Drugs designed to inhibit vascular endothelial growth factor in patients with wet age-related macular degeneration have revolutionized treatment—but physicians and researchers alike think there is room for improvement. This improvement might consist of a therapy that enables ophthalmologists to reduce the number of injections patients need, a modality that yields better vision results or even one that might finally have an effect on geographic atrophy. With this in mind, here’s a look at the current results from the drugs leading the charge, the four agents that have either begun their Phase III AMD trial or have announced that such a trial is imminent.
Fovista
Retina experts view Ophthotech’s anti-platelet-derived growth factor drug Fovista as the furthest along the road to approval for the treatment of exudative AMD, with its Phase III trial already under way. It’s designed to work alongside an anti-vascular endothelial growth factor drug such as ranibizumab.
Wills Eye Hospital’s Richard Kaiser, MD, describes where Fovista fits in as a therapy, based on the way in which wet AMD develops. “The theory is that there are two types of cells recruited into a choroidal neovascular membrane,” he says. “These are endothelial cells and pericytes. The recruited pericytes bind to the outer walls of the endothelial cells, stabilizing the lesion and limiting the effect of anti-VEGF therapy as the lesion becomes more mature.”
Dr. Kaiser’s colleague at Wills, Sunir Garg, MD, says it’s for these advanced lesions that Fovista may be useful. “Anti-VEGF agents do a good job of causing the choroidal neovascular membrane to stop leaking, bleeding and growing,” Dr. Garg says. “However, anti-VEGF doesn’t do a good job of getting the vessels to regress, especially after the choroidal neovascularization has matured. If we are able to treat wet AMD of very recent onset with anti-VEGF agents alone, they will work really well. However, the more typical AMD patient presents with a more mature choroidal neovascular membrane in which anti-VEGFs help, but they don’t get the abnormal blood vessels to disappear.
“Anti-PDGF agents such as Fovista work through a different mechanism,” Dr. Garg continues. “As blood vessels mature, pericytes surround and stabilize them. Fovista weakens the pericytes, which allows the anti-VEGF agent to act on more of the vessels, which will hopefully get more of the lesion to regress to a greater extent than it would with anti-VEGF alone.”
In terms Fovista’s effectiveness, the latest data that’s available is from the drug’s Phase II trial. In the three-armed, prospective, controlled trial, researchers randomized 449 patients with exudative AMD to a 0.3-mg dose of Fovista combined with Lucentis, a 1.5-mg dose combined with Lucentis or Lucentis alone.1 The company reports that the 1.5-mg treatment arm gained a mean of 10.6 letters at 24 weeks compared to a gain of 6.5 letters for the Lucentis monotherapy patients, a difference that was statistically significant (p=0.019). They add that, for treatment endpoints such as visual gains greater than three, four and five letters and final vision of 20/40 and 20/25 or better, the results favored the 1.5-mg Fovista combination treatment arm. Also, using masked readers and in a retrospective subgroup analysis, Ophthotech reports that patients receiving the 1.5-mg combination therapy showed a greater mean change of neovascularization area in two subgroups for which that data was available at baseline and 24 weeks.
Ophthotech has three Phase III studies planned, two of which are currently under way.2 The inclusion criteria are as follows: patients age 50 or over; active subfoveal CNV secondary to AMD; and the presence of subretinal hyper-reflective material on optical coherence tomography. The exclusion criteria are as follows:
any prior treatment for AMD in the study eye prior to the day-one visit, except oral supplements of vitamins and minerals;
any intravitreal treatment in the study eye prior to the first visit;
any intraocular surgery or laser within three months of entry, and any prior laser in the macular region, regardless of indication;
subjects with subfoveal scar or subfoveal atrophy; and diabetes mellitus.
