Ophthotech Refocuses After Trial Setback
Company will have $175 million for new initiatives.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Ophthotech Corporation is down but not out after the stunning failure of 2 major phase 3 clinical trials for the combination of Lucentis and its proprietary anti-PDGF drug Fovista in wet AMD. After accounting for the $100 to $115 million in expenses associated with discontinued studies and drastic headcount reductions, the company said it will have at least $175 million to employ in new initiatives.
Speaking on a February 28 conference call, company Chairman David Guyer, MD, said Ophthotech would like to now leverage its deep experience in ophthalmology to license the rights to promising ophthalmic drugs, preferably, but not limited to investigational back-of-the-eye therapies that have demonstrated encouraging results in early-stage clinical trials.
“It is early in the process, but all options are on the table,” said Dr. Guyer. “I think a lot of companies would like to collaborate with us, given our depth of experience in ophthalmolgy.” He also noted that Ophthotech has hired Leerink Partners as a financial adviser to explore “all strategic options.”
Dr. Guyer said a third phase 3 clinical trial in wet AMD using a combination of Fovista with either Eylea or Avastin would continue to completion later this year.
He said given that the two Fovista/Lucentis trials demonstrated no benefit in any subgroup, he thought it “unlikely” that the Eylea/Avastin study will succeed, but that “we have made a commitment to complete the trial.” He also noted that the Regeneron anti-PDGF drug had failed in combination with Eylea, creating more evidence that anti-PDGF might not be the way to go.
In the case of Ophthotech’s other drug, Zimura, for both wet AMD and geographic atrophy, he noted that early results from a competitor’s phase 3 trial would be a key to whether to continue Zimura’s phase 2 study in geographic atrophy. The competitor is almost certainly Genentech’s promising drug lampalizumab.
Noting that the Ophthotech and competitor’s drugs both have similar mechanisms of action targeting complement factors, Dr. Guyer said success of the competitor’s drug in phase 3 would be a positive sign for continuing to study Zimura.
“It’s really a timing issue,” he said. “The competitor’s data will come out first and we will have a chance to see how it might relate to Zimura.”
The surprising failure of the 2 major phase 3 trials has played havoc with Ophthotech’s stock price, which has fallen from $38 a share to a current price of about $4 a share. However, the company has been quick to refocus and turn to possible new initiatives in medical retina, where new concepts abound.
■ Aerpio raises $40 million for drug development. Aerpio Pharmaceuticals has raised $40 million in new funding from venture capital investors to continue the development of AKB-9778, its proprietary Tie2 activator for the treatment of DR. The company plans to soon begin a 150-patient phase 2b clinical trial using once- and twice-daily dosing of AKB-9778 for 12 months to combat moderate to severe DR without DME.
“Tie2 has steadily gained momentum as one of the most scientifically validated pathways for stabilizing vasculature and now stands at the forefront of new mechanisms being studied to treat retinal disease,” noted Joseph Gardner, PhD, Aerpio president and CEO, in a press release. “The potential of AKB-9778 for patients with DR is significant. Reversing the progression of diabetic eye disease, without repeated injections into the eye, could positively impact the lives of millions of people.”
■ ADA cites role of anti-VEGF in DME. In its first position paper on diabetic retinopathy since 2002, the American Diabetes Association has acknowledged the important role of anti-VEGF therapy in the treatment of DME. The paper also cites positive study results achieved by anti-VEGF when compared to panretinal laser photocoagulation in proliferative DR.
In addition, the paper notes that OCT has emerged as a recommended option for the evaluation of diabetic retina disease. The position statement is available at http://care.diabetesjournals.org/content/40/3/412 .
Money Talks in Drug Development
Regeneron and Roche pour resources into research.
■ Despite the large amount of new investment by many companies in investigational therapies for retinal disease, Roche/Genentech and Regeneron, the developers of Lucentis and Eylea, have the resources and financial muscle to maintain leadership positions in anti-VEGF therapy. Both companies have created sophisticated platforms designed to produce promising biologic drug candidates that can be developed quickly and efficiently. What’s more, profits from their existing drugs can fund a high level of research activity. Small, fledgling drug companies can burn through cash quickly, sometimes betting their future on a single investigational drug. George Yancopoulos, chief scientific officer for Regeneron, told Bloomberg BusinessWeek that a small drug company that fails a phase 3 trial usually doesn’t survive (Piore A. “The X-Men Approach to Medicine.” Bloomberg BusinessWeek. June 9, 2016).
In terms of sophisticated drug development, Regeneron relies heavily on its revolutionary VelocImmune technology, which has essentially created a highly engineered research mouse in which mouse-like attributes have been removed and replaced by human-like attributes. This allows the mice to produce humanized antibodies, greatly speeding up the process of identifying and evaluating the best new drug candidates. Regeneron has earned hundreds of millions of dollars in fees by licensing VelocImmune to companies like Astellas and Astra Zeneca.
