This article is more than 5 years old. Information may no longer be current.
Pazopanib eye drops fail to reduce frequency of Lucentis injections for neovascular AMD
Study co-author says that anti-VEGF monotherapy has ‘reached its ceiling’ and that combination treatment is the next step.
Click Here to Manage Email Alerts
Administering pazopanib eye drops did not reduce the number of ranibizumab intravitreal injections in patients with neovascular age-related macular degeneration, according to a multi-country, dose-ranging study.
“The primary endpoint of the study was to reduce treatment burden by 50%, which is quite an ambitious primary endpoint,” co-author Pravin U. Dugel, MD, an OSN Retina/Vitreous Board Member, said. “That endpoint was not achieved.”
Pravin U. Dugel
The study was not designed to assess whether any regimen reduced frequency of injections by less than 50%.
Downstream mechanism
Dugel and colleagues were partially drawn to the study because the pazopanib compound inhibits angiogenesis fairly far downstream. At the time the study began, the only drug approved to treat neovascular AMD was Lucentis (ranibizumab, Genentech), whose mechanism of action occurs further upstream, Dugel said.
“[Pazopanib] may actually have a pretty broad action as opposed to something that is further upstream,” Dugel said.
In addition, monthly injections of ranibizumab were considered optimal therapy at the time.
“However, we realized such a regimen was not logistically sustainable,” Dugel said. “Plus, we know now that the best treatment strategy is an individualized treatment strategy.”
A previous study by Danis and colleagues suggested that the combination of ranibizumab and pazopanib would be effective, particularly for a specific genotype, Dugel said.
“The fact that this combination was not effective in reducing treatment burden in our larger study was the biggest surprise,” he said.
Study method
The 510 patients in the current study, all of whom underwent treatment with ranibizumab injections, were divided into seven groups: 73 patients received placebo four times daily; 72 patients received pazopanib 5 mg/mL three times daily; 74 patients received pazopanib 5 mg/mL four times daily; 73 patients received pazopanib 10 mg/mL twice daily; 73 patients received pazopanib 10 mg/mL three times daily; 72 patients received 10 mg/mL four times daily; and 73 patients received ranibizumab monthly.
All eye drop treatment groups were given ranibizumab as needed.
None of the regimens improved best corrected visual acuity beyond ranibizumab injections alone.
On the other hand, the study found no major safety concerns with the eye drops.
Patient blood samples indicated a relationship between the dose of pazopanib and the amount of systemic exposure.
“It was felt that enough of the drug was going in,” Dugel said. “However, how the drug was being used and where it was going in, frankly, we do not know. The drug is sequestered mainly by melanin. Whether it is sufficient to be sequestered by melanin or whether the drug should go in the vitreous instead, we do not know because we did not take any vitreous samples. Hence, we do not know whether the drug went where it should go.”
Tyrosine kinase inhibitors
Developing an eye drop that would reduce the frequency of injections and perhaps even improve visual outcomes is a challenge.
“Every eye drop tested thus far has not worked,” Dugel said, perhaps because “not enough of the drug reaches the back of the eye or the formulation is too difficult to make.”
Still, Dugel is encouraged that pazopanib’s family of compounds, tyrosine kinase inhibitors, will help in the treatment of neovascular AMD.
“Tyrosine kinase blocks the action of all VEGF receptors — 1, 2 and 3 — further downstream,” he said. “It also inhibits the extremely important compound platelet-derived growth factor.”
“We have come to the realization that anti-VEGF monotherapy has reached its ceiling,” Dugel said. “The next logical step is combination treatment for patients with neovascular AMD.” – by Bob Kronemyer
References:
Csaky KG, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2014.09.036.Danis R, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2013-303117.
For more information:
Pravin U. Dugel, MD, can be reached at Retinal Consultants of Arizona, 1101 E. Missouri Ave., Phoenix, AZ 85014; email: pdugel@gmail.com.Disclosure: Dugel reports no relevant financial disclosures.