Ophthotech to Explore Sustained Release for Wet AMD
Company commits to “multiple and flexible” therapeutic options.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ In a stunning endorsement of recent thinking in the retinal community that the era of anti-VEGF monotherapy delivered by intravitreal injection may be reaching its therapeutic limits, Ophthotech Corporation (New York, NY) has signaled that it will pursue diverse pharmacologic approaches for the treatment of retinal diseases.
With its major anti-VEGF, anti-PDGF (Fovista) combination-drug program for the treatment of wet AMD via intravitreal injection currently in three major phase 3 clinical studies, Ophthotech has now obtained the rights to tivozanib, a small-molecule VEGF tyrosine kinase inhibitor from AVEO Pharmaceutical (Cambridge, MA), a developer of oncology drugs. Ophthotech, which has acquired only the nononcologic rights for conditions of the eye, will initially study tivozanib as a maintenance therapy for wet AMD, delivered in a sustained-release format.
Ophthotech’s move confirms recent thinking among leading retinal drug researchers that sustained-release delivery may work best with small-molecule drugs that have the specific characteristics to be effective in the sustained-release format. These characteristics would include the stability to maintain efficacy over a period of months while residing in an implant or reservoir-type device.
“What we need to do now is to marry the right drug to the appropriate delivery system, which may require a whole new category of retinal drugs,” says Pravin Dugel, MD, of Retinal Consultants of Arizona. “This is what we are now seeing from companies such as Novartis (Basel, Switzerland) and Ophthotech.”
“While Fovista’s development strategy continues to remain agnostic with respect to the choice of the anti-VEGF agent administered in combination with Fovista, this agreement continues our quest to develop multiple and flexible therapeutic options,” said Samir Patel, MD, president and vice chairman of Ophthotech. “The unmet needs in wet AMD include treatment burden and disappointing long-term visual outcome in the chronic phase of wet AMD therapy. The potential to develop a sustained release formulation with the properties of this anti-VEGF inhibitor, a highly potent and selective small molecule, is very attractive. In addition, this agreement may provide the opportunity to expand into other ocular indications such as diabetic retinopathy. This structured option agreement allows us to make payments only after reaching certain key milestones, while retaining total control over the decision whether to continue any further development.”
■ Cuts in Medicare vitrectomy, injection reimbursement. The 2015 Medicare Fee Schedule contains some bad news for retina specialists: reimbursement for four different vitrectomy procedures has been slashed 9% to 29%. In addition, reimbursement for the 67028 (injection of eye drug) code has been reduced by 3.47% and payment for the 67108 (repair of retinal detachment) code has been cut by 3.37%.
The codes affected and the cuts in vitrectomy reimbursement include 67036 (-9%), 67039 (-25%), 67041 (-16%), and 67042 (-26%). These codes represent some of the most commonly performed vitrectomy procedures.
Overall, ophthalmology was one of the hardest-hit medical specialties in terms of reimbursement cuts, with many high-volume procedures seeing reductions for 2015.
■ Retinal prothesis study for dry AMD. Second Sight Medical Products Inc. (Sylmar, CA) is planning the world’s first study aiming to establish whether blind patients with total central vision loss from dry AMD can benefit from an artificial retina: the company’s Argus II Retinal Prosthesis System. Previously, the Argus II and other implants currently available have been indicated in patients with retinitis pigmentosa.
The five-patient feasibility study was scheduled to begin before year-end. The study will be led by Paulo Stanga, MD, consultant ophthalmologist and vitreoretinal surgeon at the Manchester Royal Eye Hospital in the United Kingdom.
Dry AMD is a much more common disease than RP. Worldwide, an estimated 1.5 million people are afflicted with RP compared to 20 to 25 million who have dry AMD. Currently, no FDA-approved treatments exist for the dry form of AMD.
Second Sight recently raised $32 million from a successful public stock offering. The stock is being traded on NASDAQ under the symbol EYES. Some of the funds from the offering will be used to expand the company’s research into AMD.
Telescopic Lens Helps Patients With Dry AMD
Inventors seek to begin US clinical trials.
■ London Eye Hospital Pharma, a London-based medical device and pharmaceutical company, has initiated discussions with potential US clinical investigators to begin clinical trials for its iolAMD lens system. Already approved in Europe with the CE mark, iolAMD is a novel intraocular lens system designed to restore lost vision and provide an independent lifestyle for patients with early, intermediate, and advanced dry AMD and other macular diseases, including diabetic maculopathy.
Depending on the visual potential remaining in the eye, the company says iolAMD patients could regain the ability to drive, read, or see faces — significantly improving their quality of life. In an 18-eye European clinical trial, patients with dry AMD achieved a mean 67% improvement in distance vision and a mean 50% improvement in near vision at four months.
