INP104: A Drug Evaluation of a Nonoral Product for the Acute Treatment of Migraine

Abstract

Migraine is a highly prevalent, disabling neurological disorder that is also associated with gastrointestinal symptoms, autonomic dysfunction and allodynia. Despite the availability of multiple acute agents for migraine, an unmet need remains for effective, well-tolerated drugs that are nonoral and noninvasive. Here, we provide a drug evaluation of INP104, a novel drug-device combination product of dihydroergotamine (DHE) mesylate – a molecule with a long history of efficacy familiar to headache specialists – which is delivered to the difficult-to-reach upper nasal space where it is rapidly and consistently absorbed via Precision Olfactory Delivery (POD^®). In clinical trials, INP104 exhibited favorable pharmacokinetics, a well-tolerated safety profile, and rapid symptom relief, highlighting its potential as a suitable acute therapy for migraine.

Plain Language Summary

INP104: a drug evaluation of a nonoral product for the acute treatment of migraine

Migraine is a very common headache disorder that often presents with pain and gastrointestinal symptoms. There are many available treatments for migraine, but some patients still need an option that works well for them, that is noninvasive, or does not need to be taken orally. Here we provide a drug evaluation of INP104, an approved acute treatment for migraine that combines a drug and a device: the medication dihydroergotamine (DHE) mesylate, which has been used for decades for treating acute symptoms of migraine, and the Precision Olfactory Delivery (POD^®) device, which delivers DHE mesylate to the hard-to-reach upper regions of the nose. Targeting this region helps medication to be absorbed faster and more consistently. In clinical trials, INP104 demonstrated favorable drug properties, came with few adverse events, and provided fast relief from migraine symptoms.

Tweetable abstract

There remains a need for more effective migraine therapies. INP104 is a novel upper-nasal delivery product combining dihydroergotamine mesylate and Precision Olfactory Delivery (POD^®) for fast, well-tolerated migraine relief.

Keywords::

• drug delivery
• INP104
• migraine
• pain
• pharmacokinetics
• Precision Olfactory Delivery
• upper nasal space

Practice points

• Migraine is a debilitating, recurrent headache disorder with high prevalence, particularly in women. Reliable, well-tolerated nonoral routes of administration for acute therapies for migraine remains an important, but unmet, need.

• It is increasingly recognized that oral delivery of migraine therapies may not always be optimal, which is especially important for patients who experience symptoms of autonomic dysfunction, who have gastrointestinal comorbidities or symptoms, or who find themselves cycling through several oral treatments for migraine without adequate relief.

• Dihydroergotamine (DHE) mesylate has a long-standing reputation as an effective acute treatment for migraine among headache specialists; however, it is commonly administered intravenously (IV), which provides rapid and sustained relief, but is frequently accompanied by systemic adverse events, such as nausea and vomiting, and is not suitable for at-home use or for those with a fear of needles.

• INP104 is a novel drug-device combination product of DHE mesylate and Precision Olfactory Delivery (POD^®) approved for the acute treatment of migraine, and it was developed to overcome the limitations of IV administration and the shortcomings of available DHE mesylate nasal sprays.

• Advantages of POD include rapid and consistent delivery of DHE mesylate to the previously unexplored upper nasal space - offering a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance because of its nasal architecture and nonmotile cilia - as well as easy administration by patients and caregivers.

• In a phase I trial (STOP 101) in healthy adults, INP104 achieved plasma levels comparable with IV DHE mesylate within 30 min of administration but with a lower incidence of nausea and vomiting (despite pretreatment with an antiemetic), which is likely because of the lower peak concentration of DHE mesylate from INP104.

• Compared with an existing DHE mesylate nasal spray (MIGRANAL^®) in the STOP 101 study, INP104 provided better, faster drug absorption with more consistent delivery of DHE mesylate and improved bioavailability.

• In a phase III, open-label, long-term, safety study (STOP 301), no major safety concerns were identified, including those relating to the upper nasal space, over 24 and 52 weeks of INP104 treatment.

• Patient-reported exploratory efficacy outcomes were also assessed in the STOP 301 study for the first INP104-treated migraine attack. Pain freedom, most bothersome symptom freedom, and pain relief all at 2 h after INP104 were self-reported by 38.0, 52.1 and 66.3% of patients, respectively. Low rates of recurrence were also self-reported, and INP104 was efficacious regardless of the timing of administration relative to attack onset.

• INP104 has the potential to deliver rapid symptom relief for migraine that is noninvasive, convenient and well tolerated.

Migraine is a highly prevalent, disabling disorder with notable socioeconomic and personal impacts [1–3]. The International Headache Society defines migraine as a recurrent headache disorder with moderate or severe attacks lasting 4–72 h. To be classified as migraine, it requires two of the four typical features: unilateral location, pulsating quality, moderate or severe intensity and aggravation by/causing avoidance of routine physical activity. Further, the classification criteria include migraine that is often associated with nausea and/or photophobia and phonophobia. This presentation is commonly referred to as migraine without aura, while migraine with aura is primarily characterized by transient focal neurological symptoms (visual, sensory, or speech) that usually precede or sometimes accompany the headache [1]. Additionally, up to two-thirds of individuals with migraine also experience allodynia and hyperalgesia [4], adding to the existing disability already present with migraine. Chronic migraine is defined as individuals experiencing 15 or more headaches per month, and episodic migraine is characterized by 0–14 headaches per month [1]. The 2016 Global Burden of Disease Study ranked migraine as the sixth most prevalent disorder globally. Although 1 billion individuals experience migraine, the prevalence is almost twofold greater in women (18.9%) than men (9.8%), and it predominantly affects younger, working-age adults [3]. The financial burden of migraine is also substantial; direct costs associated with migraine can reach US$11.07 billion annually and are further compounded by indirect costs, including reduced productivity [5,6]. In fact, migraine is the most common cause of workdays lost to disability in adults younger than 50 years of age, with a substantial burden of workplace absenteeism, presenteeism and cost to employers [7,8]. Effective migraine treatment can significantly reduce the burden of migraine; however, for many patients, adequate relief is not achieved with available therapeutic options [9]. In this drug evaluation of INP104, we will explore the pharmacology, safety and tolerability and clinical efficacy of INP104, a newly approved nonoral, nasally delivered, drug-device product for the acute treatment of migraine.

