Clinical Trial Spotlight

Genzyme tests viral vector for wet AMD


Going Viral

Genzyme is testing an adeno-associated viral vector for wet AMD.


Since anti-VEGF agents were found to be effective in halting the progression of wet AMD and, in the case of ranibizumab, reversing ocular damage, VEGF has been a key focus of research on vision-threatening disorders. Anti-VEGF agents such as ranibizumab are derived from antibodies, which are typically identified with the body's immune system.

The role of VEGF in vision loss may become more pronounced thanks to a trial for AAV2-sFLT01, an adeno-associated virus that Genzyme Corporation (Cambridge, MA) hopes will help patients with wet AMD. Abraham Scaria, PhD, who is a senior scientific director at Genzyme, talked with us about the trial.


Dr. Scaria explained AAV2-sFLT01's mechanism of action, describing it as “an adeno-associated viral vector that carries the gene construct for a secreted chimeric protein — sFLT01 — that binds to VEGF.” Simply put, AAV2 is a virus that affects humans but is not linked to any known disease, and the AAV2-sFLT01 vector expresses a protein that can bind and eliminate VEGF.

Beyond that key similarity between sFLT01 and the anti-VEGF agents currently approved by the FDA, AAVsFLT01 also holds a key difference and promise that none of the anti-VEGF agents can offer. “AAV2-sFLT01 has the potential to deliver the VEGF binding protein sFLT01 for more than a year with a single intravitreal injection,” Dr. Scaria said, indicating that the single injection would cause retinal cells to secrete sFLT01 into the vitreous.

In a therapeutic environment that has been weighing the pros and cons of repeated injections vs. the possible long-term effects of “treat and extend” dosing, this is a potentially groundbreaking development. With the on-label indications for pegaptanib sodium (Macugen) and ranibizumab prescribing dosing every six weeks or monthly, respectively, AAV2-sFLT01 could one day offer an option to retinal physicians not currently available in a monotherapeutic agent.


Dr. Scaria reports that the preclinical results from testing of AAV2-sFLT01 in mice and monkeys have been positive. “AAV2-sFLT01 was effective in two models of retinal angiogenesis in mice and in the laser-induced choroidal neovascularization model in monkeys,” he said.

Another year-long study in monkeys found no adverse effects at an intraocular dose of 2 x 109 vector particles per eye. At a dose of 2 x 1010, Dr. Scaria said, “a mild and prolonged but self-resolving vitreal inflammation was observed.” No effects were observed with either electro retinogram or fluorescein angiography.

With AAV2-sFLT01 thus shown safe in animals, the agent will now be tested in patients with choroidal neovas-cularization consequent to wet AMD.


Genzyme plans to enroll 34 patients in this first clinical trial, with three study centers. The first center, at the University of Massachusetts Medical School in Worcester, MA, has already begun enrolling patients. Ophthalmic Consultants of Boston, a private practice, is set to enroll in the coming weeks. The third center will be Johns Hopkins University School of Medicine in Baltimore.

Safety and tolerability are the primary endpoints in the study, although enrolled patients will be screened to determine whether injections decrease central retinal thickness. Four groups of six patients each will receive one of four different doses of AAV2-sFLT01 in the first, unrandomized part of the trial. Then, in the randomized second portion of the study, the highest tolerated dose will be studied in 10 additional patients, with follow-up to continue out to 52 weeks.

More information on this trial can be found on 'Clinical Trials Update' of this issue. RP