In the iolAMD procedure, two advanced, foldable, hydrophobic acrylic IOLs are placed inside the eye using microincisional surgical techniques familiar to cataract surgeons. The two iolAMD lenses work together to act like a Galilean telescope, says the company, gently magnifying the image entering the eye and diverting it to a healthier part of the retina. This section of healthier retina receives the image, taking over the role of the macula and providing the iolAMD patient with significantly improved vision.
The magnification achieved is around 1.3x, which allows for bilateral implantation. The company says visual acuity is improved and visual field is maintained.
According to London Eye Hospital Pharma, the iolAMD lenses contain hyperaspheric surfaces and unique wavefront characteristics that reduce optical distortions normally associated with high-powered lenses, as well as creating an increased tolerance of relative lens positioning. More information on their design and history can be found at www.iolAMD.com.
A rendering of the iolAMD dual-lens telescopic vision system implanted in the sulcus and capsular bag.
■ Ranibizumab effective in limiting DR severity. In an effort to evaluate the long-term effects of early treatment with ranibizumab (Lucentis, Genentech, South San Francisco, CA) on the severity of diabetic retinopathy (DR), Michael S. Ip, MD, and colleagues randomized 759 participants with DME in two phase 3 clinical trials to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab intravitreal injections.
At two years, the percentage of participants with DR progression (worsening by ≥2 or ≥3 steps) was significantly reduced in ranibizumab-treated eyes compared with sham-treated eyes, and DR regression (improving by ≥2 or ≥3 steps) was significantly more likely. The cumulative probability of clinical progression of DR as measured by the composite outcome at two years was 33.8% of sham-treated eyes compared with 11.2% to 11.5% of ranibizumab-treated eyes.
The researchers, who recently reported their findings in the online edition of Ophthalmology, concluded that intravitreal ranibizumab reduced the risk of DR progression in eyes with DME, and many ranibizumab-treated eyes experienced improvement in DR severity.
The FDA has granted Genentech priority review for the use of ranibizumab for the DR indication.
■ Ireland, Belgium, Netherlands approve Iluvien. Alimera Sciences said three more European countries — Ireland, Belgium and the Netherlands — approved the company’s Iluvien sustained-release implant for the long-term treatment of chronic DME. The two approvals bring to 14 the number of countries approving Iluvien therapy, including the United States, where the FDA recently approved Iluvien for patients who had a previous course of corticosteroids without a resulting clinically significant increase in IOP.
Alimera also announced that it has created a direct sales force of 32 representatives to market Iluvien in the United States.
Aerpio to Study First-in-class Drug for DME
Tie2 activator may complement anti-VEGF therapy.
■ Aerpio Therapeutics, Inc. (Cincinnati), a clinical-stage biopharmaceutical company focused on advancing innovative therapies for diabetic eye disease and diabetes complications, has announced completion of patient enrollment for the company’s 144-patient TIME-2 phase 2 trial, evaluating AKB-9778, a Tie2 activator, alone and in combination with ranibizumab (Lucentis), for the treatment of DME. AKB-9778 is a first-in-class inhibitor of human protein tyrosine phosphatase beta (HPTPβ) that activates the Tie2 pathway to promote vascular stability, preventing abnormal blood vessel growth and vascular leakage.
“The Angiopoietin/Tie2 pathway is a central pathway controlling the maintenance and stabilization of retinal blood vessels,” said Kevin Peters, MD, chief scientific officer and vice president of R&D at Aerpio. “Results from our earlier phase 1b study demonstrated promising monotherapy activity with AKB-9778 in both treatment-naïve and treatment-resistant DME patients. We expect the current phase 2 trial will allow us to expand our understanding of the efficacy of AKB-9778, both as monotherapy and in combination with ranibizumab.” Dr. Peters added, “Given that Tie2 activation is complementary to the action of anti-VEGF agents, we look forward to determining how our drug performs as a monotherapy and as an adjunct to anti-VEGF therapy.”
“While intravitreal anti-VEGF treatments have become the standard of care in patients with DME, at least one-quarter of patients receiving monthly treatments do not have total resolution of their edema, and 40% do not achieve 20/40 vision,” said David S. Boyer, MD, Retina-Vitreous Associates Medical Group. “The need for new therapies in DME is significant.”
The randomized, double-masked, placebo-controlled, phase 2 study is designed to assess the safety and efficacy of AKB-9778 administered over three months as monotherapy and as an adjunct with ranibizumab in subjects with DME. The study enrolled 144 subjects at nearly 40 sites in the United States, randomizing patients 1:1:1 into three groups: 1) AKB-9778 monotherapy: AKB-9778 15 mg BID subcutaneous administration with monthly sham intravitreal injections; 2) combination therapy: AKB-9778 15 mg BID with monthly intravitreal injections of ranibizumab 0.3 mg; and 3) a control group of placebo BID subcutaneous injection plus ranibizumab 0.3 mg monthly intravitreal injection. The primary endpoint of the study is change from baseline in central retinal thickness in the groups treated with AKB-9778 monotherapy and AKB-9778 as an adjunct with ranibizumab compared to ranibizumab monotherapy.
