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EMA401 for Treating Neuropathic Pain

Tue, 12/04/2012 - 4:00pm
Tom McCarthy, PhD, Chief Executive Officer, Spinifex Pharmaceuticals, Melbourne, Australia

Figure 1: Design of the Phase 2 clinical trial of EMA401 in postherpetic neuralgia patients. (Source: Spinifex Pharmaceuticals)Neuropathic pain is a type of chronic pain and is defined by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain as “pain arising as direct consequence of a lesion or disease affecting the somatosensory system”.1 The causes of neuropathic pain are diverse and include diabetes (diabetic neuropathy), cancer or its treatment (e.g. chemotherapy-induced neuropathy), viruses (e.g. postherpetic neuralgia), and nerve trauma (peripheral nerve injury-induced neuropathy). NeuPSIG treatment guidelines specify first-line therapy as secondary-amine tricyclic antidepressants (nortriptyline and desipramine), dual reuptake inhibitors of serotonin and norepinephrine (duloxetine and venlafaxine), calcium channel α2-δ ligands (gabapentin and pregabalin), and topical lidocaine (5% lidocaine patch).2,3 Opioid agonists are only recommended as first-line therapy in certain clinical circumstances (e.g. neuropathic pain due to cancer).

Despite these treatment options, many neuropathic pain patients do not experience adequate pain relief and/or cannot tolerate the central nervous system (CNS) side effects that are a feature of all of these agents except for topical lidocaine. As a result, there is significant interest in the development of neuropathic pain agents that would offer a better therapeutic index and address this unmet medical need.

One approach to the treatment of neuropathic pain currently in clinical development is the use of angiotensin II type 2 (AT2) receptor antagonists. Both nonclinical and Phase 2 clinical data were recently presented at the 14th World Congress of Pain in Milan, Italy.

The AT2 receptor was originally discovered during antihypertensive drug discovery efforts in the late 1980s and early 1990s. At the time, the goal was to find molecules that blocked the binding of angiotensin II to what at that stage was thought to be a single type of receptor.4 During this medicinal chemistry process, scientists discovered that the tissue they were using for their radio-ligand assays actually contained two main types of receptor that bound angiotensin II, specifically the AT2 receptor and what became known as the angiotensin II type 1 (AT1) receptor. Ultimately, it was shown that only antagonists at the AT1 receptor reduced blood pressure, and a range of highly selective AT1 receptor antagonists have now been developed as medicines to treat hypertension (this class of medicine is referred to as ARBs).5 Despite the success of marketed ARBs for hypertension, developers were unable to identify a human pharmaceutical use for selective AT2 receptor antagonists.6,7

In the mid-2000s, Maree Smith from the University of Queensland, Australia, established that AT2 receptor antagonists provided relief of symptoms in nonclinical models of neuropathic8 (and inflammatory9) pain. These foundational nonclinical studies, as well as more recent mechanism of action work, were presented at The 14th World Congress of Pain. Smith’s presentation was complemented by a presentation of AT2 receptor localization and pharmacology studies in human tissue from the laboratory of Praveen Anand (Imperial College London and Hammersmith Hospital), which showed that EMA401, a small-molecule oral AT2 receptor antagonist, inhibited neuronal outgrowth and inhibited hypersensitive responses in human neuronal tissue.

Having acquired Smith’s intellectual property, and building on their collaboration with Anand, Spinifex Pharmaceuticals also presented data from a Phase 2 clinical trial of EMA401 in postherpetic neuralgia patients. The design of the study is shown in Figure 1 and was a randomized, double-blind, placebo-controlled study of the safety, tolerability, and efficacy of 100-mg EMA401 administered twice daily for 28 consecutive days with a single dose on the morning of day 29 for pharmacokinetic purposes. This study met its primary endpoint: reduction in mean daily pain score versus placebo over the last week of 28 days of treatment. Results show a statistically significant and clinically meaningful reduction in mean pain intensity from baseline to week four for subjects on active treatment when compared to placebo. On an intent-to-treat basis, the mean pain intensity reduction from baseline after four weeks treatment was as follows: EMA401: -2.34; Placebo: -1.64; p = 0.006. A significantly greater proportion of patients on active treatment also reported a more than 30% reduction in mean pain intensity score compared to baseline (EMA401: 56.5%; Placebo: 34.1%; p = 0.003), meeting a key secondary endpoint. EMA401 was generally safe and well tolerated with no serious treatment-related adverse events reported. Full results from this study are being prepared for publication and a Phase 2 proof-of-concept study in chemotherapy-induced neuropathy is ongoing at Hammersmith Hospital, London.

References

1. Haanpää, et al. Pain.2011:152(1);14-27.

2. Dworkin, et al. Mayo Clin Proc. 2010:85(Suppl);S3-S14.

3. Dworkin, et al. Pain.2007:132; 237-251.

4. VanAtten, et al. Journal of Medicinal Chemistry.1993:36(25); 3985-3992.

5. Wexler, et al. Journal of Medicinal Chemistry.1996:39(3);625-656.

6. Steckelings, et al. Peptides.2005:. 26;1401-1409.

7. Porrello, et al. Frontiers in Bioscience.2009:14;958-972.

8. Smith and Wyse, PCT/AU2005/001975 & US 11/315,354. 

9. Smith, PCT/AU2007/000339.2. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012 13(5):358-69.

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