Please login to the form below

Not currently logged in
Email:
Password:

Migraine drugs' headache

Most of the many drugs in the pipeline are aimed at alleviating symptoms rather than addressing the root cause, but there are opportunities in this largely untapped market
the-pill

Migraine is a neurological disorder, characterised by severe headaches, that affects over 30 million people in the US alone. The underlying cause of the condition is still unknown, which has made it difficult to develop curative therapies. Current medications instead focus on symptomatic relief and usually include simple analgesics such as non-steroidal anti-inflammatory drugs or stronger medicines such as triptans or dihydroergotamine.

While headache is the primary symptom, approximately half of patients also experience nausea/vomiting, which can limit the use of orally administered therapies. Injectable therapies are invasive and difficult to administer, while other therapies that exist, such as Zogenix's Sumavel DosePro needleless, are considered painful and can result in bruising.

Nasal sprays
Other options include nasal sprays, but these can exacerbate nausea due to their unpleasant aftertaste. Evidence to support this is the fact that non-oral formulations of triptan accounted for only 4 per cent of total triptan units sold in the US during 2010. Pharmaceutical companies have identified this large market need and multiple promising candidates are in development. The medium-to-late-stage pipeline offers an interesting mix of new formulations of existing therapies and new chemical entities.

One of the most promising candidates in development is NuPathe's Zelrix, a transdermal formulation of sumatriptan. This formulation utilises an iontophoretic patch that uses a mild electrical current to force sumatriptan into the skin, providing a constant release of drug over four hours. It is the first transdermal patch for use in migraine.

NuPathe submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) in October 2010, which was met with a complete response letter in August 2011 requesting more data prior to approval. While the FDA confirmed that suitable efficacy had been demonstrated, it addressed concerns around the safety, manufacturing and chemistry of the product. This submission included data from a phase III study which showed significant analgesic effects two hours after application. Interestingly, only 2 per cent of patients had triptan-related adverse events during the first month, with no such events reported between months two and 12.

This formulation utilises an iontophoretic patch that uses a mild electrical current to force sumatriptan into the skin, providing a constant release of drug

A key downside of this therapy over injected formulations is the delay in onset of action, which is comparable to the oral formulation. At the American Headache Society meeting in June, attendees expressed tempered excitement over Zelrix, but most agreed that there was a market for the agent. Although not enthusiastic about the efficacy, which is on a par with oral sumatriptans, conference attendees were impressed by the novel route of administration that bypasses the gastro-intestinal tract, as well as by Zelrix's lack of triptan-related adverse events. Researchers inThought estimate US sales of $143m by 2018.

Another compound undergoing FDA review is MAP Pharmaceuticals' Levadex, an inhaled formulation of dihydroergotamine mesilate. The company believes the formulation will have a fast onset of action, similar to that of an IV infusion, but with the advantage of patients being able to use it at home. Furthermore, inhalation of this product does not leave a bad taste.

Results from the pivotal FREEDOM301 trial showed significant improvement in pain relief, phonophobia, photophobia and nausea and evidence suggests it may also have a cardiovascular safety advantage over the intravenous formulation, as the former does not show agonistic activity at the serotonin2A and serotonin2B receptors at therapeutic levels. MAP Pharmaceuticals submitted the NDA for this product in May 2011 and the FDA accepted it for filing in August 2011. A decision on marketing approval is expected in March 2012. Analysts at inThought predict a 79 per cent probability of approval and have modelled US sales to reach $171m by 2018.

Joining the queue of compounds undergoing regulatory review is an oral dispersible film formulation of zolmitriptan that was developed by APR Applied Pharma Research, Labtec and MonoSol Rx. This product utilises proprietarily RapidFilm technology which allows fast disintegration upon contact with water or saliva. The companies believe this formulation will enhance patient compliance. However, it is unclear how those with nausea will respond to the therapy. Regulatory review is underway in the EU via the decentralised procedure and US-based clinical development is being planned.

Botanical drug
Lupin in India is conducting phase III development on an intranasally administered botanical drug known as LLL 2011. While not much is known about the new chemical entity, it is being specifically developed for migraine and is at a late stage of development. Lupin is likely to put the licence for this compound out to tender to a multinational company once trials are complete.

Another interesting drug in development is an intranasal formulation of sumatriptan, administered using a breath-actuated device which is undergoing phase II clinical development with OptiNose. The device has been designed to deliver sumatriptan to the mucosa beyond the nasal valve, where it is able to exert a fast-acting and consistent therapeutic effect. Importantly, this formulation does not have a bitter aftertaste common with other sumatriptan nasal sprays, making it suitable for use in subjects with severe nausea. Results from a phase II study showed that this formulation significantly improved pain and headache while maintaining a good safety profile. OptiNose anticipates launching the product in 2013.

