Oral pazopanib (15 mg) was well-tolerated and associated with improvements in visual acuity, central retinal lesion thickness, and central retinal thickness in some patients with age-related macular degeneration (AMD), according to a small trial published online October 10 in JAMA Ophthalmology.
"Due to the treatment burden of frequent intravitreal injections for AMD, [we studied] an investigational product with an alternative route of delivery," lead author Megan M. McLaughlin, MS, clinical director and development lead, GlaxoSmithKline Ophthalmology in King of Prussia, Pennsylvania, told Medscape Medical News. "Pazopanib is a potent antiangiogenic that inhibits the same pathway as the intravitreal antivascular endothelial growth factor [VEGF] standard of care by inhibiting the receptor instead [of] inhibiting the ligand. Mouse studies predicted that doses of pazopanib lower than that used to treat cancer may be effective in AMD, [and] lower doses were also likely to be better tolerated in the elderly AMD population."
To determine a suitable dose of oral pazopanib for further investigation in AMD, the investigators conducted a 14-day, placebo-controlled, dose-rising study (5 - 30 mg daily) in 72 healthy participants. They also performed a 28-day, phase 2a open-label study of 15 mg oral pazopanib daily in 15 patients with subfoveal choroidal neovascularization secondary to AMD. Study endpoints included safety, pharmacokinetics, best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29.
Vision Improved in Some Patients
Tolerability of oral pazopanib was good at all doses tested in healthy participants and at 15 mg daily in patients with AMD. There were no clinically relevant effects on blood pressure, liver function, or thyroid function in this small study at lower doses, however, whereas in previous phase 3 clinical trials of 800 mg of daily pazopanib in cancer patients, hypertension, hepatic toxic effects, hypothyroidism, and proteinuria were reported.
Before day 29, 6 of 15 patients needed rescue therapy, and all of these patients had the CFH Y402H CC "high-risk" genotype for AMD. This group lost 5 letters of visual acuity during the study and had no mean decrease in macular edema.
The remaining 9 patients completed the study without need for rescue therapy, with improvements from baseline in best-corrected visual acuity (8 Early Treatment Diabetic Retinopathy Study letters), central retinal lesion thickness (−50.94 μm), and central retinal thickness (−50.28 μm).
"Interestingly, all 6 of the rescued patients carried the complement factor H genotype that has been associated with AMD risk and with poorer outcomes for patients in a number of studies of anti-VEGF therapy," McLaughlin said. "The 9 patients that completed 1 month of pazopanib without requiring rescue therapy showed average improvement of both vision and macular edema."
Preliminary Findings May Warrant Further Study
"The limited sample size and short follow-up are 2 of the main limitations of this study when assessing for safety and efficacy," Sumit P. Shah, MD, vitreoretinal surgeon at Retina Vitreous Center, NJ Retina, Rutgers, and Robert Wood Johnson University Hospital in New Brunswick, New Jersey, told Medscape Medical News when asked for independent comment. "Longer-term studies are warranted to assess both safety and efficacy of oral pazopanib, focusing on the pharmacogenetic efficacy findings of this study."
Dr. Shah agreed with the study authors' assessment that "oral pazopanib monotherapy in the overall exudative AMD population is unlikely in the future, given the highly effective and safe standard of care with local therapy via intravitreous injections of anti-VEGF medications."
Another study limitation is that patients included only those with occult and minimally classic choroidal neovascularization, precluding generalizability to other patients. This exploratory analysis should therefore be interpreted with caution.
"If oral pazopanib is shown to be an effective adjunctive therapy, even if only in a subset of patients, this may lessen the high level of treatment burden that most patients currently face with monthly injections or monthly follow-up," Dr. Shah said. "It is possible that this therapy could be used as an adjunct to the current standard of care. What is even more exciting is the possibility of utilizing complement factor H genotyping to more accurately predict a patient's response and generate an individual patient's treatment strategy."
The investigators suggest that the subset of patients with AMD most likely to benefit from pazopanib would be those carrying a T allele of CFH, representing approximately 70% of white individuals and 99% of East Asian individuals. On the basis of their preliminary findings, they suggest that additional trials may be warranted in this population.
"The treatment will unlikely completely supplant the use of intravitreal injections but would likely be used as an adjunct to intravitreal injection therapy," coauthor Mike Tolentino, MD, director of the Center for Retina and Macular Disease in Winter Haven, Florida, told Medscape Medical News. "It may have the potential to be used as the sole treatment in patients with early onset wet AMD.... It also should be tested to see if it can be used to maintain eyes that have been stabilized by intravitreal injections and are receiving injections in order to prevent recurrence."
Dr. Tolentino, who is also clinical associate professor at the University of Central Florida in Orlando, noted that this was an early-phase study and that much more research was needed on a larger scale, particularly to determine whether pazopanib can be used in adjunct to intravitreal injections.
"The rapidly increasing elderly population and the subsequent increase in the incidence of wet macular degeneration will strain the resources of our healthcare system, which is already being burdened with the leading edge of the baby boom generation," Dr. Tolentino concluded. "If an alternative to intravitreal injections is not developed, wet AMD will become one of the most expensive diseases for our healthcare systems, both from a financial and societal perspective.... Twenty years ago, when I was with the team that developed anti-VEGF therapies, we felt that intravitreal injections would be an intermediary treatment on the path to either an oral or eyedrop formulation [and] were never meant to be the final solution for the treatment of retinal diseases."
GlaxoSmithKline financially supported this study and employs McLaughlin and 5 other study authors. GlaxoSmithKline participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. McLaughlin receives GlaxoSmithKline stock as part of her compensation. Dr. Tolentino reported receiving research grants from GlaxoSmithKline, Regeneron, Bayer, Ophthotech, Quark, Pfizer, Lpath, Aerpio, Xoma, Santen, Notal Vision, Alcon, and Novartis and being a consultant to Bayer Health, Regeneron, Valeant, Promedior, Catalyst, and Artic Dx. Dr. Shah has disclosed no relevant financial relationships.
JAMA Ophthalmol. Published online October 10, 2013. Full text
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Cite this: AMD: Oral Pazopanib May Improve Vision, Retinal Thickness - Medscape - Oct 11, 2013.