The trials’ structures will be similar to the Phase II trials. In the Fovista+Lucentis trial, 622 patients will be randomized to either combination therapy with 1.5-mg Fovista and 0.5-mg Lucentis or a sham Fovista injection combined with 0.5-mg Lucentis. They’ll be treated for two years, but the primary endpoint, mean change in acuity, will be evaluated at 12 months.
In the other Phase III Fovista combination trial that’s recruiting patients, 622 patients will be randomized between two groups. The first group will receive Fovista and either 1.25-mg Avastin or 2-mg Eylea. The second group will receive sham Fovista combined with either Avastin or Eylea.
“The Phase II studies theoretically showed that anti-PDGF could bring about regression of the choroidal neovascular membrane, which wasn’t seen in any anti-VEGF study,” Dr. Kaiser says. “Stripping the pericytes may cause lesions to actually regress as opposed to remaining a fibrovascular, static lesion. The Phase II data was encouraging, so that’s why they’re doing the Phase III trials.”
Lampalizumab
As daunting as it’s been to find a treatment for wet AMD, dry AMD has proven to be even tougher, with no known treatment aside from the support of AREDS vitamins. Now, however, Phase III trials have begun on Roche’s lampalizumab, which demonstrated an effect on geographic atrophy in dry AMD in Phase II trials. If the late-stage trials are successful, it would be the first approved therapy for dry AMD. The Phase III trials are about to start.
According to Roche, lampalizumab is an antigen-binding fragment of a humanized, monoclonal antibody directed against the enzyme known as complement factor D. Complement factor D is a rate-limiting enzyme involved in the activation of the alternative complement pathway, a part of the immune system. Genetic polymorphisms as well as hyperactivity of the ACP have been implicated in the development of AMD, including GA.
The MAHALO Phase II trial of lampalizumab was the springboard for the larger-scale Phase III trials. In it, 129 patients were divided into two sham-injection groups (monthly, n=21; bimonthly, n=21) and two treatment groups who received lampalizumab 10 mg monthly (n=43) or bimonthly (n=44). Treatments lasted 18 months.
In the Phase II study, an analysis of the change in GA size, the primary outcome measure, showed a 20.4-percent reduction in mean change from baseline with a p-value less than a prespecified significance level of 0.2. There was no significant change in the rate of atrophy growth in the bimonthly patients.3
Dr. Garg says one particular finding of MAHALO helped shape the structure of the Phase III trials. “The other thing they’re looking at in the lampalizumab trials has to do with the fact that, in MAHALO, there was a genetic biomarker, complement factor I, which seemed to correlate with the patients’ response to the drug,” he says. “In MAHALO, patients with the complement factor I biomarker had a 44-percent reduction in progression compared to the 20.4-percent in the overall trial. So, in Phase III, the researchers want to see if the geographic atrophy in patients with this biomarker progress differently and/or respond differently to the drug than patients who don’t have this biomarker. This is one of the first instances in our field in which a patient’s genetic biomarker may help predict response to a medication. It could be one of our first forays into personalized medicine.”
Even though the treatment slowed the rate of progression but didn’t cause the atrophy to regress, Frank Holz, MD, director of the eye clinic at the University of Bonn in Germany, says its effect can still be beneficial. “In many areas of medicine, if there is no cure or improvement in something, then the next best goal is to slow progression,” he says. “We’re used to that in glaucoma, and it’s a common theme in oncology. Of course, we’d prefer something that restores vision, but to save the life of the foveal tissue for a longer period of time in order to preserve good central vision is still of high clinical impact.”
Lampalizumab will be studied in two identical, double-masked, randomized, prospective Phase III trials named Chroma and Spectri. Each will enroll approximately 936 patients and will compare a 10-mg dose of the drug given via intravitreal injection every four or six weeks to sham injections. To test the results in complement factor I, 188 biomarker-positive and 124 biomarker-negative patients each will be enrolled in the sham, lampalizumab q4w and lampalizumab q6w groups in each study. The primary endpoint is the rate of GA progression, which will be evaluated at one year.