Migraine is a highly prevalent, disabling disorder with notable socioeconomic and personal impacts [1–3]. The International Headache Society defines migraine as a recurrent headache disorder with moderate or severe attacks lasting 4–72 h. To be classified as migraine, it requires two of the four typical features: unilateral location, pulsating quality, moderate or severe intensity and aggravation by/causing avoidance of routine physical activity. Further, the classification criteria include migraine that is often associated with nausea and/or photophobia and phonophobia. This presentation is commonly referred to as migraine without aura, while migraine with aura is primarily characterized by transient focal neurological symptoms (visual, sensory, or speech) that usually precede or sometimes accompany the headache [1]. Additionally, up to two-thirds of individuals with migraine also experience allodynia and hyperalgesia [4], adding to the existing disability already present with migraine. Chronic migraine is defined as individuals experiencing 15 or more headaches per month, and episodic migraine is characterized by 0–14 headaches per month [1]. The 2016 Global Burden of Disease Study ranked migraine as the sixth most prevalent disorder globally. Although 1 billion individuals experience migraine, the prevalence is almost twofold greater in women (18.9%) than men (9.8%), and it predominantly affects younger, working-age adults [3]. The financial burden of migraine is also substantial; direct costs associated with migraine can reach US$11.07 billion annually and are further compounded by indirect costs, including reduced productivity [5,6]. In fact, migraine is the most common cause of workdays lost to disability in adults younger than 50 years of age, with a substantial burden of workplace absenteeism, presenteeism and cost to employers [7,8]. Effective migraine treatment can significantly reduce the burden of migraine; however, for many patients, adequate relief is not achieved with available therapeutic options [9]. In this drug evaluation of INP104, we will explore the pharmacology, safety and tolerability and clinical efficacy of INP104, a newly approved nonoral, nasally delivered, drug-device product for the acute treatment of migraine.

Overview of the field

With regard to pathophysiology, migraine can be considered a neurovascular disorder involving peripheral and central sensitization of nociceptors [4,10]. Although the precise mechanisms driving migraine attacks remain unknown, one hypothesis suggests that migraine attacks may be triggered by prolonged trigeminovascular activation by peripheral stimuli via dural blood vessels [4,11]. Frequent migraine attacks and accompanying neuronal activation may produce neuroplastic changes that lower the threshold for subsequent episodes and influence the hypersensitivity that burdens many individuals [4,10–12]. For example, peripheral sensitization of first-order trigeminovascular neurons (ie, meningeal nociceptors in the dura) are thought to underly the throbbing pain that individuals experience during migraine attacks when they bend over, climb stairs or exercise, cough, or sneeze. In contrast, central sensitization of second-order trigeminovascular neurons (i.e., medullary dorsal horn neurons receiving input from the dura and skin) may contribute to thermal and mechanical hypersensitivity [11]. Indeed, differences in the connections between the periaqueductal gray and nucleus cuneiformis to pain-processing hubs in the brain stem, thalamus, cerebellum and frontal/temporal pain-modulating regions have been documented in individuals with both migraine and cutaneous allodynia compared with those with migraine alone [4]. Such desensitization, therefore, can contribute not just to migraine attacks but also to manifestations of the many pain triggers experienced by individuals with migraine [4,10].

In addition to the pain associated with migraine, there are a wide range of gastrointestinal (GI) symptoms, including nausea, vomiting, diarrhea, abdominal pain and several additional GI comorbidities [13–15]. Autonomic dysfunction, such as cutaneous vasoconstriction, vasodilation, piloerection, diaphoresis, nasal congestion and rhinorrhea can also be associated with migraine [16–19]. Nausea, vomiting and delayed gastric emptying associated with migraine may limit proper absorption of oral drugs and could lead to reluctance to take oral medications [13,20–22]. It is particularly important to recognize GI and autonomic dysfunction symptoms in individuals with migraine because the efficacy of acute therapies, especially orally administered products, may be affected, which may result in frequent cycling of medications [13].

The main goal of acute therapies for migraine should be sustained pain-free response, but they can also include treating migraine attacks rapidly and consistently without recurrence, restoring function, minimizing rescue medication use, reducing subsequent use of resources (e.g., emergency department visits, diagnostic imaging, healthcare provider and ambulatory infusion center visits), being cost-effective, and having minimal or no adverse events (AEs) [23,24]. There are several evidence-based pharmacological acute treatments available, which are either migraine nonspecific (e.g., NSAIDs, acetaminophen) or migraine specific (e.g., triptans, dihydroergotamine [DHE] mesylate, gepants, ditans) [23]. Triptans (5-hydroxytryptamine [HT]_1B/1D agonists) are generally recommended as first-line acute therapeutics for moderate to severe migraine attacks, and there are several triptan products available with multiple routes of administration (i.e., oral, nasal, injection) [25–27]. However, the efficacy and tolerability of triptans can vary among agents and patients and between attacks (particularly if taken several hours into an episode), and this can be associated with variable consistency of pain relief, an incomplete pain response, symptom recurrence, or tolerability concerns in some patients and they are also contraindicated in patients with cardiovascular disease [27–31]. Tolerability concerns associated with some triptans may also lead to a delay in administering or complete avoidance altogether [32]. Timing of administration can also influence the efficacy of orally administered triptans – some have been shown to be more effective when administered early in an attack or when the attack is still mild [33,34]. Furthermore, a once-effective triptan may elicit a different response upon repeat exposure in some patients, complicating the decision of whether a second triptan or an alternative route should be suggested for future migraine attacks [35]. Gepants and ditans are newer orally administered therapies that have shown clinical efficacy in patients for the acute treatment of migraine [36–39]. Gepants are a class of small molecules that act as antagonists to the CGRP receptor, and rimegepant (Nurtec^® ODT, Biohaven Pharmaceuticals, Inc., CT, USA) and ubrogepant (Ubrelvy^®, Allergan USA Inc., NJ, USA) are the only approved second-generation gepants for the acute treatment of migraine [36,38,39]. Lasmiditan (REYVOW^®, Eli Lilly, IN, USA) is a 5-HT_1F receptor agonist that is the only approved ditan for the acute treatment of migraine [40–42]. Clinical trial data support the efficacy of gepants and ditans [36–41]; however, results from real-world data of 106 patients from a tertiary headache center who used ubrogepant (UBRELVY^®, Allergan, Dublin, Ireland) to acutely treat their migraine demonstrated that 60.0% (63/105) of patients reported that ubrogepant never completely aborted their migraine within 2 h [43]. Similar to some triptans, a post hoc analysis of phase III clinical trial data reported higher rates of efficacy with ubrogepant administered when the migraine attack pain was still mild compared with when pain was moderate or severe [44]. In addition, therapies that block the CGRP pathway have also been shown to cause constipation in some patients, suggesting that these agents may not be the best option for patients with GI symptoms [45]. The prescribing information for lasmiditan includes driving restrictions for at least 8 h after each dose, which limits its convenience of use [42].

