Abicipar Pegol Is Non-Inferior to Lucentis With Less-Frequent Dosing in Wet AMD, But May Have Safety Concerns. What Does This Mean for Wet AMD?
Allergan announced on July 19th, 2018 that its vascular endothelial growth factor (VEGF) inhibitor abicipar pegol hit the primary end point in two Phase III trials in wet age-related macular degeneration (AMD), matching the efficacy of Roche/Novartis’s Lucentis at one year with a more-convenient dosing profile.1 Abicipar pegol, as an engineered ankyrin repeat protein (DARPin), offers a novel approach for targeting VEGF-A. In the CEDAR and SEQUOIA trials in treatment-naïve wet AMD patients, abicipar pegol demonstrated non-inferiority to Lucentis on maintenance of visual acuity (defined as losing < 15 letters of best-corrected visual acuity [BCVA] from baseline) at one year, a standard primary outcome measure in pivotal wet AMD trials. Importantly, over 90% of patients treated with abicipar pegol had maintenance of vision when the drug was administered via intravitreal injections every eight weeks (Q8W) or every twelve weeks (Q12W) after three loading doses, while Lucentis was dosed every four weeks (Q4W). Although Regeneron/Bayer HealthCare/Santen’s VEGF inhibitor Eylea is already approved for Q8W dosing in wet AMD, no therapy has yet been approved with Q12W dosing in wet AMD. Allergan reported that patients in the Q12W treatment arm only received six injections of abicipar pegol in one year (patients received eight injections in the Q8W dosing arm), compared with 13 injections of Lucentis. The outcome of this trial suggests that abicipar pegol could address the large unmet need for therapies with less-frequent dosing but comparable efficacy to the standards of care. However, lingering questions about abicipar pegol’s risk/benefit profile, in addition to the future competitive landscape of the wet AMD market, could impact the clinical and commercial potential of the drug in the multi-billion dollar wet AMD market.
Less-Frequent Dosing, But A Greater Risk of Ocular Inflammation?
Although Allergan reported that the rate of treatment-related adverse events was comparable across the abicipar pegol and Lucentis treatment arms in the CEDAR and SEQUOIA trials, the rate of ocular inflammation with abicipar pegol reached 15-16% over one year, compared with less than 1% with Lucentis. Given the low rate of ocular inflammation typically observed with Eylea and Lucentis (2% and 3% in Eylea’s VIEW trials to one year, respectively)2, we question whether retinal specialists and their patients would be willing to accept an added safety risk for Q12W dosing, especially in a market where treat and extend and prn regimens are widely used. Allergan noted during a conference call discussing the trial results that the majority of cases of ocular inflammation were mild-to-moderate and easily treatable,3 which could provide some reassurance to the retinal community, but complete trial results are needed to fully evaluate the potential impact of this adverse event, such as on patients’ visual acuity. Allergan also announced during the conference call that optimization of the drug formulation was continuing and a new formulation is being evaluated in the ongoing Phase II MAPLE trial. Data from this trial are expected in H1 2019 and the company stated that these data will be added to results from CEDAR and SEQUOIA for abicipar pegol’s BLA. If the MAPLE trial shows a lower rate of ocular inflammation, these results would likely increase retinal specialists’ confidence in administering abicipar pegol to their wet AMD patients. However, given that this is a small open-label trial without an active comparator arm, the new formulation will lack robust clinical data versus an active comparator, which may be needed to quell regulators’ safety concerns.
Abicipar Pegol and the Future Competitive Landscape in Wet AMD
Allergan expects to file abicipar pegol with the FDA in the first half of 2019, following a pre-BLA meeting with the agency; we presume that submissions to regulatory authorities in other regions will follow the U.S. submission. Such a filing in the United States suggests a possible approval and launch in 2020, but other market dynamics may undermine the commercial potential of abicipar pegol in wet AMD. For example, although Eylea already has a well-established position in the wet AMD market, Regeneron submitted an sBLA to the FDA for Eylea’s labeling to be broadened to include Q12W dosing, with an expected PDUFA of August 11th, 2018.4 With this, abicipar pegol would enter the U.S. wet AMD market with at least one therapy already approved with an extended dosing frequency. However, Eylea’s sBLA was based on an integrated analysis of results from the second year of the VIEW-1 and VIEW-2 trials, in which patients were treated as needed, with a minimum mandatory dosing interval of Q12W. As such, it remains unclear if expanded labeling will allow Eylea to be dosed Q12W from the initiation of treatment or only after one year of continuous treatment, as in the VIEW trials. Thus, abicipar pegol could have an advantage of a label allowing Q12W dosing from treatment initiation, having demonstrated efficacy with Q12W dosing with a fixed-dosing regimen in the CEDAR and SEQUOIA trials.
