This year’s annual meeting of the American Society of Gene Therapy is in San Diego. I’ve been to several interesting talks thus far, and plan to post entries on a few. For now, here’s an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.
1- Last year, I predicted that the first gene transfer applications were nearing licensure. Not so fast. Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics. Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer). Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro. Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same). The data behind the product are less than earth shaking. According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm. And the product caused “increases” in hemiparesis, aphasia, and fever.
2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled “late stage industry clinical trials.” To me, late stage means phase 3. But three talks centered on phase 1/2 studies, and none presented phase 3 results. The first talk was given by Ceregene on their Parkinson’s disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.
3- Last year, the “buzz” at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children. I will look forward to attending Jean Bennett’s talk on Friday; her abstract reports that her LCA study has enrolled “9 children and young adults” ranging from age 8 to 26 years. The abstract claims improvement in “subjective and objective” measures of vision. To be continued… (photo credit: slack12, 2008)
“Since 2005, we’ve started seeing the big 20 pharma corporations making investments [in gene therapy],” says a deputy head in European Medicine Agency (EMEA) in the October 2008 issue of Nature Biotechnology (“Ark floats gene therapy’s boat, for now,” by Randy Osborne). “When you want to know what season is there and when the weather will change, you have to see which birds are flying.”
All this should be very encouraging for the field. Yet the story also describes the many travails of companies seeking regulatory approval for their gene transfer products. One is Introgen, which sought approval for its adenovirus-p53 cancer product Advexin. FDA returned Introgen’s submission with a “refuse to file” letter indicating that the materials were incomplete. The study on which this filing was based was presented at the American Society of Gene Therapy meeting last Spring. As I indicated in my June 10 posting, a major concern with this study was that its efficacy claims were based on a subgroup analysis of genetic profiles. Others, like TheStreet.com columnist Adam Feuerstein, have been far less guarded in their assessment of Advexin; Feuerstein called Introgen “a living textbook for what investors need to be wary of when considering a biotech investment.”
The second product profiled in the Nature Biotechnology story is Ark’s Cerepro, which uses herpes simplex virus vectors to deliver a gene, thymidine kinase, to the tumor bed of patients with malignant glioma (a highly aggressive form of brain cancer); the gene then converts a pro-drug, ganciclovir, into a toxin that kills tumor tissue. Ark is reportedly planning to file a license application to EMEA. Preliminary data in a randomized controlled trial against standard of care vs. standard of care + Cerepro indicate a median extension of survival by 42 days (with serious side effects).
One last product profiled briefly is Amsterdam Molecular Therapeutic’s product, Glybera, for a very rare genetic disease lipoprotein lipase deficiency. Amsterdam intends to file for licensure “later this year.”
The fortunes of clinical gene transfer might indeed be flying North. But with some lead products showing such incremental gains in survival and dependence on combination with standard care, clinical application seems less likely to arrive with a bang than with a modest honk. (photo credit: denis collette, 2007)