Browsing by Author "Maturi, Raj K."
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Item Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): phase 2 trials in treatment-naïve and anti-VEGF pretreated patients(Springer Nature, 2024) Pereira, Daniel S.; Maturi, Raj K.; Akita, Kazumasa; Mahesh, Vinaya; Bhisitkul, Robert B.; Nishihata, Toshiaki; Sakota, Eri; Ali, Yusuf; Nakamura, Emiko; Bezwada, Padma; Nakamura, Yoshikazu; Ophthalmology, School of MedicineBackground/objective: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are the first-line treatment for exudative age-related macular degeneration (nAMD). Due to the limitations of these standard therapies, targeting alternative mechanisms of action may be helpful for treatment of this very common disease. Here, we investigated an anti-fibroblast growth factor-2 (FGF2) aptamer, umedaptanib pegol, a next generation therapeutic for the treatment of nAMD. Methods: Three phase 2 studies were designed. First, a multicentre, randomized, double-masked TOFU study assessed the efficacy of intravitreal injections of umedaptanib pegol monotherapy or in combination with aflibercept, compared to aflibercept monotherapy in 86 subjects with anti-VEGF pretreated nAMD. Second, 22 subjects who had exited the TOFU study received 4 monthly intravitreal injections of umedaptanib pegol (extension, RAMEN study). Third, as an investigator-sponsored trial (TEMPURA study), a single-center, open-label, 4-month study was designed to evaluate the safety and treatment efficacy of umedaptanib pegol in five naïve nAMD patients who had not received any prior anti-VEGF treatment. Results: The TOFU study demonstrated that umedaptanib pegol alone or in combination with aflibercept did not improve best-corrected visual acuity (BCVA) and central subfield thickness (CST) over aflibercept alone. However, the change in BCVA and CST at primary endpoint was marginal in all the three treatment groups, suggesting that umedaptanib pegol is effective to prevent the disease progression. The RAMEN study confirmed the cessation of disease progression. In the TEMPURA study, naïve nAMD patients showed improvement and no further macular degeneration, with striking improvement of visual acuity and central subfield thickness in some of the patients. Conclusions: These results demonstrate, for the first time, clinical proof of concept for aptamer based anti-FGF2 therapy of nAMD.Item Defining “Strong” versus “Weak” Response to Anti-VEGF Treatment for Center-Involved Diabetic Macular Edema(Wolters Kluwer, 2023) Sun, Jennifer K.; Beaulieu, Wesley T.; Melia, Michele; Ferris, Frederick L., III; Maturi, Raj K.; Nielsen, Jared S.; Solomon, Sharon D.; Jampol, Lee M.; DRCR Retina Network; Ophthalmology, School of MedicineBackground/purpose: To define "strong" versus "weak" antivascular endothelial growth factor (anti-VEGF) treatment response in eyes with center-involved diabetic macular edema (CI-DME). Methods: Exploratory analyses of three DRCR Retina Network randomized trials of eyes with CI-DME treated with aflibercept, bevacizumab, or ranibizumab. Thresholds of 5-, 10-, and 15-letter gain defined strong visual acuity (VA) response when baseline VA was 20/25-20/32, 20/40-20/63, or 20/80-20/320, respectively. Thresholds of 50, 100, or 200- µ m reduction defined strong anatomical response when baseline central subfield thickness (CST) was <75, ≥75 to <175, or ≥175- µ m above standard thresholds. Additional thresholds from regression equations were calculated. Results: At 24 weeks, outcomes for strong response were achieved by 476 of 958 eyes (50%) for VA and 505 eyes (53%) for CST. At 104 weeks among the 32% of eyes with strong VA and CST response at 24 weeks, 195 of 281 (69%) maintained strong VA and CST response, whereas 20 (7%) had neither strong VA nor strong CST response. Outcomes rates were similar across protocols and when defined using regression equations. Conclusion: These phenotypes are suitable for efforts to identify predictive biomarkers for response to anti-VEGF therapy for DME and might