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Diabetic Neuropathy Patient Stratification, Chances Boosted

• Phase II signals encouraging for positive Phase III translation

• Capsaicin as stratification tool shows promise for responder selection

• Topical application to reduce side effects compared to oral treatments

BioDelivery Sciences International’s [NASDAQ:BDSI] topical clonidine gel has pain experts optimistic on Phase III painful diabetic neuropathy (DN) trial outcome thanks to its strategic inclusion criteria.

BDSI did not respond to a request for comment.

Clonidine is a α2 adrenergic agonist and imidazoline receptor agonist that has been in clinical use for over 40 years in a number of conditions, such as high blood pressure, anxiety disorders and attention-deficit/hyperactivity disorder, amongst others.

Topical clonidine gel is under investigation in a 140-patient Phase III trial investigating its efficacy and safety in the treatment of pain associated with DN, according to The primary outcome measures are a change in average pain score over time and a change from baseline in the numeric pain-rating scales score assessing the average pain in the past 24 hours, according to the site.

On 8 December the company announced randomisation of patients had been completed and noted it expects the trial to report results at the end of March 2015. BDSI plans to begin a second pivotal Phase III study during 1Q15, according the company press release.

Phase II results and patient stratification provides optimism

In the Phase II trial there was no statistically significant difference between clonidine gel and placebo (p=0.07), however in any subjects who felt any level of pain after being exposed to capsaicin, clonidine was superior to placebo (pless than0.05). In subjects with a capsaicin-induced pain rating of two or more, the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (p=0.01) [Campbell CM et al. Pain (2012); 153(9):1815-1823].

Capsaicin is the active component of chilli peppers and is an irritant which causes the sensation of burning; it is often used as topical cream to relieve pain in a number of indications including diabetic neuropathy.

In the Phase II trial, capsaicin was used to test whether the pain nerves in patients were functioning, a higher pain score indicated functioning neurons, noted Dr Aristidis Veves, professor of Surgery, Beth Israel Deaconess Medical Cente, Boston, Massachusetts.

In the Phase III trial the inclusion criteria notes that the subject must have a pain score of at least two on the 11-point Numeric Pain Rating Scale, within 30 minutes following topical 0.1% capsaicin application, according to ClinicalTrials. gov.

By using capsaicin, there is a higher likelihood of identifying clonidine gel responders for a better chance at Phase III success, noted Veves and Dr David Armstrong, professor of Surgery, University of Arizona College of Medicine, Tuscon.

The argument is that if you have pain receptors present and responding to capsaicin then clonidine gel will work on these abnormally functioning receptors, noted Dr Rayaz Malik, professor of Medicine and consultant physician, Division of Cardiovascular Medicine, Manchester Royal Infirmary, UK.

Pain can be caused by a number of mechanisms, in some cases pain from neuropathy could be caused by factors other than dysfunctional neurons, such as cross talk from other neurons or gating issues in the spine, and those patients would not be helped by clonidine gel, said Veves. Thus it is important to stratify patients and a capsaicin test provides a useful way to do this, he added.

The overall result in the Phase II trial was not far from statistical significance in the overall population and likely failed as it included an unselected population including those that could not benefit as they did not have intact cutaneous or epidermal nerve fibres, said Charles Ponte, professor of Clinical Pharmacy and Family Medicine, West Virginia University School of Pharmacy. The fact that the Phase III trial is stratified for patients responding to capsaicin means there is a better chance of success because patients are selected with intact nerves, he added.

There is a definite signal in the Phase II study that shows performing a capsaicin test to check nerve function is a good way to stratify patients for this treatment in clinical trials, noted Malik.

It is a really “elegant idea” to stratify patients according to how their pain receptors respond, it is like the equivalent of performing a biopsy, said Armstrong. What is also encouraging about this medication is that it appears to be effective in the patients with pain receptors that are still functioning and these are the ones that have the biggest need for treatment, he added.

Topical clonidine gel is under investigation in a 140-patient Phase III trial investigating its efficacy and safety

Strong tolerability data expected

Currently there are a number of options for painful DN including pregablin and duloxetine, both of which are oral treatments, noted Veves. However, many patients cannot tolerate the side effects of these oral treatments, noted Veves and Malik. Topical gel should limit the side-effect profile and there are not likely to be systemic effects, noted all of the experts interviewed. The side-effect profile was virtually non-existent in the Phase II trial, it was an extremely clean drug, they added.

From the point of view of a patient, this is a favourable treatment as the patient has more control over the application of the drug as compared to an oral treatment, noted Armstrong. It is also favourable from the point of view of a doctor as the patient must apply the treatment to their feet which means they are more likely to be made aware of any developing complications, he added.

BDSI’s market cap is USD 771m.

February 2, 2015

Hamish McDougall

Reporter, BioPharma Insight

Hamish has a BSc in Neuroscience from the University of Sussex and is primarily covering the neuroscience indications for BioPharm Insight. Prior to joining us he was assistant commissioning editor for a well-known collection of biomedical journals at Expert Reviews, including Expert Review of Gastroenterology & Hepatology, Expert Review of Clinical Pharmacology and Expert Review of Respiratory Medicine.


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