When Novartis announced initial 48-week results from its two large, pivotal phase 3 clinical trials for its wet AMD drug RTH258 (brolucizumab) in late June, the data confirmed earlier phase 2 findings that RTH258 could bring 12-week (or longer) retreatment intervals for the majority of patients. Longer retreatment intervals would do much to ease the time-consuming burden of often-repeated tests and injections that retina practices and their patients now endure.

Of the two currently approved wet AMD drugs — aflibercept (Eylea, Regeneron) and ranibizumab (Lucentis, Genentech) — Eylea is indicated for every 8-week dosing and Lucentis for monthly dosing, or less frequently with regular assessment.

Because individual patients show a wide range of responses to anti-VEGF therapies, both Eylea and Lucentis are commonly used in so-called “treat-and-extend” regimens that can lengthen the retreatment intervals somewhat beyond label indications for some patients. But the advent of 12-week (or longer) retreatment intervals would set a meaningfully higher standard.

NDA PLANNED FOR NEXT YEAR

Viewed as highly promising based on its earlier trials, RTH258 went head-to-head with Eylea in the phase 3 HAWK and HARRIER studies and proved to be non-inferior, with the majority of patients in both studies able to be dosed 6 mg of RTH258 at 12-week intervals. RTH258 is a small molecule, humanized single-chain antibody fragment that can be delivered in high concentrations, providing superior tissue penetration and rapid clearance from the systemic circulation. According to Novartis, RTH258 has a high affinity to all types of VEGF-A isoforms.

Novartis said it expects to complete final manufacturing studies and file a New Drug Application with the FDA in 2018.

“These results clearly and convincingly demonstrate RTH258 has the potential to reduce injection burden while providing excellent visual outcomes,” as stated by Vas Narasimhan, global head, drug development, Novartis, in a news release. “Based on these robust data, we are looking forward to working with regulatory agencies to bring this pioneering treatment to patients.”

FOUR MORE CANDIDATES

Although Novartis is the first company to announce any new phase 3 wet AMD results, the competition for next-generation therapies in this indication remains keen. At least four other companies are conducting mid- and late-stage clinical trials for investigational drugs that have also demonstrated good efficacy along with signs of a durable response. These include the following:

Allergan, collaborating with Swiss-based Molecular Partners, has just begun two 900-patient phase 3 clinical trials (SEQUOIA and CEDAR) for its proprietary anti-VEGF DARPin formulation abicipar pegol. DARPin therapeutics are a new class of small protein therapeutic agents derived from natural ankyrin repeat proteins, one of the most common binding proteins in nature and responsible for diverse functions, such as cell signaling and receptor binding.

Prospects seem promising, as DARPin has already demonstrated the potential for every 12-week dosing in the phase 2b PALM trial for DME.

Roche/Genentech now has its bispecific anti-VEGF/ANG2 inhibitor in two phase 2 trials for wet AMD, including the 271-patient AVENUE and the 75-patient STAIRWAY study for extended dosing intervals. The company also has RG7716 in the 230-patient, phase 2 BOULEVARD trial for DME.

The RG7716 formulation is one of the first drugs to come from the company’s proprietary CrossMab platform for the development of biologics and demonstrated a durable response in a 24-person, phase 1 study of “difficult-to-treat” patients led by Ursa Chakravarthy, MD, of the Royal Victoria Hospital, Belfast, U.K.

Regeneron has begun a phase 2, 360-patient clinical trial in wet AMD (ONYX) for a co-formulation of Eylea and a proprietary ANG2 inhibitor (nesvacumab), a combination for which Chief Scientific Officer George Yancopoulos, MD, PhD, has cited promising early data in company news releases. Regeneron has also begun a 300-patient, phase 2 trial of the same co-formulation in DME (RUBY). It should be noted that in the second year of the pivotal VIEW trial for Eylea, a significant percentage of patients were able to do well with 12-week dosing intervals, as recently reported by investigator David Boyer, MD, of Los Angeles.

And while Roche/Genentech has the CrossMab platform to spur efficient drug development, Regeneron has VelocImmune — a lab mouse with its mouse-like attributes engineered out and humanized attributes engineered in. This allows preclinical mouse studies to produce humanized antibodies, thus generating better drug candidates at an earlier stage and speeding the development process.

Allegro Ophthalmics has developed an integrin peptide therapy called Luminate that has shown potential for a durable response in both wet AMD and DME. The most recent data from the phase 2b DEL MAR study for DME demonstrates 12-week durability as monotherapy and also in combination with, or in sequence with, Avastin, according to company President Vicken Karageozian, MD.

SUSTAINED-RELEASE HAS POTENTIAL IN WET AMD

While the five companies mentioned above are developing drugs that are administered intravitreally, Genentech also has a widely watched program under way to deliver a 4-to-6 month dose of Lucentis via a sustained-release platform in an office-based procedure.

