Novel drug delivery system reduces treatment burden in neovascular AMD
Intravitreal injection of antiangiogenic agents is the standard of care for neovascular age-related macular degeneration (nAMD), however, frequent injections represent a considerable treatment burden for patients. Results of the Ladder and Archway studies, presented at the 38th Annual Meeting of the American Society of Retina Specialists (ASRS 2020), showed that administration of ranibizumab through a port delivery system (PDS) considerably reduced treatment burden, while maintaining comparable efficacy and safety vs intravitreal injections. In an interview with MIMS Doctor, Dr Timothy Lai of Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, discusses how PDS may transform the management of nAMD.
PDS is a permanent, refillable implant surgically inserted through a small incision in the sclera at the pars plana. It contains a reservoir of the anti-vascular endothelial growth factor (VEGF) agent, ranibizumab, which is continuously released into the vitreous over time and can be refilled without the need for implant removal. [Ophthalmology 2019;126:1141-1154]
The phase II Ladder trial evaluated the safety and efficacy of ranibizumab (10 mg/mL, 40 mg/mL and 100 mg/mL) PDS vs monthly intravitreal ranibizumab (0.5 mg) in 220 nAMD patients. Results showed that the PDS was generally well tolerated. At 9 months, PDS ranibizumab 100 mg/mL demonstrated comparable visual and anatomic outcomes vs monthly intravitreal injection of ranibizumab 0.5 mg. [Ophthalmology 2019;126:1141-1154]
Updated results at 22 months
After a mean follow-up of 22 months, the mean changes in best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) central foveal thickness remained comparable between patients receiving PDS ranibizumab 100 mg/mL and monthly ranibizumab 0.5 mg. [Eichenbaum D, et al, ASRS 2020]
“Notably, the median time to first refill was 15.8 months in patients on PDS ranibizumab 100 mg/mL,” reported investigator Dr David Eichenbaum of the Retina Vitreous Associates of Florida, St Petersburg, Florida, US. “In those who required ≥1 refill, the median time to first and second refills was consistent, at 8.8 months each.”
The safety profile of PDS was consistent with the primary analysis, with no new safety signals observed.
In 68 patients with evaluable pharmacokinetic (PK) profile, PDS continued to release ranibizumab through ≥16 months without refill. The PK profile of ranibizumab was consistent following PDS implantation and multiple refills. [Dhoot DS, et al, ASRS 2020]
“In addition, the serum concentrations of ranibizumab among patients receiving PDS 100 mg/mL were within the range of concentrations of those receiving intravitreal ranibizumab injection,” said investigator Dr Dilsher Dhoot of the California Retina Consultants, Santa Barbara, California, US.
PDS ranibizumab 100 mg/mL was further evaluated in the phase III, noninferiority Archway trial in 415 nAMD patients with documented response to prior anti-VEGF therapy. The patients were randomized in a 3:2 ratio to receive PDS ranibizumab 100 mg/mL refilled every 24 weeks (n=248) or intravitreal ranibizumab 0.5 mg every 4 weeks (n=167).
Efficacy and safety results
“The study’s primary endpoint was met, with PDS ranibizumab 100 mg/mL demonstrating noninferiority and equivalence to intravitreal ranibizumab 0.5 mg in terms of change in BCVA score from baseline averaged over weeks 36 and 40 [difference in adjusted mean, -0.3; 95 percent confidence interval, -1.7 to +1.1],” reported investigator Professor Peter Campochiaro of the Johns Hopkins University School of Medicine, Baltimore, Maryland, US. (Figure 1) “A transient postsurgical drop in vision was noted at week 4 in the PDS arm, which improved at week 8 and normalized at week 12.” [Campochiaro P, et al, ASRS 2020]
Likewise, maintenance of OCT central point thickness was comparable between PDS and intravitreal injection through week 36 (change from baseline, +5.4 µm vs +2.6 µm).
