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SUBSPECIALTY NEWS

SUBSPECIALTY NEWS

Will Anti-PDGF Tame Wet AMD?

Very early data has been highly promising.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ When a patient with wet AMD receives an injection of an anti-VEGF agent, the eye responds by producing more platelet-derived growth factor (PDGF) to protect the VEGF from the outside attack. This response makes the therapeutic task of the anti-VEGF drug more difficult.

Researchers have for years believed that introducing an anti-PDGF agent to act in combination with anti-VEGF would optimize the effect of the anti-VEGF drug and produce better and more durable vision gains than anti-VEGF monotherapy.

Now, this concept is fast becoming a reality, with companies such as Ophthotech (New York, NY), Regeneron (Tarrytown, NY), and Allergan (Irvine, CA) all strongly pursuing anti-VEGF/anti-PDGF combinations for the treatment of wet AMD and other retinal diseases. Genentech (South San Francisco, CA) is also looking into a range of combination therapies for the treatment of retinal diseases.

Just in recent months, two small studies have provided an indication that an anti-VEGF/anti-PDGF combination can be more effective than anti-VEGF monotherapy. A 12-patient, eight-week, phase 1 study, conducted by Jeffrey Heier, MD, of Boston, though short on details, was positive enough to convince Regeneron to move its combination into a much larger phase 2 trial. But even more telling were the early results from an investigator-sponsored 30-patient study initiated by Retinal Consultants of Arizona with 27 anti-VEGF-resistant patients.

Pravin Dugel, MD, a managing partner in the practice, recently reported that a combination of anti-VEGF and Ophthotech’s anti-PDGF therapy Fovista produced average seven-letter vision gains at three months in 27 anti-VEGF treatment resistant patients, who had an average of 25 prior anti-VEGF injections. 10 patients were pre-treated with Fovista prior to starting the combination in this group. An average vision gain of 11 letters was reported in these patients. In the three treatment-naïve patients, vision gains averaged 17+ letters at three months. Ophthotech has now commenced three major phase 3 trials using the anti-VEGF/Fovista combination, some utilizing the pretreatment strategy.

“These results were particularly encouraging and confidence building because they were consistent with the basic science of PDGF/VEGF crosstalk,” said Dr. Dugel. “We were dealing with 27 patients who previously had an average of 25 anti-VEGF injections with treatment intervals of 6 weeks or less in 89% and were no longer responding to anti-VEGF therapy. This was not an easy group to treat.”

Though cautioning that the IST was small and that data needs further confirmation in a large-scale trial, Dr. Dugel said that not only can anti-PDGF strip the pericytes that guard VEGF from attack, it also has anti-fibrotic qualities that will combat fibrosis, the major cause of vision loss in wet AMD.

“I am encouraged by the fact that several very good companies are all pursuing the PDGF target,” said Dr. Dugel. “This tells me that the science is sound and that we are now on our way to developing the next-generation therapy for wet AMD and other retinal diseases.”

IN BRIEF

Regeneron anti-PDGF with Eylea to enter phase 2. A 12-patient, eight-week phase 1 study of four different doses of Regeneron’s investigational anti-PDGF molecule REGN2176 in combination with a 2.0 mg dose of the company’s anti-VEGF drug Eylea was well-tolerated by patients, without signs of inflammation or dose-limiting toxicities. A 500-patient phase 2 study is slated to begin soon. The results of the small trial were delivered by Jeffrey Heier, MD, at the recent Bascom Palmer Angiogenesis conference. No conclusions on efficacy were possible based on this small sample of both treatment-naïve and treatment-experienced patients.

The 500-patient phase 2 Capella study will begin this Spring.

Nikon buys retinal imaging leader Optos. Japanese camera company Nikon has expanded into the medical field with its $400 million acquisition of Optos (Dunfermline, Scotland), the market leader in retinal imaging and widefield technology. Nikon believes it can leverage its expertise in optics by moving into the fast-growing medical imaging sector.

Regeneron Commits to Genetics Initiatives

Company embraces new path to drug development

■ Most people in the ophthalmic community know Regeneron primarily for Eylea, the company’s blockbuster anti-VEGF drug for treating retinal diseases. They may also know that the company is developing a rich pipeline of other therapies for a wide range of diseases. What they probably do not know is that Regeneron is one of the world leaders in initiating a drug development program that is largely based on the science of genetics. Regeneron is one of the few pharmaceutical companies that was recently invited to the White House for a Presidential conference on the potential of next-generation “precision” therapies based on individual, family, and large-group genetic characteristics. Here, we present a Q & A with Aris Baras, MD, Executive Director of the Regeneron Genetics Center.

Q. When did Regeneron get involved in integrating genetics into the company’s drug development program?

A. Regeneron has long been a leader in genomics-based medicine and science — we created the first knock-out mouse in 1992 and have been involved in mouse genetics ever since, including our participation in the NIH’s Knock-Out Mouse Project and the development of our proprietary VelociGene and VelocImmune technologies. We’ve also had great success translating genetic discoveries into treatments like Arcalyst for a rare immune disorder and alirocumab for hypercholesterolemia.

