It held out the tantalising promise of being the first marketed gene therapy product in the west, but the failure of Ark Therapeutics' product for malignant glioma, Cerepro, to gain approval from the European regulator has once again highlighted the difficulties inherent in developing these novel therapies (Ark sinking after EU rejection, December 18, 2009).
Cerepro had been the great white hope of the space and its knock back is likely to have dented confidence of an approval for a gene therapy product anytime soon. An analysis from EP Vantage shows that while there is definitely interest in the space with an impressive 133 products either in the clinic or listed as research projects, this is more than counterbalanced by the high failure rate of treatments (see table below).
A total of 168 products have been either abandoned or suspended, a sum that easily eclipses the number of products that are currently being studied. Interestingly, while the most number of products under development are pre-clinical, this is where the most failures occur. This statistic could have something to do with the nature of gene therapy, where it should be relatively easy to see early on if a treatment is working or not.
However, one the biggest disappointments in the field has been the termination of development of Introgen Therapeutics' products, in particular Advexin. The product, which had been filed in Europe, had been forecast to have sales of $200m by 2014 and was developed as a treatment for an inherited cancer syndrome, Li-Fraumeni Syndrome, as well as the much larger indication of head and neck cancer. Little has been heard of Advexin since Introgen announced that it was going into administration and was bought by Vivante.
|Count of Gene Therapy Products|
|Total Active Pipeline||133|
|Abandoned - Filed||1|
|Abandoned - Phase III||8|
|Abandoned - Phase II||20|
|Suspended - Phase II||1|
|Abandoned - Phase I||14|
|Abandoned - Pre-clinical||70|
|Suspended - Pre-clinical||1|
|Abandoned - Research project||53|
|Total Abandoned Projects||168|
In many ways the gene therapy space is very similar to that of cancer vaccines, in that while many are convinced that there is undoubtably potential in the field, what has been awry is the execution.
Gene therapy expert, Professor Farzin Farzaneh, Professor of Molecular Medicine, at Kings College London echoes these sentiments. “There are a number of examples where gene therapy has been shown to be successful in the clinic, but its not the panacea that it was originally thought to be and people hoped it might be. It has so far also not delivered any cancer treatments, despite progress in immune disorders. But I think gene therapy has a great deal of promise even if it has not yet produced the magical cure that we hoped it would.”
Also like cancer vaccines, even if they are effective, gene therapies are likely to face a long and uphill struggle to get approval from decision makers simply because of their novelty, and will require regulators to be comfortable with approving such a novel technology.
Professor Farzabeg believes that the lack of success in achieving an approved product in the west is also a reflection on the relative youth of the science, but that a break through is in sight. “I think we could see the first approved product not in the next couple of months, but maybe in the next couple of years.”
As the table below shows one solitary gene therapy product has in fact been approved, but it has been given little credence given that Epeius Biotechnologies' Rexin-G has only received the green light for marketing in the Philippines. The product that was given the nod in 2007 is also rather loosely approved for the treatment of “all” solid tumours.
Up and coming contenders
As such many see the next real hope of getting an approved product as Daiichi Sankyo and Sosei’s HGF DNA Plasmid (DS-992), which since Ark’s set back has become the next hope for the therapy area and the next treatment that will test the regulators. HGF DNA Plasmid (DS-992), which uses DNA-based delivery of hepatocyte growth factor, is being developed for indications related to peripheral arterial disease, a severe condition caused by blockage of blood vessels feeding the foot and lower leg.
Analysts have forecasts sales to start in 2010, indicating they at least are hopeful of approval. But the novelty of the treatment is shown by the fact that sales are only seen to be $39m by 2014.
Another product in late stage development that has attracted a lot of interest is Vical’s Allovectin-7. The drug is in phase III trials for metastatic melanoma and has importantly completed a second safety analysis. Vical is expecting the trial to complete recruitment of 375 patients by the end of this year.
