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Recruitment in ongoing European Phase III clinical trials of idebenone in Friedreich’s ataxia (FA) patients is proving difficult, the drug’s sponsor Santhera told Pharmawire, because of the ready availability of the drug across the continent.
US trial investigators have also said that widespread non-prescription use of antioxidants in the FA community was a complicating factor in clinical trials.
Santhera’s 150mg formulation of idebenone, shown to have cardiomyopathic and neurological benefits in Phase II trials, is currently before regulators in Europe and Canada. Phase III trials are continuing in both Europe and the US.
Santhera’s chief executive officer, Klaus Schollmeier, told this news service in an interview that recruiting Phase III trial patients in FA had proved difficult.
Positive clinical studies and widespread use of idebenone in compassionate use and named patient programs for FA mean that the drug has become a victim of its own success, at least when it comes to planning clinical trials.
A spokesman for Santhera said idebenone was already registered in Switzerland, with a limited label.
He explained that a Swiss patient group, impressed by early clinical studies suggesting idebenone’s positive effect on cardiomyopathy – a major cause of FA morbidity – had approached the drug’s originator, Takeda. Together they approached SwissMedic, the country’s regulator, and obtained temporary registration of the drug at full reimbursement.
Word spread, and several other countries, including France and Italy, established compassionate use programs. Still others, including Spain, the UK and Belgium, set up treatment centres for idebenone in FA.
Takeda’s formulation of idebenone comes in 45mg tablets. However, Santhera’s application to regulators is for a 150mg tablet, based on clinical trials suggesting that higher doses had a beneficial effect on neurological function as well as cardiomyopathy.
The spokesman said that if Santhera’s application was successful, Takeda – which has marketing rights for Europe – would switch up to the 150mg size.
Idebenone has a similar exposure problem in the US, although with ad hoc use of non-prescription idebenone and other antioxidants, bought over the internet, among FA patients.
In a recent paper published ahead of print in the Journal of Neurological Sciences, Lauren Myers and colleagues at the Department of Neurology, University of Pennsylvania Medical School, said non-prescription antioxidant use was a “major confounder” to clinical trials for novel agents for FA.
The researchers analysed antioxidant use among the 217 patients in a large, multi-centre FA study. They found 64% were using one form or another, and some were using several. The most commonly used was vitamin E (53%), followed by coenzyme Q10 (43%) and idebenone (17%). Use of idebenone was especially high in children.
Myers and colleagues said the data had important implications for clinical trial design in FA. Because antioxidants were widely used, they wrote, it would be hard to find study patients who had either never taken them or who were willing to abandon them for a clinical trial, limiting enrolment possibilities.
The researchers suggested either shrinking the placebo arm of future trials, reducing their length, or allowing for continued use of antioxidants at stable doses.
Dr Kenneth Fischbeck told Pharmawire that he and colleagues at the US National Institute of Neurological Disorders and Stroke had also found a high rate of antioxidant use in FA clinical trial patients. ”It is a potential complicating factor for placebo-controlled trials, but we found compliance to be good, at least for short-term studies,” he said.
Santhera hopes for European approval of idebenone in the third quarter of this year, and to lodge a New Drug Application with the US Food and Drug Administration in 2009. A spokesman said the company needed to ascertain how fast recruitment was picking up before it could confirm guidance on timelines.
Santhera has a market cap of about EUR 149m.
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