Ophthotech AMD Combo Fails in Phase 3
No significant benefit over Lucentis monotherapy.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Long-anticipated initial data from two large phase 3 pivotal clinical trials that studied a combination of Ophthotech’s proprietary anti-PDGF drug Fovista and Genentech’s Lucentis (ranibizumab) for wet AMD showed that the combination produced no significant benefit in visual acuity over Lucentis monotherapy at 12 months.
A highly positive 449-patient phase 2b trial of the Ophthotech combo had led many in the retina community to believe that an anti-PDGF/anti-VEGF combination would usher in the next generation of more durable and efficacious treatments for wet AMD. But the news hit stakeholders hard.
On Wall Street, Ophthotech shares immediately fell from $38 to less than $6. And the company announced recently that it was eliminating at least 125 positions, leaving just dozens behind. The future of some clinical trials also are affected.
The rationale behind anti-PDGF/anti-VEGF combinations is that the anti-PDGF agent has the ability to break down the barrier of pericytes that protect the VEGF, thus enabling the anti-VEGF agent to be more effective in eliminating the unwanted VEGF. Several companies have been active in this area of research, including Regeneron and Allergan. However, a Regeneron combination of its own proprietary anti-PDGF and its anti-VEGF Eylea has not shown a benefit in early data from a phase 2 clinical trial.
David R. Guyer, MD, CEO of Ophthotech said the company was “disappointed” with the results and “would continue to analyze the data to better understand” what happened.
Both Dr. Guyer and Ophthotech President Samir Patel, MD, are considered pioneers in the development of retina drugs, having successfully shepherded the anti-VEGF aptamer Macugen through the FDA approval process when they were principals of Eyetech Corporation a decade ago.
The two clinical trials (OPH1002 and OPH1003) were international, multicenter, randomized, double-masked, controlled phase 3 studies evaluating the safety and efficacy of 1.5 mg of Fovista administered in combination with Lucentis compared to Lucentis monotherapy. The trials enrolled an aggregate of 1,248 patients with wet AMD. The results from the trials’ databases were unmasked and analyzed concurrently.
The combined analysis showed that patients receiving Fovista combination therapy gained a mean of 10.24 letters of vision on the Early Treatment of Diabetic Retinopathy Study (ETDRS) standardized chart at 12 months, compared to a mean gain of 10.01 ETDRS letters for patients receiving Lucentis monotherapy.
In OPH1002, consisting of 619 treated patients, subjects receiving Fovista combination therapy gained a mean of 10.74 letters of vision on the ETDRS standardized chart at 12 months, compared to a mean gain of 9.82 ETDRS letters in patients receiving Lucentis monotherapy, a resulting difference of 0.92 ETDRS letters. In OPH1003, consisting of 626 treated patients, subjects receiving Fovista combination therapy gained a mean of 9.91 letters of vision on the ETDRS standardized chart at 12 months, compared to a mean gain of 10.36 ETDRS letters in patients receiving Lucentis monotherapy, a resulting difference of -0.44 ETDRS letters.
In the phase 3 trials, the anti-PDGF and anti-VEGF drugs were administered 30 minutes apart.
However, in a small investigator-sponsored trial, Pravin Dugel, MD, of Retinal Consultants of Arizona, administered the anti-PDGF a day before he injected the anti-VEGF. This “pretreatment” protocol demonstrated encouraging results in a difficult-to-treat patient cohort, Dr. Dugel reported, and may possibly be an avenue to continue to pursue.
Ophthotech has a third ongoing phase 3 trial in which combinations of Fovista and Eylea and Fovista and Avastin (Genentech) are being studied in comparison to anti-VEGF Eylea or Avastin monotherapy.
■ Santen uveitis drug effective in phase 3 Santen Pharmaceutical (Osaka, Japan) said topline data from its phase 3 SAKURA study demonstrated that its Opsiria therapy (sirolimus intravitreal injection) for noninfectious posterior uveitis met its objectives in combating inflammation as measured by vitreous haze.
The company said it would file a New Drug Application with the FDA in early 2017.
Trump’s Win Scuttles CMS Reimbursement Plan
Payment for Lucentis and Eylea were at risk.
■ A CMS “demonstration plan” that would have rewarded physicians for administering less costly Medicare Part B drugs and penalized them for using their more costly counterparts looks to have withered on the decimated Democratic vine following Donald Trump’s election victory.
Spokespersons for ophthalmic and oncologic organizations, the two specialties that would have felt the plan’s financial impact the most, said the Obama administration’s willingness to let a key, late November deadline pass without taking any action clearly signaled that the administration has conceded the battle. CMS received more than 1,300 public comments after the plan was announced in March, with the overwhelming majority opposed to implementation.
Cathy Cohen, AAO vice president for governmental affairs, said the Obama administration had proffered the demonstration plan without consulting with representatives of those medical specialties that would be most affected, thus creating widespread opposition to what the AAO considered a flawed and ill-informed plan.