“PDS was also shown to reduce nAMD treatment burden,” said Campochiaro. “Notably, 98.4 percent of patients treated with PDS ranibizumab 100 mg/mL did not require any supplemental treatments before the first refill exchange. The total number of ranibizumab treatment was 5 times lower in patients receiving PDS through week 40.” (Figure 2)
“The PDS implant insertion and refill-exchange procedures were generally well tolerated. Conjunctival bleb or conjunctival filtering bleb leak was reported in 6.5 percent of patients receiving PDS, which were all non-serious and predominately due to subconjunctival thickening. Vitreous haemorrhage occurred in 5.2 percent of the cases, all of which resolved spontaneously,” he said. “Cataract rates were comparable between PDS and intravitreal ranibizumab [4.0 percent vs 3.6 percent]. Four cases of endophthalmitis [1.6 percent] were reported in patients receiving PDS, one of which led to irreversible vision loss due to Enterococcus faecalis infection.”
“The Archway study met its primary endpoint, demonstrating noninferiority and equivalence of PDS ranibizumab 100 mg/mL every 24 weeks vs monthly intravitreal ranibizumab 0.5 mg for BCVA change at weeks 36 and 40. PDS also provided comparable control of retinal thickness vs monthly ranibizumab through week 40, and reduced the number of treatments vs intravitreal injection whilst demonstrating a favourable benefit-risk profile,” concluded Campochiaro. “These results showed that PDS maintained vision while reducing treatment burden through continuous delivery of ranibizumab in patients with nAMD.”
Optimizing nAMD management with PDS: Addressing unmet needs
nAMD is highly prevalent in societies with ageing populations such as Hong Kong, and is a chronic disease requiring long-term treatment and monitoring.
Unmet needs in nAMD treatment
“Intravitreal injections of anti-VEGF agents have been used for around 15 years in Hong Kong. The injection procedure is slightly uncomfortable for some patients in spite of local anaesthesia, mainly due to the irritation caused by the povidone-iodine antiseptic solution,” said Lai.
“Although most patients respond well to intravitreal anti-VEGF injections, a large number subsequently withdraw from treatment due to inconvenience or financial concerns,” he noted.
Intravitreal anti-VEGF treatment typically requires three initial monthly loading doses, along with close monitoring of visual acuity and the macular structure by OCT. Treatment is given regularly thereafter, gradually extending the treatment interval from 4 weeks to 8 weeks, and up to 16 weeks in some cases, subject to the duration of nAMD control in individual patients. “This proactive treat-and-extend approach ensures constant suppression of the macular neovascularization,” said Lai.
Insights from Archway trial
According to Lai, the results of the Archway trial were promising, given that 98.4 percent of patients receiving PDS did not require supplemental treatment in addition to the preplanned ranibizumab refill at 24 weeks.
“Notably, patients enrolled in Archway had relatively good baseline BCVA (mean Early Treatment Diabetic Retinopathy Study [ETDRS] letter score, 74.4–75.5),” Lai pointed out. “The transient drop of around five ETDRS letters in visual acuity observed at week 4 in the PDS arm may not have been as prominent in patients with poorer baseline BCVA.” This temporary decline could be attributed to minor vitreous haemorrhage causing haze and blurred vision, which normalized at week 12.
“The Archway trial implemented the new and improved surgical insertion technique conceived during the earlier Ladder trial, significantly reducing the risk of vitreous haemorrhage associated with PDS, as demonstrated by the large difference in vitreous haemorrhage rate before and after the procedure update in May 2016 [50.0 percent vs 5.2 percent],” he continued. “In addition, all cases of vitreous haemorrhage in Archway resolved spontaneously, suggesting that it is unlikely to be a major safety concern.”
Conjunctival retraction was the main reason for several cases of endophthalmitis in the PDS arm, indicating that proper postsurgical wound closure is of paramount importance. [Campochiaro P, et al, ASRS 2020]
Introducing PDS in clinical practice
According to Lai, uptake of PDS in Hong Kong would depend on cost, and it might have the potential for long-term cost savings and reduce the waiting time of anti-VEGF therapy especially in the public hospitals. “A treatment that is as effective as the 4-weekly injections, is more affordable, and administered only once every 24 weeks, or even less frequently, would be favoured by patients and could be a more sustainable form of treatment,” he suggested.
“Given that the PDS implantation procedure is not too straightforward, appropriate training of local retinal subspecialists would be critical to the treatment’s introduction in clinical practice,” he added. “The anticipated longer-term safety data from the Archway trial should provide further reassurance to ophthalmologists.”