SUBSPECIALTY NEWS

Is Brolucizumab the Next Big Anti-VEGF?

A very small molecule shows multiple benefits.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ An update on the progress on the investigational anti-VEGF drug brolucizumab (Alcon/Novartis) is sure to attract a great deal of attention when it is presented at the ARVO annual meeting in early May. That’s because this unique, small-molecule single-chain antibody fragment has been showing outstanding results in efficacy, durability, and the ability for targeted administration in early-stage clinical trials for wet AMD.

Pravin Dugel, MD, managing partner of Retinal Consultants of Arizona, has served as the lead investigator for brolucizumab (also known as RTH258 and ESBA-1008) and is quite enthusiastic about the drug’s prospects as it enters large-scale, worldwide phase 3 studies. He notes that the small size of the molecule allows it to be given safely in doses as high as 6 mg in an acceptable volume. In earlier-stage clinical trials with hundreds of patients, brolucizumab showed significant advantages in both efficacy and durability when matched against the currently approved anti-VEGF drugs. If phase 2 results are confirmed in the phase 3 studies, 6-mg brolucizumab could provide a durable-enough response to allow for every-12-week dosing.

Dr. Dugel also points out that, because of its ability to be given in larger molar concentrations, brolucizumab can achieve better penetration of the target tissue at higher localized drug concentrations while also achieving reductions in systemic exposure. This last feature is considered important by Dr. Dugel, as he notes that many wet AMD patients are into their sixth or seventh year of receiving anti-VEGF injections.

Another promising aspect of brolucizumab noted by Dr. Dugel is that its molecular structure and size make it an ideal candidate for sustained-release delivery.

Alcon and Novartis have shown their commitment to the development of brolucizumab by commencing two worldwide phase 3 clinical trials that will enroll more than 3,000 patients across 90 countries.

Two Studies Confirm Value of Argus II

Retinal prosthesis is both effective and durable.

■ Data from two recently released clinical trials indicate that the Argus II retinal prosthesis (Second Sight Medical, Sylmar, CA) can provide both durable and significant functional vision to patients afflicted with retinitis pigmentosa (RP). The studies point to both the long-term effectiveness of the Argus II system and its ability to significantly improve a patient’s quality of life over a period of years.

The Functional Low-Vision Observer Rated Assessment (FLORA) study, encompassed three years in the lives of 26 blind patients who have been implanted with the Argus II. A multipart instrument was developed specifically for FLORA to assess the functional visual abilities of these patients and how they use the Argus II to complete a series of common activities of daily living.

Before the development of the FLORA, researchers say there were no accepted, standardized assessments of functional vision or quality of life that could be used to assess the kind of vision that is restored by a retinal prosthesis. Common assessment tools of functional vision that are available, such as the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) or the Massof Activity Inventory, have only a few items that can be completed by those with ultra-low vision, with the majority of test items requiring higher levels of spatial vision (ability to read, recognize faces, identify colors).

Study subjects served as their own controls, and completion of tasks was compared with the system “ON” vs “OFF.” Twenty-four of 35 tasks (69%) showed a statistically significant improvement in outcome with the device “ON” vs “OFF,” while only two tasks (6%) showed a decrease in outcome. Nine tasks (26%) showed no significant change. The results were recently published in the Australian journal Clinical and Experimental Optometry.

“We are thrilled, yet not surprised, with the results of this study,” said Will McGuire, president and CEO of Second Sight. “Since the beginning, we have heard from the majority of individuals with the Argus II that our technology has changed their life and greatly enhanced their ability to perform tasks and activities of daily life. This study validates the positive feedback we’ve been receiving from our recipients all along.”

In another study, this one encompassing five years, James Handa, MD, of the Wilmer Eye Institute at Johns Hopkins University, recently presented long-term results from an ongoing clinical trial assessing 30 individuals from 10 clinical centers who were blinded (ie, with bare light perception or worse) from RP or similar disorders who were implanted with the Argus II. The data represented more than 200 cumulative patient-years of clinical trial follow-up and demonstrated the ability of the retinal prosthesis to improve visual functions over an extended duration. These functions include object detection, motion detection, and VA.

“The release of this data represents a milestone in the fight against blindness, given the long-term benefits of the Argus II in restoring some useful vision to individuals blinded by RP. The extended follow-up data clearly demonstrate the utility of the Argus II system, and we have gained considerable knowledge about how best to utilize the device through this trial,” said Dr. Handa.

