Squalamine Boosts Anti-VEGF Effect in Macular Degeneration

Caroline Helwick

November 17, 2015

LAS VEGAS — In patients with neovascular age-related macular degeneration and classic-containing lesions, the addition of 2% squalamine lactate ophthalmic solution (OHR-102, Ohr Pharmaceutical) to ranibizumab increased visual acuity, according to a phase 2 study.

"The IMPACT study showed robust vision gains with the combination of squalamine lactate and ranibizumab in classic-containing lesions," said David Boyer, MD, from the University of Southern California and the Retina Vitreous Associates Medical Group in Los Angeles.

There was a mean gain in visual acuity and in the proportion of patients with gains of three, four, and five lines — all of which were secondary end points — primarily for patients with classic choroidal neovascularization, Dr Boyer reported here at the American Academy of Ophthalmology 2015 Annual Meeting.

There was no reduction, however, in the number of ranibizumab injections, which was the primary end point of the study.

The intracellular mechanism of action of squalamine lactate inhibits angiogenesis. It alters cellular activation and cell division by blocking signals from multiple growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblastic growth factor.

Squalamine lactate is "a little different" than anti-VEGF drugs and anti-PDGF drugs, which all act extracellularly, Dr Boyer explained. "It has multiple receptors, but it acts intracellularly."

Because angiogenesis has been implicated in the growth and maintenance of choroidal neovascularization, squalamine lactate could have potential in the treatment of age-related macular degeneration, where blood vessel proliferation plays a pivotal role, he said.


The IMPACT study involved 142 patients from 23 sites in the United States with choroidal neovascularization related to macular degeneration with lesions no more than 12 disc areas in size, a central subfield of at least 300 µm on optical coherence tomography with subretinal fluid or cystoid macular edema, any lesion composition (classic or occult), and best-corrected visual acuity of 20/40 to 20/320. Patients with diabetes but no retinopathy were included in the analysis.

Mean baseline best-corrected visual acuity was 59.1 letters.

All patients received ranibizumab at baseline, and were then randomized to receive twice-daily squalamine lactate for 9 months or a vehicle solution as placebo. Patients were retreated with ranibizumab if optical coherence tomography showed cystoid macular edema, intraretinal or subretinal fluid, or elevation in retinal pigment epithelium.

For the 128 patients who completed the study, the combination of squalamine lactate plus ranibizumab was better than ranibizumab monotherapy.

Table. Changes in Visual Acuity During the Study Period

Outcome Combination Therapy Ranibizumab Monotherapy
Classic lesions (n = 65)    
   Mean change in visual activity, letters 11.0 5.0
   ≥3 line gains at 36 weeks, % 44 28
Occult lesions <10 mm² (n = 94)    
   Mean change in visual activity, letters 11.0 5.7
   ≥3 line gains, % 48 26


"In patients with classic-containing lesions, we saw a six-letter difference with the combination. This was seen as early as 12 weeks and it continued, with the end result being a 57% improvement in at least three lines," Dr Boyer reported. "We not only saw this improvement in three or more lines, but also with four and five lines."

For the population of patients with either classic-containing or occult-only lesions, the difference in letter gains between the combination therapy and ranibizumab monotherapy was less pronounced (7.8 vs 5.3 letters).

For patients with occult lesions smaller than 10 mm², the combination led to an improvement of 5.3 letters and a 54% benefit in three-line gainers. Similarly, the combination was "far superior to monotherapy" in terms of four- and five-line gainers.

But this correlation between occult size and effect was not seen with ranibizumab monotherapy.

Squalamine was generally well tolerated. Two patients discontinued because of eye pain and eye swelling, but there were no serious adverse events.

A phase 3 registration program is being initiated for treatment-naive patients with choroidal neovascularization secondary to macular degeneration. The lesions can contain either classic or occult choroidal neovascularization, but the occult component must be smaller than 10 mm².

The ceiling has been reached with anti-VEGF agents.

There is a great deal of interest in combination treatments for neovascular age-related macular degeneration, said Pravin Dugel, MD, from Retinal Consultants of Arizona in Phoenix and the University of Southern California in Los Angeles, who is conducting research on an anti-PDGF agent himself.

"The ceiling has been reached with anti-VEGF agents," he told Medscape Medical News. In the case of squalamine, which acts broadly to inhibit PDGF and other pathways, "we are talking about eye drops, which is very exciting."

Session moderator Joan Miller, MD, Henry Willard Williams Professor and chair of ophthalmology at Harvard Medical School in Boston, said she agrees.

The less invasive, the better.

"We have a lot to think about with combination therapy, and much of it has to do with neuroprotection. What we see is that 5 to 7 years out, after successful treatment with anti-VEGF agents, our patients may continue to lose vision because they have ongoing degeneration. So that's another target," she told Medscape Medical News. "In the next few years, we should see different strategies and different kinds of combinations providing better outcomes."

"It's interesting to see these data. I think there is still more to be learned as these trials go out further. Anything we can do for patients to decrease the treatment burden, such as with eye drops, and give better long-term vision, that would be great," said Dr Miller. "The less invasive, the better."

Dr Boyer has consulted for Ohr Pharmaceuticals. Dr Miller and Dr Dugel have disclosed no relevant financial relationships.

American Academy of Ophthalmology (AAO) 2015 Annual Meeting. Presented November 13, 2015.


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