Novartis announced top-line results on June 20th, 2017 from two Phase III clinical trials of RTH-258 (brolucizumab) indicating that the drug matched the efficacy of Regeneron/Bayer/Santen’s Eylea (aflibercept) for the treatment of wet age-related macular degeneration (AMD), and that it could be effectively dosed once every 12 weeks in a subset of patients. RTH-258, a vascular endothelial growth factor (VEGF) inhibitor like the treatment mainstays Eylea and Novartis/Roche’s Lucentis (ranibizumab), met both primary and secondary end points in the HAWK and HARRIER trials, showing non-inferiority to Eylea for mean change in best-corrected visual acuity (BCVA) to week 48 and for average mean change in visual acuity during weeks 36-48 in more than 1,800 patients with wet AMD. Importantly, the design of these clinical trials allowed patients to be maintained on once every 12-week (q12w) dosing of RTH-258 throughout the study (after three monthly injections) as long as their disease did not worsen—amounting to 57% and 52% of RTH-258 treated patients in the HAWK and HARRIER trials at 48 weeks, respectively. Additionally, the rate of ocular and non-ocular side effects was reported as being comparable to Eylea. Novartis concluded “these results clearly and convincingly demonstrate RTH-258 has the potential to reduce injection burden while providing excellent visual outcomes”, potentially addressing the substantial unmet need in the wet AMD market for therapies with comparable efficacy and safety to the standards of care but with less frequent dosing.

Age-related Macular Degeneration Landscape & Forecast

VEGF inhibitors, such as Lucentis and Eylea, are effective treatments for maintaining, and even improving, visual acuity in wet AMD patients, but the drugs require regular administration as intravitreal injections over the course of a patient’s lifetime. Recently, Eylea has superseded Lucentis as the market share leader in the $2 billion wet AMD market in the United States due, in part, to the product’s ability to be dosed every eight weeks (q8w) after the first three monthly injections. Lucentis is indicated in the United States for monthly dosing, although it can be dosed less frequently with the potential for decreased efficacy, and therefore carries a slightly higher injection burden for patients, physicians, and ophthalmology clinics than Eylea. RTH-258’s longer duration of action is believed to be attributed to its smaller molecular size than other VEGF inhibitors (26 kDa vs. 48 kDa for Lucentis, 115 kDa for Eylea, and 149 kDa for Roche/Genentech’s Avastin), allowing for administration of a higher molar concentration in an injection volume than current therapies. If approved, RTH-258 could help reinvigorate Novartis’s ophthalmology division, especially as Lucentis faces continued competition from Eylea and the future threat of launching biosimilars, and the company’s platelet-derived growth factor (PDGF) inhibitor Fovista (pegplenarib), developed with Ophthotech, failed in pivotal Phase III studies for wet AMD last year.

Several questions regarding the clinical and commercial advantages of RTH-258 over established VEGF inhibitors remain, but we anticipate additional insight will be gleaned when the full results of the HAWK and HARRIER trials are reported at future medical conferences. Key opinion leaders (KOLs) interviewed by DRG give varied opinions of the purported dosing duration advantage of RTH-258 compared with Eylea—some ophthalmologists expect the drug to be well received because Eylea’s dosing advantage over Lucentis has, in part, proven enough to make it the preferred approved therapy in clinical practice in some markets. However, other KOLs question whether the dosing duration of RTH-258 will remain differentiated from Eylea over the longer course of treatment, as they already use treat and extend (TAE) or PRN regimens to decrease the burden associated with wet AMD treatment. We also note that it is unclear whether the Phase III data demonstrating that 50-60% of RTH-258 treated patients can be maintained on a q12w dosing schedule over 48 weeks will be sufficient for regulators to accept a longer dosing duration in the approved product labeling, a factor that could especially impact the way it is prescribed in European markets. Finally, assuming RTH-258 launches for wet AMD, it will be competing with established current therapies for market access. Novartis has stated that it has invested in refining the manufacturing process of RTH-258 with a low cost of goods to maximize value and potentially keep the price of the product low, however, we do not presently expect the product to launch at a discount to current approved therapies in our forecast analysis.

Novartis anticipates filing RTH-258 with regulators in 2018 following the completion of a pharmacokinetic study and finalization of the formulation manufacturing process. Although the product may be the first-to-market VEGF inhibitor offering a q12w dosing interval, it is likely to be subject to competition from biosimilar ranibizumab and Allergan’s closely-following VEGF inhibitor abicipar pegol within its first few years on the market, as well as current therapies. Novartis will need to prove a clearly demonstrated dosing interval advantage to physicians to dislodge Eylea as a first-line therapy and to convey significant cost savings to health technology assessment bodies. If the company is successful, RTH-258 has the potential to capture a sizeable segment of this multi-billion dollar market.

For an in-depth analysis of competitive dynamic in the AMD market, as well as a ten-year annualized forecast, please refer to our market assessment in Dry and Wet Age-Related Macular Degeneration | Disease Landscape & Forecast. More information related to physicians’ perceptions related to unmet need in wet AMD can be found in our Wet Age-Related Macular Degeneration | Unmet Need content, while insight into current treatment of wet AMD in the United States and EU5 from the perspective of surveyed ophthalmologists/retinal specialists can be found in our Dry and Wet Age-Related Macular Degeneration | Current Treatment US and EU reports.

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