In related news, Second Sight said 21 Argus II devices had been implanted worldwide during the fourth quarter of 2015. The device has also been approved for Medicare reimbursement by the Medicare Administrative Contractor (MAC) serving Florida, Puerto Rico, and the US Virgin Islands. This is the fifth MAC (of 12) to approve Argus II reimbursement.

Biosimilar Eye Drugs Are on the Horizon

But will they have much impact?

■ In the past year, we have begun to hear a great deal about “biosimilar” drugs. The FDA has even begun to approve a few. This new class of therapies can be likened to generics, except they are intended to be the equivalent of biologics, rather than chemically formulated medications.

Because biologics are produced from living cells, manufacture of biologic equivalents can be quite complicated, so the resulting discounts to branded drugs are much smaller than the discounts offered by generics: a 50% discount vs a 15% to 25% discount. For a drug taken for a short time, a biosimilar offers only very limited savings. For chronic diseases that require regular treatment, biosimilars have greater appeal as an alternative.

Because chronic diseases are better cases for using biosimilars, it’s no surprise that Lucentis, with $4 billion in annual sales, is already a target. Pfenex, a division of Pfizer, recently stated it would begin a clinical trial of its ranibizumab biosimilar sometime this year. (Pfenex declined to be interviewed for this article.) Intas, an India-based company, has already launched Razumab, a ranibizumab biosimilar, for its domestic market.

Though the FDA has already approved several biosimilars, beginning last year with Zarxio, Novartis’ equivalent of the chemodrug Neupogen, regulatory and manufacturing hurdles may be obstacles to approval of biosimilar copies. Genentech’s US patent for ranibizumab expires in 2020, but companies often find ways to win patent extensions. Also, numerous challengers to the dominance of anti-VEGF are in clinical trials; some may prove superior, entailing the risk of branded drugs being surpassed by other agents by the time biosimilars are ready for market.

Industry analysts have noted that the combination of a difficult manufacturing process, regulatory hurdles, extended patent protection, and smaller discounts to branded biologics, may make biosimilars a limited alternative in the ophthalmic arena.

Spark to Seek Gene Therapy Approval

It would be first in US for a genetic disease.

■ Spark Therapeutics (Philadelphia) said it is preparing to file a Biologic License Application (BLA) with the FDA in the second half of this year following a successful phase 3 clinical trial for its SPK-RPE65 gene therapy in the treatment of inherited retinal dystrophies. If approved, the one-time SPK-RPE65 injection using an adeno-associated virus (AAV) as a delivery platform would be the first-ever gene therapy approved in the United States for a genetic disease.

The pivotal phase 3 trial met its primary endpoint demonstrating improvement of functional vision in the 21-patient intervention group compared to the 10-patient control group, as measured by the change in bilateral mobility testing between baseline and one year. For example, patients who received the new gene were successful in navigating a marked path in dim light, something they could not do at baseline testing. There were no serious adverse events related to SPK-RPE65 or deleterious immune responses observed in the trial.

In addition, subjects who received SPK-RPE65 outperformed control subjects across the first two secondary endpoints: full-field light sensitivity threshold testing and the mobility test change score for the first injected eye. The third secondary endpoint, visual acuity, did not show statistically significant evidence of benefit.

“We saw substantial restoration of vision in patients who were progressing toward complete blindness,” said Albert M. Maguire, MD, principal investigator in the trial and professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania.

The results represent the first successful randomized, controlled phase 3 trial ever completed in gene therapy for a genetic disease. It reflects more than a decade of innovation across all aspects of the program, including AAV vector design, manufacturing and formulation, the surgical delivery procedure and clinical trial design, as well as the development and validation of a novel endpoint.

In related news, Spark has acquired Dublin, Ireland-based Genable Technologies, a private gene therapy innovator with which Spark has collaborated since 2014 in the development of Genable’s therapeutic program targeting one of the most prevalent forms of inherited retinal disease (IRD).

With the acquisition, Spark acquires RhoNova, a potential treatment targeting rhodopsin-linked autosomal dominant retinitis pigmentosa (RHO-adRP), an IRD that routinely leads to visual impairment and in the most severe cases to blindness. Using an adeno-associated virus vector developed and manufactured at Spark, RhoNova is designed to both suppress the expression of a faulty gene and deliver normal copies of the RHO gene to restore normal expression. RhoNova has been granted Orphan Drug Designation in both the United States and Europe. There is currently no approved pharmacologic treatment for RHO-adRP, which affects an estimated 12,000 patients in the United States and the five major European markets.

Genable shareholders received $6 million in cash and 265,000 shares of Spark common stock. Additional financial terms were not disclosed. RP