Despite multiple existing treatment options, only 26% of patients with migraine reported using an oral acute prescription medication, and 95.8% reported at least one unmet acute, oral treatment need based on the 2017 Migraine in America Symptoms and Treatment study [9]. Of those patients who reported unmet needs associated with inadequate treatment response, 23.7% reported that nausea had affected their treatment; 16.4% of those patients stated that nausea made it difficult or impossible to take oral medications, and 15.5% stated that nausea made oral medication less effective [9]. These statistics highlight the large proportion of patients who are dissatisfied with their treatments and the continued unmet treatment need for safe, effective, and well-tolerated nonoral treatment options [12,30]. Importantly, inadequate acute treatment for migraine can lead to medication overuse, reduced health-related quality of life, reduced treatment adherence, and increased risk of chronification of migraine, which can result in greater disability, pharmacological tolerance to subsequent drugs and increased headache frequency [46–48]. In the American Migraine Prevalence and Prevention (AMPP) study, 3.1% of individuals with episodic migraine progressed to chronic migraine over 1 year [12]. New onset of chronic migraine over 1 year by acute treatment efficacy group was reported by 2.7% of individuals in the moderate treatment efficacy group, 4.4% in the poor treatment efficacy group, and 6.8% in the very poor treatment efficacy group. In the maximum treatment efficacy group, only 1.9% of individuals reported new onset of chronic migraine in the following year, suggesting that inadequate efficacy of acute treatment may increase the risk for new-onset chronic migraine in individuals with episodic migraine [12]. These findings align with publications on postsurgical chronic pain, which demonstrate an association between the development of chronic pain and the intensity and duration of acute pain [49]. The exact mechanisms responsible for the transition from acute to chronic pain are unknown, but peripheral and central sensitization have again been hypothesized to play a role [50]. Furthermore, the neuroplastic changes resulting from repeated attacks and treatment exposures may result in analgesic tolerance over time [50,51]. These factors can become particularly problematic for patients with acute medication overuse or medication overuse headache [48,52,53].

Compound

Dihydroergotamine (DHE) mesylate has been used for decades by clinicians to acutely treat migraine attacks, status migrainosus and cluster headache attacks rapidly, with effects lasting up to 48 h [54]. Furthermore, DHE mesylate has demonstrated benefit in the context of difficult-to-treat migraine attacks, including those with triptan-resistant migraine, migraine upon waking, migraine involving allodynia, menstrual migraine and severe or prolonged migraine [54–58]. In the context of allodynia, a proof-of-concept study in 13 patients with episodic migraine with cutaneous allodynia demonstrated that subcutaneous administration of DHE mesylate, both early (within 2 h) and late (after 4 h) in migraine initiation, resulted in most patients achieving headache relief within 2 h (>55%, 6/9 early-treated attacks, 5/9 late-treated) [59]. When administered early in the attack, DHE mesylate use resulted in a reduction in subjective cutaneous and brush allodynia after 30 min and 15 min, respectively, and after 120 min and 90 min when administered late in the attack, respectively [59]. A post hoc analysis of a large phase III randomized trial demonstrated that orally inhaled DHE mesylate provided similar efficacy in patients with or without baseline allodynia and was significantly more effective compared with placebo [57].

The most common route of administration of DHE mesylate is intravenous (IV; D.H.E. 45^®; Bausch Health Companies Inc, NJ, USA); however, its use is limited because it is invasive and inconvenient—it needs to be administered by a clinician—and has high frequency of associated nausea and vomiting, which necessitates antiemetic pre-treatment [54,60–62]. DHE mesylate can also be administered intramuscularly and subcutaneously; however, these routes can be associated with poor tolerability and are not ideal for those with a fear of needles [54]. Oral DHE mesylate tablets are available in some countries but are not used in the USA because of their poor bioavailability (<1%) [60,63]. Furthermore, the absorption and efficacy of oral migraine treatment options are limited by first-pass metabolism in the liver and variable absorption within the GI tract, which can be exacerbated by the GI symptoms frequently associated with migraine [22,64]. Nasal delivery of DHE mesylate is an appealing alternative to oral and injection therapies. MIGRANAL^® (Bausch Health Companies, Inc. or its affiliates) was the first approved nasal spray of DHE mesylate; generic versions are now available [54,65]. However, it has several potential barriers, including a variable clinical response and adverse taste, which may be the result of drug spillage from the nose or into the nasopharynx [54,63,65]. This drug loss contributes to the decreased systemic absorption and low bioavailability already exacerbated by mucociliary clearance of drugs delivered to the lower nasal space [54,63]. Another challenge of MIGRANAL is its administration: patients are required to deliver one spray in each nostril, followed by a subsequent spray in each nostril after waiting 15 min [66]. Although an orally inhaled DHE mesylate product (MAP0004; LEVADEX/SEMPRANA^®, MAP Pharmaceuticals Inc., CA, USA) showed promise in clinical trials, manufacturing issues precluded its approval, even though it was well tolerated and effective [54,67]. However, it should be emphasized that at the time of development, the FDA required four coprimary end points for approval. MAP0004 met all four self-reported coprimary end points during a phase III trial, including reduction in nausea, further highlighting the efficacy of DHE mesylate for the acute treatment of migraine [67]. MAP0004 was significantly superior to placebo in pain relief at 2 h (58.7 vs 34.5%; p < .0001), phonophobia freedom at 2 h (52.9 vs 33.8%; p < .0001), photophobia freedom at 2 h (46.6 vs 27.2%; p < .0001), and nausea freedom at 2 h (67.1 vs 58.7%; p = .0210) as well as pain freedom at 2 h (28.4 vs 10.1%, p < .0001) [67]. DHE mesylate administered by IV is typically accompanied by nausea and requires pretreatment with an antiemetic; therefore, freedom from nausea at 2 h and reduced nausea in the absence of pretreatment with an antiemetic was an important finding in studies investigating MAP0004 [54,62,63,67], suggesting that route of administration is critical to minimizing adverse events with DHE mesylate. This study also demonstrated that MAP0004 was effective regardless of timing of administration, achieving significantly greater pain relief at 2 h when administered even up to >8 h after migraine onset when compared with placebo [67].