During the public comment period, the AAO, ASCRS, and the Retina Society published a joint letter to CMS pointing out that retina specialists would almost certainly lose money on every injection of Lucentis (Genentech) and Eylea (Regeneron) if the lower proposed reimbursement amounts were put into effect. The reimbursement formula recommended by CMS would not have covered the overhead for procuring, storing, administering, tracking, and applying for reimbursement for the two leading FDA-approved anti-VEGF drugs, the letter said.
■ Genentech drug combats GCA in phase 3 The Genentech drug Actemra met both its primary and secondary endpoints in treating giant cell arteritis (GCA) — a form of vasculitis that can lead to blindness — in recently released data from a 251-patient phase 3 study. The prevalence of GCA has been estimated at over 200 per 100,000 persons in the US over the age of 50, and the disease is two to three times more likely to affect women than men.
At one year, 56% of patients on Actemra achieved disease-free remission, while 14% of patients on a steroid-only taper regimen were disease-free at six months.
Actemra was given “breakthrough” status for GCA by the FDA in October. It is the first humanized interleukin-6 (IL-6) receptor antagonist approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have used one or more disease-modifying anti-rheumatic drugs such as methotrexate, that did not provide enough relief.
■ Sustained-release format planned for Eylea Regeneron (Tarrytown, NY) will collaborate with Ocular Therapeutix (Bedford, MA) in the development of sustained-release delivery of its anti-VEGF drug Eylea (aflibercept), which is now delivered by intravitreal injection.
Ocular Therapeutix is now developing proprietary sustained-release hydrogel-based drug delivery depots that can be implanted and formulated with both small and large molecule pharmaceuticals, such as tyrosine kinase inhibitors and protein-based anti-VEGFs, respectively, with the goal of delivering sustained and therapeutic levels of drugs to targeted ocular tissues. The formulation for Eylea is in preclinical development.
Genentech’s Lucentis, the only other FDA-approved anti-VEGF for retinal disease, has been in clinical trials for sustained-release delivery for more than two years. The current phase 2 trial, called LADDER, encompasses 316 patients and employs a refillable implant.
■ Study: lopidine reduces pain from intravitreal injections Edith Wolfson Medical Center researchers in Israel found that topical apraclonidine (Iopidine) applied 30 minutes before an intravitreal injection reduces patients’ perception of pain from the injection.
In a 39-patient study of patients receiving bevacizumab, patients receiving Iopidine reported a mean score of 1.69 on a numerical pain scale (1 being the least pain) while the same patients receiving placebo on a different visit reported a mean score of 3.28. A reduction in the incidence and size of injection-related subconjunctival hemorrhage was also reported in some patients. Iopidine is generally used as an adjunct therapy to help reduce IOP in patients having laser therapy to treat glaucoma. The study appeared online in Retina.
Spark is Offering Free Genetic Testing
Screening is for inherited retinal diseases.
■ Spark Therapeutics (Philadelphia), which develops gene therapies to treat retinal and other diseases, will provide physicians and eligible patients access to genetic testing and counseling for more than 30 genes linked to certain forms of inherited retinal diseases (IRDs), a group of eye conditions believed to affect more than 100,000 people in the United States.
The ID YOUR IRD initiative was formally unveiled at the American Academy of Ophthalmology (AAO) 2016 annual meeting in Chicago. Spark has already completed a successful phase 3 trial for gene therapy in treating IRDs and is on course to have the first-ever FDA-approved gene therapy for any medical condition.
“A confirmed genetic diagnosis is a critical gateway for patients with inherited retinal diseases and this initiative will help patients, caregivers, and the medical community better understand their disease,” said Mark Pennesi, MD, PhD, associate professor of ophthalmology in the OHSU School of Medicine, OHSU Casey Eye Institute. “Genetic testing may provide valuable insight into the underlying cause of vision impairment and enable patients to connect to others living with the same condition. With the identification of new genes and the growing focus on gene therapy research, our understanding of IRDs is changing rapidly. People with IRDs are encouraged to seek testing even if they have previously been tested for a genetic disease.”
The initiative was developed in response to feedback from advocates, families affected by IRDs, and healthcare professionals about the current barriers preventing access to genetic screening for IRDs in a consistent, streamlined manner.
Spark Therapeutics is working with physicians across the country who will be equipped to facilitate IRD genetic testing for eligible patients. Eligibility will be determined by the patient’s physician.
Participating physicians will send test samples to an independent lab, which will process the sample and deliver test results that may confirm the specific genetic mutation causing the IRD. This information may help determine the best course of action for the patient. Eligible patients will receive the genetic test offered by ID YOUR IRD free of charge, subject to the initiative’s terms and conditions. The initiative also offers optional access to independent genetic counselors at no cost to eligible patient participants.
It is estimated that more than two million people live with IRDs globally, but only a small percentage of them have been genetically screened due to limited access to information about genetic testing.
People who have an IRD or their family members may initiate the process of determining eligibility by talking with their healthcare professional about the program or by visiting www.idyourid.com
The site includes a brief patient screener, complete initiative terms and conditions, and other resources.
