capsule is pierced by pressing button once


1.

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narrow nasal valve, resulting in prolonged local exposure bilaterally, rapid local absorption and low total systemic exposure. Several studies have assessed nasal deposition patterns with use of this technology for powder delivery [23,31,40]. Most recently, gamma scintigraphy performed on seven subjects in an open-label, crossover study showed that the breath-powered nasal delivery system containing lactose powder achieved significantly larger initial deposition into the upper and middle posterior nasal regions beyond the nasal valve (containing ciliated mucosa well suited to absorption) compared with a traditional hand-actuated liquid spray pump [40]. In contrast, the liquid administered by the traditional nasal spray was concentrated in the lower and middle anterior regions of the nasal cavity, which are less conducive to rapid absorption, and the floor of the nasal cavity, which is more conducive to swallowing (Figure 3). Other applications of the breath-powered delivery system

2.3

Figure 1. The breath-powered intranasal delivery system for sumatriptan powder. Reproduced from [33].

containing a capsule with 11 mg of sumatriptan dry powder. After a nosepiece is inserted into the body of the delivery system, the capsule is pierced by pushing and releasing the white button once (Figure 1). The user places the nosepiece in the nostril on the side of the headache, producing a tight seal for transfer of air pressure and also helping to expand the nasal valve. When the patient takes a deep breath and blows into the mouthpiece of the body of the delivery system, the drug is automatically released from the vibrating pierced capsule and delivered into the nasal passages. Rationale for breath-powered delivery The concept of breath-powered delivery takes advantage of two basic facts of nasal anatomy and physiology (Figure 2) [39]: 2.2

. The soft palate closes when exhaling against a resistance,

completely separating the nasal cavity from the throat. Under these breath-powered circumstances, it becomes possible to avoid deposition into the throat, lungs, or GI tract while the medication is being administered. . When the soft palate is closed and the sealing nosepiece is in place, the positive exhaling pressure is transferred into the nose. This establishes a dynamic communication behind the nasal septum, which connects the left and right nasal passages and allows the airflow to enter via one nostril, diffuse within the nasal cavity, and exit through the passage and ultimately the contralateral nostril (bidirectional delivery). By taking advantage of these features of nasal anatomy and physiology, this breath-powered system enables delivery of drug into the upper and posterior nasal regions beyond the 4

Phase III trials are currently underway using a different breath-powered bidirectional delivery system to deeply deliver fluticasone, an intranasal steroid, for treatment of chronic nasal inflammatory diseases like chronic sinusitis and nasal polyps [39], and another version of the technology to deliver oxytocin, a peptide, for treatment of autism. 3.

Clinical findings with AVP-825

AVP-825 has been well studied in a clinical development program that has provided evidence supporting the use of low-dose sumatriptan powder administered via a novel, breath-powered, intranasal delivery system for the acute treatment of migraine with and without aura in adults. Clinical trials conducted with AVP-825 include comparative PK studies in both patients with migraine and healthy volunteers versus various formulations of sumatriptan, as well as Phase II and III clinical trials evaluating the efficacy, tolerability and safety of AVP-825 in 600+ randomized adults with episodic migraine (Table 1). In the Phase II and III clinical trials in adults with episodic migraine, AVP-825 produced significantly greater rates of early pain freedom and pain relief than placebo or high-dose oral sumatriptan (100 mg) without loss of sustained efficacy, and resulted in significantly lower rates of atypical triptan sensations than high-dose oral sumatriptan [41-43]. AVP-825 clinical pharmacokinetics In a Phase I comparative PK study, 20 healthy subjects were randomized in a four-way crossover, single-dose study design comparing AVP-825 with three other routes of sumatriptan administration -- traditional liquid nasal spray (20 mg sumatriptan), oral tablet (100 mg sumatriptan) and subcutaneous injection (6 mg sumatriptan) [44]. Compared to traditional liquid nasal spray, AVP-825 demonstrated higher mean peak exposure (Cmax) and cumulative exposure (AUC) during 3.1



B. Top view

A. Side view

Sealing nosepiece


Breath actuated drug release into airflow Bi-Directional delivery

Soft palate closes automatically Blow into delivery system

Figure 2. Illustration of the breath-powered intranasal delivery system. Reproduced from [33].

