Development of new treatments for age-related macular degeneration and diabetic macular edema often overlaps, as multiple drug developers pursue parallel courses for both indications. Here, we provide snapshots of drugs that are in clinical trials and are either on track to reach important milestones this year or next, or have been sidetracked by disappointing clinical trial readouts. This list has been compiled with the help of Editorial Board Member Emmett T. Cunningham, MD, PhD, and is based on presentations at the Ophthalmology Innovation Summit and our own research and verification.
Age-related Macular Degeneration
Eylea (Regeneron Pharmaceuticals). Regeneron is on track to get Food and Drug Administration approval of 12-week dosing of aflibercept (Eylea) by the summer of this year. In December, the FDA issued a Prescription Drug User Fee Act date of August 11, 2018, for the 12-week dosing. That’s tantamount to a deadline date for a decision.
The supplemental Biologics License Application the FDA accepted for review is based on an analysis of two-year results from the pivotal VIEW 1 and VIEW 2 trials that showed 51 percent of study patients had their aflibercept dosing interval extended
to every 12 weeks at the beginning of the second year (week 52) of treatment, based on an evaluate-and-extend approach.1 They maintained the 12-week dosing interval and best-corrected visual acuity gains at two years without any new safety issues. Criteria for 12-week dosing include physician recommendation and no evidence of new or progressive wet AMD.
Brolucizumab (Novartis). This humanized monoclonal antibody, also known as RTH258, targets vascular endothelial growth factor-A. At the American Academy of Ophthalmology Retina Subspecialty Day last year, Pravin Dugel, MD, reported results of the Phase III HAWK and HARRIER head-to-head trials comparing brolucizumab and aflibercept.2
At week 16, 35 percent fewer brolucizumab 6-mg patients had intraretinal fluid (IRF) and/or subretinal fluid (SRF) in HAWK, and 33 percent fewer in HARRIER (p<0.0001 for both).2
At week 48, 31 percent fewer patients on brolucizumab 6-mg had IRF and/or SRF in HAWK and 41 percent fewer in HARRIER (p<0.0001 for both). The brolucizumab 6-mg group also demonstrated superior reductions in central subfield thickness.
Jefferies’ analyst Jeffrey Holford predicted a launch of RTH258 in the United States next year and projected peak sales of $2 billion if it also gets FDA approval for DME.
Carotuximab (Santen). Top-line results from the Phase I/II study of DE-122 (carotuximab) for refractory wet AMD were presented last month at Bascom Palmer Eye Institute’s 15th annual Angiogenesis, Exudation and Degeneration meeting. Victor H. Gonzalez, MD, study investigator and founder of Valley Retina Institute in McAllen, Texas, reported no serious adverse events. 3
Carotuximab is a novel antibody to endoglin, a protein over-expressed on endothelium essential for angiogenesis and upregulated by anti-VEGF. DE-122, a novel ophthalmic formulation of carotuximab, was active in preclinical choroidal neovascularization models and may enhance the effect of anti-VEGF agents.
A Phase IIa randomized-controlled trial is assessing the efficacy and safety of intravitreal injections in combination with ranibizumab (Lucentis, Roche/Genentech) compared to ranibizumab monotherapy in patients with wet AMD. The results so far have also suggested bioactivity of DE-122 in refractory wet AMD patients, as measured by mean change in central retinal subfield thickness based on spectral-domain optical coherence tomography.
GB-102 (Graybug Vision). Graybug expects an initial readout of top-line Phase Ia/IIb results of GB-102 for treatment of wet AMD in the first half of the year. GB-102 is an injectable formulation of sunitinib, a tyrosine kinase inhibitor that blocks multiple VEGFR pathways. The goal is to reduce treatments for wet AMD, DME and retinal vein occlusion to once or twice a year, President and CEO Jeff Cleland, PhD, reported at the Ophthalmology Innovation Summit last November.
The two-part ADAGIO trial is evaluating patients with wet AMD who are already on anti-VEGF agents and are then switched over to treatment with GB-102 alone. The company expects a preliminary readout on the safety and efficacy of the Phase I trial in the fourth quarter this year, with Phase II top-line safety and efficacy results due in 2020.
X-82 (Tyrogenex). Tyrogenex expects to report Phase II results of this oral candidate for treatment of wet AMD this year. The trial completed enrollment in March 2017 and is evaluating treatment with one of three doses of X-82 (vorolanib) or placebo after 52 weeks. The trial exceeded its enrollment target of 132 patients by 25 patients, senior VP and development director Daniel Salazar, PhD, reported last March.
RG7716 (Roche/Genentech). RG7716 is the subject of The STAIRWAY trial, which is expected to complete data collection in June. RG7716 is a novel anti-VEGF-A and anti-angiopoietin-2 (Ang-2) bispecific, monoclonal agent. It simultaneously binds to and inactivates VEGF-A and Ang-2.
The Phase II AVENUE study of RG7716 for wet AMD was due for completion in January with final data collection in September. Data from the BOULEVARD trial, which is investigating RG7716 in patients with diabetic macular edema, was presented at the Angiogenesis meeting. (See page 35 for a more detailed discussion of the DME program.)
RPDS (Roche/Genentech). RPDS stands for ranibizumab port delivery system. Genentech is developing the port to deliver ranibizumab (Lucentis) over a period of months, potentially reducing the burden of frequent injections. The RPDS is placed beneath the conjunctiva, and is refillable by injection.
The primary endpoint of the LADDER trial is time until a participant first requires an implant refill. Final data collection is estimated for September 2018. Genentech’s parent, Roche, acquired ForeSight Vision 4, which had been developing the port system, in 2017. The companies had been collaborating on RPDS since 2010.
