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.

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.

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.

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.

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.