■ Allergan founders fund advanced retina research Allergan founder Gavin Herbert and his wife, Ninetta, have pledged $5 million to advance retinal research at UC Irvine Health’s Gavin Herbert Eye Institute, the academic eye care center named in his honor.
“As longtime champions of the Gavin Herbert Eye Institute, the Herberts have shown that community leaders can have an indelible impact on academic medicine and the future of health care,” said Michael J. Stamos, MD, interim dean of the UC Irvine School of Medicine.
■ Rxi studies RNAi drug for retinal scarring About a dozen years ago, RNA interference (RNAi) was thought to be “the next big thing” in the advancement of therapies for retinal diseases. However, when companies like Sirna and Acuity failed to produce the hoped-for results, the RNAi concept lost some of its luster.
However, Rxi Pharmaceuticals (Marlborough, MA) is now conducting a small, phase 1/2 trial using intravitreal injections of its RNAi drug to combat retinal scarring in patients with advanced wet AMD. The company’s compound, RXI-109, is designed to reduce the expression of connective tissue growth factor (CTGF), a critical agent of scar formation in the eye.
Craig Mello, PhD, who chairs the company’s scientific advisory board, is a Nobel Prize winner for his work with RNA interference.
More Durable Retina Drugs in the Pipeline
Twelve-week dosing now a realistic goal.
■ The decade-long dominance of anti-VEGF monotherapy for the treatment of a range of retinal diseases will soon end if several drugs and drug combinations now in late-stage trials can live up to the potential they have shown in earlier studies.
“Anti-VEGF monotherapy is reaching its limits,” says Anthony P. Adamis, MD, global head of ophthalmology, immunology, and infectious diseases for Genentech. “But more people are doing research in eye disease than ever before. That is great for patients because competition drives us all to do better.”
Dr. Adamis’ comments are borne out by recently reported research advances. In the past year, several investigational drugs and drug combinations have demonstrated in later-stage studies that they can be dosed every 12 weeks with comparative effectiveness to approved anti-VEGF therapies that are generally dosed every four to eight weeks.
In addition, recent stepped-up efforts to develop dependable sustained-release delivery methods for suitable retina drugs by companies such as Genentech/Roche, Regeneron, Alcon, and pSivida offer the promise of much longer time periods between retreatments. For example, Genentech/Roche has initiated a 316-patient phase 2 study called LADDER that is testing the ability of a refillable implant to deliver ranibizumab (Lucentis) in a sustained-release format.
With regard to the investigational drugs and combos now in the pipeline, at least three have shown the potential — if approved — of a more durable response that should translate to less frequent dosing regimens that would ease the treatment burden on both patients and retina specialists.
All three are either in phase 3 clinical trials or set to enter phase 3 in the near future.
These include Alcon’s brolucizumab (RTH258), a small-molecule, single-chain antibody fragment that appears highly suitable for sustained-release delivery; Allegro’s Luminate, which recently showed 12-week durability in the phase 2b DEL MAR study for DME; and Allergan’s abicipar pegol (DARPin), which demonstrated eight-to-twelve week durability in the PALM2 trial.
Add to these the promising Genentech/Roche bispecific antibody RG7716, currently in the 271-patient phase 2 AVENUE study for AMD and the 150-patient phase 2 BOULEVARD study for DME.
RG7716 is both an anti-VEGF and an ANG2 inhibitor. It has shown good efficacy and durability in a small phase 1 trial in which the patient base was comprised of poor responders to anti-VEGF monotherapy.
In addition, Regeneron is studying an Eylea/anti-ANG2 combination, also in phase 2, which the company says has produced highly encouraging results in early studies.
■ Opsis to focus on cell-based retina therapies Cellular Dynamics (CDI, Madison, WI), a developer and manufacturer of induced pluripotent stem cell (iPSC) products, has a new venture, Opsis Therapeutics, focused on discovering and developing novel medicines to treat patients with retinal diseases. CDI says the Opsis Therapeutics team brings a track record of developing breakthrough technologies and building next-generation cell therapeutic programs. The venture has been founded in partnership with David Gamm, MD, PhD, a pioneer in the differentiation and transplantation of iPSC-derived retinal cells.
“No therapeutic options [are] available that can broadly mitigate or restore the permanent loss of vision and blindness [which inherited and acquired conditions] can cause,” said Dr. Gamm in a statement. “At Opsis Therapeutics, we see promise in a variety of new approaches. For example, over the past decade, it has become feasible to generate new photoreceptors from [iPSCs] and transplant them into the diseased retina, with additional advances anticipated in the future.”
■ FDA clears Navilas all-digital laser
OD-OS (Irvine, CA) Navilas said the FDA has granted 510(k) clearance and immediate US commercial availability of the Navilas 577s, a compact all-digital system for navigated focal and peripheral laser treatments.
Navilas 577s enables physicians to digitally pre-plan the entire laser therapy on fundus images as well as external diagnostic images and precisely execute this therapy plan under computer guidance. RP