Roche/Genentech has developed the patented CrossMab technology that initially enables 2 therapeutic agents to be combined in a single bispecific biologic drug, with the potential of multispecific combinations in the future. The first promising bispecific retinal drug coming out of the CrossMab platform is the Ang2 inhibiting/anti-VEGF RG7716, which is already being studied in 3 separate phase 2 clinical trials. These trials include AVENUE for wet AMD, BOULEVARD for DME, and STAIRWAY for extended dosing in wet AMD. Both companies have also made strong commitments to developing patient-friendly sustained-release formats for their mainstay anti-VEGF drugs, Lucentis and Eylea, with the Lucentis format already in a phase 2 study.
There is no guarantee that Roche/Genentech and Regeneron will continue to dominate in therapies for retinal disease. Other companies with significant research resources are also in the hunt. Allergan has had successful clinical trial results with its DARPin for wet AMD and Alcon/Novartis has a strong entrant in the small-molecule, anti-VEGF brolucizumab, which has impressed in a phase 2 clinical study.
Smaller companies that have bet their future on a single drug candidate can still compete. Both AerPio, which focuses on diabetic retinal disease, and Allegro Ophthalmics, whose Luminate may have several potential indications, have been quietly but effectively working their way through the clinical trial process. Both companies have attracted funding for their research, a sign that the ophthalmic arena has become a hot area for venture capitalists, angel investors, and the IPO market.
■ Developer of Lucentis biosimilar ousts CEO. Dr. Bertrand C. Liang has resigned as CEO of San Diego-based Pfenex, Inc., after an internal investigation revealed violations of company policies regarding approval of third-party contracts. Pfenex is currently pursuing the development of a biosimilar (a biologic medical product that is almost an identical copy of an original product manufactured by a different company) for Lucentis (ranibizumab; Genentech). Patrick K. Lucy, former head of business development for Pfenex, was appointed interim CEO.
Pfenex had been partnering with Pfizer on the development of the Lucentis biosimilar, but Pfizer opted last year to terminate the collaboration, leaving Pfenex to develop the drug alone, or until it can find another partner. An inexpensive alternative to Lucentis already exists in the form of Avastin.
Pfenex said it has conducted a successful phase 1b/2a clinical trial of its Lucentis biosimilar. Formycon, a German company, has biosimilars of both Lucentis and Eylea (aflibercept; Regeneron) in development, with the Lucentis biosimilar currently in a 650-patient phase 3 clinical trial.
EyeGate Studies Iontopheresis for Macular Edema
The company is partnering with Valeant for other indications.
■ EyeGate Pharmaceuticals believes its proprietary corticosteroid EGP-437, delivered directly through ocular tissue by electrical stimulation (iontopheresis), can be a therapy for multiple ocular issues, including macular edema. To that end, the company is now conducting its own phase 1b/2a clinical trial for that indication.
In addition, EyeGate has exclusively licensed 2 therapeutic ocular indications to Valeant Pharmaceuticals for EGP-437. These will be part of Valeant’s Bausch + Lomb business and will continue through clinical trials for both noninfectious anterior uveitis and for pain/inflammation following cataract surgery.
Based on EyeGate’s own studies and other published research, the company says ocular iontophoresis can deliver substantially higher targeted ocular drug concentrations than traditional topical applications, leading to greater bioavailability, more sustained therapeutic effect, and reduced dosing frequency. For example, in uveitis, EyeGate reports that 2 iontopheretic treatments achieved the same rate of response as 4 weeks of topical eyedrops, with less incidence of elevated IOP.
EyeGate received an upfront payment reported at $4 million and is in line for additional developmental milestone payments and future royalties that could amount to a reported more than $100 million if the product and proprietary iontophoretic delivery system are successfully commercialized. EyeGate stock, which is publicly traded, doubled to $3 a share once the deal was announced.
EyeGate has already reported positive top-line data for the drug (dexamethasone phosphate) and delivery system from a phase 1b/2a clinical trial for the indication of post-cataract pain and inflammation. The company has begun a confirmatory phase 3 trial for the uveitis indication.
“This second licensing agreement with Valeant provides an important validation of both the clinical and commercial potential of iontophoretic EGP-437,” said Stephen From, president and CEO of EyeGate. “For the approximately 3 million cataract surgery patients in the United States each year, adherence to the postoperative therapeutic regimen is imperative. As many of these patients are older and may struggle with self-administration of corticosteroid eye drops, we believe that iontophoretic EGP-437 administered by the eye care practitioner will provide a promising new treatment in addressing the needs of this large patient population.”