Squalamine (Ohr Pharmaceutical). Research into new drugs is fraught with risk, as Ohr Pharmaceutical found out. The company had much hope for its topically administered squalamine in combination with monthly ranibizumab for treatment of wet AMD. However, Ohr discontinued development of the agent after disclosing the MAKO study failed to meet its primary endpoint—mean visual acuity gain at nine months. (See “Two Drug Development Programs Halted,” News).
Dry AMD/Geographic Atrophy
APL-2 (Apellis Pharmaceuticals). Apellis Pharmaceuticals reported 18-month results of the FILLY trial of APL-2, a complement C3 inhibitor, in patients with AMD-related geographic atrophy.4 Reporting at the Macula Society meeting last month, Rishi Singh, MD, of the Cole Eye Institute at the Cleveland Clinic, said 18-month outcomes mirrored 12-month results that showed monthly intravitreal APL-2 resulted in a 29-percent reduction in the rate of GA lesion growth compared to sham (p=0.008). Every-other-month administration of APL-2 resulted in a 20-percent reduction in GA lesions (p=0.067). The Phase III trial is scheduled to begin in the second half of this year.
Zimura (Ophthotech Corporation). Last year Ophthotech Corporation moved up the time line to obtain top-line data from its ongoing Phase II/III trial of Zimura (avacincaptad pegol) monotherapy in GA by reducing the number of patients, shortening the time point for attaining the primary efficacy endpoint and reducing study costs. The modified study design incorporated patients already enrolled. Zimura targets and inhibits the complement protein C5 in the complement cascade.
Ophthotech is pursuing other Zimura programs. It has started an open-label Phase IIa trial of Zimura in combination with ranibizumab in treatment-naive patients with wet AMD and a randomized, controlled trial to assess Zimura monotherapy in Stargardt disease. It has an open-label Phase IIa trial evaluating Zimura in combination with anti-VEGF therapy for idiopathic polypoidal choroidal vasculopathy. Ophthotech also said last year that in 2018 it would launch a Phase IIa trial of Zimura monotherapy for intermediate/posterior non-infectious uveitis.
Lampalizumab (Roche/Genentech). This is one agent for geographic atrophy that will not emerge from the pipeline soon. In reporting its 2017 results earlier this year, Roche disclosed that it was discontinuing Phase III trials of the lampalizumab program. The company also removed lampalizumab from its online Produce Development Portfolio.
Diabetic Macular Edema
Luminate (Allegro Ophthalmics). This year, Allegro Ophthalmics plans to initiate a Phase III trial of its lead integrin peptide therapy candidate, Luminate, for treatment of DME, president Vicken Karageozian, MD, said at the Ophthalmology Innovation Summit 2017. Luminate is a first-in-class drug that targets the integrin receptors involved in neovascularization by disrupting growth factor production
The Phase IIb DEL MAR trial showed that sequential therapy of Luminate with bevacizumab (Avastin, Roche/Genentech) was superior to bevacizumab monotherapy and Luminate/bevacizumab combination therapy, leading to a 7.1-letter gain in best corrected visual acuity at 20 weeks vs. 6.7 letters and 1.4 letters, respectively. Allegro anticipates making major funding decisions before commencing the Phase III trial.
RG7716 (Roche/Genentech). RG7716 in DME was the subject of encouraging results reported in February at the Angiogenesis meeting in Miami.5 The BOULEVARD Phase II trial assessed two doses of RG7716 (1.5 mg and 6 mg) vs. monthly ranibizumab (0.3 mg). The study met its primary endpoint—improvement in adjusted best-corrected visual acuity at week 24: 13.9 chart-letter improvement in the 6-mg RG7716 group vs. 11.7 letters in the 1.5-mg RG7716 group and 10.3 letters in the 0.3-mg ranibizumab group.
AKB-9778 (Aerpio Therapeutics). This small-molecule agent is designed to target the Tie2/VE-PTP pathway in non-proliferative diabetic retinopathy. The drug is administered subcutaneously. AKB-9778 binds to and inhibits vascular endothelial phosphotyrosine phosphatase, a critical negative regulator of Tie2. AKB-9778 has demonstrated it activates the Tie2 receptor irrespective of extracellular levels of its binding ligands, Ang-1 (agonist) or Ang-2 (antagonist). The company is on schedule with its TIME Phase IIb clinical trial of AKB-9778, completing patient enrollment in February with a readout expected in the second quarter next year. RS
1. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537-2548.
2. Dugel P, et al. HAWK & HARRIER: 48-week results of 2 multi-centered, randomized, double-masked trials of brolucizumab versus aflibercept for neovascular AMD. Presented at: The American Academy of Ophthalmology 2017 Annual Meeting on November 10, 2017, New Orleans.
3. Gonzalez VH. Phase I/II study: Safety and bioactivity of carotuximab (DE-122) for refractory wet age-related macular degeneration. Paper Presented at: Angiogenesis, Exudation and Degeneration; February 10, 2018; Miami, Florida.
4. Singh R. APL-2, a complement C3 inhibitor, slows the growth of geographic atrophy secondary to AMD: 12-month results of a Phase 2 clinical trial (FILLY). Paper Presented at: 41st Annual Macula Society; February 22, 2018; Beverly Hills, CA.
5. Dugel P. Anti-VEGF/anti-angiopoietin-2 bispecific antibody RG7716 in diabetic macular edema: Results from the Phase 2 BOULEVARD clinical trial. Paper presented at Angiogenesis, Exudation and Degeneration; February 10, 2018; Miami, Florida