An important feature of nasal drug delivery is the location of drug deposition. The nasal cavity can be separated into the upper and lower nasal space, which have distinct vascular supply, epithelia type and mucociliary function (Figure 1) [22,68–72]. Within the lower nasal space are structures such as the vestibule and two of the three nasal turbinates; the vestibule is lined with squamous epithelium poorly suited for drug absorption, while all three of the nasal turbinates are lined with respiratory epithelium covered with mucus and motile cilia [22,72,73]. Rapid mucociliary clearance in the lower nasal space can further affect drug absorption [22,54,68,69,72,74]. Most traditional nasal products have been shown to deliver the drug to the lower nasal space, generally as a cloud of liquid drug droplets inside the nostril, potentially resulting in significant drug loss due to swallowing or nasal drip once the droplets coalesce [54,69,71]. The upper nasal space includes areas lined with olfactory epithelium, which may be more suitable for drug absorption because of its nonmotile cilia, and resulting in greatly decreased mucociliary clearance of drug [68,72]. Additionally, it may be more permeable than the respiratory epithelium found in the lower nasal space [69,72,74,75]. Although the upper nasal space has several advantageous features for drug delivery, the complex architecture of the nose presents a challenge for accessing drugs to this area. Delivery of a drug to the upper nasal space requires initial passage through the narrow opening of the nasal valve and then navigation past the nasal turbinates before its deposition [69]. Consequently, only ∼5% of drug particles are delivered to the upper nasal space by traditional nasal sprays [76].

Figure 1. Differences in nasal drug delivery.

Diagram of the nasal cavity illustrating nasal drug delivery through (A) traditional nasal routes into the lower nasal space and (B) INP104 delivery to the upper nasal space using Precision Olfactory Device (POD^®) technology [22,54,68,69,72,74].

INP104 is a drug-device combination product of DHE mesylate and Precision Olfactory Delivery (POD^®) that is approved for the acute treatment of migraine (TRUDHESA^®; Impel Pharmaceuticals Inc., WA, USA), and was developed to harness the well-established efficacy of DHE mesylate while overcoming some of the challenges presented by available treatment options [77,78]. The POD device is a handheld, manually actuated, gas-propelled administration device that was designed to gently deliver a narrow, focused stream-like plume of liquid DHE mesylate (1.45 mg) to the upper nasal space in two sprays [63,69,79]. A single photon emission computed tomography (SPECT) imaging study that compared drug delivery with a traditional nasal pump to delivery with POD demonstrated that most of the study dose was deposited in the anterior lower nasal cavity with cloud delivery by the traditional nasal pump, whereas use of the POD device resulted in increased deposition in the upper nasal space (p < 0.05) [79]. Use of INP104 does not require coordinated breathing or specific head orientation, providing greater ease of use for both caregivers and patients [69,79], which can be beneficial for patient populations who require additional assistance. The propellant, in this case hydrofluoroalkane (HFA) 134a, and drug are stored separately until the point of delivery, overcoming some of the manufacturing challenges encountered by MAP0004 [54,69,79].

Pharmacology

DHE was originally synthesized from ergotamine, with the goal of maintaining the efficacy of the original compound while improving tolerability and reducing safety concerns [54]. The result was a compound with stronger alpha-adrenergic antagonism than ergotamine, weaker arterial vasoconstrictive properties, and less dopaminergic agonism, resulting in less nausea and vomiting, lower emetic potential, and reduced uterine constriction compared with ergotamine [54,80–82]. Most acute medications for migraine have a relatively selective pharmacology, but DHE has broad pharmacology acting on several serotonergic, dopaminergic and adrenergic receptor subtypes [54,56,83–86]. This may help explain why it is effective even when administered later in an attack, and more consistently between different attacks. DHE mesylate has also been shown to slowly dissociate from 5-HT_1B/1D receptors, which may be a possible mechanism for the characteristic sustained efficacy of DHE mesylate when used to acutely treat migraine [87]. Furthermore, the central actions of DHE mesylate are thought to be able to reverse the central sensitization observed after prolonged migraine attacks [4]. Early use of triptans can reduce the development of central sensitization by blocking transmission of peripheral dural pain signals, but they are less effective in reversing established central sensitization [88]. Of note, the effects of INP104 on the central nervous system have not been evaluated in preclinical or clinical studies of INP104. INP104 has only been evaluated in the context of plasma levels of DHE mesylate.

Clinical efficacy & safety

Phase I clinical trial

STOP 101 was a phase I, 3-period, 3-way, open-label crossover study that investigated the safety, tolerability and pharmacokinetics of INP104 versus IV DHE mesylate (D.H.E. 45) and MIGRANAL. Eligible participants were healthy adult men and women with no clinically significant physical examination findings or abnormal clinical laboratory results. After a 21-day screening period, participants were randomized in a 3-treatment, 3-period, balanced crossover study of six sequences with a 7-day washout between treatments. Participants received INP104 1.45 mg (as one spray into each nostril), IV DHE mesylate 1.0 mg (infused over 1 min), and MIGRANAL 2.0 mg (two sprays per nostril, given as one initial spray per nostril followed 15 min later by an additional spray per nostril for four total, according to the prescribing information) [63]. All doses were preceded by 10 mg of IV metoclopramide (an antiemetic) to prevent nausea and vomiting, which is commonly reported with IV DHE mesylate [62,63,80]. All participants were observed as inpatients for 48 h after each dosing [63].

