Headache Management: Novel Delivery Systems Show Promise

2014 HIGHLIGHTS

by David Dodick, MD, President of American Headache Society, Editor-in-Chief of Cephalalgia, and Professor of Neurology at the Mayo Clinic.

Completion of Phase II trials of CGRP monoclonal antibodies for migraine prevention. Until now, only an acute class of drugs (triptans) have been specifically designed and approved for migraine. Monoclonal CGRP (calcitonin generelated peptide) antibodies represent a new class of biologics designed for migraine prevention. While many potential migraine drug targets have emerged over the past 30 years, none have been more thoroughly investigated and appear more promising than CGRP and its receptor. The preliminary efficacy and safety findings from these studies are very encouraging. Confirmation will await the completion of two other Phase II studies with two other antibodies and future Phase III studies.

These studies followed the results of another study, which evaluated a small molecule CGRP receptor antagonist for the acute treatment of migraine (this was the fifth positive study after four previous positive studies evaluating different compounds within the same class). Unlike others in this class, this drug was not shown to have liver toxicity in the Phase II study.

Taken together, all of these studies demonstrate the high value in targeting CGRP for both the acute and preventive treatment of migraine.

The approval by the FDA of two noninvasive minimal risk devices for the acute (sTMS) and preventive (Cefaly^®) treatment of migraine. Long term efficacy and their place in migraine therapy awaits further study and experience but they may represent a non-drug and non-invasive treatment option for some patients. In addition, another non-invasive neurostimulation device that targets the vagus nerve in the neck has shown preliminary efficacy for the treatment of cluster and migraine. Stimulation of the sphenopalatine ganglion (inserted through an incision in the upper gums) has also demonstrated preliminary efficacy for the treatment of cluster headache. These neuromodulation options demonstrate that stimulation of peripheral nervous tissue can modulate a disorder that has its origin in the brain – like migraine.

The identification of certain brain regions as responsible for the earliest symptoms of a migraine attack. These occur during the premonitory phase, before headache pain begins. This is another confirmatory piece of evidence, which illustrates that migraine is a neurological disorder whose origins are within the brain.¹

A PEEK IN THE PIPELINE

By Paul G. Mathew, MD, FAHS is Director of Continuing Medical Education at Brigham and Women’s Hospital, a member of the Department of Neurology at the John R. Graham Headache Center in Boston, Director of Headache Medicine, Cambridge Health Alliance, and a member of the Division of Neurology at Harvard Medical School.

Abortive push in the pipeline. In terms of abortive treatments for migraine, novel delivery systems are in development for sumatripan and dihydroergotamine.

Sumatriptan was the first triptan available for use, and is available in oral, intranasal, and injectable formulations. Sumatriptan nasal spray can be useful in situations where patients do not find adequate relief with tablets due to delayed gastric motility, have early vomiting as a feature of their migraines preventing the use of tablets, or needle phobia preventing the use of injectable formulations. Unfortunately, timing of the nasal spray can lead to inconsistent absorption through the nasal mucosa. As such, a device is in development that utilizes the patient’s own forced breath to create positive pressure to project the drug deep into the nasal cavity. This action of generating a forced breath for drug delivery also tends to reduce drug migration past the soft pallet and out of the nasal passage, which can be seen with conventional nasal sprays. In Phase III trials, sumatriptan delivered via this breath powered device provided statistically significant relief of migraine over placebo by 30 minutes, and was well tolerated with a low incidence of systemic adverse events.²

Another sumatriptan novel delivery system utilizes iontophoresis, which is a process by which low-level electric current is utilized to drive medication across the skin in a controlled fashion. There tends to be a linear relationship between current and drug delivery. As such, sumatriptan delivered via an inontophoresic patch tends to provide more consistent, predictable plasma concentrations than oral and intranasal formulations of sumatriptan. A 12 month study involving 183 subjects and 2089 patch applications demonstrated that two hours after patch application, 23.8 percent of subjects were headache free and 58.2 percent experienced pain relief. One advantage of inontophoresis over intranasal delivery is that the side effects of abnormal taste, nasal discomfort, and rhinitis can be avoided. In addition, a lower peak plasma concentration with sumatriptan delivered via inontophoresis reduced typical triptan side effects that can be seen with injectable sumatriptan. The patch was noted to cause application site reactions, which affected 45 percent of subjects.³

Dihydroergotamine (DHE) is a medication that has been used for decades for the abortive treatment of migraine. Unlike the triptans, DHE has very poor oral bioavailability. As such, it comes in intranasal, intramuscular, and intravenous formulations, which all have their respective limitations. Intranasal DHE can have inconsistent absorption in the nasal mucosa. Intramuscular DHE can be limited by needle phobia, and the side effects associated with rapidly reaching high peak plasma levels, such as nausea. Intravenous DHE requires inpatient or infusion center admission and monitoring. Given these limitations, a new orally inhaled formulation of DHE has been devised, which utilizes a new type of inhaler. This inhaler synchronizes with the patient’s own inhaled breath, which ensures that higher doses of medication consistently reach the lung. This delivery system reduces the oropharyngeal deposition of medication that can be seen with conventional inhalers if the patient is unable to time inhalation properly with activating the inhaler.

A Phase III, randomized, double-blind, placebo-controlled involving 903 patients demonstrated that inhaled DHE was superior to placebo in terms of pain relief, as well as photophobia, phonophobia, and nausea resolution. Inhaled DHE was well tolerated, and no serious adverse events have been noted.

1. Maniyar FH. Sprenger T. Monteith T. Schankin C. Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 137(Pt 1):232-41, 2014 Jan.
2. Cady RK, McAllister PJ, Spierings EL, Messina J, Carothers J, Djupesland PG, Mahmoud RA. A Randomized, Double-Blind, Placebo-Controlled Study of Breath Powered Nasal Delivery of Sumatriptan Powder (AVP-825) in the Treatment of Acute Migraine (The TARGET Study). Headache. 2014 Oct 30.
3. Smith TR, Goldstein J, Singer R, Pugach N, Silberstein S, Pierce MW. Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system. Headache. 2012 Apr;52(4):612-24.