And now that the Regeneron Genetics Center’s (RGC) large-scale sequencing and analysis program has established a fully operational model for the President’s Precision Medicine vision — we are leaders in terms of scale and scope, currently sequencing 50,000 exomes per year along with Geisinger Health System and our other collaborators, linking genomic data to clinical and phenotypic info. Most importantly, the RGC is fully integrated into the Regeneron drug development process.

Q. When the company established its Genetics Center did you expect the trend toward personalized medicine to gain traction as quickly as it did — or was the company looking much longer term?

A. Regeneron has always been driven by genetics, but we did realize that early last year was the perfect time to innovate and expand efforts by launching the RGC, thanks to tremendous advances (and cost reduction) in related technology, such as DNA sequencing. We are moving even quicker than expected — raising our initial goal of 100K people sequenced in five years up to 250K in the same amount of time. But as with all great scientific endeavors, this will be a long-term commitment as we work to translate information into real advances in treatment.

Q. Does the partnership with gene therapy company Avalanche also play into the company’s commitment to develop more personalized treatments based on individual genotyping?

A. This is one of the potential opportunities of the partnership. The Avalanche collaboration combines their novel gene therapy technology with Regeneron’s proprietary molecules and genetic research capabilities with the aim of creating a new class of next-generation biologics in ophthalmology.

Q. In terms of development of new drugs for retinal diseases, should all patients involved in clinical trials now be genotyped so that researchers can determine a drug’s efficacy in various subsets of patients? Would Regeneron genotype patients in future clinical trials for retinal drugs?

A. We have collected samples from volunteers in previous ophthalmology studies and will be incorporating genotyping and sequencing into future studies as well; we are actively pursuing such pharmacogenetic studies. We have always considered participation in genomic research optional, and the number of volunteers may increase as initiatives like this raise awareness about the potential benefits of collecting this data.

Q. What was the company’s “take away” from the White House conference? Does the invitation solidify Regeneron as an acknowledged leader in the area of customized therapies?

A. We are thrilled to see a high-level commitment to innovative science that can bring new hope to patients in need. America’s biomedical research enterprise — including the NIH, academia and industry — is one of our greatest strengths and has made this country the global leader in improving the lives of patients with serious diseases. We need to keep this strong leadership position and invest in it.

We do believe this initiative underscores the importance of the sequencing program at the RGC. We believe in precision medicine, and will continue working to advance innovative treatments for patients.

Pfenex in Pact to Develop Lucentis Biosimilar

Hospira will make $51 million upfront payment.

■ Pfenex (San Diego), a clinical-stage biotechnology company engaged in developing biosimilar therapeutics, and Hospira, Inc. (Lake Forest, IL), a leading provider of injectable drugs and infusion technologies, and a global leader in biosimilars, said the companies have entered into an agreement to exclusively develop and commercialize PF582, Pfenex’s biosimilar candidate to Lucentis (Genentech, ranibizumab) anti-VEGF therapy for retinal diseases.

Biosimilars are a relatively new area of drug development. They are generally defined as “subsequent versions of previously approved biologics” that can demonstrate comparability in both safety and effectiveness to the original therapy.

Under the terms of the collaboration, Pfenex will receive an upfront payment of $51 million once the collaboration receives antitrust approval, and, over the next five years and beyond, will be eligible to receive a combination of development and sales-based milestone payments up to an additional $291 million, and tiered double-digit royalty on net sales of the product.

Pfenex and Hospira will share the phase 3 equivalence clinical trial costs, and Hospira will be responsible for manufacturing and commercializing the product worldwide. The agreement also allows for additional future product collaborations.

Pfenex is currently conducting a phase 1b/2a clinical trial where 24 patients have been randomized to receive monthly intraocular injections of PF582 or Lucentis for three doses and ongoing patient follow-up for 12 months. The clinical trial’s primary objective is to evaluate safety and tolerability of PF582, with secondary objectives including comparative pharmacokinetic and pharmacodynamic evaluations to help demonstrate biosimilarity to Lucentis.

“Pfenex has established expertise in the development of biosimilars, leveraging its proprietary expression technology together with differentiated bioanalytical characterization capabilities,” said Sumant Ramachandra, MD, PhD, senior vice president, chief scientific officer, Hospira.

Dow Chemical owns approximately 20% of Pfenex common stock.

IN BRIEF

Ophthotech advances Zimura into new trials. Ophthotech Corp. (New York, NY) said it has initiated a clinical trial for its complement C5 inhibitor Zimura for the treatment of polypoidal choroidal vasculopathy, a variant of wet AMD. The company also expects to advance Zimura into a phase 2/3 clinical study for geographic atrophy, a form of dry AMD, later in 2015.

In addition, Ophthotech has an ongoing study, begun in August 2014, using a combination of its anti-PDGF drug Fovista with anti-VEGF as a treatment for subretinal fibrosis.