This sustained-release format for delivering a steady and appropriate dose of Lucentis is in the phase 2,220-patient LADDER study following a small phase 1 study that established proof of concept for the system. The refillable implant offers the potential of a greatly reduced treatment burden for both physicians and patients.

“We also see the implant as reducing the possibility of undertreatment, which has been identified in studies as a major reason for differences in real-world visual outcomes compared to those achieved in highly structured clinical trials,” Jason Ehrlich, MD, PhD, global head, clinical ophthalmology, Genentech told Retinal Physician magazine in an interview earlier this year.

A clue that Genentech sees strong long-term potential in sustained release is that it recently purchased ForSight Vision4, the maker of the refillable implant.

“The technology of the implant is simple but elegant,” says Dr. Ehrlich. “We see it as a platform for delivering not only Lucentis, but also other ocular drugs.”

Regeneron is also exploring the concept of sustained-release delivery of Eylea in collaboration with partner Ocular Therapeutix.

Because it is a small molecule that can be delivered in high concentration, investigators, including Pravin U. Dugel, MD, of Retinal Consultants of Arizona, have also cited brolucizumab as a promising candidate for being delivered in a sustained-release format.

WHY A DURABLE RESPONSE IS IMPORTANT

When Lucentis was approved for wet AMD in 2006, it ushered in a whole new set of burdensome realities for retina practices and their primarily elderly patients.

Because wet AMD, DME, and RVO patients required regular monitoring and repeated anti-VEGF injections, practices were faced with administering an entirely new (and financially risky) anti-VEGF “business” that encompassed inventory, storage, billing, scheduling, and insurance claims, just to name a few of the new responsibilities. Indeed, when CMS last year proposed to reduce reimbursement for big-ticket drugs, such as Lucentis and Eylea, a joint letter to CMS from the AAO, ASCRS, and The Retina Society countered that reimbursement was already so marginal that retina practices would lose money on every injection if the reduced reimbursement go into effect. The proposal was withdrawn late in the year.

In a recent Retinal Physician article,¹ Alan J. Ruby, MD, of Associated Retinal Consultants in Royal Oak, MI, stated the following:

“In our practice, we were required to add multiple layers of control to ensure accurate monitoring of drug use. In addition to adding personnel in the billing department, we needed to train staff on ordering procedures, drug log monitoring, and inventory management, processes that came with the advent of injection therapy.”

In addition, patient visits greatly increased as regular OCTtesting was needed to determine retreatment intervals.

All of this has added up to what is commonly called the significant and onerous “treatment burden” of combating a range of retinal diseases that has come to require its own administrative infrastructure. Moving to every 12-week dosing or sustained-release for the majority of patients would go a long way toward reducing the overall treatment burden on both practices and patients, especially if efficacy in such areas as vision gains, fluid reduction, and macular thickness were also improved.

“I would expect a fairly significant impact on the practice and on patients,” Dr. Ruby told New RP in a separate interview. “Currently, (our) patients are being treated on treat-and-extend or as-needed regimens and receiving injections every 4 to 12 weeks as indicated. Anything that lengthens the time between injections would reduce the number of patient visits required and decrease the amount of drug that a practice would have to inventory. Additionally, less injections means fewer billings generated, which would reduce the workload for the billing department, as well as the need for pre-authorizations/referrals and other administrative details.”

One caveat: retina doctors who have focused on treat-and-extend regimens have already been able to move many of their patients to 3-month, and even longer, dosing intervals. Paul Yates, MD, PhD, of the University of Virginia, is a proponent of treat-and-extend dosing and has been able to extend some patients to 6-month dosing. He says that very busy practices with a large percentage of patients now being dosed every 4 to 6 weeks will probably be the most eager to embrace 12-week dosing intervals.

“If your practice is bursting at the seams, then maybe this is something you would be interested in,” says Dr. Yates. “But short of that, just a non-inferiority indication is not going to do it for most. If a medication has longer duration due to improved efficacy, it might work out for them. Otherwise, durability alone may be a bit of a hard sell.”

Referring to the initial RTH258 phase 3 data, Dr. Boyer notes that about half of the patients in the two studies were able to go 12 weeks between retreatments.

“I think this will make a big difference. The 50% who didn’t (make 12 weeks) may have gone 6 to 9 weeks, which may be an improvement compared to what we currently have (for them). And some of the patients who made 12 weeks may be able to go 15 weeks or more between injections. Hopefully, fewer visits will be good for the patients. For me, it is great.”

MORE DURABLE TREATMENTS ON THE HORIZON

Though treat-and-extend regimens have been widely adopted in the retina community, major clinical trials that set new standards for durability must be taken seriously. With five different wet AMD drugs now on the cusp of 12-week dosing, the chances of commercial success for one or more of these drugs is high. Add sustained-release to the mix and it’s a good bet that we’ll be seeing more durable therapies approved in the near future. NRP

REFERENCE

1. Ruby AJ. Management of Anti-VEGF Inventory. Retinal Physician. 2017;14:34-35.