Just before this year’s annual American Academy of Ophthalmology meeting, ophthalmologists and industry leaders got together at the Ophthalmology Innovation Summit to discuss the status of various nascent drugs, devices and ophthalmic companies, with an eye toward their current or future financial performance. Review caught up with OIS co-chair Emmett T. Cunningham Jr, MD, PhD, MPH, for his take on the highlights of the ophthalmic pipeline.
In the retina realm, several products generated buzz:
• This fall, Spark Therapeutics’ gene therapy for inherited blindness, Luxturna, received a unanimous vote for approval by the FDA review panel, and followed this up with a December approval. “I think Spark’s Phase III data was, in a word, tremendous,” Dr. Cunningham says. “This is the first gene therapy we’ve seen approved in ophthalmology, and there’s a clear efficacy benefit.” Dr. Cunningham notes that gene-therapy trials coming up behind Luxturna include GenSight’s trial for Leber’s Congenital Optic Neuropathy, AGTC’s trials in X-linked retinoschisis and achromatopsia; Nightstar’s trial for choroideremia; and Regenxbio’s trial in wet AMD.
• Novartis’ brolucizumab, a small, single-chain variable antibody fragment, was shown to be noninferior to aflibercept (Eylea, Regeneron), for the treatment of wet age-related macular degeneration. “So, it looks like we’ll have a fourth competitor coming to the AMD market,” Dr. Cunningham says. “In the study, it was suggested that a higher proportion of patients can go to a less-frequent, 12-week dosing schedule.”
• The company PanOptica is also developing a topical AMD treatment, a small-molecule tyrosine kinase inhibitor that has shown an effect. “We currently have very effective therapies in the form of intravitreal injections,” Dr. Cunningham says, “so there is a high threshold for efficacy. This always makes for a high hurdle for something that’s not administered in the eye, but rather is delivered topically.”
• Genentech is continuing its LADDER trial for extended-release ranibizumab. “It involves a surgical procedure to implant the device needed to achieve extended release,” Dr. Cunningham explains. “The intention with extended release is to decrease the frequency of injections from monthly to every three or four months, or even less frequently. It will be interesting to see how much extended-release ability LADDER shows.”
• The pharmaceutical company Graybug Vision has been studying its six-month, time-release delivery of the small molecule sunitinib for wet AMD in animal models. Dr. Cunningham, who is an investor in Graybug, says that, if the approach works, it could be a broad inhibitor of the factors that promote AMD. “The current anti-VEGF agents are all targeting VEGF isoform A,” Dr. Cunningham explains. “But there are other isoforms—particularly C and D—that also appear to be important. The sunitinib that the Graybug Vision implants should, theoretically, inhibit all isoforms over six months or more.”
• Opthea presented evidence of add-on or combination efficacy with their anti-VEGF C/D TRAP-like molecule. “Interestingly,” notes Dr. Cunningham, “they showed that they could get regression of the neovascularization in half of the patients that were treated in the current study.”
• Iconic Therapeutics is working on a tissue-factor inhibitor for wet AMD, ICON-1, that has shown an ability to reduce retinal thickness and perhaps result in a more durable effect when used in combination with ranibizumab. “ICON-1 is an anti-tissue-factor fusion protein that has a unique target,” Dr. Cunningham explains. “They showed that, when it was added to ranibizumab, there was more drying than with ranibizumab alone, though it was a small trial. The vision didn’t change with the combination, however. I believe they plan to do a confirmatory Phase II trial.”
• Allegro is working on an anti-integrin inhibitor as a treatment for diabetic retinopathy that, according to a post-hoc analysis of the Phase II data, may have enhanced efficacy in patients who are incomplete responders to anti-VEGF drugs. “There appears to be a clear drug effect.” Dr. Cunningham says. “You can see some drying. And, as monotherapy, it seems to be an improvement vs. anti-VEGF. However, now they’re trying to figure the way forward: Do they treat non-responders? All patients? They haven’t communicated their plan publicly yet.”
• Another company working on a diabetic retinopathy treatment is Clearside Biomedical. In a group of patients with diabetic macular edema in the company’s HULK exploratory clinical trial, Clearside’s CLS-TA showed some positive results. CLS-TA is a proprietary suspension formulation of triamcinolone acetonide that’s administered suprachoroidally with or without intravitreally injected aflibercept. In HULK, more than two-thirds of eyes achieved greater than 50 percent reduction in excess central retinal thickness and there was anatomic improvement in all of the treated eyes. The company will soon report results of a randomized trial in noninfectious posterior uveitis and has ongoing trials in retinal vein occlusion and diabetic macular edema.