Iontopheresis, which is essentially an injection without a needle, has a history of being used successfully to treat plantar fasciitis, bursitis, and tennis elbow. It is well suited to deliver anti-inflammatory therapies.
■ Oral wet AMD therapy enters phase 2. Tyrogenex, a privately held biopharmaceutical company, has announced the completion of enrollment in the 157-patient APEX study — a phase 2 trial of the anti-VEGF/anti-PDGF tyrosine kinase inhibitorX-82 (vorolanib) for the oral treatment of wet AMD. The study is a randomized, double-masked, placebo-controlled, dose-finding, noninferiority study of X-82 plus as-needed intravitreal anti-VEGF compared to as-needed intravitreal anti-VEGF alone in patients with neovascular AMD. Subjects are being treated for a total of 52 weeks with 1 of 3 doses of X-82 or placebo. In a 25-patient phase 1 study, the mean gain in visual acuity at 24 weeks was 5.3 letters with decreased foveal thickness.
■ Major award for OCT inventors. Ohio University and the National Academy of Engineering (NAE) have awarded the 2017 Fritz J. and Dolores H. Russ Prize to James G. Fujimoto, PhD, Adolf F. Fercher, PhD, Christoph K. Hitzenberger, PhD, David Huang, MD, PhD, and Eric A. Swanson, MS, for the invention of optical coherence tomography (OCT). The $500,000 biennial prize, which recognizes a bioengineering achievement that significantly improves the human condition, cites OCT for “leveraging creative engineering to invent imaging technology essential for preventing blindness and treating vascular and other diseases.”
■ Guardion Health to acquire Vector Vision. Guardion Health Sciences, which specializes in ocular health technologies and products, has signed a letter of intent to acquire VectorVision, Inc. in a stock transaction. VectorVision is a leader in standardized vision testing, including contrast sensitivity, glare disability, and ETDRS visual acuity testing with its CSV 1000 device.
Second Sight Getting Second Wind
Reimbursement increase should spur procedures.
■ Second Sight Medical should see a significant pick-up in procedures this year, after a difficult 2016 that saw US implantations of its Argus II retinal prosthesis drop sharply due to a delay in obtaining adequate CMS reimbursement. In November, CMS authorized a $150,000 overall reimbursement for the Argus II (up from the previous $95,000) while also authorizing 2 new CPT codes that take effect July 1 and are intended to simplify billing.
The FDA-approved Argus II provides a level of functional vision to patients afflicted with retinitis pigmentosa. Improved visual capabilities include the ability to avoid obstacles, follow lines in a crosswalk, and even sort laundry. A study of 30 patients implanted with the device showed that it was still effective after 5 years and was contributing to an improved quality of life.
Overall procedure volume dropped off sharply in 2016, with 42 devices implanted compared to 75 the year before. Almost all of the 2016 implants were in countries where the path to adequate reimbursement has been much smoother than in the United States. But there have been some bright spots, as one surgeon in Italy performed his 30th Argus II procedure recently, while UK and German health authorities have rendered favorable reimbursement decisions. In addition, Mark Humayun, MD, PhD, received the National Medal for Technology and Innovation for his work in developing the Argus II in a White House ceremony last year.
Improved US reimbursement is just one major positive development in the Second Sight story. In March, the company said it had raised $20.1 million in new funding from an oversubscribed stock rights offering. In addition, the company, which has almost 300 patents, said it was making progress in developing its next-generation Orion I Visual Cortical Prosthesis that is designed to connect directly to the brain.
In a UCLA study supported by Second Sight, a 30-year-old patient was implanted with a wireless multichannel neurostimulation system on the visual cortex and was able to perceive and localize spots of light with no significant adverse side effects.
Robert Greenberg, MD, PhD, chairman of the board of Second Sight, said in a press release, “By bypassing the optic nerve and directly stimulating the visual cortex, the Orion I has the potential to restore useful vision to patients completely blinded due to virtually any reason, including glaucoma, cancer, diabetic retinopathy, or trauma.”
Second Sight is also studying the use of the Argus II for end-stage dry AMD patients who constitute a much larger market than patients afflicted with retinitis pigmentosa.
■ Allergan and Editas to collaborate on gene editing. Allergan’s wholly owned subsidiary, Allergan Pharmaceuticals International Limited, and Editas Medicine have entered into a strategic research and development alliance under which Allergan will receive exclusive access and the option to license up to 5 of Editas Medicine’s CRISPR-based genome-editing ocular programs, including its lead program for Leber Congenital Amaurosis (LCA10), which is currently in preclinical development.
CRISPR (clustered regularly interspaced short palindromic repeats) is a versatile tool that can be programmed to target specific stretches of genetic code and edit DNA at precise locations in the human genome. The technology allows researchers to permanently modify genes and has the potential to create medicines with a durable treatment effect.
