What opportunities remain for wet AMD?

Intravitreally administered vascular endothelial growth factor (VEGF) inhibitors - Regeneron/Bayer/Santen’s Eylea, Roche/Genentech/Novartis’s Lucentis 0.5 mg, and Roche/Genentech’s Avastin - have revolutionized the treatment of wet age-related macular degeneration (AMD). Though Avastin is used off-label, Eylea and Lucentis 0.5 mg are the key approved therapies for wet AMD. These agents are efficacious in maintaining visual acuity, are safe and well tolerated for a large proportion of wet AMD patients. Given the commercial success of the approved therapies for wet AMD and the increasing patient pool, several drug developers have agents in the pipeline targeting remaining unmet needs for this indication.1,2 The clinical development pipeline for wet AMD is focused mainly on two opportunities - the development of agents offering more-convenient delivery profiles than current therapies (i.e., less-frequent intravitreal dosing, non-intravitreal routes of administration) and the development of agents offering improved visual acuity over current therapies. Of note, therapies with novel mechanism of action are being studied in clinical trials as a combination treatment to VEGF inhibitors to capitalize on the latter opportunity, although this approach looks less promising as of late given the lack of improved efficacy observed with adjunctive/co-formulated platelet-derived growth factor (PDGF) inhibitors and angiopoietin-2 (Ang-2) inhibitors over anti-VEGF monotherapy.3,4,5

Improvement in delivery profile is a lucrative option for drug developers in wet AMD given the noticeable success of Eylea in this market. Indeed, much of the impressive uptake of Eylea to date has been driven by the perception that it can elicit visual acuity outcomes similar to those of Lucentis 0.5 mg but with less-frequent dosing, as shown in Eylea’s pivotal Phase III VIEW 1 and VIEW 2 trials. Adopting a similar strategy, next generation VEGF inhibitors in late-phase development, Novartis’s brolucizumab [RTH-258] and Allergan/Molecular Partners’ abicipar pegol, promise increased dosing intervals over the current therapies and thereby target the unmet need for reduced injection burden. This strategy is progressing well for brolucizumab given that Novartis reported in June 2017 that brolucizumab was comparable to Eylea on maintenance of visual acuity at 48 weeks, the primary end point in the two large Phase III trials HAWK and HARRIER, with 57% and 52% of brolucizumab-treated patients, respectively, administered the drug every 12 weeks (Q12W) after three monthly injections.6 In addition, data presented at the American Academy of Ophthalmology 2017 Annual Meeting demonstrated that brolucizumab treatment resulted in a significantly greater effect compared with Eylea on multiple anatomic measures at 16 and 48 weeks, including a reduction in central subfield thickness and presence of intraretinal fluid and/or subretinal fluid.7 Given that ophthalmologists/retinal specialists often use treat and extend (TAE) or as needed (PRN) regimens to decrease the burden associated with wet AMD treatment, the value proposition for brolucizumab likely lies in the potential for Q12W dosing following loading doses plus the anatomic data compared with Eylea. Novartis plans to file brolucizumab with regulatory authorities in 2018 for the treatment of wet AMD,8 suggesting that it could be the next VEGF inhibitor to reach the market. Other approaches attempting to offer improvements in drug delivery, which are currently in early-phase development for wet AMD, include Roche/Genentech’s RG-3645, a sustained-release Lucentis port delivery system, Regenexbio’s RGX-314, a gene therapy to provide a long-term VEGF inhibition with a single subretinal administration, and PanOptica’s topical VEGF inhibitor PAN-90806.1

Drug developers pursuing the strategy of improvement in visual acuity over current agents for wet AMD recently suffered major setbacks, as noted by several clinical trial failures for combination therapies with VEGF inhibitors. Regeneron/Bayer’s attempts to improve on the efficacy offered by Eylea did not prove successful in several Phase II studies, in which Eylea was co-formulated with the Ang-2 inhibitor nesvacumab or the PDGF inhibitor rinucumab.4,5 Similarly, an adjunctive PDGF inhibitor, Novartis/Ophthotech’s Fovista, did not result in an efficacy benefit over the key current anti-VEGF agents in Phase III studies.9,10 The future is uncertain for the other combination therapies in development, notably for other PDGF/VEGF inhibitors (e.g., Ohr Pharmaceutical’s squalamine) and Ang-2 inhibitor (Roche’s RG-7716), although agents with other mechanisms of action are being investigated, such as Santen’s endoglin inhibitor carotuximab (DE-122).1

Opportunity remains in the wet AMD market for therapies with more-convenient delivery profiles than current anti-VEGF agents and/or with greater efficacy than current VEGF inhibitors. Indeed, the negative trial results with combination therapies highlights that current therapies for wet AMD have set the efficacy bar high for new market entrants. Brolucizumab is likely to at least partially addresses the need for therapies with less-frequent dosing, while emerging agents targeting factors other than PDGF and Ang-2 have the potential to provide superior efficacy than anti-VEGF monotherapy in wet AMD.

1. DRG’s Dry and Wet Age-Related Macular Degeneration | Disease Landscape & Forecast, 2017.
2. DRG’s Wet Age-Related Macular Degeneration | Unmet Need (US/EU), 2016.
3. Ophthotech, press release, August 14, 2017.
4. Regeneron, press release, September 30, 2016.
5. Regeneron, press release, November 27, 2017.
6. Novartis, press release, June 20, 2017.
7. Novartis, press release, November 10, 2017.
8. Novartis R&D and Investor Day presentation, November 13, 2017.
9. Ophthotech, press release, December 12, 2016.
10. Ophthotech, press release, August 14, 2017.

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