Single-fragment antibody VEGF inhibitor meets primary endpoint of non-inferiority

The small compound may allow for more targeted and less frequent injections to treat wet AMD.

A humanized single-chain antibody fragment VEGF inhibitor to treat neovascular age-related macular degeneration was found to be non-inferior to ranibizumab intravitreal injections, according to a phase 2 multicenter study.

The manufacturing of the single-fragment antibody RTH258 (formerly ESBA1008) is a collaborative venture between Alcon and Novartis.

“It is a very, very small compound, half the size of ranibizumab,” co-investigator Pravin U. Dugel, MD, an OSN Retina/Vitreous Board Member, said. “The importance of having a drug that is small is that a greater concentration of the drug can be placed in a smaller volume; thus, a lot more of the drug can be placed in the target area.” The drug also has the potential to be packaged in a delivery device.

Pravin U. Dugel

Dose-escalation study

The dose-escalation study, which appeared in Ophthalmology, compared a single intravitreal injection of RTH258 in four doses — 0.5 mg (11 patients), 3 mg (31 patients), 4.5 mg (47 patients) and 6 mg (44 patients) — with a single injection of Lucentis (ranibizumab, Genentech) 0.5 mg (61 patients).

“This new drug was non-inferior to ranibizumab, and there was a trend, although not statistically significant, toward better vision and a longer duration,” Dugel told Ocular Surgery News.

The study also found that the 6 mg dose of RTH258 provided the most potent effect.

The primary endpoint of the study was a reduction in the central subfield thickness, as measured by spectral-domain OCT. “This endpoint, which was non-inferiority to ranibizumab, was met,” Dugel said.

The two secondary endpoints were vision and duration of RTH258, both of which were encouraging. Specifically, the median time to post-baseline therapy was 60 days for the 4.5 mg group and 75 days for the 6 mg group, compared with 45 days for ranibizumab.

No adverse events of concern were found for any of the four doses of RTH258.

Dugel was also an investigator for a recent study that compared RTH258 with Eylea (aflibercept, Regeneron).

“RTH258 was found to be non-inferior to on-label use of Eylea,” he said.

Furthermore, an extension of the same trial concluded that 50% of patients could be given an injection of RTH258 once every 12 weeks.

“This finding supports the trend of greater durability,” Dugel said. “If the studies are confirmed, there may be a population of patients in whom we can give this drug once every 12 weeks instead of once every 4 weeks, which would greatly reduce treatment burden.”

Potential to reduce treatment

Dugel noted that the protocol for the definitive studies of ranibizu­mab entails an injection once every 4 weeks.

“Right now, though, the way we are administering drugs in real life is simply not the way that they were administered in clinical trials,” he said. “There is a very large disconnect. We know this through several important Medicare database analyses. The treatment burden of coming in every 4 weeks is simply too much for patients. Many patients are receiving less than half the number of recommended injections.”

A drug such as RTH258 that could be placed into a drug-delivery device would also be of benefit.

“There is a 22 times greater molar excess of RTH258 per volume than ranibizumab,” Dugel said. “Therefore, a very small amount of volume of this new drug will provide a lot of drug concentration and a lot of drug activity.”

Dugel believes it is possible that RTH258 could replace existing anti-VEGF injections.

“But we need to ensure that we are basing our treatment on good science. This will not be available until the ongoing phase 3 study is completed,” he said. “However, if the phase 3 study replicates the phase 2 study, I think there is a very good chance that RTH258 will be an important drug.” – by Bob Kronemyer

Disclosure: Dugel reports he is a paid consultant to Alcon, Novartis and Genentech.

A humanized single-chain antibody fragment VEGF inhibitor to treat neovascular age-related macular degeneration was found to be non-inferior to ranibizumab intravitreal injections, according to a phase 2 multicenter study.

The manufacturing of the single-fragment antibody RTH258 (formerly ESBA1008) is a collaborative venture between Alcon and Novartis.

“It is a very, very small compound, half the size of ranibizumab,” co-investigator Pravin U. Dugel, MD, an OSN Retina/Vitreous Board Member, said. “The importance of having a drug that is small is that a greater concentration of the drug can be placed in a smaller volume; thus, a lot more of the drug can be placed in the target area.” The drug also has the potential to be packaged in a delivery device.

Pravin U. Dugel

Dose-escalation study

The dose-escalation study, which appeared in Ophthalmology, compared a single intravitreal injection of RTH258 in four doses — 0.5 mg (11 patients), 3 mg (31 patients), 4.5 mg (47 patients) and 6 mg (44 patients) — with a single injection of Lucentis (ranibizumab, Genentech) 0.5 mg (61 patients).

“This new drug was non-inferior to ranibizumab, and there was a trend, although not statistically significant, toward better vision and a longer duration,” Dugel told Ocular Surgery News.

The study also found that the 6 mg dose of RTH258 provided the most potent effect.

The primary endpoint of the study was a reduction in the central subfield thickness, as measured by spectral-domain OCT. “This endpoint, which was non-inferiority to ranibizumab, was met,” Dugel said.

The two secondary endpoints were vision and duration of RTH258, both of which were encouraging. Specifically, the median time to post-baseline therapy was 60 days for the 4.5 mg group and 75 days for the 6 mg group, compared with 45 days for ranibizumab.

No adverse events of concern were found for any of the four doses of RTH258.

Dugel was also an investigator for a recent study that compared RTH258 with Eylea (aflibercept, Regeneron).

“RTH258 was found to be non-inferior to on-label use of Eylea,” he said.

Furthermore, an extension of the same trial concluded that 50% of patients could be given an injection of RTH258 once every 12 weeks.

“This finding supports the trend of greater durability,” Dugel said. “If the studies are confirmed, there may be a population of patients in whom we can give this drug once every 12 weeks instead of once every 4 weeks, which would greatly reduce treatment burden.”

Potential to reduce treatment

Dugel noted that the protocol for the definitive studies of ranibizu­mab entails an injection once every 4 weeks.

“Right now, though, the way we are administering drugs in real life is simply not the way that they were administered in clinical trials,” he said. “There is a very large disconnect. We know this through several important Medicare database analyses. The treatment burden of coming in every 4 weeks is simply too much for patients. Many patients are receiving less than half the number of recommended injections.”

A drug such as RTH258 that could be placed into a drug-delivery device would also be of benefit.

“There is a 22 times greater molar excess of RTH258 per volume than ranibizumab,” Dugel said. “Therefore, a very small amount of volume of this new drug will provide a lot of drug concentration and a lot of drug activity.”

Dugel believes it is possible that RTH258 could replace existing anti-VEGF injections.

“But we need to ensure that we are basing our treatment on good science. This will not be available until the ongoing phase 3 study is completed,” he said. “However, if the phase 3 study replicates the phase 2 study, I think there is a very good chance that RTH258 will be an important drug.” – by Bob Kronemyer

Disclosure: Dugel reports he is a paid consultant to Alcon, Novartis and Genentech.