■ Shire gets “Fast-Track” status for ROP preventive. Shire PLC (Dublin, Ireland) has received Fast-Track designation from the FDA for SHP607, a protein replacement therapy for the prevention of retinopathy of prematurity, the potentially blinding proliferative retinopathy unique to prematurely born infants.
The Fast Track designation facilitates the development and expedites the review of drugs to treat serious diseases that fill an unmet medical need, with the goal of delivering important new treatments to patients earlier.
SHP607 is currently in a phase 2 study that aims to compare the severity of ROP among treated patients vs an untreated control population matched for gestational age. Topline data from this study are expected in the second half of this year.
■ FDA approves Zeiss intraoperative OCT. The FDA has approved the Rescan 700 intraoperative optical coherence tomography system from Carl Zeiss Meditec (Dublin, CA), which allows for the visualization of high-definition real-time OCT images through the eyepiece of the Lumera 700 microscope.
“Intraoperative OCT allows me to see things I could not see otherwise,” said Justis P. Ehlers, MD, of the Cole Eye Institute of the Cleveland Clinic, who has been using the Rescan 700 on an investigational basis for nine months.
“I use intraoperative OCT in most of my surgeries. We have found that real-time OCT feedback during surgery can improve our understanding of anatomy and impact surgical decision-making, particularly in membrane peeling cases and complex detachments — for example, proliferative diabetic retinopathy and proliferative vitreoretinopathy.”
Allergan’s DARPin Research to Be Funded
Merger partner Actavis endorses key program.
■ In discussing future plans for its combination with Allergan (Irvine, CA), Actavis (Dublin, Ireland) CEO and President Brent Saunders said Allergan’s important designed ankyrin repeat protein (DARPin) drug development program for treating wet AMD will move forward with adequate funding. Mr. Saunders’ commitment to DARPin research removes any doubts about that aspect of the deal.
Allergan’s anti-VEGF DARPin drug, developed along with its Swiss partner Molecular Partners (Zürich), showed significant efficacy, as well as a potential three-month dosing interval in treating wet AMD as monotherapy in a phase 2 study. The priority now is to advance the anti-VEGF DARPin (abicipar pegol) into phase 3 trials. Longer range, the companies plan to combine the anti-VEGF DARPin with an anti-PDGF DARPin in a dual-action combination therapy.
In its most recent update on the DARPin program, Allergan said it has completed the top-line analysis of data from the stage 3, phase 2 study of abicipar pegol in wet AMD. The analysis showed that after 16 weeks, mean visual acuity improvement from baseline was 8.2 letters for abicipar pegol 2 mg, 6.3 letters for abicipar pegol 1 mg, and 5.3 letters for ranibizumab. After 20 weeks, (12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection) mean visual acuity improvement from baseline was 9.0 letters for abicipar pegol 2 mg, 7.1 letters for abicipar pegol 1 mg, and 4.7 letters for ranibizumab. These data, along with data from earlier studies, were reviewed with the FDA at an end of phase 2 meeting where the FDA was in accord with Allergan’s decision to advance abicipar pegol to phase 3 clinical trials and approved the proposed phase 3 study design.
“My view on DARPin after due diligence and looking at it is very bullish,” said Mr. Saunders. “We think that it could really change the paradigm for patients suffering with AMD, could really reduce the need for painful and uncomfortable injections, and so we really consider it to be a game changer. But, we have work to do on it. And we’re committed to getting that work done.”
Allergan agreed to merge with Actavis after resisting for months a merger offer from Valeant Pharmaceuticals (Laval, Canada).
■ Priority review for Eylea in DR. The FDA has accepted for priority review the supplemental biologics license application for Eylea (aflibercept, Regeneron) for the treatment of diabetic retinopathy in patients with DME. Under the Prescription Drug User Fee Act, the goal for a priority review is six months, for a target action date of March 30, 2015.
In Canada, Bayer Inc. has received approval from Health Canada for Eylea for the treatment of DME. This new indication follows the October approval of Eylea for the treatment of visual impairment due to macular edema secondary to CRVO. In 2013, Health Canada approved Eylea for the treatment of wet AMD.
■ Applied Genetic’s CEO wins Innovator award. Sue Washer, CEO of Applied Genetic Technologies Corp. (AGTC), received the 2014 Innovator Award at the Ophthalmology Innovation Summit prior to the recent American Academy of Ophthalmology annual meeting. Ms. Washer was nominated and selected by an OIS advisory committee made up of ophthalmic executives, researchers, and practitioners, as well as leaders from the financial community and government officials.