Vical, which is also involved in the development of HGF DNA Plasmid (DS-992) and is a big player in the gene therapy space, has managed to secure AnGes as a partner. To date the Japanese company has funded development of Allovectin-7 to the tune of $22.6m, in exchange for exclusive rights in Japan and other key Asian markets, in return if the drug gets approval in the US AnGes is entitled to tiered royalties on sales.
More recently, Teva Pharmaceutical Industries signed a deal to market the drug, which is injected directly into tumours to stimulate an immune response, in Israel, which although a small deal does give the product more validation.
Sanofi Aventis certain believes that there is some potential in the field. The group also has a deal with Vical, over XRP0038, another drug for peripheral arterial disease, a phase III programme is currently ongoing to evaluate the treatment’s ability to prevent major amputations or death, when critical limb ischemia has occurred. A filing is expected in 2010, which means the product could be on the market by 2011.
With potential approval of the next gene therapy product looming next year and other treatments lining up to go test both the regulators and market in 2011, while the knock back for Cerepro was certainly a blow, if one of the other late stage products does get approval in the next 12 months this risky and highly experimental field will finally have come of age.
|Selected Gene Therapy Products|
|Market Status||Product||Originator||Company||Therapeutic Category||Pharmacological Class|
|Marketed||Rexin-G||Epeius Biotechnologies||Epeius Biotechnologies||Immunostimulants||Cancer gene therapy|
|Filed||Cerepro||Ark Therapeutics||Ark Therapeutics||Other cytostatics||HSV tk gene therapy|
|HGF DNA Plasmid (DS-992)||University of Osaka||Daiichi Sankyo/Sosei/AnGes MG/Vical||Cerebral & peripheral vasotherapeutics||Hepatocyte growth factor gene therapy|
|Phase III||Allovectin-7||Vical||Vical/AnGes MG/Teva||Immunostimulants||HLA-B7 gene therapy|
|XRP0038||Aventis||Sanofi-Aventis/Vical||Cerebral & peripheral vasotherapeutics||Fibroblast growth factor (FGF) gene therapy|
|TNFerade||Asahi Chemical||GenVec||Immunostimulants||TNFa gene therapy|
|Generx||Collateral Therapeutics||Cardium Therapeutics/Bayer AG||Cardiac therapy||Fibroblast growth factor (FGF) gene therapy|
|Trinam||Stanford University||Ark Therapeutics/Crucell||Other cardiovasculars||VEGF gene therapy|
|Glybera||Amsterdam Molecular Therapeutics||Amsterdam Molecular Therapeutics/Targeted Genetics||Anti-hyperlipidaemics||Lipoprotein lipase gene therapy|
|Phase II||AAV-RPE65||Targeted Genetics||Targeted Genetics||Eye preparations||RPE65 gene therapy|
|Ad2/HIF-1a||Genzyme Biosurgery||Genzyme||Cerebral & peripheral vasotherapeutics||HIF-1 alpha gene therapy|
|CERE-120||Neurologic Gene Therapeutics||Ceregene/BioSante Pharmaceuticals/Genzyme||Anti-Parkinson's agents||Neurturin gene therapy|
|EG011||Stanford University||Ark Therapeutics||Other cardiovasculars||VEGF gene therapy|
|LentiGlobin||Genetix Pharmaceuticals||Genetix Pharmaceuticals||Anti-anaemics||Haemoglobin gene therapy|
|MetXia||Boston University/Dana-Farber Research Institute||Oxford BioMedica||Other cytostatics||CYP2B6 gene therapy|
|Mydicar||Celladon||Celladon/Targeted Genetics||Cardiac therapy||SERCA2a gene therapy|
|ProSavin||Oxford BioMedica||Oxford BioMedica||Anti-Parkinson's agents||Dopamine gene therapy|
|tgAAC94||Immunex||Targeted Genetics/Amgen||Other anti-rheumatics||TNFa inhibitor gene therapy|