A. Breath powered

B. Traditional liquid nasal spray

Figure 3. Gamma scintigraphy data. Gamma camera images 2 min after delivery of powder with breath-powered delivery system (A) or using a traditional liquid spray (B). Data are from a single patient with findings representative of the overall findings from the seven patients included in the study. Reproduced from [33].

the first 30-min post-dose, suggesting that more sumatriptan reaches the systemic circulation early after dosing despite the delivery of a lower dose (average delivered dose of AVP-825 is ~ 15 -- 16 mg). Compared to the conventional nasal spray and despite the lower exposure, AVP-825 produced a faster rise in mean plasma sumatriptan concentration (Tmax), 27% higher peak exposure (Cmax), 75% greater exposure at 15 min (AUC0 -- 15 min) and 61% greater exposure at 30 min (AUC0 -- 30 min), indicating that on average a greater

proportion of sumatriptan is absorbed from the nasal cavity following administration of AVP-825 (Table 2, Figure 4A). While the PK profile of both nasal formulations demonstrated bimodal peaks consistent with early nasal absorption and later GI absorption, AVP-825 produced plasma concentrations that suggest a greater early nasal peak and lower later GI peak, which would be consistent with more efficient nasal absorption compared to liquid sumatriptan nasal spray (Table 2, Figure 4B).


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Table 1. Summary of key AVP-825 clinical studies. Trial

Treatments compared

Outcomes evaluated

Study design n = Number randomized

Results for the primary endpoint

Comparative pharmacokinetics Obaidi et al. (2013)

AVP-825 versus other sumatriptan formulations (oral, liquid nasal spray and subcutaneous injection)

Pharmacokinetic parameters

Randomized, open-label, four-way crossover Healthy adult subjects (n = 20) Single dose

Phase II Djupesland et al. (2013) [42]

AVP-825 or 11 mg sumatriptan powder versus placebo delivery system

Efficacy, tolerability and safety

TARGET NCT01462812 Phase III Cady et al. (2015)

AVP-825 versus placebo delivery system

Efficacy, tolerability, and safety

AVP-825 versus 100 mg oral sumatriptan

Efficacy, tolerability and safety

Randomized, double-blind, placebocontrolled, parallel group Adults with episodic migraine with or without aura (n = 117) Single-attack study Moderate or severe migraines treated in-clinic Randomized, double-blind, placebo-controlled, parallel group Adults with episodic migraine with or without aura (n = 230) Single-attack study Moderate or severe migraines treated at home Randomized, double-blind, double-dummy, active-comparator, crossover Adults with episodic migraine with or without aura (n = 275) Multi-attack study Patients treated mild, moderate or severe migraines within 1 h of onset

AVP-825 is a more efficient form of drug delivery, producing: -- A higher and earlier peak exposure (Cmax) and greater systemic exposure within the first 30-min post-dose (AUC0 -- 30 min) versus traditional liquid nasal spray -- Faster absorption and greater systemic exposure over the first 15-min post-dose versus oral sumatriptan -- A lower peak and overall systemic exposure versus oral or subcutaneous injection of sumatriptan AVP-825 produced significantly greater rate of pain freedom at 2-h post-dose versus placebo A significantly greater proportion of subjects in both dose groups were pain-free at 120 min compared with placebo Headache relief at 2 h after treatment was reported by significantly more patients taking AVP-825 compared with use of the same delivery system containing placebo


[44]

[41]

COMPASS NCT01667679 Phase III Tepper et al. (2015) [43]

AVP-825 produced greater reduction in migraine pain intensity from baseline through 30-min post-dose (SPID-30) which was statistically significant versus high-dose oral sumatriptan