facilitate comparison of treatment response among diverse cohorts with DME.Item Dexamethasone Intravitreal Implant as Adjunctive Therapy to Ranibizumab in Neovascular Age-Related Macular Degeneration: A Multicenter Randomized Controlled Trial(Karger, 2015-09) Kuppermann, Baruch D.; Goldstein, Michaella; Maturi, Raj K.; Pollack, Ayala; Singer, Michael; Tufail, Adnan; Weinberger, Dov; Li, Xiao-Yan; Liu, Ching-Chi; Lou, Jean; Whitcup, Scott M.; Department of Ophthalmology, IU School of MedicinePurpose: To evaluate the efficacy and safety of dexamethasone intravitreal implant 0.7 mg (DEX) as adjunctive therapy to ranibizumab in neovascular age-related macular degeneration (nvAMD). Procedures: This was a 6-month, single-masked, multicenter study. Patients were randomized to DEX implant (n = 123) or sham procedure (n = 120) and received 2 protocol-mandated intravitreal ranibizumab injections. The main outcome measure was injection-free interval to first as-needed ranibizumab injection. Results: DEX increased the injection-free interval versus sham (50th percentile, 34 vs. 29 days; 75th percentile, 85 vs. 56 days; p = 0.016). 8.3% of DEX versus 2.5% of sham-treated patients did not require rescue ranibizumab (p = 0.048). Visual acuity and retinal thickness outcomes were similar in DEX and sham-treated patients. Only reports of conjunctival hemorrhage (18.2 vs. 8.5%) and intraocular pressure elevation (13.2 vs. 4.2%) were significantly different in the DEX versus the sham treatment groups. Conclusion: DEX reduced the need for adjunctive ranibizumab treatment and showed acceptable tolerability in nvAMD patients.Item Double-Masked, Randomized, Phase 2 Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Neovascular Age-Related Macular Degeneration(Mary Ann Liebert, 2018-11-09) Callanan, David; Kunimoto, Derek; Maturi, Raj K.; Patel, Sunil S.; Staurenghi, Giovanni; Wolf, Sebastian; Cheetham, Janet K.; Hohman, Thomas C.; Kim, Kimmie; López, Francisco J.; Schneider, Susan; Ophthalmology, School of MedicinePURPOSE: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. METHODS: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients (n = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). RESULTS: In the abicipar 1 mg (n = 25), abicipar 2 mg (n = 23), and ranibizumab (n = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 μm at week 16 and 116, 103, and 138 μm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. CONCLUSIONS: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported.Item Effect of Intravitreous Anti-Vascular Endothelial Growth Factor vs Sham Treatment for Prevention of Vision-Threatening Complications of Diabetic Retinopathy: The Protocol W Randomized Clinical Trial(American Medical Association, 2021) Maturi, Raj K.; Glassman, Adam R.; Josic, Kristin; Antoszyk, Andrew N.; Blodi, Barbara A.; Jampol, Lee M.; Marcus, Dennis M.; Martin, Daniel F.; Melia, Michele; Salehi-Had, Hani; Stockdale, Cynthia R.; Punjabi, Omar S.; Sun, Jennifer K.; DRCR Retina Network; Ophthalmology, School of MedicineImportance: The role of anti-vascular endothelial growth factor injections for the management of nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) has not been clearly established. Objective: To determine the efficacy of intravitreous aflibercept injections compared with sham treatment in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR. Design, setting, and participants: Data for this study were collected between January 15, 2016, and May 28, 2020, from the ongoing DRCR Retina Network Protocol W randomized clinical trial, conducted at 64 US and Canadian sites among 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43-53), without CI-DME. Analyses followed the intent-to-treat principle. Interventions: Eyes were randomly assigned to 2.0 mg of aflibercept injections (n = 200) or sham (n = 199) given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed. Main outcomes and measures: Development of CI-DME with vision loss or PDR through May 2020, when the last 2-year visit was completed. Results: Among the 328 participants (57.6% men [230 of 399 eyes]; mean [SD] age, 56 [11] years), the 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs 43.5% with sham. The overall hazard ratio for either outcome was 0.32 (97.5% CI, 0.21-0.50; P < .001), favoring aflibercept. The 2-year cumulative probability of developing PDR was 13.5% in the aflibercept group vs 33.2% in the sham group, and the 2-year cumulative probability of developing CI-DME with vision loss was 4.1% in the aflibercept group vs 14.8% in the sham group. The mean (SD) change in visual acuity from baseline to 2 years was -0.9 (5.8) letters with aflibercept and -2.0 (6.1) letters with sham (adjusted mean difference, 0.5 letters [97.5% CI, -1.0 to 1.9 letters]; P = .47). Conclusions and relevance: In this randomized clinical trial, among eyes with moderate to severe NPDR, the proportion of eyes that developed PDR or vision-reducing CI-DME was lower with periodic aflibercept compared with sham treatment. However, through 2 years, preventive treatment did not confer visual acuity benefit compared with observation plus treatment with aflibercept only after development of PDR or vision-reducing CI-DME. The 4-year results will be important to assess longer-term visual acuity outcomes.Item Effects of Shambhavi Mahamudra Kriya, a Multicomponent Breath-Based Yogic Practice ( Pranayama), on Perceived Stress and General Well-Being(Sage Publications, 2017-10) Peterson, Christine Tara; Bauer, Sarah M.; Chopra, Deepak; Mills, Paul J.; Maturi, Raj K.; Medicine, School of MedicineStress-induced disorders such as anxiety represent the leading causes of adult disability worldwide. Previous studies indicate that yoga and other contemplative practices such as pranayama, or controlled yogic breathing techniques, may be effective in the treatment of mood disorders and stress. In this study, 142 individuals (mean age = 43 years; SD = 13.90) participated in a 3-day retreat program during which they learned Shambhavi Mahamudra kriya, which is a yogic practice that includes both deep breathing and meditation techniques. Participants were instructed to practice the kriya each day for 21 minutes. After 6 weeks of daily practice, participants reported subjectively lower levels of perceived stress (Perceived Stress Scale) and higher levels of general well-being (General Well-Being Scale) compared to baseline. These results support the notion that Shambhavi Mahamudra kriya may represent a natural treatment for stress reduction.Item Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Patients With Neovascular Age-Related Macular Degeneration: Studies in Japan and the United States(Slack, 2019-02) Kunimoto, Derek; Ohji, Masahito; Maturi, Raj K.; Sekiryu, Tetsuju; Wang, Ying; Pan, Grace; Li, Xiao-Yan; Schneider, Susan; Ophthalmology, School of MedicineBACKGROUND AND OBJECTIVE: To evaluate comparability of abicipar pegol (abicipar) effects in patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in Japan and the United States. PATIENTS AND METHODS: Phase 2, multicenter, randomized, double-masked, 20-week studies (BAMBOO, Japan; CYPRESS, United States). Patients (n = 25 each study) received three monthly intravitreal injections of abicipar 1 mg or 2 mg or five monthly intravitreal injections of ranibizumab 0.5 mg. RESULTS: Mean best-corrected visual acuity change from baseline at week 16 (primary endpoint) for abicipar 1 mg, abicipar 2 mg, and ranibizumab was +7.8 letters, +8.9 letters, and +17.4 letters (BAMBOO); +4.4 letters, +10.1 letters, and +15.2 letters (CYPRESS). Mean central retinal thickness change from baseline was −187.3 μm, −196.5 μm, and −230.4 μm (BAMBOO); −106.5 μm, −112.8 μm, and −124.4 μm (CYPRESS). Uveitis or vitritis was reported in three abicipar-treated patients. CONCLUSION: Abicipar demonstrated extended duration of effect and safety that were comparable between Japanese and non-Japanese patients with nAMD. Abicipar effectively treated Japanese patients with polypoidal choroidal vasculopathy.Item Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy(American