38 healthy participants were enrolled and randomized, with 36 participants in the safety population (ie, administered at least one dose of study medication) and 27 participants in the pharmacokinetic (PK) population (i.e., all randomized participants who received all scheduled doses of INP104 and both reference products, and who provided a sufficient number of adequate blood samples for noncompartmental PK analysis). Participants in the safety population had a mean age of 28.8 years and 50% were female. Based on the safety population, INP104 demonstrated rapid increases in DHE plasma levels, attaining 93% of C_max at 20 min, with similar levels to IV DHE mesylate from 30 min (1219 ng/ml for INP104, the C_max, vs 1224 ng/ml for IV DHE mesylate) to 48 h (Figure 2). Compared with INP104, the C_max after administration of IV DHE mesylate (14,190 pg/ml) was over tenfold higher, while the C_max of MIGRANAL was more than fourfold lower (299.6 pg/ml). Furthermore, MIGRANAL took longer to reach C_max (47 min) compared with INP104 (30 min). Compared with MIGRANAL, INP104 demonstrated more consistent delivery of DHE based on a lower intersubject coefficient of variation (CV%) for C_max (51.4 vs 91.8%) and AUC_0-inf (41.8 vs 74.7%). Based on the PK population, the absolute bioavailability (compared with 100% for IV DHE mesylate) was 58.9% for INP104 and 15.2% for MIGRANAL. Notably, the faster and more efficient pharmacokinetic profile of INP104 was achieved with lower doses than MIGRANAL (1.45 mg compared with 2 mg). Since AUC_0–2 h has been suggested to be predictive of DHE mesylate efficacy, it was assessed in this study post hoc with values of 1595, 3019, and 428.7 h*pg/ml for INP104, IV DHE mesylate, and MIGRANAL for the PK population, respectively [63]. This INP104 AUC_0–2 h of 1595 h*pg/ml was very similar to that obtained with the MAP0004 product at 1447 h*pg/ml [62]. Full pharmacokinetic parameters are found in Table 1.

Figure 2. INP104 Pharmacokinetics From the STOP 101 Study.

Mean plasma dihydroergotamine concentrations from (A) 0–4 h and (B) 0–48 h postdose from the STOP 101 Study (Safety Population) [63].

^aMeasures dihydroergotamine free base on a semilog scale.

^bDoses represent dihydroergotamine mesylate.

^cn = 31 for time points of 5, 10, 30, and 40 min in (A), and for (B), n = 31 for time points of 5, 10, 30, and 40 min and 12 and 36 h, n = 30 for time point of 8 h.

^dn = 30 for time point of 48 h.

Note: Dihydroergotamine concentration measurements begin at the 5-min time point. Represented as mean (SD). For the calculation of mean values, individual BLQ values were set to 0 before determining the mean. Figure was created using data from [63].

BLQ: Below limit of quantitation data; IV: Intravenous; SD: Standard deviation.

Table 1. INP104 Pharmacokinetic Parameters From the STOP 101 Study (Safety Population).

Parameter	INP104 1.45 mg (n = 31) ±SD	IV DHE Mesylate 1 mg (n = 31) ±SD	MIGRANAL^® 2 mg (n = 34)^† ±SD
Cmax (pg/mL)	1301 ± 668	14,190 ± 5248	299.6 ± 275.1
Cmax, CV (%)	51.4	37.0	91.8
AUC0-last (h*pg/mL)	5930 ± 2521	7091 ± 1225	1834 ± 1590
AUC0-inf (h*pg/mL)	6275 ± 2621	7490 ± 1246	2199 ± 1643
AUC0-inf CV (%)	41.8	16.6	74.7
Tmax (median [min, max])	0.50 (0.33, 2.05)	0.08 (0.07, 0.78)	0.78 (0.50, 3.08)
T½ (h)	11.8 ± 2.8	14.2 ± 3.5	10.4 ± 3.1
Kel (L/h)	0.06 ± 0.01	0.05 ± 0.01	0.07 ± 0.03
CL/F (L/h)	267 ± 224	118 ± 20	1293 ± 917
Vz/F (L)	4314 ± 2859	2432 ± 771	16,860 ± 9380
Absolute bioavailability (%)^‡	58.9	100	15.2

† n = 31 for AUC_0-inf, K_el, T_1/2, CL/F, and Vz/F.

‡ PK population, n = 27 each for INP104, IV DHE mesylate, and MIGRANAL arms.

Note: Table was reused from [63].

AUC_0-inf: Area under the drug concentration-time curve from time 0 to infinity; AUC_0-last: Area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration; CL/F: Apparent clearance; C_max: Maximum Observed plasma concentration; CV: Coefficient of variation; DHE: Dihydroergotamine; IV: Intravenous; K_el: Apparent terminal elimination rate constant; PK: Pharmacokinetic; SD: Standard deviation; t_1/2: Apparent elimination half-life; T_max: Time to maximum plasma concentration; Vz/F: Apparent volume of distribution at the terminal phase.

Across all treatment arms in STOP 101 (INP104, IV DHE mesylate, and MIGRANAL), 80.6% of participants experienced AEs, which were all mild or moderate in severity except for one serious treatment-emergent adverse event (TEAE) of acute myeloid leukemia during the follow-up period that was considered unrelated to any of the three study treatments. The frequency of study drug-related TEAEs (possibly or probably related to treatment) was 1.5-times higher with IV DHE mesylate administration (50.0% [16/32]) compared with INP104 (19.4% [6/31]) or MIGRANAL (11.8% [4/34]). The most common treatment-related TEAEs in the IV DHE mesylate group (>5%) were headache (15.6%), dizziness (15.6%), somnolence (12.5%), nausea (9.4%), vomiting (6.3%), restlessness (6.3%) and hot flush (6.3%). Treatment-related TEAEs in the INP104 group were headache, somnolence, nasal discomfort, fatigue, gastroenteritis viral, metrorrhagia and pruritus, each of which occurred in 3.2% of patients. Treatment-related TEAEs in the MIGRANAL group were headache, somnolence, vomiting, nausea, restlessness, intranasal paranesthesia, upper respiratory tract infection, metrorrhagia and breast tenderness, each of which occurred in 2.9% of patients. Although participants were pretreated with an antiemetic, two participants (6.3%) on IV DHE mesylate and one participant (2.9%) on MIGRANAL experienced treatment-related vomiting, but no participants taking INP104 experienced treatment-related vomiting. Likewise, no participants taking INP104 experienced treatment-related nausea, compared with three participants (9.4%) on IV DHE mesylate and one participant (2.9%) on MIGRANAL [63]. The higher incidence of nausea and vomiting with IV DHE mesylate may be the result of higher peak concentrations of DHE compared with INP104 [62,63]. Full safety parameters are found in Table 2. No clinically significant changes were observed in vital signs, clinical labs, or electrocardiogram measurements. When participants were asked which delivery device they preferred, 69% reported that they preferred INP104 (POD device), while 24% preferred MIGRANAL and 7% IV DHE mesylate. Collectively, results suggest that INP104 delivers DHE mesylate with improved bioavailability and a faster C_max than MIGRANAL but with lower peak plasma concentrations than IV DHE mesylate, which may confer improved tolerability [63].

