Positive Phase 2 Bispecific Antibody Data Presented
RG7716 meets primary endpoint in BOULEVARD Phase 2 DME trial.
BY REHAN M. HUSSAIN, MD
■ Dr. Pravin U. Dugel, managing partner of Retinal Consultants of Arizona and clinical professor at the Roski Eye Institute, USC Keck School of Medicine, presented the results of the phase 2 BOULEVARD trial at the Angiogenesis, Exudation, and Degeneration conference in Miami, Florida, on February 10, 2018. The trial tested the efficacy and safety of RG7716 (Hoffman-La Roche), the first anti-VEGF-A/Antiangiopoietin-2 (Ang-2) bispecific antibody designed for intravitreal use in patients with DME.
Dr. Dugel explained, “Targeting additional pathways beyond VEGF could improve BCVA outcomes and decrease treatment burden. Evidence supports rationale for Ang-2 inhibition. Ang-2 has been shown to be elevated in the vitreous of patients with DR and contributes to retinal microvascular inflammation, blood retinal-barrier breakdown, capillary sprouting, and remodeling.”
The BOULEVARD trial met its primary endpoint, as RG7716 demonstrated statistically significant BCVA gains over ranibizumab at week 24 in anti-VEGF treatment-naïve patients with DME. Of the 229 patients with center-involving DME who were enrolled in the study, 168 were treatment naïve. When factored into a linear model adjusting for baseline BCVA and randomization factors, the 6.0-mg RG7716 group gained a mean of 13.9 letters from baseline, which was an improvement of 3.6 letters over the 10.3 letters gained by the 0.3-mg ranibizumab group (P=.03). According to Dr. Dugel, “Ranibizumab performed as expected, with an improvement of visual acuity up to week 16, and a plateau effect thereafter. RG7716 had a dose-dependent response. There was no plateau effect at all. There was a linear relationship that continued to improve over time, suggesting that a second mechanism of action may be at play, namely Ang-2 inhibition.”
The secondary functional and anatomic endpoints supported the BCVA primary outcome. The 6.0-mg RG7716 group had a mean CST reduction of 226 µm compared to 205 µm in the ranibizumab group. Thirty-nine percent of patients in the 6.0-mg RG7716 group had a ≥2 step improvement in Diabetic Retinopathy Severity Score, compared to 12% in the ranibizumab group. The safety profile of RG7716 was comparable to other anti-VEGF drugs, with no new safety signals observed.
Apellis Plans Phase 3 GA Trials
Building on success of a strong phase 2 study.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Apellis Pharmaceuticals said that following discussions with the FDA, it has finalized the trial design for its planned phase 3 program evaluating the C3 complement inhibitor APL-2 for patients with geographic atrophy (GA) associated with AMD.
The phase 3 program, planned to begin in the second half of 2018, will consist of 2 identical 600-patient prospective, multicenter, randomized, double-masked, sham-injection controlled studies to assess the efficacy and safety of multiple intravitreal injections of APL-2 in patients with GA. The phase 3 trials will be similar in design to Apellis’ ongoing phase 2 FILLY trial, which, at 12 months, showed a 29% reduction in the growth of GA lesions in the monthly treatment group and a 20% reduction in the every-other-month group. The primary endpoint, change in GA lesion size from baseline to month 12 as compared to sham, is unchanged from phase 2, as are enrollment criteria, which will include patients with a history of wet AMD in the fellow eye. Patients whose treatment eye develops wet AMD will continue to be treated with APL-2 along with anti-VEGF therapy.
“Our phase 3 trial design is intended to address a patient population similar to the one we studied in phase 2, which we believe is representative of the general population of patients with GA in the United States,” said Cedric Francois, MD, PhD, founder and CEO of Apellis. “Currently, there are no approved treatments for the approximately 1 million patients suffering from GA in the United States. We believe that by slowing the rate of degeneration of retinal tissue through broad C3 inhibition, we may be able to delay or prevent the progression to blindness in these patients.”
Squalamine Eye Drop Fails in Wet AMD
No benefit seen when combined with Lucentis.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ After an odyssey of more than 20 years of clinical trials for various diseases (including lung cancer and foot ulcers), the aminosterol antiangiogenic squalamine, synthesized from the liver of the dogfish shark, may have run out of chances for commercialization.
The latest effort, the phase 3, 237-patient MAKO trial for wet AMD conducted by Ohr Pharmaceuticals, failed to add any benefit when a squalamine eye drop was used in combination with monthly Lucentis (Genentech). In fact, at 9 months, patients on Lucentis monotherapy achieved a mean gain of 10.58 letters compared to a mean gain of 8.33 letters in the combination group. These results were despite the fact that Ohr had used its phase 2 IMPACT trial to select patients most likely to benefit from its therapy.
