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MAP Pharmaceutials 505(b)(2) Dihydroergotamine Orally Inhaled Product Meets Phase 3 Goals
MAP Pharmaceuticals recently reported good Phase 3 data on its new product in development, Levadex – dihydroergotamine (DHE) orally inhaled. DHE is an old drug that has been used for a long time as an injectable – a couple of generics exist. MAP says that their product is a new formulation and their website compares it to the injectable. No mention is made of Valeant’s Migranal, a nasal spray of DHE, also containing caffeine. Wouldn’t it be the RLD vs the injectable? Levadex formulation seemed designed for immediate and sustained action. Does Levadex have a pk advantage/difference over Migranal?
Camargo’s Chief Medical Officer, Dr. Sam Kaba, a board certified neurologist, has a broad background in clinical development. While Camargo has not been involved with the Levadex development (wish we were!) Dr. Kaba offers the following background and possible explanation of the development of this product.
DHE for Migraine, MAP0004, and 505(b)(2)
Dihydro Ergotamine Mesylate (DHE for short) has been in use for migraine for many years. The interest in DHE for migraine started when Wolf published his theory on the vascular origin of headache in migraine in the 1940s. This theory stated that vasodilatation in the meningeal vessels is the main reason for headache during a migraine attack. DHE was immediately considered as a potential therapy because of its potent effects as a vasoconstrictor.
Early clinical trials showed good results from ergotamine compounds on migraine symptoms, mostly on headache. However, its use was always hampered by its dismal bioavailability (around 1%) and the common GI side effects (nausea and vomiting) after oral administration. Other problems associated with DHE included the risk of causing cardiovascular spasm leading to ischemia and the rare risk of retroperitoneal fibrosis. Despite these shortcomings, DHE was commonly used in combination with caffeine and sometimes acetaminophen in oral preparations, and a single agent in IV preparations.
In the early nineties, there was a renewed interest in the administration of DHE via nasal route and studies were conducted on Migranal® (a combination with caffeine, Valeant) with good results. However, around the same time sumatriptan (Imitrex® GSK) was introduced in the US market with good efficacy results and a better safety profile than ergotamine. Sumatriptan was followed by a wave of other triptans with a range of different Tmax, half life, and duration of action. This immediately relegated DHE to the role of a second line therapy for patients who cannot take triptans or do not respond well to them. In the last decade or so, the most common use of DHE was in a condition called status migrainosus when a patient would have a long lasting refractory migraine attack that last for many hours or days. In these cases the preferred route was IV infusion, commonly with anti-nausea drugs (to reduce side effects). The high success rate of D.H.E 45® (the IV formulation of DHE, Novartis) in treating protracted refractory migraines, along with its rapid onset and the low incidence of headache recurrence led to a renewed interest in DHE delivered via other routes.
The intranasal preparation of DHE, Migranal, could not bank on the popularity of D.H.E 45 for a number of reasons. First the bioavailability of DHE after nasal administration, although better than the oral route, was still not optimal (around 30%). The slow absorption of DHE from the nasal mucosa also led to a relatively long Tmax (30-40 minutes) and delayed onset of effect (over 30 minutes), rendering Migranal much less effective than D.H.E 45. In addition, Migranal produced inconsistent levels in the serum in different patients and even in the same patient in repeated administrations. The reasons for this variability were mostly related to the variable conditions of the nasal mucosa (congestion, allergy, etc.), small absorption area, and the user-dependent technique techniques of administration (the depth of the nozzle, strength of squirt, etc.). Finally, Migranal often leaked into the mouth causing bad aftertaste and further reduction of absorption. Recently, Valeant Pharmaceuticals introduced a new and improved metered dosing system for intranasal Migranal.
For all of these reasons, the search continued for a new route of administration that would more closely imitate the popular IV route. Early PK studies on inhaled DHE (MAP0004) were very promising, showing a PK profile that is much closer to the IV administration than oral, nasal, or even IM or SC routes, especially in regard to Tmax that is essential to rapid onset of efficacy in migraine therapy. (Schrewsbury et al. Headache 2008)
Additional safety and PK studies in asthmatic patients revealed a similar PK profile of MAP0004 to that reported in non-asthmatic patients with no additional adverse events. (Schrewsbury et al. Curr Med Res Opin 2008). This data is very relevant because of the common association of migraine and asthma in the same patient.
From Kori et al, AHS 2008
From Kori et al, AHS 2008
The recently announced results of a large phase 3 study (792 patients) confirms that this favorable PK profile does translate into clinical benefits to the patients. The beneficial effects of MAP0004 (LEVADEX®) started as early as 10 minutes (statistical trend) and was statistically significant (compared to placebo) at 30 minutes. Pain relief was reported in 58.7 percent of patients who received LEVADEX compared with 34.5 percent for placebo (p<0.0001); similar effects on nausea, photophobia, and phonophobia were reported. A statistically significant reduction in migraine symptoms was long lasting, up to 48 hours in many patients. The rate of headache recurrence was very low, especially compared to most triptans’ historical data. No serious adverse events that could be attributed to the drug were reported so far in clinical trials.
Perhaps the most important feature of MAP0004 is the consistent delivery of DHE to the systemic circulation. This is most likely due to the more stable pulmonary environment compared to the nasal one, and the larger area of absorption available in the lungs compared to the nasal mucosa. One of the more important factors in producing consistent levels of DHE after using LEVADEX is the use of the proprietary Tempo® inhalers. This inhaler system is designed to minimize the impact of user’s technique and eliminate the need for synchronizing inhalation with activation of the system. This produced accurate and reproducible levels of DHE in clinical trials (Cook et al. ICH 2007).
The development of MAP0004 represents a great example of a successful 505(b)(2) program. Since the phase 3 protocol was submitted under Special Protocol Assessment agreement with the U.S. Food and Drug Administration (FDA), it is expected that the positive results will lead to a successful filing and approval in the US.
An important observation in this program is that the sponsor elected to use the IV formulation of DHE (D.H.E. 45) as an RLD instead of the intranasal one. On the surface, it would seem that using the intranasal product as RLD is more appropriate since both Migranal and LEVADEX are for non-parenteral use, patient administered, and use metered dosing systems for delivery. However, upon further scrutiny, the IV formulation becomes a more attractive RLD for a number of reasons. First the IV formulation is considered more effective than the intranasal and represents the gold standard ergotamine in migraine therapy. Second, the PK profile of MAP0004 was shown early on to resemble the IV formulation more than that of the nasal one. Therefore, using the IV formulation as RLD allows for easier comparison in a comparative bioavailability study and makes bridging easier. Third, the inconsistent levels achieved with the nasal formulation would make PK data following nasal administration hard to interpret or even unusable for successful bridging. Finally, there is more data available in the public domain on the safety and efficacy of D.H.E 45 to leverage in a 505(b)(2) program than the nasal formulation.
Ultimately, the success of any drug development program is judged by how well it meets unmet medical needs and the number of patients that stands to benefit from the product under development.
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