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Allergan’s DARPin in Pivotal Phase 3 Trial

The small molecule demonstrates durability.

BY LOUISE GAGNON, CONTRIBUTING WRITER

■ Two large-scale, 900-patient, phase 3 pivotal clinical trials, CEDAR and SEQUOIA, both now under way for wet AMD, will determine the future of Allergan’s promising anti-VEGF DARPin (abicipar pegol).

The small size of the abicipar pegol molecule makes its use for treating macular diseases attractive because it will likely permit longer extended intervals between treatments, according to investigator Tarek S. Hassan, MD, of Associated Retinal Consultants, Royal Oak, Michigan. Abicipar pegol is one of a new class of therapeutics referred to as designed ankyrin repeat proteins (DARPins) that bind with high affinity to one or more target proteins. In the case of abicipar pegol, it binds to soluble isoforms of VEGF-A.

“You can use it in smaller doses, get better tissue penetration, and see a longer-lasting effect,” explains Dr. Hassan, in an interview with Retinal Physician. “Its best feature may be its small size. As a tiny recombinant protein only 34 kDa in size, it can potentially better penetrate tissues than larger-sized antibodies like Lucentis (ranibizumab; Genentech) or Eylea (aflibercept; Regeneron) as well as Avastin (bevacizumab; Genentech).”

“The DARPin is highly soluble, so we think it can cross into the target tissues well and be easily delivered. If smaller doses can be given less frequently to get even the same effect as existing drugs given more frequently, we will have an exciting new addition to our armamentarium.”

Phase 2 data in the PALM trial for DME did in fact support that approach. The trial involved 3 different arms where abicipar pegol was delivered: 1mg every 8 weeks, 2 mg every 8 eight weeks, and 2 mg every 12 weeks. “It could really be a game changer if we can use it every 12 weeks as opposed to every 8 weeks,” he says.

The 2-mg dose given at either 8 weeks or 12 weeks produced the same level of VA and anatomical improvement in terms of reduction in central retinal thickness as the ranibizumab control group injected more frequently.

“There were fewer injections in the abicipar group over the 28-week length of the trial,” says Dr. Hassan. “People who receive these injections for DME tend to be more pressed for time than AMD patients. They are a younger population more likely to be in the work force and have families to support.

“It would be much better for these patients to come in every 12 weeks,” he says, noting the DME patient population is about 15 to 20 years younger than the macular degeneration patient population. “They have many other medical concerns and are likely going to doctor after doctor while trying to maintain some work-life balance.”

One of the concerns with abicipar pegol in the phase 3 trial is the slight elevation in inflammation observed in the DME trial, but that was effectively managed. “It was very controllable with topical drops, and it quickly went away,” says Dr. Hassan. “Assuming that manageable situation maintains itself with repeat dosing over many months and years, this could be a game changer.”

In terms of clearing fluid, the 2 therapies fared similarly in the phase 2 DME trial. “Although not statistically significant, the reduction in central retinal thickness was greater with the abicipar group than with ranibizumab,” he says.

Because abicipar pegol is such a small and highly soluble molecule, it represents a good candidate for a sustained-release platform, says Dr. Hassan.

It would also appear the time to use multiple therapies for conditions such as DME is on the horizon, but more research is needed to demonstrate how to integrate new medications as this era is ushered in, says Dr. Hassan.

“Blocking other biochemical pathways is the direction we are headed,” says Dr. Hassan. “More work needs to be done to show the advantage of blocking VEGF-C and VEGF-D. If you will block something so highly sensitive and specific, as this drug does for VEGF-A, and you add something else to block, you have to work out the safety.”

One caution in real-world practice is that intervals between injections should not be too spaced out, for patients will ultimately receive far fewer injections than they would in a randomized, controlled trial. “Vigilance decreases with time, and patients get fewer injections than what is deemed necessary in the clinical trials,” he says, noting outcomes are less than optimal when time between injections are too long.

Low-Vision Aid Wins ASRS Innovation Competition

iLoopes takes “Winning Pitch” prize.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ iLoopes, a New Jersey-based start-up developing “smart glasses” that enhance the functional sight of visually impaired persons, won the first “Winning Pitch” competition and $10,000 at the recent ASRS meeting over 3 other finalists. Winning Pitch was designed specifically to enable early-stage innovators in the retina community to present their problem-solving concepts to potential investors in an open, competitive forum.

Judges for the inaugural event comprised a blue-ribbon panel, including notable ophthalmic venture capitalists William Link, PhD, Eugene de Juan, MD, and Emmett T. Cunningham Jr., MD, plus ophthalmic industry veteran Matthew Chapin of Ora and private equity specialist Bill Voss. The iLoopes presentation to the judges was made by noted retina specialist Jeffrey Heier, MD, of Ophthalmic Consultants of Boston.

iLoopes has been pursuing vision enhancement for about the past 18 months, and has been testing monocular prototypes on about 25 people at both the Scheie Eye Institute of the University of Pennsylvania and the Wills Eye Hospital in Philadelphia, according to Jon Fox, MD, an orthopedic surgeon and company CEO. He says the reviews of the device have thus far been good.