In related news, Ophthotech has received a $50 million milestone payment from Novartis for reaching a second enrollment goal in its pivotal phase 3 multinational trial for its anti-PDGF drug Fovista combined with an anti-VEGF agent to treat wet AMD.

CMS to ease meaningful use reporting burden. CMS said it is considering “multiple” proposals that would ease providers’ reporting requirements under the Medicare and Medicaid Electronic Health Records Incentive Program. No final decision on any changes in regulations is expected until later this spring.

“The new rule would be intended to be responsive to provider concerns about software implementation, information exchange readiness, and other related concerns in 2015,” CMS said in a statement. “It would also be intended to propose changes reflective of developments in the industry and progress toward program goals achieved since the program began in 2011.”

Lucentis approved for diabetic retinopathy in patients with DME. The FDA has expanded the use of ranibizumab (Lucentis, Genentech) to treat diabetic retinopathy (DR) in patients with DME. The approval came following the indication previously being given “breakthrough therapy” status.

The drug’s safety and efficacy to treat DR with DME were established in two clinical studies involving 759 participants who were treated and followed for three years. In the two studies, participants being treated with Lucentis showed significant improvement in the severity of their DR at two years compared to patients who did not receive an injection.

Iluvien Implant for DME Debuts in US

Persistence pays off for Alimera Sciences.

■ After years of wending its way through the FDA approval process and overcoming several obstacles to approval, Alimera Sciences’ (Alpharetta, GA) Iluvien long-term, sustained-release implant for the treatment of DME has made its commercial debut in the United States.

“I give Alimera a lot of credit for persisting in pursuing a path to approval,” says Pravin Dugel, MD, of Retinal Consultants of Arizona. “I don’t know if many other companies would have done so. The good thing is that we now have a large volume of information on Iluvien, which will help us determine when and in whom to use this implant.”

Dr. Dugel notes that the anti-VEGF drugs that are typically used as first-line therapy for DME may be either ineffective or of limited effectiveness in about half of all DME patients, according to the DRCRnet trials.

“About 50 percent of our DME patients are going to need something more than anti-VEGF,” says Dr. Dugel. “Once DME evolves into a primarily inflammatory disease, we may be able to successfully treat it with steroid devices such as the shorter-term Ozurdex (Allergan, Irvine, CA) and long-duration Iluvien implants. I believe there is definitely an important place for Iluvien in our arsenal.”

Though Iluvien is known to cause side effects such as cataracts and an increase in IOP, Dr. Dugel says he would never let the prospect of cataract formation stop him from treating a serious, blinding disease.

“Actually, patients who have the Iluvien implant on board do better after cataract surgery,” he says. “And increase in IOP is not glaucoma. The percentage of patients with the Iluvien implant who do require IOP-lowering surgery is small — less than 5% — so I do not let these side effects stand in the way of treating a very serious disease.”

Iluvien, which is approved for both phakic and pseudophakic patients in the United States, is implanted in an office-based procedure and is designed to continuously provide fluocinolone acetonide for a 36-month period. It is now approved for use in 17 countries worldwide. RP

IN BRIEF

France and Italy begin Argus II implants. Second Sight Medical Products (Sylmar, CA) said that three new centers in France and two in Italy had achieved successful implantations of the company’s Argus II retinal prosthesis. The device is capable of bringing a level of functional vision to patients afflicted with retinitis pigmentosa.

The new centers in France and Italy bring to 11 the number of countries in which the Argus II is being implanted. The Argus II was approved by the FDA for use in the United States in 2013.

Second Sight became a public company in November 2014, trading under the symbol EYES.

Eylea approved for DR in patients With DME. Regeneron Pharmaceuticals, Inc. (Tarrytown, NY) said the FDA has approved Eylea (aflibercept) for the treatment of diabetic retinopathy in patients with DME

The approval follows the recent FDA approval of Lucentis (Genentech, ranibizumab) for the same indication.

“Diabetic retinopathy coupled with DME is a serious complication of diabetes that can threaten the vision of many working-age adults,” said George D. Yancopoulos, MD, PhD, chief scientific officer of Regeneron. “In addition to improve visual acuity in people with DME, Eylea also improves these patients’ retinal vessel damage, or retinopathy.”

The recommended dosage in patients with DR in DME is 2 mg every eight weeks after five initial monthly injections.

Approval was based on two-year data from the VISTA-DME and VIVID-DME, which compared Eylea 2 mg monthly, Eylea 2 mg every two months (after five initial monthly injections), and macular laser photocoagulation.

Patients in both Eylea groups gained, on average, two additional lines on an eye chart, compared with almost no change in the control group.

Corrections & Clarifications

■ In the March 2015 issue, the article “Emerging Treatments for Retinitis Pigmentosa,” pages 53 and 54, two images were switched. The image currently appearing on page 53 is of a retinal implant and should appear on page 54; the image on page 54 is the fundus photo that should appear on page 53. We apologize for the error.