Helping patients who do not respond to anti-VEGF therapy

Study rejects notion of ‘nonresponders’ to therapeutic option

This article was reviewed by Saghar Bagheri, MD, PhD, and Demetrios G. Vavvas, MD, PhD

Anti-vascular endothelial growth factor (VEGF) drugs reduce vision loss in patients with neovascular age-related macular degeneration (AMD). As a result, these drugs have become the primary go-to therapies for ophthalmologists. 

However, a substantial number of patients do not respond to this therapy, or do so to an inadequate degree. Those calculations have been reported to range from 10% to 50% depending on the study, despite receiving monthly injections of anti-VEGF therapies.

Related: Anti-VEGF targeted as potential treatment for nAMD

A team of researchers from Harvard disagree with the notion that there are high percentages of patients who do not respond to anti-VEGF therapy for neovascular AMD. In fact, they claim there are no nonresponders to anti-VEGF therapy.

They maintain that the so-called non-responders actually respond, but for a shorter duration than most, according to principal investigator Demetrios G. Vavvas, MD, PhD, associate professor of ophthalmology, and co-first author Saghar Bagheri, MD, PhD, clinical research fellow at Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, at Harvard Medical School, in Boston.

The investigators pointed out that for many patients, the maximum anti-VEGF treatment effect occurs prior to the standard week-4 assessment, and on average occurs at 3 weeks postinjection.

They explain that this was anticipated by the pharmacokinetic data. For this reason, the phase 2 tolerability and efficacy study of dose escalation of ranibizumab (Lucentis, Genentech Inc) included a cohort of patients dosed at 2-week intervals. 

This study showed that the 2-week interval was tolerated and showed trends for superior outcomes compared with the longer interval. However, in the phase 3 study, only monthly dosing was tested out of convenience.

The PrONTO study recorded data on weeks 1, 2, and 4 after the first injection of Lucentis (40 patients) and reported that visual acuity levels were similar at 2 and 4 weeks. They also reported that the status of subretinal or intraretinal fluid was not statistically significantly different between these time points (~30%-25% of patients had subretinal fluid).

This study unfortunately reported averages of all patients and did not report details on the cohort with persistent subretinal fluid.¹Related: Anti-VEGF injections and glaucoma: Surgeons must watch IOP elevation 

A previous pharmacokinetic study reported that the optimal dose interval is less than 4 weeks and more likely 2 to 3 weeks.² This finding was confirmed by a recent biweekly bevacizumab study (Avastin, Genentech, Inc), which showed that 20% of patients had improved central macular thickness and total macular volume.

Based on the lack of prior consensus, cofirst authors Bagheri and Georgios Bontzos, MD, and colleagues conducted a multicenter observational study that included 48 patients with neovascular AMD; 25 patients were treatment-naive, and the remainder had been treated with ranibizumab (mean number of previous injections, 8.5). 

All patients in the study were treated with ranibizumab (0.5 mg/0.05 mL) and were examined weekly for 4 weeks using spectral-domain optical coherence tomography.

The investigators assessed the time to maximal reduction of the central retinal thickness (CRT) and the presence of sub- and intraretinal fluid. The main outcome measure was the time to the maximal reduction of the CRT and the intra- and subretinal fluid, Bagheri recounted. 

Related: Quest for data increases debate for anti-VEGF therapy approach

Value of weekly assessments
The study comprised 19 men and 29 women (mean age, 74 years). Interestingly, during week 1 after injection, 3 patients (6.3%) had the smallest CRT value, 11 patients (22.9%) had the smallest value during the second week, and 17 patients (35.4%) each had the smallest value during the third and fourth weeks. Considered together, 

“Two-thirds (64.6%) reached the maximal CRT reduction earlier than the standard 4-week interval,” they emphasized. 

Analysis also showed that 20% of patients who were treatment-naive and 34.8% of patients who underwent treatment had a CRT at week 4 that was actually more than 35 mm thicker than the earlier lowest CRT value.

The study showed the time to reach the lowest CRT value was not associated with the axial length, age, lens status, or history of injections.

Related: Study shows similarity in anti-VEGF injection intervals for wet AMD

The authors suspect that disease load and drug clearance from the eye rather than ocular volume and intraocular drug concentration may be stronger determinants responsible for the duration of anti-VEGF treatment effect and time to maximal structural response. Invasive studies with aqueous tap will be needed to determine the variability of anti-VEGF response with more certainty.

The important points of this study are that optimal dosing might be shorter than 4 weeks for a sizable percentage of patients, and most patients who were considered poor or nonresponders may be seen as responding if they are evaluated prior to the standard 4-week assessment.

The authors conclude that these results imply that with a current dosing regimen of 4 weeks or more, there is a partial escape of VEGF suppression for many patients, which may have implications for progression of neovascular and nonneovascular components of the disease. 

Finally, the disease load seems to drive the anti-VEGF treatment duration rather than the ocular volume. The limitations of this study are the small patient number, the investigation of structural treatment response without description of visual outcomes, and the short study duration. The results were reported in Ophthalmology Retina.³Read more by Lynda Charters

Saghar Bagheri, MD, PhD
e: Saghar_Bagheri@meei.harvard.edu
Dr Bagheri is a consultant to NASA and medical director of clinical research at OliX Pharmaceuticals, Inc.Demetrios G. Vavvas, MD, PhD
e: vavvas@meei.harvard.edu
Dr. Vavvas is a consultant to OliX Pharmaceuticals, Inc and to Valitor, Inc.

References:

Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.

Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic Rationale for Dosing Every 2 Weeks Verus 4 Weeks With Intravitreal Ranibizumab, Bevacizumab, and Aflibercept (Vascular Endothelial Growth Factor Trap-eye).Retina 2012;32: 434-457.

Bontzos GB, Bagheri SB, Ioanidi L, et al. Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study. Ophthalmol Retina. 2019 Nov 11;S2468-6530(19)30628-1.