SUBSPECIALTY NEWS

Are Doubts on siRNAs Valid?

OPKO's Top Researcher Defends Bevasiranib.

■ "SiRNAs won the Nobel Prize for medicine — and with good reason."

So says Sam Reich, executive vice president of OPKO Ophthalmics and codeveloper of bevasiranib, OPKO's injectable treatment for wet AMD and currently the only siRNA (small interfering RNA) drug that has reached a pivotal phase 3 trial. Merck is also developing a siRNA drug for the treatment of wet AMD.

Reich agreed to be interviewed by Retinal Physician to discuss the siRNA gene-silencing concept in general and bevasiranib in particular. The siRNA concept has been under fire recently following a much-quoted article in the online edition of the journal Nature in which Jayakrishna Ambati, MD, of the University of Kentucky, contended that these drugs could produce harmful side effects by inhibiting necessary blood vessel growth in healthy areas of the body. He also asserted that siRNAs are generic and do not target specific genes.

An initial University of Kentucky news release stated that the harmful side effects were limited to intravenous administration of a siRNA drug, but in a response to a question from Retinal Physician Dr. Ambati said that even a localized injection of a siRNA into the eye could activate the TLR3 receptor and induce adverse effects.

While Reich made it clear that he did not want to rebut Dr. Ambati on specific issues or contest the reliability of the mouse model that Dr. Ambati used to draw his conclusions, he pointed to 6 years of "validated" data on bevasiranib demonstrating the safety and effectiveness of the drug.

"We have a comprehensive body of data including multiple experiments on mice, rats, rabbits, and monkeys with all demonstrating positive results," said Reich. "We now also have 2 years of data on 200 human patients receiving multiple injections that tell us that bevasiranib is a safe drug that potently silences VEGF via the RNA interference mechanism."

Reich said that bevasiranib had been administered both by intravitreal injection (in humans and animals) and intravenously (in animals) and that neither form of administration had caused harmful side effects.

"We have a tremendous body of evidence that bevasiranib is safe," Reich asserted. "The safety issue is no contest."

On the question of whether bevasiranib actually targets cells rather than triggering a general immune response, Reich said that he is currently preparing a paper on the "ocular bio-distribution of siRNA after ocular injection" that will deal with that issue.

"The drug goes where it needs to go," he said. "We can provide ample evidence that bevasiranib gets to the back of the eye to treat wet AMD. It gets inside cells to silence genes."

Reich appeared to be philosophical in discussing the controversy that has erupted around the siRNA concept.

"Academic models can produce novel findings but to say that they have clinical relevance requires a huge leap of faith," he noted. "The huge preponderance of the hundreds, even thousands of papers on siRNAs at every kind of medical meeting testifies to their potential value. Every pharmaceutical and biotech company that I know of has an interest in siRNAs."

In response to a specific question about the 2-year phase 3 trial for bevasiranib that began last August, Reich said that all the data remain masked but that no significant safety issues had been reported.

Gene Therapy for Leber Disease

Patients in Study Show Marked Improvement.

■ Researchers from The University of Pennsylvania have used gene therapy to safely restore vision in 3 young adults with a rare form of congenital blindness. Although the patients have not achieved normal eyesight, the preliminary results set the stage for further studies of an innovative treatment for this and possibly other degenerative retinal diseases.

An international team led by The University of Pennsylvania, The Children's Hospital of Philadelphia, the Second University of Naples, and the Telethon Institute of Genetics and Medicine (both in Italy), and several other American institutions reported their findings in an online article in the New England Journal of Medicine.

"This is the first gene therapy trial for a non-lethal pediatric condition," said Albert M. Maguire, MD, associate professor, Department of Ophthalmology, University of Pennsylvania School of Medicine, and a physician at The Children's Hospital of Philadelphia. Dr. Maguire, together with his wife, Jean Bennett, MD, PhD, professor of ophthalmology at Penn and senior investigator at the F.M. Kirby Center for Molecular Ophthalmology at Penn's Scheie Eye Institute, have been researching inherited retinal degenerations such as Leber congenital amaurosis (LCA), for 18 years. LCA usually begins stealing sight in early childhood and causes total blindness during a patient's 20s or 30s. Currently, there is no treatment for LCA.

"Patients' vision improved from detecting hand movements to reading lines on an eye chart," Dr. Maguire said. In 2001, Drs. Bennett and Maguire were part of a team that reported successfully reversing blindness using gene therapy on dogs affected by the same naturally occurring form of congenital blindness.

The scientists used a vector, a genetically engineered adeno-associated virus, to carry a normal version of the gene, called RPE65, that is mutated in one form of LCA. The 3 patients, one 19 years old and 2 age 26, received the gene therapy via a surgical procedure that was performed by Dr. Maguire between October 2007 and January 2008 at The Children's Hospital of Philadelphia, where the gene vector was manufactured at the hospital's Center for Cellular and Molecular Therapeutics (CCMT).

