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Combination treatment with squalamine lactate ophthalmic solution 0.2% and ranibizumab PRN resulted in improved visual function in patients with neovascular age-related macular degeneration compared with treatment with ranibizumab alone.
Take-Home Message: Combination treatment with squalamine lactate ophthalmic solution 0.2% and ranibizumab PRN resulted in improved visual function in patients with neovascular age-related macular degeneration compared with treatment with ranibizumab alone.
By Nancy Groves; Reviewed by Jason S. Slakter, MD
New York-Final results of a phase II study show that squalamine lactate ophthalmic solution 0.2% (OHR-102, Ohr Pharmaceuticals) used in combination with ranibizumab PRN (Lucentis, Genentech) in the treatment of neovascular age-related macular degeneration (AMD) produces a very robust visual effect, particularly in eyes with classic-containing CNV lesions.
“We are very hopeful that it will have a place in the management of patients with wet AMD,” said Jason S. Slakter, MD, chief medical officer for Ohr Pharmaceutical. He also is in private practice with Vitreous-Retina-Macula Consultants of New York.
Results of the IMPACT trial were similar to those from other combination treatments targeting similar patient populations, said Dr. Slakter, adding that new findings suggest that both lesion size and composition are critical for OHR-102 and likely for combination therapy outcomes in general.
The IMPACT Study was conducted at 23 U.S. sites in treatment-naive patients with wet AMD who exhibited a wide range of characteristics. All lesion compositions and lesions up to 12 disc areas in size were allowed in the study. Visual acuity ranged from 20/40 to 20/320. Diabetic patients without diabetic retinopathy were eligible as well.
All patients received a single mandatory injection of ranibizumab at baseline and, then, were randomly assigned to receive OHR-102 eye drops or placebo eye drops twice a day throughout the study. Patients were seen monthly over the study period and underwent visual acuity, clinical, and optical coherence tomography (OCT) assessments. Further ranibizumab injections were performed on an as-needed basis, as determined by SD-OCT criteria at each monthly visit.
Initial enrollment was 142 patients (the intent to treat [ITT] population); 128 completed the 9-month study (the modified ITT population [mITT]). The mean age of patients was 79 years; 54% were female. Baseline vision was a mean of 59.1 letters, and retinal thickness was a mean of 414 µm. Classic-containing lesions accounted for 49% of the total, while occult-only lesions accounted for the remaining 51%.
Reviewing the results, Dr. Slakter said the mean number of injections between the treatment groups was not meaningfully different. The mean retreatment rate per month was 0.6 in both arms.
“Using the combination approach didn’t seem to reduce the need for injections,” he added, suggesting that the treatment-naive, active-stage disease status of the study population may have been a factor. “It’s possible that as you go farther into the disease state, you could in fact reduce the need for additional anti-VEGF injections with continued use of OHR-102.
“On the other hand, we saw some very impressive visual outcome findings,” said Dr. Slakter. The data were analyzed for the overall patient population and also by the subgroup of patients with classic CNV-containing lesions, a characteristic that has been particularly associated with benefit from treatment in other studies of combination therapy.
The mean change in visual acuity in the overall mITT population at week 36 was about 8 letters for the group receiving OHR-102 eye drops and PRN ranibizumab. The group receiving placebo drops and PRN ranibizumab had a mean change of about 5 letters at week 36 after peaking at 7 letters at week 24. The percentage of the mITT population with a gain of ≥3 lines at week 36 was about 31% for the OHR-102/ranibizumab group and 25% for the placebo/ranibizumab group.
The study also analyzed the subgroup of completers with classic containing lesions (OHR-102/ranibizumab, n = 37; placebo/ranibizumab, n = 28) and found a dramatic difference in outcomes of the 2 treatment approaches.
“By month 9, the combination group had gained 11 letters versus only 5 letters with ranibizumab alone, so there was a very robust difference between using the combination treatment and using ranibizumab monotherapy,” Dr. Slakter said.
The subgroup analysis also showed a large difference in the proportion of patients in the mITT population with a mean change of ≥3 letters: 44% for combination therapy versus 29% for ranibizumab monotherapy.
Dr. Slakter also highlighted the percentage of eyes in this subgroup with gains of 4 or 5 lines. Over 20% of patients using combination therapy gained ≥4 lines, and over 15% gained ≥5 lines, compared to about 7% of patients in the monotherapy group in both of those categories.
“You’re seeing more than doubling, almost tripling, of the likelihood of getting dramatic vision gains when you use the combination therapy,” Dr. Slakter said. “It’s extremely exciting from the point of view of what this therapy offers with regard to vision improvement for these patients.”
He also observed that OHR-102 is particularly promising because it blocks at least three different molecular targets: VEGF, platelet-derived growth factor, and basic fibroblast growth factor activity. Also, it is taken up into the endothelial cells and binds to calmodulin, which is critical for downstream receptor activation activity, Dr. Slakter said. “Squalamine pulls the calmodulin away from the inner surface of the receptor. Essentially, it’s silencing receptor activity.”
The safety results of the IMPACT trial suggest that OHR-102 drops were very well tolerated. Two patients in the combination therapy group discontinued the study because of adverse events, such as eye pain or swelling. However, no treatment-related serious adverse events were reported, and the ocular adverse effects were generally mild,
“From a safety point of view, the idea that you could take an eye drop, add it to an existing standard of care treatment and markedly improve the vision outcomes was extremely exciting and very positive,” Dr. Slakter said.
Investigators went beyond the clinical outcomes and safety findings to investigate the mechanism by which OHR-102 works. After studying lesion characteristics, they theorized that the outcomes might be driven by the occult component of neovascularization.
“The occult vessels are probably the biggest target for combination therapy,” Dr. Slakter added.
An exploratory analysis of occult CNV area, looking at occult vessels <10 mm2 at baseline, showed a mean visual gain at 36 weeks of 11 letters with combination therapy and 5.7 letters with ranibizumab alone. At week 36, 40% of patients receiving combination therapy had a ≥3-line visual acuity gain compared to about 26% of those in the ranibizumab-only group.
The analysis included 48 patients treated with combination therapy and 46 receiving ranibizumab monotherapy. This 94-patient group was larger than the subgroup with classic lesions (n = 65), suggesting that the findings related to occult CNV area would have broader applicability in clinical practice, Dr. Slakter said.
The data also support moving forward to a phase III clinical development program, expected to begin later this year.
Jason S. Slakter, MD
This article was adapted from Dr. Slakter’s presentation at the 2015 meeting of the Association for Research in Vision and Ophthalmology. Dr. Slakter is chief medical officer for Ohr Pharmaceutical Inc.