Table 2. Safety summary of INP104 from the STOP 101 study (safety population).

Safety Outcomes	INP104 1.45 mg (n = 31)	IV DHE Mesylate 1 mg (n = 32)	MIGRANAL^® 2 mg (n = 34)
Any related TEAE, n (%)	6 (19.4)	11 (34.4)	4 (11.8)
Headache	1 (3.2)	5 (15.6)	1 (2.9)
Somnolence	1 (3.2)	4 (12.5)	1 (2.9)
Dizziness	0	5 (15.6)	0
Mental impairment	0	1 (3.1)	0
Lethargy	0	1 (3.1)	0
Nausea	0	3 (9.4)	1 (2.9)
Vomiting	0	2 (6.3)	1 (2.9)
Abdominal pain	0	1 (3.1)	0
Restlessness	0	2 (6.3)	1 (2.9)
Agitation	0	1 (3.1)	0
Oropharyngeal pain	0	1 (3.1)	0
Nasal discomfort	1 (3.2)	0	0
Intranasal paresthesia	0	0	1 (2.9)
Fatigue	1 (3.2)	0	0
Feeling hot	0	1 (3.1)	0
URTI	0	0	1 (2.9)
Gastroenteritis viral	1 (3.2)	0	0
Myalgia	0	1 (3.1)	0
Musculoskeletal discomfort	0	1 (3.1)	0
Metrorrhagia	1 (3.2)	0	1 (2.9)
Breast tenderness	0	0	1 (2.9)
Hot flush	0	2 (6.3)	0
Pruritus	1 (3.2)	0	0
Serious AEs, n (%)	1 (3.2)	0	0
Discontinued for AEs, n (%)	1 (3.2)	0	1 (2.9)

Note: Table was reused from [63].

AE: Adverse event; DHE: Dihydroergotamine; IV: Intravenous; TEAE: Treatment-emergent adverse event; URTI: Upper respiratory tract infection.

Phase III clinical trial

STOP 301 was a phase III, long-term, open-label study that assessed the safety, tolerability and exploratory efficacy of INP104 for the acute treatment of migraine over 24 weeks and 52 weeks [77]. Eligible patients were adult men and women with a documented diagnosis of migraine (by International Classification of Headache Disorders, third edition, criteria) with or without aura, with ≥2–14 migraine attacks per month for the previous 6 months and also during the 28-day screening. After a 28-day screening period, during which patients used their best usual care to acutely treat their migraine attacks, eligible patients were instructed to self-administer INP104 (1.45 mg) for self-recognized migraine attacks, even if the pain was mild, for 24 weeks, and for an additional 28 weeks for a subset of patients (52-week period). Dosing was limited to ≤2 doses per 24 h and ≤3 doses per 7 days and consisted of one spray in each nostril. Rescue medication included an additional dose of INP104 or nonergot, nontriptan therapies to be used after 2 h after INP104 administration. The 24-week full safety set (FSS) comprised all patients who were enrolled and received ≥1 dose of INP104, and the 52-week FSS comprised all patients who qualified, consented, enrolled into and received ≥1 dose of INP104 in the additional 28-week treatment period. Antiemetic or antinausea medications were allowed during the study and were taken by 3.1% (11/354) of patients in the 24-week FSS. Primary end points included the number of patients reporting TEAEs, change in nasal mucosa (endoscopically assessed using the specially designed Quantitative Scoring Scale for Evaluation of the Nasal Mucosa [QSS-NM]), and change in olfactory function (University of Pennsylvania Smell Identification Test [UPSIT]) at 24 and 52 weeks. Exploratory end points included several measures of self-reported efficacy and a patient acceptability questionnaire (PAQ) [77].

Of the 893 patients who consented and were screened, 360 were enrolled and 354 were included in the 24-week FSS, with 73 continuing into the 52-week treatment period (52-week FSS). Of the 360 enrolled patients, 74% completed 24 weeks of treatment. Of the 73 patients who continued into the 28-week extension period, 90.4% completed 52 weeks of treatment. Patients in the 24-week FSS were a mean age of 41.3 years, mostly female (≥85.0%) and White ≥75.0%), had a mean migraine history of 19.5 years, a mean of 4.6 migraine attacks during the 28-day screening period, and a mean of 31.0% of their migraine attacks included aura. The most frequent most bothersome symptoms (MBS) during screening (>10%) were light sensitivity (49.4%), nausea (16.4%) and sound sensitivity (14.1%). The maximum severity of headache pain (i.e., the worst severity score among all migraine attacks within 28 days prior to patient’s enrollment to the study on day 0) was severe for 65.3% of patients. Acute medication categories used before initiation of INP104 were acetaminophen (43.8%), NSAIDs (37.6%), triptans (28.2%), combination analgesics (16.1%), opioids (2.5%), barbiturates (1.7%), other ergots (0.6%), or ‘other’ (29.9%). Although a small percentage (7.1%) of patients reported not taking any acute medications, patients could be taking more than one category of medication at baseline. The STOP 301 study provided long-term safety data demonstrating that INP104 was well tolerated over 24 and 52 weeks. In the 24-week FSS, 36.7% of patients reported INP104-related TEAEs, most of mild (31%) or moderate (33%) intensity, with the most common (>5%) being nasal congestion (15%), nausea (6.8%), nasal discomfort (5.1%) and abnormal taste (5.1%), while 45.2% of patients reported INP104-related TEAEs in the 52-week FSS, with the most common being nasal congestion (17.8%), nausea (6.8%), nasal discomfort (6.8%), olfactory test abnormal (6.8%) and package-associated injury (5.5%). No serious INP104-related TEAEs were reported over the 24- or 52-week study periods. The most frequent nasal and GI-related TEAEs that resulted in treatment discontinuation were nasal congestion (1.4%), nasal discomfort (1.1%), nausea (1.1%) and sinus congestion (0.6%) [77]. Full safety parameters are found in Table 3. No significant cardiac adverse events were reported during the trial, and there were few vascular events; however, the trial excluded patients with known significant risk factors for, or with current, cardiovascular disease, although patients with stable hypertension on treatment were allowed to enroll [89]. Nasal-related TEAEs, upper nasal endoscopy (QSS-NM), and UPSIT scores suggested no significant change in olfactory mucosal integrity or function over 24 and 52 weeks of treatment with INP104. A total of 45.8% and 58.9% of patients reported a nasal TEAE over 24 and 52 weeks, respectively. Most nasal TEAEs were mild or moderate, with a single case of severe congestion, and none were reported as serious. The most commonly reported nasal TEAEs (≥5%) in the 24-week FSS were nasal congestion (16.7%), upper respiratory tract infection (10.7%), nasopharyngitis (8.5%) and nasal discomfort (5.4%). Changes in olfactory function as detected by UPSIT and upper nasal mucosa as graded by the QSS-NM were minimal over 24 weeks and 52 weeks of INP104 treatment at all time points. No patient reported persistent subjective olfactory loss over the course of the study. Nasal safety data were reviewed by a Nasal Safety Review Committee comprising three independent otolaryngologists, who suggested INP104 was safe and tolerable on the nasal mucosa and who suggested that nasal endoscopy or UPSIT testing would not be necessary in future clinical trials, or in clinical practice, with INP104 [90].