Table 2. Sumatriptan pharmacokinetic (PK) results for AVP-825 compared with 20-mg nasal spray, 100-mg tablet and 6-mg subcutaneous injection. PK parameters

AVP-825* Mean ± SD (n = 20)

20 mg nasal spray Mean ± SD (n = 20)

100 mg oral tablet Mean ± SD (n = 20)

6 mg s.c. injection Mean ± SD (n = 20)

Cmax (ng/ml) AUC0 -- ¥ (ng*h/ml) AUC0 -- 15 (ng*h/ml) AUC0 -- 30 (ng*h/ml)

20.8 ± 12.2 64.9 ± 20.6 2.1 ± 1.6 5.8 ± 4.1

16.4 ± 5.7 61.1 ± 17.8 1.2 ± 0.7 3.6 ± 1.9

70.2 ± 25.3 308.8 ± 92.4 0.7 ± 0.7 8.1 ± 5.0

111.6 ± 21.6 128.2 ± 17.4 16.2 ± 4.0 39.7 ± 7.1

*Sumatriptan powder delivered using the breath-powered delivery system, mean delivered dose ~ 15 -- 16 mg. Data taken from [44]. SD: Standard deviation.

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A. Plasma concentration (ng/ml)

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80 60

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Sumatriptan nasal spray 20 mg Sumatriptan injection 6 mg s.c.

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AVP-825 Sumatriptan nasal spray 20 mg

16 Plasma concentration (ng/ml)


120

14 12 10 8 6 4 2 0 0

0.5

1

1.5

2

2.5

3

3.5

4

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Figure 4. (A) Sumatriptan plasma concentration-time profiles over the entire 14-h sampling period for AVP-825, 20-mg nasal spray, 100-mg tablet and 6-mg subcutaneous injection and inset for AVP-825, 20-mg nasal spray and 100-mg tablet over the first 15-min post-dose. (B) Sumatriptan plasma concentration-time profiles over the first 4 h after AVP-825 compared with 20-mg nasal spray. Figure 4A. Modified from [44]. Figure 4B. Reproduced from [44].

Another Phase I clinical study in 12 patients with migraine showed fast absorption of AVP-825 (median Tmax of 20 vs 10 min for subcutaneous injection of 6 mg sumatriptan) [45]. The nasal peak for sumatriptan powder is very similar in the two PK studies, occurring early in both patients with migraine and healthy volunteers. However, the later peak, assumed to represent predominantly GI absorption, is substantially smaller in the study performed in patients with

migraine. This likely reflects the delayed and decreased GI absorption associated with autonomic dysfunction observed in patients with migraine. Compared to oral tablets and subcutaneous injections, the low sumatriptan dose from AVP-825 also produced a significantly lower peak (Cmax) and total systemic exposure, suggesting the potential for improved tolerability with AVP-825. Despite significantly less overall exposure, AVP-825 produced