Abicipar
Though patients’ vision is at the forefront of companies’ research into AMD treatments, reducing the frequency of injections has also emerged as a priority, since doing so would reduce the treatment burden for patients. It’s the twin goals of improved vision and a less-frequent dosing schedule that drive the current research of abicipar pegol for the treatment of wet AMD. In early July, Allergan began enrolling patients in the Phase III study of the drug as part of its partnership with the Swiss biotech firm Molecular Partners.
Abicipar is from a class of drugs known as DARPins. “DARPins are highly potent therapeutic proteins that we’ve developed here at Molecular Partners,” says Christian Zahnd, MD, PhD, chief executive officer of the company. “They’re derived from a natural class of binding proteins called ankyrin and repeat proteins, which nature has evolved to specifically attach to other proteins in a way similar to antibodies. We used our molecular library to identify a DARPin that’s highly potent for neutralizing VEGF, abicipar. Specifically, it blocks several splice variants of VEGF-A from binding to its receptor, similar to what Lucentis does. However, abicipar is a pegylated DARPin, so it carries a polyethylene tail. The reason for this is to provide a longer intravitreal half-life. Its longer half-life in the vitreous is proposed to lead to a longer duration of action and thus less-frequent dosing for patients.” In preclinical testing at Molecular Partners, Dr. Zahnd says that, in a rabbit model, abicipar had a vitreous pharmacokinetic duration of action of six days, compared to three days and 4.5 days for ranibizumab and aflibercept, respectively.
Though the abicipar Phase II REACH study wasn’t powered to show statistical significance, it showed enough positive trends in efficacy to give Allergan and Molecular Partners the confidence to go ahead with Phase III. In REACH, 25 patients were randomized to abicipar 1 mg, 23 to abicipar 2 mg and 16 to ranibizumab. All patients received doses at the start of the trial and then at four and eight weeks. Ranibizumab patients received additional doses at 12 and 16 weeks, while abicipar patients got sham injections at those visits. Everyone was followed for 20 weeks.
After 16 weeks, mean acuity improvement was 8.2 letters for abicipar 2 mg, 6.3 for abicipar 1 mg and 5.33 letters for ranibizumab. After 20 weeks, which was 12 weeks after the last abicipar injection and four after the last injection of ranibizumab, acuity improvement from baseline was nine letters for abicipar 2 mg, 7.1 for abicipar 1 mg and 4.7 letters for ranibizumab. Two patients in the abicipar 2-mg group and three in the 1-mg group experienced inflammation.
Dr. Zahnd says the inflammatory reaction is being addressed. “The inflammation rate in REACH was at around 10 percent, which was still too high,” he says. “After significant improvements of the manufacturing process for Phase III, it’s expected that inflammation is under control.”
Abicipar’s Phase III program will consist of two trials, CEDAR and SEQUOIA, each recruiting around 900 patients. In each trial there will be three arms. The first arm will consist of abicipar 2-mg injections on day one, week four and week eight, followed by injections every eight weeks through week 96. The second arm will be abicipar 2-mg injections on day one, week four and week 12, with injections every 12 weeks through week 96. The third arm, the control, will consist of ranibizumab injections on day one and then every four weeks until week 96.
Squalamine Lactate
The anti-angiogenic drug squalamine lactate (Ohr Pharmaceutical) has gone through a couple of iterations over the years, and its current form is a topical drop. As its treatment protocol is currently configured, the drop is to be administered b.i.d. in combination with Lucentis injections in the hope that it will boost visual acuity gains and/or reduce the number of anti-VEGF injections a patient needs. Ohr recently completed the Phase II trial of squalamine and, though it didn’t decrease the number of Lucentis injections (the primary endpoint), the company says the drug showed enough potential to increase visual acuity gains vs. Lucentis alone that a Phase III trial is warranted and will start this year.