Starting 2 weeks after the injections, all 3 patients reported improved vision in the injected eye. "Standard vision tests showed significantly improved vision in the patients," said Alberto Auricchio, MD, a study leader from the Telethon Institute of Genetics and Medicine and University of Naples Federico II. The researchers also reported that each injected eye became approximately 3 times more sensitive to light, and each was improved compared to the uninjected, previously better functioning eye.

The LCA gene therapy vector showed no signs of causing inflammation in the retina or other toxic side effects. One of the 3 patients had an adverse event, a hole in the retina that did not affect eyesight and may have been surgery-related, rather than related to biological effects of the therapeutic gene or the vector used to carry it.

The patients enrolled in the study to date were identified at the Department of Ophthalmology at the Second University of Naples, an institution with longstanding experience in collecting and studying patients with inherited retinal diseases.

Testing continued over 6 months following the gene therapy vector administration. One patient was better able to navigate an obstacle course compared to before the injection. The patients also had less nystagmus, which is common in LCA. In the patient who experienced better vision even in the uninjected eye, the researchers suggest that the reduced nystagmus benefited both eyes.

"The current clinical trial will continue with more patients and with ongoing follow-up to monitor results," said Dr. Bennett. "We expect improvements to be more pronounced if treatment occurs in childhood, before the disease progresses.

"Much of the funding for degenerative retinal disease research is being provided by wealthy venture capitalist Gordon Gund and the Foundation Fighting Blindness. Gund, who has a rare form of retinitis pigmentosa, is blind.

VEGF-Trap Shows Durable Response

Positive Phase 2 Data for Wet AMD Therapy.

■ Regeneron Pharmaceuticals Inc. and Bayer HealthCare AG said that VEGF Trap-Eye dosed prn for wet AMD for 20 weeks maintained the visual acuity (VA) gains achieved after an initial 12 weeks of fixed dosing. In addition, 55% of the patients who received the highest dose (2 mg) monthly for the initial 12 weeks did not require any additional injections throughout the entire 20-week prn dosing period.

A full analysis of the 32-week results of a 52-week phase 2 study was recently presented at the 2008 Association for Research in Vision and Ophthalmology (ARVO) meeting.

Study results showed that across all dose groups in the study population, the 6.6 mean letter gain in visual acuity achieved vs baseline at the week 16 evaluation visit, following 12 weeks of fixed dosing, was maintained out to week 32 using a prn dosing schedule. A decrease in retinal thickness was also maintained for all dose groups combined at week 32.

In this double-masked, prospective, randomized, multicenter trial, 157 patients in 5 dose groups were treated with VEGF Trap in 1 eye. Two groups initially received monthly doses of 0.5 or 2 mg of VEGF Trap for 12 weeks and 3 groups received quarterly doses of 0.5, 2, or 4 mg of VEGF Trap (at baseline and week 12). Following the initial 12-week fixed-dose phase of the trial, patients continued to receive therapy at the same dose on a prn dosing schedule based on prespecified criteria.

Patients were monitored for safety, retinal thickness, and visual acuity.

Patients receiving monthly doses of VEGF Trap-Eye, either 0.5 or 2 mg, for 12 weeks followed by prn dosing thereafter achieved mean improvements in VA of 8.0 and 10.1 letters, respectively, and mean decreases in retinal thickness of 141 and 162 μm at week 32, respectively. Dosing prn also maintained the improvements in retinal thickness following a fixed quarterly dosing regimen, but results achieved with the quarterly regimen were generally not as robust as obtained with initial monthly dosing.

VEGF Trap-Eye was generally safe and well tolerated, and there were no drug-related serious adverse events. There was one reported case of culture-negative endophthalmitis/uveitis in the study eye, which was deemed not to be drug-related. The most common adverse events were those typically associated with intravitreal injections.

After the last fixed-dose administration at week 12, patients from all dose groups combined required, on average, only 1 additional injection over the following 20 weeks to maintain the VA gain established during the fixed-dosing period. As noted above, 55% of the patients who received 2 mg monthly for 12 weeks did not require any additional treatment throughout the next 20-week prn dosing period. Moreover, 97% of the patients who received 2 mg monthly for 12 weeks did not require redosing at the week 16 evaluation visit, indicating that an 8-week dosing schedule may be feasible.

"Due to its high affinity for all isoforms of VEGF-A and PlGF, potent mediators of blood vessel overgrowth in wet AMD, as well as its long residence time in the eye, it is anticipated that VEGF Trap-Eye may be able to be dosed at a frequency less than once monthly, especially on a chronic basis, without compromising visual acuity," said primary investigator Quan Dong Nguyen, MD, MSc, assistant professor of ophthalmology, Wilmer Institute, the Johns Hopkins University School of Medicine, Baltimore.