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200% greater exposure at 15 min (AUC0 -- 15 min) compared to oral sumatriptan 100 mg tablets (Table 2, Figure 4). The results of this study showed that more sumatriptan is absorbed at early time points with AVP-825 compared to other sumatriptan formulations, giving AVP-825 the potential to provide earlier onset of action than either the traditional liquid nasal spray or oral tablets with substantially lower total drug exposure, offering the potential for improved tolerability relative to oral tablet or subcutaneous injection of sumatriptan. AVP-825 Phase II clinical trial In a Phase II, randomized, double-blind, placebo-controlled, parallel-group, single-attack trial, two doses of sumatriptan powder delivered via the breath-powered system were compared to an identical placebo delivery system (containing an empty capsule) in adults with episodic migraine with or without aura. At the onset of an attack, subjects with a migraine of moderate or severe intensity were treated in a clinic [42]. Both doses of sumatriptan powder (delivery system containing 22 mg [n = 35] and delivery system containing 11 mg [n = 37]) produced statistically significantly greater rates of pain freedom at 120-min post-dose and pain relief at every time-point post-dose between 60 and 120 min compared with the identical placebo delivery system (n = 32). When considering results specific to AVP-825 (delivery system containing 22 mg sumatriptan powder), pain freedom rates at 120 min were 57 versus 25% for placebo (p < 0.05). In addition, a significantly greater proportion of subjects experienced sustained pain freedom (defined as pain freedom within 120 min and no use of rescue medication or relapse within 48 h) from 120 min up to 48 h post-dose. Patients using AVP-825 were significantly more likely to report subjective meaningful relief of their migraine pain within 2-h post-dose than patients using the placebo delivery system (AVP-825 71 vs 44% placebo; p < 0.05). Additionally, the median time to meaningful relief was significantly faster for AVP-825 patients (50 min) compared with placebo device where the median was not achieved prior to the 120-min cutoff (p < 0.05). Active treatment was generally well tolerated, with no discontinuations due to adverse events, no serious adverse events and no systemic triptan-related adverse events (such as chest discomfort or pain, paresthesia, or asthenia). Dysgeusia, reported as a bitter or metallic taste, was the most commonly occurring treatment-emergent adverse event, reported by 13% of patients for AVP-825, 10% of patients for the lower dose of sumatriptan powder, and 0% for the placebo delivery system. The results of this trial indicated that AVP-825 had the potential to provide early onset of efficacy for moderate or severe migraines without loss of sustained efficacy, combined with a low risk of systemic triptan-related adverse events.


3.2

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3.3

AVP-825 Phase III clinical trials The TARGET study: AVP-825 versus placebo

3.3.1

AVP-825 was evaluated against a visually identical placebo delivery system containing lactose powder in a Phase III, randomized, double-blind, parallel-group, single-attack trial (TARGET study; NCT01462812) in adults with episodic migraine with or without aura [41]. A total of 230 patients were randomized to treat one migraine of moderate to severe intensity (116 AVP-825 and 114 placebo delivery system), and 212 were analyzed for efficacy (108 AVP-825 and 104 placebo delivery system). Headache relief after treatment was reported by more patients taking AVP-825 compared with placebo, reaching statistical significance as early as 30-min post-dose (42 vs 27%, p = 0.03) and at every time point up to 2-h post-dose (68 vs 45%, p = 0.002; primary endpoint; Figure 5A). In addition, significantly more patients treated with AVP-825 reported sustained pain relief at 24 and 48 h post-dose compared with placebo. AVP-825 also demonstrated superior efficacy on numerous other secondary endpoints, including clinical disability and meaningful relief at 2 h. As in the Phase II trial, there were no serious adverse events and no discontinuations due to adverse events in the active treatment arm. Abnormal taste (22% AVP-825 vs 4% placebo), nasal discomfort (13 vs 2%), rhinorrhea (5 vs 3%) and rhinitis (3 vs 0%) were the most commonly reported adverse events, with the majority described as mild. Systemic triptan-related adverse events were only reported in one patient (mild paresthesia in the AVP-825 group). The results of this trial were consistent with the Phase II study, demonstrating that AVP-825 provided early onset of efficacy for moderate or severe migraines without loss of sustained efficacy, and was associated with a low risk of systemic triptan-related adverse events. The COMPASS study: AVP-825 versus oral sumatriptan

3.3.2

AVP-825 was directly compared to high-dose oral sumatriptan (100 mg) in a Phase III, randomized, double-dummy, crossover, multi-attack study with two 12-week double-blind treatment periods (COMPASS study; NCT01667679) [43]. A total of 275 adults with episodic migraine with or without aura were randomized to AVP-825 plus oral placebo tablet or the identical placebo delivery system (containing lactose powder) plus 100 mg oral sumatriptan tablet for the first double-blind treatment period. Treatments were switched for the second double-blind treatment period. Patients treated up to 5 migraines per period within 1 h of onset, even if pain was mild. A total of 185 (67.3%) patients treated at least 1 migraine in both periods and were analyzed for efficacy, for a total of 1531 migraines assessed (765 AVP-825, 766 oral sumatriptan). The primary endpoint (SPID-30, sum of pain intensity differences through 30 min post-dose) showed significantly



A.

