RNA interference seen as next step in fighting macular degeneration

Two companies are in the clinical testing phase with short-interfering RNA molecules to stop the production of VEGF proteins.

With drugs that inhibit vascular endothelial growth factor showing promise in the treatment of wet age-related macular degeneration, some biotech companies are investigating the next step in treating this disease. Two companies are working to develop retinal applications for short-interfering RNA.

Peter K. Kaiser

The two RNA interference (RNAi) drugs (in particular, short-interfering RNA or siRNA) currently in clinical trials are designed to stop the production of vascular endothelial growth factor (VEGF) or its receptor.

“Although this technology is being looked at for cancers and tumors, the first time it was actually injected into a human was in ophthalmology,” said Peter K. Kaiser, MD, OSN Retina/Vitreous Editorial Board member and an investigator in the clinical trials.

In theory, these drugs could be used proactively before AMD becomes “wet” or in conjunction with other VEGF inhibitors to either resolve or prevent progression of the disease.

“It could offer a more potent inhibition of VEGF and, theoretically, a longer inhibition of VEGF. That’s theoretical, though; we haven’t proven that,” Dr. Kaiser said. “It still needs to be tested in patients long term.”

RNA interference

Dr. Kaiser said this technology is fairly new to the scientific community, which has learned about it only within the past 5 years.

“It’s a natural mechanism in all living creatures,” he said. “It’s a protective mechanism to protect the body against viruses because usually viruses have different RNAs, so your body tries to break this down.”

Based on this natural breakdown process, Dr. Kaiser explained, if a double-stranded RNA is injected into a cell, it can attach itself to the RNA-induced silencing complex (RISC) in the nucleus, unbinding one of the strands.

“Now this RISC protein will go out and find complementary mRNA [messenger RNA] to that strand,” Dr. Kaiser explained. “Once it finds it, it will bind it and break it down. It will keep doing this.”

In AMD, the activated RISC “turns off” the mRNA so that the VEGF protein is no longer produced or received by the cells. This action earlier in the VEGF pathway makes these drugs “theoretically much more potent” than VEGF antagonists such as bevacizumab or ranibizumab, he said, because production of VEGF is curtailed.

The technology can be specifically created to affect certain mRNA or certain genes, Dr. Kaiser said. Hopefully, this type of treatment could be applied to many diseases in the future, he said.

“We expect that this whole approach could be used to treat many different diseases down the road, dozens of diseases potentially,” Lawrence J. Singerman, MD, said.

Currently, ophthalmology is the only specialty in which this technology in humans, with two companies recently presenting data from phase 1 and phase 2 trials. Acuity Pharmaceuticals’ bevasiranib was the first siRNA to be injected into an eye, with Sirna’s drug Sirna-027 following just weeks later.

“The difference between them is subtle but important because the Acuity Pharmaceuticals drug, bevasiranib, blocks the production of VEGF protein so it works upstream,” Dr. Kaiser said. “The Sirna molecule, Sirna-027, blocks VEGF receptor 1 production. It actually works downstream at blocking the VEGF receptor.”

Bevasiranib

Dr. Singerman presented data from phase 2 trials of bevasiranib, formerly known as Cand5, at the annual meeting of the American Society of Retina Specialists. Dr. Singerman spoke with Ocular Surgery News about the drug.

“Lucentis (ranibizumab, Genentech/Novartis), Avastin (bevacizumab, Genentech) and Macugen (pegaptanib sodium, OSI/Pfizer) are all VEGF inhibitors, so they neutralize existing VEGF,” Dr. Singerman explained to OSN. “The problem is that it comes back.”

Dr. Singerman said that the phase 2 study demonstrated that bevasiranib can stall the growth of choroidal neovascular lesions, but it does not immediately neutralize existing VEGF. The elimination of growth could potentially complement the VEGF inhibitors and prevent the recurrence of AMD.

The study showed that there was an initial delayed clinical manifestation of about 6 to 8 weeks during which there was little to no growth of choroidal neovascularization (CNV). After the “VEGF hangover,” in which the CNV dissipated, the effects of bevasiranib became clear.

“We showed that the effect of inhibiting CNV was 100% from 9 weeks to 18 weeks,” Sam Reich, co-founder and vice president of research and development at Acuity, told OSN. He speculated that bevasiranib could be combined with a VEGF inhibitor for a combination therapy or used proactively before wet AMD occurs.

The combination therapy, if effective, would ensure that the patient was “treated in both phases of their treatment with the most appropriate drug: initiation with a protein blocker and then maintenance with a drug that stops the protein from coming back,” Mr. Reich said. He said the company was still deciding whether to use VEGF inhibitors before bevasiranib in an upcoming phase 3 trial.

Dr. Singerman suggested that this therapy could provide long-term relief for patients, eliminating the need for frequent intraocular injections.

