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.”

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.

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