The IMPACT trial raised hopes that squalamine could be effective in achieving additional visual gains when used as a topical supplement to anti-VEGF injections. Patients in the phase 2 study with classic disease achieved a mean vision gain of 6 additional letters when using squalamine in combination with Lucentis.
The MAKO study was a multicenter, randomized, double-masked, placebo-controlled clinical trial to evaluate the efficacy and safety of squalamine combination therapy for the treatment of wet AMD. Subjects were randomized 1:1 to receive topical squalamine lactate ophthalmic solution, 0.2%, twice daily and monthly Lucentis injections or topical placebo twice daily and monthly Lucentis injections.
Eligibility criteria included new diagnosis with wet AMD and no previous treatment, occult neovascularization, if present, measuring less than 10 mm2 as assessed by fluorescein angiography, and visual acuity between 20/40 and 20/320. A total of 237 subjects were randomized. Visual acuity was measured monthly using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart. The primary efficacy endpoint was the mean visual acuity gain at 9 months, using a mixed-effects model for repeated measures analysis.
Squalamine was originally developed by Magainin Pharmaceuticals in the mid 1990s based on the work of researcher Michael Zasloff, but failed in several indications. It was later tried in wet AMD by Genaera Corp., which sold the rights to Ohr in 2009.
ONL Preparing for First Clinical Trial
Combating cell death in retinal detachment.
■ ONL Therapeutics expects to soon commence an intriguing — and potentially groundbreaking — phase 1/2 clinical study of its neuroprotective ONL1204 peptide therapy in an effort to prevent cell death (apoptosis) following retinal detachment. If this study is successful, the company plans to follow up by employing ONL1204 to combat cell death in geographic atrophy.
The trial will be the culmination of research led by David N. Zacks, MD, PhD, of the Kellogg Eye Center at the University of Michigan. Dr. Zacks has spent more than 15 years studying photoreceptor cell death and has concluded that inhibiting the FAS pathway through medical intervention is key to stopping unwanted photoreceptor cell death in retinal detachment, wet and dry AMD, geographic atrophy, and diabetic retinopathy. The target for the initial trial is the 25,000 annual US cases of “macula-off” retinal detachment. a group for which surgical results have been excellent but visual outcomes poor.
Dr. Zacks says ONL1204 should also be able to provide neuroprotection in a range of retinal diseases, treating the root cause of vision loss, which is photoreceptor cell death. Overall, the potential market opportunity for the use of ONL1204 in a variety of indications exceeds $12 billion annually. The FDA has already given ONL1204 orphan drug designation.
In a recent interview with Retinal Physician, Dr. Zacks said that both funding for the trial and recent preclinical research have been going well and expressed a high level of confidence in the potential of ONL 1204.
“The trial design will be critical,” Dr. Zacks asserts. “For example, how do we define success?”
Another challenge is conducting the trial. Patients will come into the clinical sites as emergency cases and must be treated within hours of the retinal detachment.
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Topcon Triton Imaging System Gets FDA Approval
■ The FDA has given 510(k) clearance to Topcon’s much-awaited DRI OCT Triton Series, an imaging system that features easy image capture and a 1-micron, 1,050-nm light source with a scanning speed of 100,000 A-scans/second. The multimodal instrument incorporates a built-in retinal camera, eye tracking during capture of selected scans, and combines OCT imaging, color, red-free, FA, and FAF imaging with the diagnostic power of swept-source OCT, according to the company.
In addition to anterior segment scanning, Topcon says the Triton can visualize deeper pathology, rapidly penetrating ocular tissues such as the choroid and the sclera, without being obscured by media opacities or hemorrhage.
Novartis Buys Priority Review “Lottery Ticket”
■ Novartis recently paid $130 million to Ultragenyx for a priority-review pass, which Ultragenyx had originally received as a reward for developing a successful therapy for a rare pediatric disease. Priority review passes are valuable because they can shave 4 months or more off the FDA approval process for an investigational drug. Priority review passes can be sold or traded among pharmaceutical companies that have investigational drugs.
Novartis now has 2 priority review passes, one which it earned on its own, and speculation has begun that the company may use the pass to advance its very promising anti-VEGF agent brolucizumab, which has already demonstrated impressive 12-week dosing in two large phase 3 trials for wet AMD.
Novartis has several promising drugs in advanced clinical trials, so it is not a sure thing the company will use the pass on brolucizumab. However, the faster brolucizumab goes through the approval process, the faster it can take on Lucentis (Genentech) and Eylea (Regeneron) in the lucrative wet AMD marketplace.