Table 3. Safety summary of INP104 from the Phase III STOP 301 Study (full safety set).

Safety Outcomes	24-week treatment period (weeks 1–24; n = 354)	52-week treatment period (weeks 1–52; n = 73)
Any INP104-related TEAE, n (%)	130 (36.7)	33 (45.2)
INP104-related TEAEs (≥1% of patients in the 24-week FSS), n (%)
Nasal congestion	53 (15.0)	13 (17.8)
Nausea	24 (6.8)	5 (6.8)
Nasal discomfort	18 (5.1)	5 (6.8)
INP104 taste abnormal	18 (5.1)	3 (4.1)
Vomiting	9 (2.5)	2 (2.7)
Olfactory test abnormal	8 (2.3)	5 (6.8)
Sinus congestion	7 (2.0)	—
Package associated injury	6 (1.7)	4 (5.5)
Dizziness	5 (1.4)	3 (4.1)
Nasal mucosal disorder	5 (1.4)	1 (1.4)
Epistaxis	5 (1.4)	1 (1.4)
Dysgeusia	4 (1.1)	1 (1.4)
Rhinorrhea	4 (1.1)	1 (1.4)
Serious INP104-related TEAEs, n (%)	0 (0)	0 (0)
Discontinued treatment due to AEs, n (%)	24 (6.8)	1 (1.4)

Note: Table was reused from [77].

AE: Adverse event; FSS: Full safety set; TEAE: Treatment-emergent adverse event.

STOP 301 also included exploratory efficacy outcome measures. Over 24 weeks, 5099 INP104 doses were self-administered by 354 patients to treat 4515 migraine attacks and 90 (nonmigraine) headaches. For the first INP104-treated migraine attack, 38% and 52.1% of patients self-reported pain and MBS freedom, respectively, 2 h after INP104, while 30.1 and 46.4% self-reported pain and MBS freedom, respectively, at 2 h on best usual care for their last treated migraine attack during the screening period. Although patients were instructed to treat their migraine attack within 2 h of initiation, INP104 provided similar efficacy when administered at later-time intervals for the first INP104-treated migraine attack. In patients who administered their first dose of INP104 between 2 and 4 h after migraine initiation, 39.4% self-reported pain freedom and 57.6% self-reported MBS freedom for their first treated migraine attack at 2 h after dosing. In patients who administered INP104 more than 4 h after migraine attack onset, 30.9% self-reported pain freedom and 40% self-reported MBS freedom for their first treated migraine attack at 2 h after dosing. Of the 38% of patients who self-reported pain freedom at 2 h for their first INP104-treated migraine attack, 93 and 85% were recurrence-free at 24 and 48 h after INP104 administration, respectively (i.e., no onset of a new headache before 24 or 48 h post-INP104 administration) [77]. These findings are consistent with the DHE plasma concentrations that matched IV DHE mesylate in the phase I STOP 101 trial [63]. Pain relief (i.e., a decrease from severe or moderate pain to mild or no pain, or a decrease from mild pain to no pain) was self-reported as early as 15 min for 16.3% of patients, with 29.6, 47.6, and 66.3% self-reporting pain relief at 30 min, 1 h, and 2 h after INP104 for the first treated migraine attack (Table 4). Collectively, these data suggest that INP104 can provide fast and sustained pain relief from migraine attacks [77].

Table 4. Summary of self-reported exploratory efficacy data from the phase III STOP 301 study for the first INP104-treated migraine attack (full safety set).

Exploratory efficacy outcomes	INP104 (n = 354)
Pain freedom at 2 h, % (n/N)
Treated within 2 h of migraine onset	38.0 (126/332)
Treated >2–4 h of migraine onset	39.4 (13/33)
Treated >4 h of migraine onset	30.9 (17/55)
MBS freedom at 2 h, % (n/N)
Treated within 2 h of migraine onset	52.1 (173/332)
Treated >2–4 h of migraine onset	57.6 (19/33)
Treated >4 h of migraine onset	40.0 (22/55)
Pain relief, % (n/N)^†
15 min	16.3 (42/257)
30 min	29.6 (76/257)
1 h	47.6 (121/254)
2 h	66.3 (167/252)
Recurrence, % (n/N)^‡
24 h	7.1 (9/126)
48 h	14.3 (18/126)

† Pain relief was defined as a decrease from severe or moderate pain to mild or no pain, or a decrease from mild pain to no pain. Only patients with Time 0 pain assessments and pain assessments at the post-treatment time points are included in the analysis.

‡ Recurrence was defined as the onset of a new headache before 24 or 48 h after dosing in patients who were pain-free at 2 h after dosing.

Note: Table was created using data from [77].

