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Sonepcizumab alone or in combination with anti-VEGF does not provide any short-term benefit to the visual acuity in patients with wet AMD, who were considered to be subresponders to anti-VEGF therapy. However, a combination of therapies may have different results.
Take-home: Sonepcizumab alone or in combination with anti-VEGF does not provide any short-term benefit to the visual acuity in patients with wet AMD, who were considered to be subresponders to anti-VEGF therapy. The combination of high-dose sonepcizumab with anti-VEGF therapy may provide long-term, visual acuity stabilization and further investigation may be warranted.
Reviewed by Thomas A. Ciulla, MD, MBA
Thomas Ciulla, MD, MBAIndianapolis––Sonepcizumab (iSONEP, Lpath), a monoclonal antibody, did not meet expectations for improving the visual acuity in age-related macular degeneration (AMD) patients. However, further analysis from the Nexus Study offers hope for long-term stabilization of visual acuity in some patients.
Sonepcizumab reportedly did not improve the visual acuity at the primary day-120 time point when used alone or with adjunctive anti-vascular endothelial growth factor (anti-VEGF) treatments in patients with exudative AMD.
When a post-hoc analysis of the 9-month results from the Nexus Study was conducted, it found a progressive decrease in the lesion size in the arms containing sonepcizumab, which correlated with maintenance of best-corrected visual acuity (BCVA) gains.
“When considered in the context of the recent Comparison of AMD Treatments Trials 5-year data that highlighted the limitations of current anti-VEGF therapies, there may be rationale for further study of sonepcizumab and other new agents with mechanisms of action that could extend the durability of anti-VEGF therapeutic responses,” said Thomas Ciulla, MD, MBA, who is in private practice in Indianapolis.
The Nexus Study, which was designed to evaluate the efficacy of the drug in patients with wet AMD, was a multicenter, double-masked, prospective, randomized trial that included 160 patients who had not responded as well as hoped to 3 or more anti-VEGF injections
Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that is derived from retinal pigment epithelial cells in patients with AMD and is involved in angiogenesis, fibrosis, and inflammation, according to Dr. Ciulla.
The hope for successful treatments with sonepcizumab, a recombinant humanized monoclonal antibody that binds to S1P, was based on the results observed in animal models in which sonepcizumab inhibited retinal and choroidal neovascularization (CNV) by blocking infiltration of macrophages and subretinal fibrosis.
The so-called subresponders in the Nexus Study were defined as those with residual subretinal or intraretinal fluid seen on spectral-domain optical coherence tomography (SD-OCT) images, leakage on fluorescein angiography, and a central subfoveal thickness (CSFT) exceeding 250 µm despite treatment with ranibizumab (Lucentis, Genentech), bevacizumab (Avastin, Genentech), or aflibercept (Eylea, Regeneron Pharmaceuticals) within the previous 12 month.
The patients were randomized to 1 of 4 arms (40 patients per group): anti-VEGF monotherapy, sonepcizumab monotherapy, or a combination of anti-VEGF therapy plus high-dose (4.0 mg) or low-dose (0.5 mg) sonepcizumab. The patients received 4 monthly treatments with the primary endpoint at 120 days. The follow-up period was 5 months, and patients could be treated with anti-VEGF monotherapy based on the decision of the investigator.
The primary endpoint was the mean change in the BCVA; the secondary endpoints were the proportion of patients with 1, 2, and 3 gains or losses of lines of visual acuity, the proportion of patients with 20/40 or better visual acuity, changes in the total lesion area, changes in the CSFT out to 120 days, and the ocular and systemic safety and tolerability, Dr. Ciulla explained.
The demographic data, CNV lesions types (predominantly classic, minimally classic, occult, unreadable, and missing), and the BCVA were similar in the 4 patient groups, with the exception of the visual acuity in the sonepcizumab-monotherapy group, which was slightly worse than in the other 3 groups.
“The primary endpoint of the mean BCVA change from baseline to day 120 was not met by any of the arms containing sonepcizumab compared with anti-VEGF monotherapy,” Dr. Ciulla reported.
Regarding the secondary endpoints, the sonepcizumab-monotherapy arm was inferior, while the sonepcizumab-combination arms did not show any added benefit compared with the anti-VEGF monotherapy arm.
After the 120-day endpoint was reached, all patients continued to be seen monthly and they were treated for 5 more months with anti-VEGF monotherapy at the investigator’s discretion. The patients underwent a final evaluation at the month-9 study visit.
“The mean visual acuity gain from a baseline of 3.5 letters in the anti-VEGF monotherapy arm was lost completely, but remained stable in the sonepcizumab 4.0 mg plus anti-VEGF therapy group,” Dr. Ciulla reported.
In like fashion, after the 4 initial monthly injections, the mean change in the total lesion area in the anti-VEGF monotherapy arm remained stable. “However, the results showed a progressive decrease in the lesion area in the arms containing sonepcizumab,” he said.
Potential causal relationship
The investigators conducted a post-hoc correlation analysis to identify a possible causal relationship between possible improvements in the BCVA and the mean decreased lesion area at month 9. “The only significant and positive correlation between the 2 factors was seen in the high-dose sonepcizumab plus anti-VEGF arm, in which the visual acuity improved with decreases in lesion area,” Dr. Ciulla pointed out.
A slightly higher proportion of patients in the sonepcizumab 4.0 mg plus anti-VEGF group received at least 1 re-treatment from day 120 to month 9 compared to the VEGF alone arm: 89% versus 75% respectively. However, the mean number of anti-VEGF retreatments was similar between treatment groups: 2.5 injections.
Sonepcizumab was found to be safe and well tolerated by the study patients in the phase IIa Nexus Study. The treatment-related adverse events were similar between the sonepcizumab groups compared with the anti-VEGF monotherapy group. Serious adverse events developed more often in the anti-VEGF groups compared with the high- and low-dose sonepcizumab groups.
“Although the primary endpoint was not met, the eligibility criteria of anti-VEGF therapy nonresponders may have selected the most difficult-to-treat cases,” Dr. Ciulla explained. “Longer term follow-up through month 9 suggested the potential for disease modification by sonepcizumab, as maintenance of BCVA gains correlated with reduction in total lesion area on post-hoc analysis.
“This correlation between the BCVA and total lesion area is consistent with the effects of sonepcizumab in preclinical models of CNV,” he added. “Based on the data from the Nexus Study, further study of the role of bioactive phospholipids, like S1P, in CNV may be warranted.”
Thomas A. Ciulla, MD, MBA
Dr. Ciulla is a consultant to and has received grant support from Lpath Inc. This article was adapted from Dr. Ciulla’s presentation that he delivered at Retina Subspecialty Day during the 2015 American Academy of Ophthalmology meeting.