A multicenter, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine

In the acute treatment of episodic migraine (ie, patients with fewer than 15 headache days per month [1]), 5-HT_1B1D agonists (triptans) are recommended as first-line therapy for moderate and severe attacks and for mild attacks that have been unresponsive to analgesics or nonsteroidal anti-inflammatory drugs in the past [2]. Oral sumatriptan, the most widely used drug in the triptan class [3‐5], is effective and safe [6], but it may not be an optimal choice for many attacks. Its poor bioavailability (15%) and slow absorption (T_max ≥ 2 h) lead to a slow onset of action (45–60 min) [7], an issue exacerbated in many patients by migraine-associated gastric stasis [8‐10]. To varying degrees, poor absorption and relatively delayed onset of action limit the clinical utility of all oral triptans [4, 6].

For attacks associated with nausea or vomiting, as well as in patients who cannot tolerate or experience dysphagia with oral triptans, evidence-based guidelines recommend the use of non-oral migraine-specific formulations [2]. Currently available alternatives, however, are of limited clinical utility in many patients. Subcutaneous (SC) sumatriptan 6 mg has good efficacy (60% pain-free at 2 h) and a fast onset of action (10 min post-dose) [11], but most SC sumatriptan-treated patients (59%) have injection site reactions, nearly half (42%) experience atypical sensations (eg, tingling, warm/hot, tightness/pressure [12]), and many migraineurs are averse to using injectable formulations [13, 14]. Transdermal sumatriptan, which has been linked with burns and scars at the application site [15] and has very limited efficacy (18% pain-free at 2 h [16]), has been voluntarily taken off the market. With the commercial formulation of sumatriptan intranasal spray (Imitrex® Nasal Spray, Imigran® Nasal Spray, GlaxoSmithKline), because the drug is not well absorbed through the nasal mucosa [17] (T_max 0.88–1.75 h) [18]), its onset of action (30 – 45 min) is only slightly faster than oral sumatriptan [7]. Poor absorption is also a problem with intranasal zolmitriptan (T_max ~3 h) [19], and sumatriptan nasal powder has reported a T_max of 20 min to as long as 2 h [20, 21]. These important clinical limitations, particularly in light of the attributes of acute treatment that are most important to migraineurs (rapid onset of action, complete relief, no recurrence, lack of side effects [22‐24]) highlight a gap in migraine pharmacotherapy and emphasize the unmet need for a safe and highly effective non-oral migraine medication with a rapid onset of action.

DFN-02 — sumatriptan 10 mg plus 0.20% 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM), a permeation-enhancing excipient — is a new intranasal migraine treatment under clinical development that is designed to overcome many of the limitations to currently available acute medications. Sumatriptan is a well-known headache medicine that has been extensively studied and described [4, 5, 25]. DDM, on the other hand, belongs to a class of surfactants known as alkylglycosides, which are non-ionic and metabolized to simple carbohydrates and alcohols or acids that have shown promise as permeation enhancers for intranasal medication [26‐28]. DDM appears to loosen cell-cell junctions and enhance paracellular movement through the nasal epithelium by altering mucosal viscosity and membrane fluidity, increasing blood flow, and inhibiting ciliary beat frequency and drug metabolizing enzymes [28‐32].

In a pharmacokinetic (PK) study in healthy subjects, DFN-02 had a markedly more rapid sumatriptan absorption profile than commercial intranasal sumatriptan, systemic exposure was similar to 4 mg SC sumatriptan, and plasma sumatriptan concentration peaked 5 min earlier than 4 mg SC and 6 mg SC [33] — results that suggest it may have efficacy comparable to a 4-mg SC dose of sumatriptan, which has not yet been demonstrated in migraine patients. With efficacy expected based on PK equivalency data, the sole objective of this study was to evaluate the safety and tolerability of DFN-02’s unique formulation in the acute treatment of migraine over a 6-month period, based on treatment-emergent adverse events (TEAEs), clinical laboratory results, and electrocardiograms.

This was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura. The protocol, the patient information and consent form, and other relevant study documentation were approved by the Institutional Review Board (IRB) for each study center before initiation of the study. Protocol amendments were approved by the IRB before implementation or submitted to the IRB for information, as required. The study followed the Guidelines of the World Medical Association Declaration of Helsinki in its revised edition (Brazil, 2013), The International Council for Harmonisation guidelines for current Good Clinical Practice, the United States Food and Drug Administration Code of Federal Regulations, and the demands of national drug and data protection laws and other applicable regulatory requirements. Investigators and study staff recruited patients at the individual study sites; written consent to participate was provided after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment. The study was registered with ClinicalTrials.gov (NCT02279082).