FSS: Full safety set; MBS: Most bothersome symptom; min: Minutes.

A PAQ administered at week 24 that summarized the frequency of response to questions (strongly agree, agree, neutral, disagree, strongly disagree) demonstrated that most patients agreed or strongly agreed that INP104 was easy to use (∼84%). Most patients reported that INP104 kept their migraine from coming back for a longer time, allowed them to return to normal activities of daily living faster, and had a faster and more consistent onset of effect compared with their previous treatment [77].

Regulatory affairs

DHE mesylate has a broad receptor pharmacology, binding to several serotonergic, adrenergic and dopaminergic receptor subtypes, some of which may be present on the smooth muscles of cranial and coronary arteries [82,84–86,91]. Furthermore, it has been hypothesized that DHE mesylate alleviates migraine symptoms through vasoconstriction of cranial blood vessels [84,85]. Therefore, the use of DHE mesylate can potentially pose a risk for cardiovascular adverse events [85]. The FDA-approved label for all DHE mesylate products carries a black-box warning: “Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated.” [65,78,79] However, it should be noted that few vascular AEs (five patients experienced hypertension and one patient experienced a hematoma) and zero specific cardiac events were reported during the STOP 301 clinical trial – although patients with significant cardiovascular disease were excluded [89]. In addition, previous work with MAP0004 revealed little effect on DHE mesylate levels when co-administered with ketoconazole, a potent CYP 3A4 inhibitor [92].

Conclusion

Migraine is a multifaceted, disabling headache disorder with a high prevalence. Although the armamentarium of acute treatment options for migraine continues to grow, oral therapies dominate the treatment landscape; however, their efficacy can be limited by the rate of GI absorption and first-pass hepatic metabolism. Additionally, migraine is associated with GI symptoms and autonomic dysfunction, all of which can affect the absorption of oral drugs and may discourage administering oral drugs. Injection of acute therapies is an alternative option that can provide rapid symptom relief, but its use may be limited by systemic and local side effects, inconvenience of use and needle-phobia. Nasal drug delivery is a promising avenue to address the unmet treatment need for acute therapies for migraine because it can provide rapid, effective symptom relief and is well tolerated, noninvasive and easy to administer. However, an important consideration of nasal delivery is the target of drug deposition within the nose. The upper nasal space may be ideally suited for drug delivery because of its abundant vascularization, permeable epithelia and reduced mucosal clearance rates, all of which may increase absorption of drug into the systemic circulation. INP104 is a novel drug-device combination product that delivers DHE mesylate to the upper nasal space using POD technology and is approved for the acute treatment of migraine. DHE mesylate has a long and established history as an effective acute treatment for migraine among headache specialists, providing rapid and sustained symptom relief even for difficult-to-treat migraine attacks. In a phase I study of INP104 in healthy participants, INP104 demonstrated rapid absorption, with peak blood plasma levels of DHE mesylate comparable to those achieved through IV administration from 30 min to 48 h, but with better tolerability likely because of a lower C_max than IV DHE mesylate. Although this is the only clinical trial that compared DHE mesylate delivered by POD (INP104) to a traditional nasal pump (MIGRANAL), results demonstrated that with INP104, there was an almost fourfold higher absolute bioavailability and more consistent delivery of DHE mesylate than with MIGRANAL. In a phase III open-label study in migraine patients, INP104 was well tolerated with no major safety concerns identified, including those relevant to nasal and cardiovascular safety, with long-term use up to 24 and 52 weeks. Self-reported exploratory efficacy demonstrated that INP104 was associated with rapid pain relief and low rates of recurrence, as well as pain and MBS freedom, regardless of time of administration for the first INP104-treated migraine attack. Several features of INP104 may be responsible for these findings, which include consistent absorption of DHE mesylate when delivered to the upper nasal space by the POD device, a previously underutilized target of drug delivery; the broad receptor pharmacology of DHE mesylate, which has a long history of efficacy and familiarity among clinicians; and the nonoral route of delivery that circumvents possible GI-related complications. Taken together, these findings suggest that INP104 may be a promising nonoral option for the acute treatment of migraine and may help address the significant unmet needs of patients, particularly for the many people who would benefit from a nonoral option.

Acknowledgments

The authors were fully responsible for the content, editorial decisions, and opinions expressed in the current article.

Financial & competing interests disclosure

This study was fully funded by Impel Pharmaceuticals Inc. Amaal J. Starling has received consulting fees from AbbVie, Allergan, Amgen, Axsome Therapeutics, Eli Lilly & Company, Everyday Health, Impel Pharmaceuticals, Lundbeck, Med-IQ, Medscape, Neurolief, Novartis, Satsuma Pharmaceuticals, Teva Pharmaceuticals, and Theranica. Theresa Mallick-Searle has served on speaker bureaus for Averitas Pharma, Impel Pharmaceuticals, and Salix Pharmaceuticals. Stephen B. Shrewsbury was a former full-time employee and an officer of Impel Pharmaceuticals during the development of this manuscript. He remains a stockholder. Sheena K. Aurora is a full-time employee of Impel Pharmaceuticals and is a stockholder in Impel Pharmaceuticals. The authors have 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.

Medical writing support was provided by Veronika Khariv, PhD, from IMPRINT Science, New York, NY, USA, and was funded by Impel Pharmaceuticals Inc.

Additional information

Funding

This study was fully funded by Impel Pharmaceuticals Inc. Amaal J. Starling has received consulting fees from AbbVie, Allergan, Amgen, Axsome Therapeutics, Eli Lilly & Company, Everyday Health, Impel Pharmaceuticals, Lundbeck, Med-IQ, Medscape, Neurolief, Novartis, Satsuma Pharmaceuticals, Teva Pharmaceuticals, and Theranica. Theresa Mallick-Searle has served on speaker bureaus for Averitas Pharma, Impel Pharmaceuticals, and Salix Pharmaceuticals. Stephen B. Shrewsbury was a former full-time employee and an officer of Impel Pharmaceuticals during the development of this manuscript. He remains a stockholder. Sheena K. Aurora is a full-time employee of Impel Pharmaceuticals and is a stockholder in Impel Pharmaceuticals. The authors have 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. Medical writing support was provided by Veronika Khariv, PhD, from IMPRINT Science, New York, NY, USA, and was funded by Impel Pharmaceuticals Inc.