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Pain relief

Sustained pain relief

Percentage of patients

80 §

60

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*

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10 min *p < 0.05;

‡p

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< 0.01;

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60 min 90 min 120 min 24 h Time post-dose AVP-825 (n = 108) Placebo delivery system (n = 104)

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Percentage of attacks achieving pain relief

Pain relief

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AVP-825 + placebo tablet (n = 509 attacks) *p < 0.05; ‡p < 0.01; §p < 0.001

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60 min 90 min 120 min 24 h 48 h Time post-dose Placebo delivery system + sumatriptan tablet (n = 532 attacks)

80 Sustained pain freedom

Pain freedom Percentage of attacks achieving pain freedom


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AVP-825 + placebo tablet (n = 765 attacks)

45 min

60 min 90 min 120 min 24 h 48 h Time post-dose Placebo delivery system + sumatriptan tablet (n = 766 attacks)

‡p < 0.01; §p < 0.001

Figure 5. (A) Pain relief in the AVP-825 TARGET study. (B) Pain relief in the AVP-825 COMPASS study. (C) Pain freedom in the AVP-825 COMPASS Study. Figure 5A. Reproduced from [41]. Figure 5B. Reproduced from [43]. Figure 5C. Reproduced from [43].


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greater early reduction in migraine pain intensity with AVP-825 versus oral sumatriptan. Significantly greater rates of pain freedom and pain relief with AVP-825 versus oral sumatriptan were observed as early as 15 min and at every time point through 90- min post-dose (Figure 5B). Pain relief and pain freedom at 120 min, as well as sustained pain relief and pain freedom through 24 and 48 h, were achieved in a similar percentage of attacks for both treatments (Figure 5C). Significantly more patients experienced early reductions in migraine-associated symptoms (photophobia, phonophobia, and nausea) with AVP-825 versus oral sumatriptan. AVP-825 also provided early improvement in clinical disability and meaningful relief at 10 min, with statistical significance versus oral sumatriptan persisting through 90 min for disability and 60 min for meaningful relief. Most subjects in this study treated multiple attacks, and a significantly greater proportion had consistency of pain relief at 30 min across multiple migraines with AVP-825 versus oral sumatriptan. At no time point and for no efficacy endpoint were the statistical comparisons in favor of oral sumatriptan. Treatment with AVP-825 was well tolerated with no unexpected adverse events compared to prior clinical trials. No serious adverse events occurred, and less than 2% of patients in either treatment sequence experienced an adverse event leading to discontinuation (4 [1.8%] AVP-825 and 3 [1.3%] oral sumatriptan). Abnormal taste (26% AVP-825 vs 4% oral sumatriptan) and nasal discomfort (16 vs 1%) were more common with AVP-825 but were deemed mild in nearly 90% of cases and led to only one discontinuation. In this study, patients were asked to report atypical sensations occurring within 120-min post-dose for each attack, and the results demonstrated significantly lower rates with AVP-825 versus oral sumatriptan (2% of 512 attacks vs 5% of 512 attacks, p = 0.02). The results of this trial showed that AVP-825 provides an earlier reduction of migraine pain intensity and higher rates of pain relief and pain freedom, without loss of sustained efficacy, than the most effective dose of oral sumatriptan (100 mg) despite substantially lower drug exposure. 4.

Conclusion

AVP-825 provides an innovative intranasal method to deliver low-dose sumatriptan powder to the difficult-to-reach, but highly vascular mucosa beyond the narrow nasal valve, which is an area conducive to rapid drug absorption directly into the systemic circulation. Results from clinical PK and Phase II and III trials are consistent with fast sumatriptan absorption following AVP-825 administration and demonstrate that AVP-825 produces early improvement in migraine pain, disability and associated symptoms (vs placebo or 100 mg oral sumatriptan) as well as sustained efficacy, and favorable tolerability with minimal triptan-related adverse effects. If approved, AVP-825 will provide migraine patients with a novel nasal delivery system for low-dose sumatripan, with 10

the potential for early onset of efficacy and improved tolerability. 5.