AGTC is in the forefront of investigating gene therapy as a long-term, ground-breaking treatment for serious retinal diseases. The company expects to begin human trials in three blinding “orphan” retinal diseases in 2015.
■ EyeGate to offer shares to the public. EyeGate Pharmaceuticals (Waltham, MA) has filed with the SEC to sell $30 million in stock through an initial public offering. The funds will be used to continue ongoing clinical trials using iontophoresis as a drug delivery system for treating a range of eye diseases, including uveitis, dry eye, and wet AMD.
Iontophoresis is an active method of drug delivery in which an electrical field created by a low-level of electrical current is used to ionize a drug and to modify the permeability of the cells so that the drug can be delivered through different tissues to targeted areas. Iontophoretic drug delivery is not new. It has been approved by the FDA for dermatologic applications,
EyeGate shares will trade on NASDAQ under the symbol EYEG.
AMD Treatment Market to Reach $10 Billion
Drug sales expected to double in a decade.
■ The AMD treatment market across seven major countries (the US, the UK, Germany, France, Spain, Italy, and Japan) will almost double in value from $5.1 billion in 2013 to $10.1 billion by 2023, according to research and consulting firm GlobalData.
The company’s latest report states that the main drivers for this considerable expansion, which will occur at a Compound Annual Growth Rate of 7.1%, are the new therapies entering the market and a global aging society, which will lead to increasing numbers of elderly people developing the age-related retinal disease.
Catherine Daly, PhD, the GlobalData analyst covering ophthalmology, says: “The global AMD treatment market is overwhelmingly dominated by anti-VEGF drugs, including Lucentis, Avastin, and Eylea, which together accounted for 98% of sales for AMD in 2013. However, the anti-VEGF monopoly is set to take a dramatic tumble due to the (potential) launch of novel adjunctive therapies for wet AMD.”
Daly names the anti-PDGF drug Fovista (Ophthotech), the amino-sterol eyedrop squalamine (Ohr Pharmaceutical), and the introduction of two therapies for dry AMD, lampalizumab (Genentech) and emixustat (Acucela), during the forecast period.
“These entrants will cause the anti-VEGFs’ stronghold on the market to drop to 64% by 2023,” she predicts.
The GlobalData report also states that the United States had the largest AMD treatment market among the seven major countries in 2013, due to its large population, relatively higher drug prices, and overall higher drug treatment rates. The United States accounted for 49% of the global AMD therapeutics market in 2013 and will achieve a 55% share by 2023, with its market value forecast to more than double from $2.5 billion to $5.6 billion over the same period.
Daly comments: “The new therapies entering the market will be the main drivers of growth in the US, with the wet AMD drugs Fovista, squalamine, and abicipar pegol (Allergan) launching in 2017, 2018, and 2020, respectively. Fovista is undergoing an extensive phase 3 development program, and the data released to date have shown that this drug provides added benefit over the standard of care (anti-VEGF monotherapy). This indicates that the drug will enjoy good market success during the forecast period, with its US sales reaching $603 million by 2023.” RP
■ Retinal changes can be early sign of dementia. Researchers have found a direct correlation with functional cell loss in the retina and signs of dementia in people at genetic risk for frontotemporal dementia (FTD). The study, by scientists from the University of Alabama, Birmingham (UAB), Gladstone Institutes, and the University of California, San Francisco, was published in the Journal of Experimental Medicine. It shows that retinal changes occur much earlier than changes in the patient’s behavior.
Li Gan, PhD, lead investigator at Gladstone Institutes said, “Retinal degeneration was detectable in mutation carriers prior to the onset of cognitive symptoms, establishing retinal thinning as one of the earliest observable signs of familial FTD. This means that retinal thinning could be an easily measured outcome for clinical trials.”
The researchers used an electroretinogram as the measuring device in their subjects. Effectively an EKG for the eye, ERG measures the electrical signal activity of ganglion cells located near the inner surface of the retina. The researchers compared ganglion cell activity in healthy subjects with subjects with FTD, noting a significant decrease in cell activity in the retinas of subjects with dementia.
“The results of this study show that we can use the thinning of retinal cells as a marker for this type of dementia,” said Eric Robertson, MD, PhD, associate professor at UAB, Department of Vision Sciences. “Further studies may also help determine whether the changes in the retina can be utilized as a marker of disease progression.”
■ QLT merger agreement terminated. QLT Inc. (Vancouver, Canada), the developer of Visudyne PDT for the treatment of wet AMD, was left at the altar when its prospective merger partner, Auxilium Pharmaceuticals (Chesterbrook, PA), agreed to be acquired by Endo International (Dublin, Ireland). QLT did not walk away empty-handed, as it will receive a termination fee of $28.4 million.
Since selling its Visudyne business to Valeant Pharmaceuticals in 2012, QLT has focused on synthetic retinoids to treat inherited retinal diseases.