New frontiers in headache therapy
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- Rapoport, A. Neurol Sci (2011) 32: 105. doi:10.1007/s10072-011-0542-3
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There are numerous headache therapies available for our patients, more for migraine than for any of the other primary headache disorders. Only four medications have been approved for migraine prevention in the last few decades in the US and onabotulinumtoxinA was recently approved in the UK and the US for chronic migraine. We have been more fortunate in the acute care arena where in the US we have had seven triptans and one nonsteroidal anti-inflammatory medication approved by the FDA and currently available. There are several other acute care medications in various stages of development and there are two new methods of administering a triptan and others under investigation. We are always looking for faster, easier and more efficient administration of medications with fewer adverse events, as optimal migraine therapy requires these characteristics. What follows is a brief review of the progress in development for four of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch, sumatriptan powder for use in the OptiNose apparatus and the dihydroergotamine oral inhaler. I will not include transcranial magnetic stimulation, a 5-HT1F agonist, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development .
KeywordsMigraine treatmentMigraine pipelineCGRP antagonistsSumatriptanDihydroergotamine
Migraine is a chronic and often disabling disorder, consisting of attacks of moderate to severe intensity throbbing, unilateral headache, various associated symptoms (i.e. nausea, vomiting, phonophobia, photophobia, osmophobia and worsening with exertion) and sometimes visual, sensory or speech auras. Hemiplegia associated with migraine is now called hemiplegic migraine by the International Headache Society. Migraine affects about 12% of the population of the US and other Western countries. There are several categories of acute care medications currently available, including over-the-counter substances and prescription medications. The categories are simple analgesics, combination analgesics, NSAIDs, prescription analgesics, ergots and triptans. In Europe and Canada, injectable sumatriptan was the first triptan launched in 1991. In the US, it was first available in 1993 and today there are seven triptans available with a variety of formulations including tablets, injections, orally disintegrating tablets and nasal sprays. Although triptans are usually considered as the first-line treatment for acute care of migraine attacks, some patients cannot afford them, over one-third of patients do not respond ideally to triptans and over half are willing to try other treatments than the one they are currently taking. Only five preventive medications are approved by the FDA and available in the US at this time, two beta blockers, two antiepileptic medications and onabotulinumtoxinA specifically for chronic migraine. However, none of these medications work in more than 50% of patients and they all have significant possible adverse events.
CGRP receptor antagonist (telcagepant)
Calcitonin gene-related peptide (CGRP) is structurally closely related to calcitonin and amylin and has been intensely studied over the last 25 years as an agent possibly related to migraine pathophysiology. CGRP is involved in sensory neurotransmission and can be found in most sensory nerves, especially those trigeminovascular afferents in the meninges involved in migraine . It is one of the most potent vasodilators known. CGRP levels measured in the jugular venous system are elevated after migraine and cluster headache attacks, and are normalized by therapy with sumatriptan. Early researchers thought that CGRP caused migraine pain due to extreme vasodilation and blocking CGRP was considered a goal to prevent migraine pain. It is now known that migraine pain can be blocked without overt vasoconstriction, but only with anti-inflammatory action. So it is probable that the vasodilation produced by CGRP is a secondary phenomenon and not responsible for migraine pain.
If and when they gain approval in the US by the FDA and in other countries, CGRP receptor antagonists would be the first non-serotonergic, non-vasoconstricting, migraine-specific medication. CGRP has been shown to have several sites of action including blood vessels, mast cells in the meninges and at the trigeminal ganglion, as a facilitator of pain at the synapse of the first and second order neurons in the brain stem, in neurons of the trigeminal nucleus caudalis and in smooth muscle of the meningeal vasculature; but it probably does not excite or sensitize meningeal nociceptors . CGRP can be blocked by a fragment of the peptide containing amino acids 8-37 (CGRP 8-37).