Medical Association, 2023) Maturi, Raj K.; Glassman, Adam R.; Josic, Kristin; Baker, Carl W.; Gerstenblith, Adam T.; Jampol, Lee M.; Meleth, Annal; Martin, Daniel F.; Melia, Michele; Punjabi, Omar S.; Rofagha, Soraya; Salehi-Had, Hani; Stockdale, Cynthia R.; Sun, Jennifer K.; DRCR Retina Network; Ophthalmology, School of MedicineImportance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, setting, and participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main outcomes and measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME.Item Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results(Dove Press, 2023-05-11) Callanan, David; Khurana, Rahul N.; Maturi, Raj K.; Patel, Sunil; Wykoff, Charles C.; Eichenbaum, David; Khanani, Arshad M.; Hassan, Tarek; Badger, Hanh; Mehta, Shraddha; Le, Grace; Attar, Mayssa; Seal, Jennifer; Li, Xiao-Yan; Ophthalmology, School of MedicinePurpose: To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD). Methods: A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24. Outcome measures included proportion of patients with stable vision (<15-letter loss from baseline; primary endpoint), change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and adverse events. Results: Overall, 8.9% (11/123) of patients experienced intraocular inflammation (IOI) and discontinued treatment. IOI cases were assessed as mild (2.4% [3/123]), moderate (4.9% [6/123]), or severe (1.6% [2/123]) and resolved with steroid treatment. Visual acuity in most patients with IOI (8 of 11) recovered to baseline BCVA or better by study end. No cases of endophthalmitis or retinal vasculitis were reported. Stable vision was maintained for ≥95.9% (≥118/123) of patients at all study visits. At week 28, treatment-naïve patients showed a greater mean improvement from baseline in BCVA compared with previously treated patients (4.4 vs 1.8 letters) and a larger mean CRT reduction from baseline (98.5 vs 45.5 μm). Conclusion: Abicipar produced using a modified manufacturing process showed a moderately lower incidence and severity of IOI compared with Phase 3 abicipar studies. Beneficial effects of treatment were demonstrated.Item Intravitreal sirolimus for persistent, exudative age-related macular degeneration: a Pilot Study(BMC, 2021-02-16) Minturn, Robert J.; Bracha, Peter; Klein, Margaret J.; Chhablani, Jay; Harless, Ashley M.; Maturi, Raj K.; Ophthalmology, School of MedicineBackground and objective: To evaluate the safety and efficacy of intravitreal sirolimus for persistent, exudative age-related macular degeneration (AMD). Methods: This institutional review board approved, registered (NCT02357342), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative Age-related macular degeneration compared intravitreal sirolimus monotherapy (every 2 months) versus monthly anti-vascular endothelial growth factor (VEGF) over six months. Results: 20 subjects were randomized to each arm of the trial. Upon completion of the trial 20 patients were analyzed in the control (anti-vascular endothelial growth factor) group and 17 patients were analyzed in the treatment (sirolimus) group. On average, subjects had 33 previous anti-VEGF injections prior to entry. The primary end-point, mean central subfield thickness (CST), increased by 20 µm in the anti-vascular endothelial growth factor group and decreased by 40 µm in the sirolimus group (p = 0.03). Visual acuity outcomes were similar between groups. Serious ocular adverse events in the sirolimus group included one subject each with anterior uveitis, central retinal artery occlusion and subretinal hemorrhage. Conclusion: Monotherapy with intravitreal sirolimus for subjects with persistent, exudative age-related macular degeneration appears to have a limited positive anatomic benefit. The presence of adverse events in the experimental group merits further evaluation, potentially as an adjuvant therapy. Trial registration This trial was registered with the clinicaltrials.gov, NCT02357342, and was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.