Squalamine lactate is described as a small-molecule, anti-angiogenic agent that acts against aberrant neovascularization by inhibiting multiple protein growth factors, including VEGF, PDGF and basic fibroblast growth factor. “In order for VEGF, PDGF and bFGF to exert their negative effects, they bind to the receptor and signal intracellular actions that cause leakage, vascular growth, scarring and all the other things we’ve come to expect from neovascular diseases,” says Jason Slakter, MD, Ohr’s chief medical officer. “When you apply squalamine it reaches the back of the eye and is taken up into the endothelial cells. There, it binds to a molecule called calmodulin and pulls it away from the inside of the receptors, silencing the receptor activity.”
The most recent results with squalamine are from the Phase II trial, named IMPACT. In IMPACT, 142 patients with wet AMD were randomized between two groups: squalamine drops b.i.d. combined with Lucentis as-needed and a group receiving placebo drops plus Lucentis as-needed. Everyone got an initial dose of Lucentis.
In a modified intent-to-treat population with lesions containing classic CNV that consisted of 37 squalamine+Lucentis patients and 28 Lucentis-only patients, Ohr reports that the former group showed visual acuity gains.4 In the combination-therapy group, patients gained a mean of 11 letters, vs. a mean gain of five letters with Lucentis alone, a difference the company says was clinically meaningful. In addition, 44 percent of the combination patients gained three or more lines of vision at nine months, vs. 29 percent in the Lucentis monotherapy group. Also, 22 percent of the combination patients gained four or more lines and 14 percent gained at least five lines at nine months, compared to 7 percent and 7 percent, respectively, for the Lucentis monotherapy group. In the overall population, though, with either classic-containing or occult-only lesions, Ohr says the mean gain was just 7.8 letters for the combination group and 5.3 for Lucentis.
Dr. Slakter says the Phase II results will help design a Phase III study. “From a regulator’s standpoint, it doesn’t matter what your primary endpoint was in Phase II,” he says. “It only matters what it is in Phase III. What’s more important is that you have a valid endpoint to pursue for approval. From the point of view of regulators, it’s all about vision. The fact that we didn’t find a difference in the number of injections but did show a robust effect in visual outcomes allows us to sit back and say, ‘Great, now we have the capability to design and execute a Phase III study with a high likelihood of success based on a visual acuity endpoint.’ ”
In terms of the better results occurring in predominantly classic lesions, that finding set Ohr researchers on a new course. “We carefully analyzed the data based on emerging information,” Dr. Slakter explains. “When you look at the type of vessels that might be more affected by the combination of an anti-VEGF and an agent that’s going to inhibit something such as PDGF, the occult vessels may be more likely to be affected by this combination.
“So, instead of rushing forward with a Phase III trial based on a group of patients with classic-containing lesions, we went back and looked at how the size of the occult neovascularization component made a difference in the outcome,” Dr. Slakter adds. “We found that, if you look at eyes with occult CNV at baseline of less than 10 mm2, or four disc areas in size, you get a very dramatic difference in outcome with the combination treatment: an 11-letter mean gain in vision vs. a six-letter gain for Lucentis alone. What’s more, we actually had a larger group of patients who met this occult size criteria compared to those with predominantly classic lesions: three-quarters of the patients vs. 50 percent. We’re now in the process of finalizing what our patient population will be in Phase III. Though we haven’t fully defined this population yet, we believe that occult size may be one of the most important factors in determining it.”
Dr. Kaiser has a financial interest in Ophthotech and Dr. Holz is a consultant to Roche. Dr. Garg receives research support from Genentech and Allergan. Dr. Slakter is employed by Ohr Pharmaceutical.
1. Data on file, Ophthotech.
2. www.clinicaltrials.gov. Phase III Fovista trials. Accessed 6 July 2015.
3. Rhoades W, Dickson D, Do D. Potential role of lampalizumab for treatment of geographic atrophy. Clin Ophthalmol 2015;9:1049–1056.
4. Data on file, Ohr Pharmaceutical.