The first effective CGRP receptor blocker was BIBN4096 (olcegepant). It was reported that intravenous administration produced headache relief in 66% of patients compared to 27% of the placebo patients, without constricting blood vessels in preclinical studies . Telcagepant, previously termed MK-0974, was the first reported oral formulation of a CGRP receptor antagonist. It has been reported to work well in migraine in a phase IIB study published in Neurology and then a robust phase III study published in Lancet [5, 6]. Other trials have been performed. Preclinical data suggest that telcagepant is not a vasoconstrictor and clinical studies show it to be as effective as rizatriptan and zolmitriptan and as tolerable as placebo. In a recently published article, telcagepant 300 mg was found to be as effective as zolmitriptan with fewer adverse events . This was a randomized, parallel treatment, placebo and active-controlled, double-blind, trial performed at 81 sites in Europe and the USA of adults with migraine diagnosed by International Headache Society criteria. Patients with moderate or severe migraine attacks were treated with either oral telcagepant 150 or 300 mg, zolmitriptan 5 mg, or placebo. There were five co-primary endpoints: pain freedom, pain relief and absence of nausea, photophobia and phonophobia, at 2 h after treatment.
According to Dr. Ho’s  article, ‘‘1,380 patients were randomly assigned to receive telcagepant 150 mg (n = 333), 300 mg (n = 354), zolmitriptan 5 mg (n = 345) or placebo (n = 348). Telcagepant 300 mg was more effective than placebo for pain freedom [95 (27%) of 353 patients vs. 33 (10%) of 343 (p < 0.0001)], pain relief [194 (55%) of 353 vs. 95 (28%) of 343 (p < 0.0001)], and absence of phonophobia [204 (58%) of 353 vs. 126 (37%) of 342 (p < 0.0001)], photophobia [180 (51%) of 353 vs. 99 (29%) of 342 (p < 0.0001)], and nausea [229 (65%) of 352 vs. 189 (55%) of 342 (p = 0.0061)]. The efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo.’’ The measurement of 2–24 h sustained pain freedom was slightly better numerically for telcagepant 300 mg versus zolmitriptan 5 mg, but there was no statistical difference. A potential benefit of telcagepant and other CGRP receptor antagonists is the lack of vasoconstriction in animal models. This suggests that they may be able to be given to patients with vascular disease, such as coronary artery disease, cerebrovascular disease and peripheral vascular disease. This was not studied in the phase III trials.
During development of this drug, Merck performed a clinical trail to determine if taking a dose of telcagepant twice per day would be a safe and effective treatment possibility for migraine prevention. In that trial there was some evidence of liver toxicity and the trial was halted. Merck suspended further studies and discussed the situation with the FDA. The result was an FDA request for further study of the safety of intermittent dosing of telcagepant for acute care of migraine. These studies are close to completion in the second quarter of 2011. If they are free of serious adverse events, it is suspected that Merck will file for an indication for acute treatment of migraine for telcagepant with the FDA in 2011. If the FDA approves the application, the drug could be available in 2012–2013.
Transdermal iontophoretic sumatriptan patch (Zelrix)
Recently, sumatriptan became the first of the seven triptans to become generic in several countries, which has led to the development of generic formulations of available products and to the design of some novel products containing the generic formulation, including needle-free injection (launched in the USA as Sumavel DosePro), lingual spray, intranasal powder in a novel delivery system (under study as OptiNose) and a patch formulation. Naratriptan is also now generic in the US and elsewhere and we may see novel uses of it in the future. One of the more interesting products in development, which may address the unmet need of the nauseated migraineur and/or the patient who does not absorb oral medication optimally during a migraine attack, is a sumatriptan patch. NP101, from NuPathe, is an iontophoretic patch that delivers sumatriptan transdermally. It utilizes a small electric current to drive sumatriptan across the skin delivering 6 or 12 mA/h and maintaining sumatriptan plasma levels above the target level of 10 ng/ml for greater than 7 h . There is a linear relationship between the voltage of the applied current and the amount of drug delivery. As a result, drug delivery is precisely controlled at desired levels, providing consistent therapeutic drug levels. In pK studies, the patch delivered sumatriptan more consistently than either the 100 mg oral tablet or 20 mg nasal spray providing more predictable delivery by bypassing absorption through the GI tract. At the intended plasma concentrations delivered by the patch, both patches studied were well tolerated. No subject reported atypical pain and pressure sensations or other common triptan adverse events after application of NP101 patches. The most common adverse event for NP101 was application site-related pruritus, which was generally mild and resolved without treatment. No subject withdrew from the study due to local skin delivery of sumatriptan.