“These patients have very long lives,” Mr. Reich said. “They’re wet AMD patients, and they don’t have a life-threatening disease. They have a vision-threatening disease, and they will need a VEGF inhibitor for many years.”

In a patient with dry AMD at risk of progression toward neovascularization, Mr. Reich said he hoped that bevasiranib could be used to prevent wet AMD from occurring.

“When a proactive therapy is approved, the physicians really for the first time feel the responsibility to treat the patient in that way,” Mr. Reich said. “By stopping the gene from coming back, physicians can be proactive, and the proactive patients may be a much larger group of patients out there, including patients that are highly at risk for wet AMD but don’t yet have it.”

Mr. Reich added that no systemic side effects were seen in the phase 1 and 2 trials for bevasiranib.

Sirna-027

Sirna Therapeutics presented phase 1 data for its RNAi-based drug, Sirna-027, a month before the presentation of bevasiranib’s phase 2 data.

Sirna-027 works by blocking production of VEGF receptor 1, which is thought to have an antagonistic affect on VEGF receptor 2, the main receptor involved in angiogenesis and permeability,

“It actually works downstream by blocking the receptor. VEGF is still being produced and released, but if there’s no receptor 1 around, it can’t activate receptor 1,” Dr. Kaiser said. “Now, the main issue with this approach is that receptor 2 is the key receptor involved in angiogenesis and permeability.”

He said receptor 1 also binds placental growth factor (PLGF), which is another angiogenic factor and part of the VEGF family. The theory is that if receptor 1 production is blocked, it cannot be activated by PLGF or VEGF, Dr. Kaiser explained.

The data from phase 1 trials with Sirna-027 showed that increasing doses were safe and well tolerated in 26 patients, all of whom showed visual acuity stabilization 8 weeks after a single injection.

Of the 26 patients, five showed at least three lines of visual improvement. Two patients demonstrated a reduction of three lines or more. The company said the best indication of biological activity of Sirna-027 is the decrease in foveal thickness seen in some patients.

In a news release from the company, Sirna’s chief medical officer, Roberto Guerciolini, MD, said, “These data represent an important milestone toward the demonstration of the potential therapeutic benefit of Sirna-027 and the clinical validation of RNAi as a therapeutic modality.”

Dr. Guerciolini also said that a longer-lasting therapy could reduce the need for frequent injections.

Future

As the next phase of clinical trials begins for both drugs, the experts who spoke to Ocular Surgery News explained why this technology is a promising step for treatment of AMD.

“Physicians are ready and expecting newer and better drugs,” Mr. Reich said. “Now physicians who can effectively treat patients with Lucentis are asking the question, ‘After I’ve used a VEGF protein blocker to initially treat the patient, what can I do now?’”

With the use of VEGF inhibitors on the rise and two potential RNAi treatments in development, there is the possibility of combination therapy.

“For instance, if you have an extracellular blocker of VEGF and a receptor blocker, you could have dramatically increased efficacy,” Dr. Kaiser said. “Or maybe its efficacy is as good as what we see with Lucentis, but we only have to inject it once every 12 weeks.”

Acuity will be investigating that prospect of less frequent or tapered injections in its phase 3 trial, Mr. Reich said.

“These patients have a lot of life to live, and a chronic therapy needs to be safer, needs to last longer to reduce the burden of doctor’s visits while providing the best possible therapeutic approach,” he said.

Continuing research may add to the abilities of RNAi, allowing additional modification if needed.

“The beauty of it is that we can block any gene that we want, so if we find that a different gene or a different area is more important for angiogenesis, it would be simple to take this new gene and produce an RNA-interfering molecule against it,” Dr. Kaiser said. “The technology is robust and able to be used for many different diseases.”

He added, “There are many ways that this may be used in the future. It really depends on how efficacious it is and how long a duration it has.”

For more information:

• Roberto Guerciolini, MD, chief medical officer of Sirna Therapeutics, can be reached at 185 Berry St., Suite 6504, San Francisco, CA 94107; 415- 512-7200; fax: 415-512-7022; e-mail: info@sirna.com.
• Peter K. Kaiser, MD, can be reached at Cole Eye Institute, Division of Ophthalmology, A31, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-6702; e-mail: pkkaiser@aol.com.
• Sam Reich, co-founder and vice president of research and development at Acuity Pharmaceuticals, can be reached at 3701 Market St., Philadelphia, PA 19104; 215-966-6191; e-mail: info@acuitypharma.com.
• Lawrence J. Singerman, MD, can be reached at Retina Associates of Cleveland, 3401 Enterprise Parkway, Suite 310, Beachwood, OH 44122; 216-831-5700; fax: 216-831-1959; e-mail: lsingerman@retina-assoc.com.

• Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.