Expert opinion

The AVP-825 delivery system represents a significant technological achievement in the nasal delivery of sumatriptan for acute treatment of migraine. AVP-825 effectively deposits sumatriptan powder into the regions of the nasal mucosa where it adheres to ciliated epithelium that is more vascular and hence able to absorb powder sumatriptan more readily than liquid sumatriptan delivered via traditional nasal spray. In addition, delivering the drug on exhalation closes the soft palate, which prevents drug deposition into the lungs and minimizes swallowing of medication. Pharmacokinetics of the first 30-min post-dose indicates that more sumatriptan reaches the systemic circulation early after dosing with AVP-825 versus traditional liquid nasal spray, suggesting the potential for superior early efficacy with AVP-825. Though a head-to-head efficacy trial of AVP-825 versus traditional liquid nasal spray has not been conducted, the classification of abnormal product taste with AVP-825 as ‘mild’ by ~ 90% of those who experienced this adverse event in the COMPASS clinical trial is of particular note, since bad taste is a frequent reason for lack of use of traditional sumatriptan liquid nasal spray. Relative to oral sumatriptan tablets, AVP-825 stands to provide patients with faster and more consistent early efficacy without the loss of sustained efficacy, as demonstrated in the head-to-head COMPASS trial. In addition, the significantly lower rate of atypical sensations with AVP-825 versus oral sumatriptan observed in COMPASS indicates the potential for superior tolerability with AVP-825. This breath-powered system will be especially valuable as an acute treatment option for patients who have insufficient and/or unsatisfactory migraine relief with oral medications or those who experience poor or marginal oral absorption of medications in the context of a migraine. From a research perspective, interpretation and comparison of migraine trial data is complicated by the complexity of migraine presentation and the lack of standardized methodology in migraine trial design. As migraine experts and researchers seek to better standardize outcomes, future trials are likely to prioritize the use of comprehensive measures such as total migraine freedom, which assesses pain as well as the migraine-associated symptoms of nausea/vomiting, photophobia and phonophobia. Since not all migraines are stereotypic in terms of symptoms of impact, inconsistencies in treatment outcome observed with patients due to different presentations of migraine (e.g., early morning-onset migraine or migraine with significant nausea or vomiting) must be considered when interpreting the treatment effects of any anti-migraine agent. Differences in the benefits observed with various treatments also can be impacted by the headache severity, the presence of associated symptoms at the time of



Table 3. Newer sumatriptan delivery methods. Technology

Method of administration

FDA approval status

Dose range

Comments

Non-needle sumatriptan injection

Abdomen or thigh application; high-pressure delivery of drug subcutaneously Patch applied to upper arm

Approved

6 mg, no > 2 doses in 24 h

Excellent for severe rapid-onset migraine or severe migraine with significant nausea and vomiting or rescue

Approved

6.5 mg over 4 h

Oral tablet taken with water

Approved

85 mg sumatriptan + 500 mg naproxen

Breath-powered intranasal delivery

Approval anticipated end of 2015

22 mg

Contraindications of note: history of contact dermatitis. Likely valuable in slowly developing migraine with early nausea or triptan AEs with tablets Contraindications of note: any indication of kidney disease, cannot take while on blood thinners (NSAID-related). May have lower recurrence rates than oral sumatriptan alone Rapid onset means potentially useful at all phases of acute migraine but particularly early in attack. Useful with impaired GI absorption or triptan AEs observed with oral tablets or injection


Iontophoretic sumatriptan patch Combination tablet: sumatriptan and naproxen sodium AVP-825 (22 mg sumatriptan intranasal powder)

AE: Adverse event.