It is suspected that NP101 (Zelrix) may offer significant clinical utility for migraine patients, including circumventing underlying migraine-associated GI disturbances including nausea and gastric stasis. The patch, which contains a battery and microcomputer and is easy to use, also provides consistent, predictable delivery of desired drug levels over a 4-h period. Drug delivery is programed to stop at 4 h even if the patch remains on the skin. Zelrix offers the potential to avoid atypical pain, pressure and other sensations commonly associated with current triptan formulations. In January 2011, after the completion of a successful safety study, NuPathe, the makers of this patch (brand name Zelrix), filed with the FDA for approval of the patch in the USA for the acute care of migraine.
The only phase III trial, not yet fully published, is entitled, “The Efficacy and Tolerability of Zelrix, a Sumatriptan Iontophoretic Transdermal Patch, in the Treatment of Acute Migraine.” It was a randomized, double-blind, placebo-controlled study. Patients had to wait till their migraine attack was moderate or severe before applying the patch. There were 265 patients who received Zelrix and 265 who received placebo. The intention-to-treat numbers were 226 and 228, respectively. The primary endpoint was pain free at 2 h and the four secondary endpoints were pain relief at 2 h, nausea free at 2 h, photophobia free at 2 h and phonophobia free at 2 h. The results for pain freedom at 2 h was 18% for Zelrix and 9% for placebo which was significant at the (p = 0.0092 level). The 2 h pain relief rate was 53% for Zelrix versus 29% for placebo (p = 0.0001). Pain relief was significant at 30 min and was comparable to oral and nasal triptans at 1 h. The three secondary endpoints were all statistically significant. Sustained pain relief results from 2–24 h were 34% of Zelrix patients compared to 21% of placebo (p = 0.0015). Triptan adverse events including atypical sensations and pain and pressure sensations were each 1.7% compared to 0% for placebo. Triptan adverse events in product labeling is up to 14% for oral tablets and 47% for injections of sumatriptan. Application site reactions were from 7–23% compared to 6–15% for placebo and no patients dropped out of the study due to adverse events.
There were two 12-month long-term safety trials performed. They too demonstrated strong, consistent efficacy within 2 h, with headache relief in 58% of migraines treated and pain freedom in 24% of migraines treated. There was nausea freedom for 79% of migraines treated. Only three patients (1.6%) reported a triptan AE. The most common AEs were related to the application site: itching (21.9%), pain (21.3%) and hypersensitivity (6.0%).
NuPathe petitioned the FDA not to have to do a second phase III trial and that request was granted. The company expects a decision for the indication of acute treatment for migraine with and without aura by the end of 2011. This product will be a welcome addition for the acute treatment of migraine especially when it is important to bypass the GI tract. It will also be useful in patients who need a triptan but cannot tolerate the triptan adverse events. It provides more consistent and predictable therapeutic plasma concentration compared to the tablet and nasal spray preparations .
Oral inhaler of DHE (Levadex)
Three drugs have been tested in inhalers: DHE, prochlorperazine and loxapine. The last two are dopamine antagonists, a class of drugs that has been shown to treat migraine acutely when given intravenously. DHE (dihydroergotamine mesylate) is an ergot that stimulates serotonin and other receptors and has been available in various forms for over 50 years. It still remains the mainstay of treatment at major headache centers in the US when patients have daily headache and have already developed central sensitization and chronic headache syndromes. In that situation it is usually given several times per day intravenously in small gradually increasing doses. It is also used in the US and Canada as an acute care medication, in a nasal spray form. The intravenous preparation is the most effective, but cannot be used at home and when used in the hospital often causes the patient to become more nauseated and vomit, even with pretreatment by an antiemetic.