Twenty-five US investigator sites participated in the study. The first subject was enrolled into the study on 06 October 2014, and the last subject completed the study on 19 August 2015.

In this 6-month, multicenter, open-label safety study — during which study medication was used to treat more than 2000 migraine attacks — DFN-02 was safe and tolerable for the acute treatment of patients with episodic migraine with and without aura. Adverse events with DFN-02 were similar in pattern, frequency, and severity to those seen in previous research with triptans and nasally administered medications [17, 35], and no novel safety signals were seen. As expected, dysgeusia and application site pain were the most commonly reported tolerability issues; most TEAEs were mild, however, which may have been a factor in the high rate of study completion (77.5%).

Although there were no efficacy assessments completed in this study, findings on other measures indicate that subjects using DFN-02 appear to have experienced migraine relief. For example, the vast majority of subjects completed the study, treating multiple attacks over the 6-month study period, and rescue medication was only used in about 18% of attacks (2.4 doses for an average of 13 attacks). Moreover, although repeat dosing of DFN-02 was permitted at least 1 h after the initial dose, approximately two thirds of qualifying attacks were treated with a single dose of DFN-02. Since subjects were provided with multiple canisters of DFN-02 and could repeat the dose as needed to control their symptoms, the high proportion of attacks treated with a single dose suggests that DFN-02, which contains only 10 mg sumatriptan, provided most subjects with adequate migraine relief.

Previous research with the commercial formulation of intranasal sumatriptan 20 mg demonstrated good safety and tolerability; the incidence of individual AEs was similar to placebo [17, 35]. The persistent exception is bad, bitter, or unpleasant taste, which affected 19–36% of subjects in randomized, placebo-controlled studies [35] and 22%–27% of subjects in a pooled analysis [17]. With DFN-02, dysgeusia was similarly common (21% of subjects), but symptoms were mostly mild, and no subjects cited it as a reason for discontinuation. Application site pain with DFN-02 was more common than in previous research with intranasal formulations (30.5% vs 4% [17, 35]); these events may be related to the presence of the permeation enhancer DDM in DFN-02. In clinical practice, however, the kinetics of DFN-02 have been shown to be about the same as sumatriptan 4 mg SC [33], with migraine patients expected to experience similar times to onset of action and rates of pain freedom, which suggests that the risk of site reactions with DFN-02 could be about 30% lower than with comparable acute treatments, such as 4 mg SC (30.5% vs 43% [36]). Since most TEAEs were mild, the study completion rate was high, and few subjects withdrew, the relative frequency of application site pain does not seem a likely barrier to care with DFN-02.

This study provides clinically useful data but has some limitations. Subject eligibility was based on ICHD-2, while the current version is ICHD-3 (beta). At the time of the study set-up, ICHD-3 (beta) [1] was newly available and still collecting feedback from experts; therefore, the study proceeded using the previous version. Nevertheless, ICHD-2 and ICHD-3 (beta) are identical with respect to diagnosis of acute episodic migraine. Lacking a placebo control, the true incidence of AEs related to DFN-02 could not be determined. Additionally, in the absence of a direct comparison of DFN-02 with the commercially available intranasal formulation of sumatriptan, it was not possible to assess the relative safety of DFN-02 and marketed products. Given the well-established safety profile of intranasal sumatriptan, however, it is unlikely that any of these factors influenced the generalizability of these results or the long-term safety outcomes seen with DFN-02.

Sumatriptan is widely used and has been available in oral tablet, nasal spray, and injectable formulations for decades [25]. However, nearly 30% of migraineurs report dissatisfaction with acute therapies [37], with the most common complaint being that pain relief takes too long [22]; close to 90% of patients express a willingness to try new acute treatments [23, 24]. Because the PK of DFN-02 are compatible with a possible rapid onset of action and a favorable safety profile without the disadvantages associated with oral or SC therapies, DFN-02 may be useful for patients who prefer not to treat their condition with injectable medications, as well as patients in whom nonresponse, dysphagia, nausea, or vomiting preclude the use of orally administered drugs. As seen with similar triptan delivery systems [38, 39], ease of use may make DFN-02 especially convenient for treatment at home, work, and while traveling [35].

In this multicenter, open-label safety study, DFN-02, a novel intranasal spray formulation composed of sumatriptan 10 mg and a permeation-enhancing excipient DDM, was safe and tolerable for the acute treatment of episodic migraine over a 6-month study. Adverse events with DFN-02 were similar in pattern, frequency, and severity to those seen in previous research with intranasal sumatriptan.