• Drug company Aerpio is also angling to enter the diabetic retinopathy space with its twice-daily subcutaneous injection of AKB-9778, a small-molecule inhibitor of VE-PTP, which it describes as a critical regulator of Tie2 in diseased blood vessels. The idea is to restore healthy Tie2 activity. “It needs to be injected subcutaneously twice daily, but patients with diabetes are used to injections,” says Dr. Cunningham, “so they might not see that as a huge issue. Also, activating Tie2 is good for vessels in general, not just in the eye, so there may be some systemic benefits from this treatment, as well.
“This is the first and only direct Tie2 activator,” Dr. Cunningham adds. “Others, most notably Regeneron and Genentech, were seeking to increase Tie2 by inhibiting its inhibitor, Ang 2. This may be meaningful, and the company says it should get superior activation because of its direct Tie2 activation.” Based on the results of a Phase IIa proof-of-concept study in which AKB-9778 improved patients’ underlying retinopathy two or more steps on the ETDRS diabetic retinopathy scale in both eyes, the company has begun a Phase 2b study, codenamed TIME-2b.
• In the dry-AMD realm, Apellis Pharmaceuticals recently shared positive results from a Phase II trial of its complement inhibitor. Specifically, it inhibits complement-3. (Complement is believed to contribute to the pathogenesis of AMD.) “This development is fascinating because we’ve had multiple failures of complement inhibitors, such as eculizumab (which targeted C5) and lampalizumab (which targeted Factor D),” Dr. Cunningham muses. “But then Apellis comes with anti-C3 showing a benefit in Phase II. However lampalizumab showed a benefit in Phase II also, reinforcing the idea that Phase II doesn’t always predict Phase III success. This raises the question: Why would C5 inhibitors fail but a C3 inhibitor work? Many of the diagrams we see that illustrate complement inhibition show a path that goes through C3 and then to a C5-mediated membrane attack complex. However, an equally valid depiction has three effector arms, not just one: The other two are chemotaxis—or bringing immune cells and promoting adaptive immunity so the body can learn to recognize these antigens—and coating or opsonization that will mediate phagocytosis of these bad bits in and around the sites of inflammation. C3 is important for all three effector arms, and so in this way could be the better target.”
• Allergan is working on an implant designed to release brimonidine over time to battle geographic atrophy, and it showed a therapeutic benefit in a 2016 study. In the study, reported at the 2016 AAO Retina Subspecialty Day, the 132-µg and the 264-µg implants reduced the rate of geographic atrophy progression by 19 and 28 percent, respectively.
• Allergan is also studying a time-release bimatoprost implant, the Artemis, for glaucoma. The company is currently enrolling patients in its Phase III trial of the delivery system. The trial will compare two sizes of implant—
10 µg and 15 µg, administered every 16 weeks—to daily timolol drops.
• Taking a different approach to glaucoma and macular telangiectasia treatment, Neurotech is pursuing encapsulated cell therapy with a therapy designated NT-501. In ECT, an implanted device releases ciliary neurotrophic factor over time, and Dr. Cunningham says the company has Phase I/II data that appear to show a drug effect. “The issue with that platform is the manufacturing complexity,” he explains. “This isn’t like synthesizing a small molecule and putting it in a bottle that has a two-year shelf life. It’s a device with encapsulated cells.” A recent communiqué from Neurotech announced positive Phase II results in macular telangiectasia, and it’s expected that a Phase III trial is on its way.
• In the uveitis arena, Dr. Cunningham says that both pSivida and Clearside Biomedical are using sustained-release corticosteroids and have produced some very promising results. In pSivida’s case, in a six-month study of the Durasert implant in uveitis conducted in India, 22 percent of patients in the study group vs. 54 percent of sham patients had a recurrence of the uveitis (n: 153; p<0.001).
Clearside has a Phase III study of a microneedle injection of 100 µL of triamcinolone acetonide. The study’s enrollment is complete and data from it is expected in the first quarter of 2018.
In a somewhat surprising setback, Santen received a complete response letter from the FDA in December 2017, informing them that the submission of their uveitis treatment sirolimus was not approvable as submitted. When combined, the company’s SAKURA studies of sirolimus remain the largest study of noninfectious uveitis of the posterior segment to date (n: 347 and n: 245). Officially, the company says it’s reviewing the letter, and is working closely with the agency to chart the “best path forward.” REVIEW