flosz schreef op 17 november 2011 08:21:
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Proving Efficacy
Glybera’s rejection is another in a long string of late-stage clinical trial or regulatory failures for gene therapies. In December 2009, CHMP rejected Ark Therapeutics’ malignant glioma treatment, Cerepro. According to EMA, Cerepro’s trial data was statistically underpowered and failed to show sufficient efficacy in terms of postponing death or re-intervention. Cerepro was the first gene therapy to be considered for approval by CHMP.
The decision sent Ark’s share price into a nosedive, as it dropped 43% to barely above the value of its cash assets; the company still hopes the EMA decision may be reversed on appeal. “The interpretation of the latest study was complicated by the changing standard of treatment for malignant glioma as the study was being carried out,” according to Ark.
Other notable gene therapeutic failures include Introgen’s Advexin for head and neck cancer and Li-Fraumeni syndrome. FDA refused its summer 2008 BLA, citing an incomplete application. Advexin was a replication-impaired adenviroal vector carrying the p53 gene. The Austin-based company filed for Chapter 11 bankruptcy protection in December 2008.
More recently, in March 2010, GenVec discontinued its Phase III trial of TNFerade™ in patients with locally advanced pancreatic cancer. The product was an adenovector that delivers the tumor necrosis factor alpha gene to cancer cells. After conducting an interim analysis of overall survival after the 184th death (two-third of total expected events) and consulting with its independent Data Safety Monitoring Board, the firm concluded that the trial would not meet the goal of demonstrating persuasive evidence of clinical effectiveness.
A common theme among discontinued or stalled gene therapy candidates in the recent past has been problems with demonstrating sufficient efficacy for these treatments, Aldag pointed out. “If you look at the regulatory process in Europe, there don’t seem to have been any gene-therapy specific risks mentioned.”
Pulling from his own experience, he explained that “specific risks usually associated with gene therapy, such as carcinogenicity, were not show stoppers with respect to Glybera and the adeno-associated viral vectors.” The company said that it has been able to design and validate a stable and scalable AAV production platform that can be applied to a large number of orphan diseases caused by one faulty gene.
Will Gene Therapy Deliver?
Aldag’s conclusion about factors impacting gene therapy development and approval was validated by Global Industry Analysts. It released a report last January stating that while safety concerns were once considered the major roadblock to successfully developing a gene therapy for market approval, efficacy is now the key challenge hindering quick entry of products onto the market.
The report went on to predict that the gene therapy market will reach $316 million by 2015 despite there being only one such product available, only in China. It suggested that demand for novel and efficient therapies to treat cancers and indications with high unmet needs will drive market growth.
Currently, however, the prospects for a gene therapy to gain approval in Europe or the U.S. does not seem to be close at hand. While researchers are continuously tweaking the science to improve efficacy of gene therapy candidates, another factor remains to be worked out: the pathway for getting a gene therapy approved and on the market.
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