pazopanib and Wet-Macular-Degeneration

Topics: Algorithms; Cholestanols; Double-Blind Method; Indazoles; Indoles; Intravitreal Injections; Ophthalmic Solutions; Phenylurea Compounds; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Vascular Endothelial Growth Factor A; Wet Macular Degeneration

To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).. Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops.. A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections.. Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed.. The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24.. At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported.. Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Biomarkers; Double-Blind Method; Female; Fluorescein Angiography; Humans; Indazoles; Intravitreal Injections; Male; Neoplasm Proteins; Ophthalmic Solutions; Pharmacogenetics; Pyrimidines; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Tomography, Optical Coherence; Visual Acuity; Wet Macular Degeneration

To evaluate pazopanib 10 mg/mL eye drops (pazopanib) in healthy subjects and in subjects with previously untreated subfoveal choroidal neovascularization secondary to age-related macular degeneration.. Study 1 (single center, randomized, placebo-controlled, double-masked) included 3 cohorts of 12 to 13 healthy subjects each who instilled pazopanib or placebo 4 times daily for 2 weeks. Study 2 (multicenter open-label) included 19 subjects with neovascular age-related macular degeneration who instilled pazopanib 4 times daily for 12 weeks. Both studies evaluated pharmacokinetics and safety. Study 2 also evaluated efficacy.. Steady-state concentrations of pazopanib in plasma seemed to be reached by Week 2. At Week 4 (Study 2), there were no meaningful changes from baseline in the mean central retinal thickness (37.9 μm) or best-corrected visual acuity (0.1 letters) (primary endpoint), retinal morphology, choroidal neovascularization size, or total lesion size. Complement Factor H genotype had no effect on changes from baseline in the best-corrected visual acuity or central retinal thickness. The most common pazopanib-related ocular adverse events included eye irritation (Study 1, n = 7) and instillation site pain (Study 2, n = 3). No serious adverse events were reported.. Pazopanib was well tolerated. In subjects with previously untreated neovascular age-related macular degeneration, pazopanib instilled 4 times daily as monothereapy did not seem to improve the best-corrected visual acuity or decrease the central retinal thickness.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Biological Availability; Double-Blind Method; Female; Healthy Volunteers; Humans; Indazoles; Male; Middle Aged; Ophthalmic Solutions; Protein-Tyrosine Kinases; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Retina; Sulfonamides; Tissue Distribution; Visual Acuity; Wet Macular Degeneration; Young Adult

Neovascular age-related macular degeneration (AMD) is managed with intravitreal anti-vascular endothelial growth factor therapy; however, the burden of care is high and alternate approaches could be beneficial. OBJECTIVE To identify an acceptable dose of oral pazopanib for investigation in AMD.. Fourteen-day, placebo-controlled, dose-rising study in 72 healthy participants and 28-day phase 2a open-label study in 15 patients with subfoveal choroidal neovascularization secondary to AMD at a clinical unit for healthy participants and outpatient for patients with AMD.. Oral pazopanib tablets, 5 to 30 mg daily (healthy participants) and 15 mg daily (patients with AMD).. Safety, pharmacokinetics, best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29.. Oral pazopanib up to 30 mg daily in healthy participants and 15 mg daily in patients with AMD was well tolerated. Six of 15 patients received rescue therapy before day 29; all had the CFH Y402H CC "high-risk" genotype for AMD. Nine patients completed the study without rescue 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). There was a trend for association between the CFH Y402H T allele ("low risk" for AMD, n = 6) and improvement.. Oral pazopanib (15 mg daily) was well tolerated and resulted in improvements in mean best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29 in a per-protocol, nonrescued AMD population (n = 9). It is postulated that CFH Y402H genotype may help predict which patients respond to pazopanib. The size and length limitations of this study warrant further investigation to determine if oral pazopanib may be an appropriate treatment for a subset of neovascular patients with AMD or as an adjunct to standard of care.. clinicaltrials.gov Identifier: NCT01051700 and NCT01154062.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Complement Factor H; Female; Genotype; Humans; Indazoles; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Single-Blind Method; Sulfonamides; Treatment Outcome; Visual Acuity; Wet Macular Degeneration; Young Adult

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Choroid; Choroidal Neovascularization; Female; Humans; Intravitreal Injections; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors; Pyrimidines; Rats; Vascular Endothelial Growth Factor Receptor-2; Wet Macular Degeneration

Multikinase inhibitors (MKI) interfere effectively at different levels of the neovascularisation cascade. Early clinical and experimental data suggest that MKIs represent a promising novel approach for the treatment of neovascular age-related macular degeneration (AMD). However, so far little is known about the biocompatibility of MKIs regarding human ocular cells. This in vitro study investigates and compares the biocompatibility of three MKIs, axitinib, pazopanib, and sorafenib regarding ocular cells of the anterior and posterior segments, as well as organ-cultured donor corneas.. Primary human optic nerve head astrocytes (ONHA), trabecular meshwork cells (TMC), and retinal pigment epithelium (RPE), human corneal endothelial and lens epithelial cells (CEC and LEC) were treated with different concentrations of axitinib, pazopanib, or sorafenib (0.1 to 100 µg/mL). To simulate oxidative stress, the cells were additionally co-incubated with 400 µM hydrogen peroxide. Induction of cell death and cellular viability were examined by live-dead assay and tetrazolium dye reduction assay (MTT). In addition, the influence of the three substances on human corneal endothelium was evaluated in seropositive donor corneas in organ culture by phase contrast microscopy.. Up to a concentration of 7.5 mg/mL of the substances tested in any cell type examined, no toxic effects were found. Even after 10 days of incubation of organ-cultured donor corneas with 7.5 µg/mL, axitinib, pazopanib, or sorafenib, no evidence for endothelial toxicity was found.. All three MKIs tested, axitinib, pazopanib, and sorafenib showed a good biocompatibility on the investigated ocular cells. Even under conditions of oxidative stress, there were no toxic effects up to a concentration of 7.5 µg/mL. Only at higher concentrations, there was a dose-dependent decrease in cellular viability and pronounced induction of cell death. These effects on cellular viability and induction of cell death appeared to be stronger with pazopanib, followed by sorafenib, than with axitinib.

Topics: Angiogenesis Inhibitors; Astrocytes; Axitinib; Cell Survival; Cornea; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Corneal; Humans; Imidazoles; Indazoles; Lens, Crystalline; Microscopy, Phase-Contrast; Niacinamide; Optic Disk; Organ Culture Techniques; Oxidative Stress; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Retinal Pigment Epithelium; Sorafenib; Sulfonamides; Trabecular Meshwork; Wet Macular Degeneration