Oral inhalation seems to provide similar efficacy to the intravenous form with the ease of home use and fewer adverse events. Studies were performed with a specially designed device called the Tempo Inhaler (MAP Pharma), to deliver DHE deep into the lung automatically after breath actuation . A phase I study of four doses of orally inhaled DHE delivered by the specially designed inhaler versus 1 mg of IV DHE (n = 18) was performed. There was a rapid systemic absorption of DHE with a tmax of 12 min with a 0.88 mg respirable dose (vs. a 6 min tmax with the IV preparation). The systemic levels attained were slightly lower than with IV DHE, with the ratio of AUC 0–infinity of inhaled versus IV approximately 0.77. The Tempo inhaler is a proprietary, novel, breath-actuated device that is expected to deliver most of the drug deep into the lung, thereby minimizing oropharyngeal deposition and decreasing the urge to cough. Phase II data suggest an onset of action comparable to IV administration of DHE, with relief that is both rapid and sustained .
Phase II results demonstrate that 32% of patients achieve pain relief as early as 10 min (p = 0.019) at 0.5 mg dose. This is somewhat lower that the usual dose IV. DHE delivered by this inhaler was well tolerated in phase II studies with no serious adverse events. There was decreased nausea and no clinically significant changes observed in pulmonary function tests, clinical lab findings, heart rate, blood pressure or respiratory rate.
A phase III trial was conducted under a Special Protocol Assessment agreement with the FDA. The results are available but not published. There were 792 patients included in the primary data analysis of this double blind, placebo-controlled trial. The patient population studied had more severe migraine pain than expected with 46% of the patients reporting severe pain and 54% reporting moderate pain prior to administration of the study drug. There were four co primary endpoints studied: pain relief was 58.7% of Levadex patients compared with 34.5% for placebo (p ≤ 0.0001); phonophobia free was 52.9% of Levadex patients compared with 33.8% for placebo (p ≤ 0.0001); photophobia free was 46.6% of the Levadex patients compared with 27.2% for placebo (p ≤ 0.0001) and nausea free was 67.1% of the Levadex patients compared with 58.7% for placebo (p = 0.02).
Pain relief was achieved in 30 min, and this was statistically significant versus placebo. While not statistically significant, 50% more of the patients receiving Levadex therapy than the patients receiving placebo reported pain relief at 10 min in a post-hoc analysis, Levadex was just as effective in treating patients with and without allodynia, early or late in the attack and with or without disability.
Levadex was also found to have a low recurrence rate at both 24 and 48 h irrespective of the definition used. Two large meta-analyses have calculated the cumulative recurrence rate for triptans to be 22 and 29% over 24 h. Using the same definition, this analysis found Levadex to have a recurrence rate of 6.5% over 24 h and 10.3% over 48 h. No 48 h recurrence data was reported in the triptan analyses. Factors found to affect the rate of recurrence in the triptan meta-analyses include gender of the patient, age group (below 35 and above 35), and severity of headache pain at the time of treatment (moderate vs. severe). In this analysis, both age and severity of pain at the time of treatment were associated with higher recurrence rates in the placebo group. This data corroborates the clinical finding that patients treated with DHE acutely usually do not have recurrence of their headache in the next 2 days or considerably longer. This phase III trial and additional trials required by the FDA suggest that inhaled DHE will work quickly, with limited adverse events, even in patients treated late in the migraine attack or those with allodynia and disability. Being able to give DHE to patients at home will make it a very useful treatment for acute migraine attacks.