A promising first-in-class specific AMPA (GluR1, GluR2) and kainite (GlurR5) antagonist has completed phase II development with Raptor Pharmaceuticals. AMPA and kainite receptors are located throughout the brain and spinal cord and have been implicated in pain perception. Raptor conducted an end-of-phase-II meeting with the FDA and has subsequently received approval for a phase III programme. Raptor is currently seeking a partner to aid or finance phase III development and will not initiate studies until one is found.

CoLucid Pharmaceuticals is developing lasmiditan, which specifically agonises the serotonin 1F receptor. This receptor is predominantly expressed in the trigeminal pathway and CoLucid believes it will not display the vasoconstrictive properties of previous generations of migraine therapies. Results from a phase IIb trial presented in June 2010 showed that the primary endpoint of headache response was achieved. Both oral and intravenous formulations have been tested, with the oral formulation likely to advance into phase III first. Eli Lilly had previously conducted phase II evaluations on a serotonin 1F receptor agonist known as LY 334370. However, this compound was discontinued following results of animal toxicity studies.

Until the aetiology of this potentially debilitating condition is known,a true curative therapy is unlikely to be found

A new target to emerge in recent years is the calcitonin gene-related peptide (CGRP) receptor, an endogenous 37 amino acid neuropeptide that is known to be a potent dilator of intracranial vessels. It is expressed in trigeminal ganglia nerves and is released after nerve activation. CGRP can also cause the release of inflammatory agents from meningeal mast cells. In addition, CGRP is involved in the transmission of pain stimuli from intracranial vessels to the central nervous system. It is thought that CGRP receptor antagonists could alleviate migraine symptoms by blocking these pathophysiological activities of CGRP. An advantage of CGRP antagonist treatment is that it counteracts the dilation of intracranial arteries without the vasoconstriction associated with triptans. Boehringer Ingleheim (BI) is conducting phase II development of a CGRP antagonist known as BI 44370 and a research programme evaluating candidates is underway with Bristol-Myers Squibb (BMS).

The most advanced CGRP antagonist, telcagepant, was under development with Merck. The company anticipated filing an NDA during 2011, but it discontinued development during late phase III following an analysis of data. The company had previously aimed to submit an NDA in 2009, but filing was delayed due to marked elevation in liver transaminase levels. Only time will tell if BI's and BMS's compounds will undergo the same fate. 

NeurAxon has completed several clinical trials of its first-in-class therapy NXN 188. This compound works through the inhibition of nitric oxide synthase and agonism of serotonin receptors. A phase II trial completed in 2010 failed to meet its primary endpoint, but NeurAxon still described study findings as 'promising'.

A dopamine D2 receptor antagonist known as prochlorperazine has completed phase II development with Alexza Pharmaceuticals. This product utilises Alexza's Staccato handheld disposable inhaler technology. Phase II development has been completed and an end-of-phase-II meeting has been held with the FDA. Phase III development will not be initiated until a suitable development partner is found.

An additional compound, which entered phase II development in March 2011, is Eli Lilly's LY 2300559, an orally available antagonist of leukotriene D4 receptors and a modulator of metabotropic glutamate receptor 2.

Outlook

Until the aetiology of this potentially debilitating condition is known, a true curative therapy is unlikely to be found. The challenge for the industry is to develop symptomatic therapies that are easy to use, fast-acting and effective without unpleasant effects. While therapies in the pipeline have begun to address these issues, opportunities still exist in this largely untapped market.

The Author
Pipeline was written by Josh Subramaniam of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight (www.adisinsight.com) and inThought (www.in-thought.com).
For further information on Adis services, contact Kuljeet Sohanpal on +44 (0)20 7981 0714 or Email: Kuljeet.Sohanpal@wolterskluwer.com

To comment on this article, please use the commenting feature below

1st November 2011

Share

Featured jobs

Subscribe to our email news alerts

PMHub

Add my company
Hamell

Hamell is a full-service agency with a clear focus on delivering evidence-based, sustained behaviour change. So, whether you are looking...

Latest intelligence

Is the pharma business model ready for precision medicine?
Precision medicine promises to revolutionise patient outcomes and reduce costs for industry but is pharma ready for it? Blue Latitude Health co-founder Head of Strategy Fred Bassett explores the challenges...
ABPI2018
The NHS and ABPI at 70: inching closer to the triple win
The NHS and UK pharma’s ABPI both turn 70 this year. After years of transactional relationships, there’s a will to work more closely - but friction on prices and value...
What pharma marketers can learn from behavioural science
Pharma behavioural science and traditional emotional marketing create a powerful mix of techniques that have impact on real lives....

Infographics