Under the terms of the agreement, Editas Medicine will receive an upfront payment of $90 million for the development of 5 candidate programs. Editas Medicine has the potential to earn additional payments for achieving near-term milestones specifically related to LCA10.
■ Surgical robot helps dissolve RVO blood clot. Surgeons at the University Hospitals Leuven (Belgium) are the first to operate using a surgical robot on a patient with RVO. The robot uses a needle of barely 0.03 mm to inject the thrombolytic drug ocriplasmin into the retinal vein. The Catholic University of Leuven team developed the robot and needle specifically for this procedure. The operation was successful and shows that it is technically possible to safely dissolve a blood clot from the retinal vein with robotic support. A phase 2 trial now must show what the clinical effect is for patients with RVO.
Opthea Plans Phase 2b Trial in Wet AMD
Company has unique “pan-VEGF” approach.
■ Australia-based Opthea Limited, whose “pan-VEGF” approach to combating retinal disease has been deemed highly promising by leading retina researchers, has met with the FDA to discuss parameters of the company’s upcoming phase 2b clinical trial.
Opthea has completed a Type C meeting with the FDA. The purpose of the meeting was also to obtain overall regulatory guidance on the clinical development program of OPT-302, Opthea’s novel VEGF-C and -D “trap” therapy for the treatment of wet AMD. Used as monotherapy or in combination with either Lucentis or Eylea, OPT-302 offers the potential of attacking VEGF-A, -C, and -D.
Opthea CEO Megan Baldwin, PhD, said in a press release, “The outcomes from this meeting provide a clear path forward to Opthea as we continue to execute our plan to initiate a larger, randomized and controlled phase 2b study in wet AMD patients in 2017.”
Opthea’s meeting with the FDA follows the completion of enrollment in the phase 2a dose expansion cohorts of its ongoing phase 1/2a clinical trial. The trial in wet AMD patients who were either treatment naïve or previously treated with anti-VEGF-A therapy enrolled 20 patients in the phase 1 dose escalation and 31 patients in the phase 2a dose expansion. Patients received OPT-302 administered by intravitreal injection either as a monotherapy (n=13) or in combination with the selective VEGF-A inhibitor Lucentis (Genetech) (n=38) monthly for 3 months.
Primary analysis data from the phase 1 dose escalation study demonstrated safety and tolerability of OPT-302 administered as a monotherapy and in combination with Lucentis. Encouraging signs of clinical activity of OPT-302 in the phase 1 study suggest that combined administration of OPT-302 and Lucentis may lead to improved visual acuity and anatomical outcomes over Lucentis alone. Best results were with 4 treatment-naïve patients who received an OPT-302/Lucentis combination and had a mean gain in visual acuity of 16.5 letters at week 12 along with a significant reduction in central subfield thickness.
Lead investigator Pravin Dugel, MD, of Retinal Consultants of Arizona, says the early-stage results for safety and biological response have been encouraging but no conclusions can yet be drawn for efficacy and durability.
Dr. Dugel notes that what intrigues him the most about the Opthea drug is that it represents an effort to achieve pan-VEGF inhibition, attacking 3 types of VEGF (A, C, and D) that contribute to the development of wet AMD. Used in combination with Lucentis or Eylea (Regeneron), which both combat VEGF-A, OPT-302 may have unique therapeutic capabilities not seen in previous AMD drugs.
“It’s also encouraging that OPT-302 does not inhibit VEGF-B, which offers the neuroprotective qualities that we want to retain,” says Dr. Dugel.
■ Lin Bioscience licenses dry AMD drug. Lin Bioscience and Columbia Technology announced that Lin has licensed the intellectual property portfolio and development program for a promising first-in-class medication, LBS-008, intended to slow or halt the progression of atrophic dry AMD.
Under the terms of this globally exclusive licensing agreement and collaboration model, the National Institute of Health’s Blueprint Neurotherapeutics Network, which funded the medication’s discovery and development, will provide financial support through phase 1.
The oral therapeutic candidate LBS-008 works by reducing retinol in circulation and reducing excess retinal uptake, leading to the formation of toxic byproducts that build up under the retina and cause dry AMD, and similarly in Stargardt macular dystrophy, the juvenile onset form of macular degeneration. It is expected to enter phase 1 clinical trials this year for dry AMD and for Stargardt disease as an orphan indication.
■ Dr. Sarayba joins Allegro. Allegro Ophthalmics announcead that Melvin Sarayba, MD, has joined the company as vice president of clinical affairs. In his new role, Dr. Sarayba is responsible for Allegro’s US and international clinical program for the integrin peptide therapy Luminate, which met its primary and secondary endpoints in the DEL MAR Phase 2b clinical trial for DME and is also being studied for the treatment of vitreomacular traction and other indications. RP