“Our goal is to come to market with a simple, unobtrusive device needing only brief patient training that we can initially sell for under $2,000, with the price dropping to perhaps $1,000 as we scale up volume. Unlike some of our more expensive potential competition, the iLoope does not disorientate or nauseate the wearer,” says Dr. Fox. “The iLoope is not for the blind and is not for anyone with a correctable vision problem.

“In 2012, the National Eye Institute estimated there were 13 million Americans with low vision, and that this number would grow to 26 million by 2052,” says Dr. Heier. “In the same year, the World Health Organization estimated there were 240 million visually impaired globally. Many of these individuals could benefit from such an easily usable device like iLoopes.”

The device falls into the emerging category of wearable technology. It consists of smart glasses, a microcamera, microphone/speaker, enhanced display, and an Internet connection. The wearer can give a voice command, such as “zoom in” and the object will be magnified by about 5 times. The wearer can also activate filters to improve contrast.

“Right now, we are using commercially available glasses made by Vucix but we would like to develop our own manufacturing capability for a proprietary wearable that would improve our IP patent protection,” says Dr. Fox.

“In a typically busy retina practice, retina specialists see several patients daily who are desperate for some form of help with low vision,” notes Dr. Heier. “Current low-vision aids help many of these patients, but for a variety of reasons, many are not helped. iLoopes is easy to use, relatively affordable, and easy to update, with low-vision patients adapting to the imaging and voice commands quickly, often within minutes. The potential to dramatically impact many visually impaired patients is significant!”

Currently, iLoopes is being self-funded “on a shoestring” with limited R&D capability. Dr. Fox says an outside investor could help expand R&D while also opening up the possibility of internal manufacturing. He is hopeful that the exposure gained from the “Winning Pitch” presentation will attract either “angel” or venture capital investment.

“This is a product that we can get to market fairly quickly and that can be of immediate help to people with low vision,” says Dr. Fox. “We’d like to work with low-vision specialists who will be able to see the value of the iLoope in their practice.”

The other three finalists in the Winning Pitch competition were a concept using CTX1 for dry AMD (David Almeida, MD), a drug-eluting bioabsorbable, inflatable balloon intravitreal implant (Jeffrey Benner, MD), and the Drop-Let eye drop application aid (Edward Ryan, MD).

Apellis Encouraged by Phase 2 GA Study

Complement factor inhibitor slows progression.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Apellis Pharmaceuticals said its complement C3 inhibitor, APL-2, will soon move into phase 3 studies after meeting its primary endpoint in the phase 2, 246-patient FILLY trial in patients with geographic atrophy (GA) associated with AMD. At 12 months, APL-2, administered monthly via intravitreal injection, showed a 29% reduction in the rate of GA lesion growth compared to sham. With every-other-month administration, a 20% reduction was observed. The primary endpoint was the change in GA lesion size from baseline to month 12, compared to sham.

Additionally, in a post-hoc analysis, a greater effect was observed during the second 6 months of the study: a reduction in growth rate of 47% with monthly administration, and a reduction of 33% with every-other-month administration.

Apellis confirmed that it is currently genotyping all the participants in the FILLY trial to identify subsets of patients who may be better or weaker responders to APL-2. In Genentech’s MAHALO study for GA, the researchers found significant differences in response to lampalizumab among identifiable subsets.

The most frequently reported adverse events in the study eye were associated with the injection procedure. A higher incidence of exudative AMD was observed in the treatment groups, predominantly in subjects with a history of exudative AMD in the fellow eye, and was managed with the administration of standard-of-care therapies.

David Boyer, MD, of Retina-Vitreous Associates Medical Group, said, “These results are very exciting for all people afflicted with dry AMD with GA. It is currently an untreatable condition, and the reduction of the progression of atrophy in this trial offers new hope for vision maintenance for our patients.”

APL-2 is designed to inhibit the complement cascade centrally at C3, and, according to Apellis, may have the potential to treat a wide range of complement-mediated diseases more effectively than is possible with partial inhibitors of complement. APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, effectively blocking all 3 pathways of complement activation (classical, lectin, and alternative).

Pfenex Mulls Fate of Lucentis Biosimilar

Company still looking at strategic options.

■ Pfenex says it is continuing to explore strategic options for its Lucentis (Genentech) biosimilar after Pfizer chose to end its collaboration on the retina drug last year. The Pfenex biosimilar, known as PF582, completed a successful phase 1/2, 25-patient clinical trial in 2016.

Biosimilars are a relatively new area of drug development. They are generally defined as “subsequent versions of previously approved biologics” that can demonstrate comparability in both safety and effectiveness to the original therapy. Biosimilars do not have to be identical to the branded drug, but they must demonstrate therapeutic equivalence.

Pfenex initiated its Lucentis biosimilar program with partner Hospira in 2015 on the premise that a less expensive, FDA-approved version of the best-selling retina drug would appeal to both Lucentis prescribers and doctors who were using the much cheaper off-label Avastin (Genentech). Avastin must be prepared by a compounding pharmacy and incidents of tainted Avastin leading to infection had raised safety concerns.