■ Letter to the Editor
Thank you for the excellent article, “The Importance of Assessing Low Vision in Retina Practice,” in the November/December issue of Retinal Physician. Referral for low-vision services is an idea whose time has come. As founder of The International Academy of Low Vision Specialists and as a Low Vision Diplomate in the American Academy of Optometry, I am intimately aware of the scarcity of referrals to low vision.
By having such articles in Retinal Physician, the culture can be changed to include those with vision loss. As I see it, the focus of the eyecare profession needs to be on the prevention and treatment of vision loss.
One question I have for the authors is about their explanation of The American Academy of Ophthalmology’s SmartSight Program. SmartSight level 2 for patients with moderate contrast sensitivity loss or VA <20/200 has a recommendation of referring patients to their internist or primary care providers. I understand the need to assess the risk for the comorbidities mentioned, but I am puzzled as to why referral to a low-vision doctor, who can actually help the patient function, is absent from the recommendations.
— Richard J. Shuldiner, OD, FAAO, FIALVS
Dear Dr. Shuldiner,
Thank you for your letter regarding our article. You are correct that referral of these patients to a low-vision specialist is a must. Although the guidelines do not specifically address this, they give several different recommendations. The Academy recommends referring patients with vision of less than 20/200 to internists and/or primary care provider for several reasons: risk of falls with subsequent morbidity is increased, which may endanger the patient’s life; increased depression in patients with these levels of vision, mostly because their independence is greatly reduced; and increased risk for Charles Bonnet syndrome (visual hallucinations), which may put the patient at risk for a wrong diagnosis of psychiatric disorder.
Overall, the approach to low-vision management is multidisciplinary. Having a capable team that includes the ophthalmologist, optometrist, and internist or primary care provider is crucial to comprehensive management, with better outcomes for both patients and their families. We hope this clears up any confusion.
— Manuel Paez-Escamilla, MD
SciFluor Eye Drop Promising in Wet AMD
■ SciFluor Life Sciences said it had encouraging topline data from its phase 1/2 trial treating wet AMD patients with its integrin inhibitor SF0166, the company’s lead eye drop drug for back of the eye diseases. The double-masked study assessed the safety, tolerability, and preliminary efficacy of SF0166 in 42 subjects (15 treatment naïve) who were randomized 1:1 to self-administer an eye drop containing either a 2.5% or a 5% solution of SF0166 twice a day for 28 days. The primary outcome measure of safety was achieved with no drug-related serious adverse events observed in the study throughout the course of treatment as well as during a 28-day follow-up period.
Oculus Surgical Will Distribute Vortex Products
■ Oculus Surgical, Inc., has announced a distribution partnership with Vortex Surgical Inc. The partnership encompasses the distribution of all Vortex products in the United States, including the Actu8 premium disposable forceps and procedural Convenience Kits, which were released at the November AAO meeting in New Orleans.
Spark to Charge $850,000 for IRD Gene Therapy
■ Spark Therapeutics, which recently received FDA approval for its one-time gene therapy treatment Luxturna for inherited retinal disease (IRD) says it will charge $850,000 ($425,000 per eye) but will be offering several new and innovative programs to insurers for spacing out payments tied to the procedure’s effectiveness and durability. The payment programs may serve as a model for future one-time gene therapy procedures.
“We have been working with stakeholders across the health care sector to help ensure that appropriate patients have access to a product that challenges all of the current conventions of how patients are treated, how products are delivered, and how payments are handled,” said Jeffrey Marrazzo, CEO of Spark Therapeutics.
“Our work is not done, but we believe that the offerings we are announcing will help ensure that eligible US patients have the coverage and financial support they need to gain access to both Luxturna and the specialized medical care required to deliver the product at treatment centers.”
FDA Fails to Approve Sirolimus for Uveitis
■ The FDA has sent a complete response letter to Santen saying that it cannot approve the nonsteroidal immunoregulator sirolimus for noninfectious posterior uveitis based on the current data from the phase 3 SAKURA trial. The FDA has requested additional supportive data for intravitreal sirolimus from Santen.
Novartis Licenses International Luxturna Rights
■ Spark Therapeutics has granted Novartis the international rights to its FDA-approved Luxturna gene therapy treatment for IRD. The deal includes a large upfront payment to Spark and future milestone and royalty payments that overall could amount to $170 million. Spark, which will retain the US rights to Luxturna, will be responsible for shepherding the drug through the European Medicines Agency approval process.
The Luxturna procedure is a one-time injection that replaces a biallelic mutation of the RPE365 gene with a healthy replacement.