A randomized, double blind, placebo controlled, three-way, crossover pharmacodynamic trial was performed in 24 healthy adults and was designed to compare the acute effects of Levadex, IV DHE and placebo on pulmonary artery pressure by taking regular echocardiogram measurements over a 2-h period. The trial compared the pK of Levadex and IV DHE and its metabolites, the effects of both routes of delivery on cardiac function, including echocardiograph findings, 12-lead ECG, and vital signs. In addition, the trial evaluated the pharmacodynamics and pK of two doses of Levadex administered 2 h apart as compared to a single dose of 1.0 mg IV DHE. There was no statistically significant difference between the Levadex and placebo groups in the primary endpoint of pulmonary artery pressure over 2 h after administration.
A clinical trial was performed comparing the pharmacokinetics (pK) and safety of Levadex orally inhaled migraine therapy with intravenous DHE in smokers and non-smokers. The trial was designed to measure whether systemic absorption and exposure in smokers is greater than in non-smokers. The trial included healthy adult volunteers, of whom 23 were smokers and 24 were non-smokers. Levadex was well tolerated and no drug-related serious adverse events were reported. In the trial, the systemic absorption of Levadex was not higher and systemic exposure to DHE was not greater in smokers than in non-smokers.
A randomized, double-blind, placebo-controlled, three-way, crossover trial in 54 healthy adults compared the acute effects of a supra-therapeutic dose of Levadex (approximately three times the anticipated commercial dose), oral moxifloxacin (400 mg) and placebo on the cardiac QT interval as measured by electrocardiogram. Moxifloxacin is a positive control known to increase the QT interval. Results of the trial showed that a supratherapeutic dose of Levadex does not increase QTc intervals.
Unique nasal powder delivery system of sumatriptan (OptiNose)
There is a new bi-directional, breath-activated delivery system for sumatriptan powder delivered into one nostril called (OptiNose). It consists of a mouthpiece and a sealing nozzle which fits into one nostril. The patient blows hard into the device which causes the soft palate to rise, isolating the nasal cavity from the oropharynx. As the patient continues to blow, the device releases sumatriptan deep into the nasal cavity on one side. The drug coats most of the nasal mucosa and air flow carries it through a posterior communication between the two nasal passages and forwards, exiting through the other nostril. This improved deposition of drug throughout the nasal cavity increases absorption and speeds delivery to the nasal vasculature. Traditional nasal delivery methods deliver much of the dose anterior to the nasal valve and low in the nasal cavity. A large percentage of the dose is then swallowed and is absorbed slowly via the GI tract.
In a phase I study, OptiNose proved to have more extensive absorption across the nasal mucosa than the existing sumatriptan liquid nasal spray device on the market . A phase II study was designed to evaluate the efficacy and safety of a single dose of 10 or 20 mg of a powder formulation of sumatriptan delivered with the OptiNose device in comparison with placebo, in 117 adults with a moderate to severe intensity migraine attack.  In terms of efficacy, a greater proportion of subjects who received sumatriptan 10/20 mg were pain-free at 2 h compared with those who received placebo (54%/57% vs. 25%, (number needed to treat = 3.1/3.4, p < 0.05). Pain relief at 2 h for the two doses was (84%/80% vs. 44%, (number needed to treat = 2.5/2.8, p < 0.001). Pain relief was noted as early as 60 min (73%/74% vs. 38%, p < 0.01) and at 48 h, sustained pain-free results were impressive (47%/49% vs. 27%, (number needed to treat = 4.55/5, p < 0.05). The most common adverse event following sumatriptan delivery was dysgeusia, or metalic taste, in 10% of subjects receiving the 10 mg dose and 13% receiving the 20 mg dose. No significant adverse events occured. Specifically there were no cases of chest discomfort or pain, paresthesia or asthenia in the active treatment groups.
The four innovative medications and/or drug-delivery systems above look like they will be approved for use in the US within the next 1–2 years, unless problems arise. This is a good situation as each will fill a special nitch and be useful in certain specific headache situations.
Conflict of interest
A. Rapoport is on the Advisory Boards of NuPathe and MAP, an author of the Phase IIB study on telcagepant, and on the speakers bureau for Merck.