The outlook for Pfenex brightened later in 2015 when pharmaceutical giant Pfizer purchased Hospira and indicated it was very interested in developing biosimilars. However, Pfizer later chose to end the collaboration on the Lucentis biosimilar, leaving Pfenex to either find another partner, develop the drug alone, or terminate the Lucentis biosimilar program. When asked by Retinal Physician for a status report on the Lucentis program, Pfenex offered the following statement:

“Pfenex has completed a phase 1/2 first-in-human study for PF582, a biosimilar candidate to Lucentis. This study met the primary objective of demonstrating similar safety and tolerability between PF582 and Lucentis. At this time, we continue to evaluate strategic options for PF852 with an intent to update the market on the status of this review as appropriate.”

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Lampalizumab disappoints in pivotal phase 3 trial

■ Genentech announced that its lampalizumab complement factor inhibitor for the treatment of GA did not meet its primary endpoint of reduced lesion progression when compared to sham at 48 weeks. The first preliminary data from the 900-patient SPECTRI study came as a major disappointment, as lampalizumab had shown promising results in an earlier phase 2 trial and GA is still an unmet medical need with no FDA-approved therapies to treat the disease.

Genentech is also conducting another identical phase 3 trial for lampalizumab called CHROMA, but no data from that study have yet been tabulated. Dosing of patients in the SPECTRI study has been halted until data from the CHROMA trial are available.

Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody directed at complement factor D and its role in the alternative complement pathway.

ICON-1 has mixed results in wet AMD trial

■ Iconic Therapeutics said its ICON-1 anti-tissue factor fusion protein showed promising results at 6 months in treatment-naïve wet AMD patients when used in combination with Lucentis (ranibizumab; Genentech) but demonstrated minimal benefit as monotherapy.

Iconic Therapeutics believes tissue factor (TF) may play a particularly important role in the pathogenesis of AMD. The intracellular signaling pathways driven by TF promote inflammation and angiogenesis, key drivers of the retinal injury and vision impairment that characterize wet AMD. Under normal conditions, retinal endothelial and smooth muscle cells do not express TF. By contrast, TF is dramatically increased in the retinal tissues of patients with AMD and proliferative DR. The data from the 88-patient phase 2a EMERGE study were announced at the recent ASRS meeting by Christine Gonzales, MD, an ophthalmologist at the Retina and Vitreous Center of Southern Oregon.

“We did have favorable anatomic outcomes in the combination group at 6 months compared with the ranibizumab (only) group, with fewer retreatments and a longer treatment-free interval,” said Dr. Gonzales. “This improved control in CNV was noted in terms of reduction in CNV area, greater proportion of complete drying of the retina, and a greater proportion of resolution of sub-RPE fluid.”

Iconic Therapeutics said it intends to advance ICON-1 into a longer trial in combination with anti-VEGF with a larger dose than the 0.3 mg given intravitreally in the EMERGE study. The company said the drug’s safety profile was excellent.

Ophthotech’s Fovista fails in third phase 3 trial

■ After seeing its Fovista anti-PDGF therapy fail in 2 pivotal phase 3 wet AMD trials in combination with an anti-VEGF, Ophthotech cautioned that the result would likely be the same in the third and final phase 3, with Fovista in combination with either Eylea (Regeneron) or Avastin (Genentech). Recently released data from the 640-patient study confirmed this, showing no demonstrable additional benefit from adding Fovista to anti-VEGF.

Ophthotech, with approximately $150 million in cash to invest, is refocusing its strategy to study its complement inhibitor Zimura in GA and other indications, and by also seeking opportunities to collaborate with other companies developing ophthalmic drugs.

AGTC gets orphan drug designation for IRD

■ The FDA has granted Applied Genetic Technologies Corporation (AGTC) an orphan drug designation for its adeno-associated virus-based gene therapy treatment for X-linked retinitis pigmentosa (XLRP) and the company has announced that it has filed an investigational new drug application to conduct a phase 1/2 clinical trial for the treatment of XLRP caused by mutations in the RPGR gene. Preclinical data indicated that treatment with an investigational gene therapy product slowed the loss of visual function in canines with XLRP caused by mutations in the RPGR gene.

Study begins of gene mutations that cause vision loss

■ The first patient has been enrolled in a natural history study of people with mutations in the USH2A gene that are the leading cause of the combined vision and hearing loss associated with Usher syndrome type 2A and vision loss from autosomal recessive retinitis pigmentosa. There are currently no treatments for the vision loss associated with these inherited retinal diseases.

The Rate of Progression in USH2A-related Retinal Degenerations (RUSH2A) study, funded by the Foundation Fighting Blindness’ Clinical Research Institute, will follow 100 patients for 4 years and an additional 20 patients at a single clinical visit. The first patient was enrolled at the Retina Foundation of the Southwest, in Dallas, Texas, where David Birch, MD, is the principal investigator.

Bascom Palmer again tops in ophthalmology

■ For the 14th year in a row, Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine has topped the U.S. News and World Report survey of physicians as the best in ophthalmology. Bascom Palmer was followed by Wills Eye in Philadelphia, Wilmer Eye Institute in Baltimore, and Mass. Eye and Ear in Boston.