treatment, and the timing of when migraine treatment is administered relative to onset [46]. In addition, migraine sufferers often vary in their frequency of migraine attacks or previous use of triptan interventions [47]. These factors are often not accounted for in clinical trial designs, even though treatment response to a given drug may be influenced by these factors. The limitations of our current literature are noted here to underscore the context and value that a direct head-to-head crossover trial, such as COMPASS, can provide in characterizing clinical utility of an agent, especially against a treatment standard. Currently, the most commonly prescribed migraine treatment is oral sumatriptan [9], and the COMPASS trial, which was conducted in nearly 200 patients assessing treatment response in over 1500 migraines, demonstrated that AVP-825 provided superior early efficacy, without loss of sustained efficacy, compared with the most efficacious dose of oral sumatriptan [43]. The favorable tolerability and low rate of adverse events, including the significantly lower rate of atypical sensations observed with AVP-825 compared with oral sumatriptan, are likely due to the lower total drug exposure achieved with this unique breath-powered delivery method. Importantly, the safety profile of AVP-825 also included a low rate of events generally categorized as cardiovascular, which is notable given the potential for vasoconstrictive effects of triptans as a drug class, even though the clinical significance of which is still being debated [16]. In addition, for some patients who may respond well to triptans but have been hindered by adverse events at higher triptan exposure, the novel delivery method employed by AVP-825 may offer the efficacy potential of sumatriptan therapy without the typical safety and tolerability drawbacks. In

addition, it may be a welcome alternative to those patients exhibiting an over-reliance on oral tablets that may not be consistently effective. Alternative routes of sumatriptan administration beyond conventional oral tablets are important to those patients who have difficulty swallowing an oral medication, patients with migraine-associated nausea and/or vomiting, or patients with the need for faster relief of pain and migraine-associated symptoms. Some examples of other acute migraine treatments being developed with novel delivery options are summarized in Table 3. AVP-825 has the potential to be used at all phases of a migraine attack. While historically early intervention has optimized the efficacy of oral tablets, the COMPASS study suggests that AVP-825 provides superior efficacy at early time points over tablets. AVP-825 is also likely to be more effective in advanced migraine with nausea or other settings of impaired GI function since the absorption of nasally delivered sumatriptan powder does not rely on the GI tract. If approved, AVP-825 may also be of clinical value as a rescue medication for attacks initially treated with an oral formulation of sumatriptan. A significant challenge in the management of migraine is identifying an effective treatment for the wide range of clinical presentations of migraines and across multiple migraine attacks. Clinical trial data demonstrate that AVP-825 will be very helpful in consistently treating migraines across multiple attacks, and may be less influenced by headache severity or GI symptoms. Over the next several years, I expect the characterization and study of migraine therapies outside of the triptan drug class to steadily increase as more data become available. Some drugs for acute treatment of migraine may be particularly valuable for attacks that are advanced or for which


11

R. Cady

triptans have been ineffective. I also watch with particular interest ongoing studies to better understand factors contributing to the progression from episodic migraines to chronic migraines [48] and strategies for migraine prevention.

Declaration of interest


This paper was funded by Avanir Pharmaceuticals, Inc., Aliso Viejo, CA. R Cady is a consultant for Allergan Inc., Amgen, Boston Scientific Corporation, Novartis AG, OptiNose US Inc., Amgen Inc., Avanir Pharmaceuticals, Inc.; is on the speaker bureau for Allergan Inc., Impax Laboratories, Inc., Bibliography

Merck & Co., and Novartis AG; and has received research grants from Alder, Amgen, Allergan Inc., Avanir Pharmaceuticals, Inc., Electrocore, Labrys, Tian Medical, Fortis Spectrum, GlaxoSmithKline plc., Questcor Pharmaceuticals, and Primary Care Education. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Editorial assistance was provided by Jennifer Hepker, PhD (Prescott Medical Communications Group, Chicago, IL) and funded by Avanir Pharmaceuticals.

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Affiliation Roger Cady MD Director, Headache Care Center, 3805 S. Kansas Expressway, Ste. B, Springfield, MO 65807, USA Tel: +1 417 841 3615; Fax: +1 417 886 4498; E-mail: [email protected]

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