Abicipar pegol would also face competition from Novartis’s emerging VEGF inhibitor brolucizumab in the major markets, which will also address the need for therapies with less-frequent dosing. Positive top-line data from brolucizumab’s pivotal HAWK and HARRIER trials in wet AMD were announced in June 2017, in which the drug showed non-inferiority to Eylea for mean change in BCVA to week 48, the primary end point in the trial.5 Rather than having fixed Q8W and Q12W treatment arms as in abicipar pegol’s CEDAR and SEQUOIA trials, the design of brolucizumab’s trials allowed patients to be maintained on Q12W dosing after three monthly loading injections if their disease did not worsen, a new approach for a wet AMD trial but one which more closely replicates how U.S. retinal specialists typically treat their wet patients in clinical practice. Given the differences in the trial design between brolucizumab and abicipar pegol, direct comparison between Phase III results is difficult, although we note that over half of brolucizumab-treated patients were maintained on Q12W in the HAWK and HARRIER trials to 48 weeks. Importantly, brolucizumab demonstrated superiority to Eylea on multiple secondary end points, with the overall rate of ocular and non-ocular side effects reported to be similar between the therapies; ocular inflammation was not among the most-frequently cited adverse events for brolucizumab. Novartis plans to file with regulatory authorities beginning in late 2018, suggesting that the therapy is likely to reach the market before abicipar pegol.
Both current and emerging therapies in the wet AMD market will have to compete with biosimilar ranibizumab and biosimilar aflibercept in the coming years as Lucentis and Eylea lose patent exclusivity. With biosimilar ranibizumab in late-phase development and positive top-line data already announced for Formycon/Bioeq’s biosimilar FYB-201,6 the first Lucentis biosimilar could launch as early as 2020 in the United States and 2022 in Europe. This time frame is similar to the potential launch of abicipar pegol, and could potentially limit its commercial potential.
Is Abicipar Pegol Likely to Succeed in Wet AMD?
Allergan plans to report the complete results from abicipar pegol’s Phase III trials at an upcoming scientific conference, providing a more complete picture of the performance of the drug on additional efficacy and safety measures compared with Lucentis. The company appears confident that the Phase III data from the CEDAR and SEQUOIA trials will be sufficient to gain regulatory approval of abicipar pegol for wet AMD,3 but we continue to question whether its risk/benefit profile will be acceptable to regulators, retinal specialists, and patients. However, given Allergan’s commitment to improve the abicipar pegol formulation and their longstanding experience and reputation in the ophthalmology space, we are cautiously optimistic that the drug will gain approval and launch for wet AMD, even if such events are ultimately later than our forecast launch date of 2020 in the United States and Europe.7
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 the Dry and Wet Age-Related Macular Degeneration | Disease Landscape & Forecast. Additional insight related to the current treatment of AMD in the United States from the perspective of surveyed ophthalmologists/retinal specialists can be found in our Dry and Wet Age-Related Macular Degeneration | Current Treatment: Physician Insights | US, while information on wet AMD treatment in the United States using patient-level claims data can be located in our Treatment Algorithms: Claims Data Analysis | Wet Age-Related Macular Degeneration | US. For an in-depth analysis of the potential success of brolucizumab in wet AMD, please refer to our related blog post on this topic.
- Allergan, press release, July 19, 2018
- S. Eylea prescribing information
- Allergan, SEQUOIA and CEDAR Phase 3 topline results presentation and conference call, July 19, 2018
- Regeneron, press release, December 11, 2017
- Novartis, press release, June 20, 2017
- Formycon AG, press release, May 2, 2018
- Dry and Wet Age-Related Macular Degeneration | Disease Landscape & Forecast
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Emma McFadden, Ph.D., is a Director in the Central Nervous System/Ophthalmology disorders group. Dr. McFadden joined DRG in 2011 and oversees ophthalmic indications, such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema, and other diseases, including schizophrenia. Prior to joining DRG, Dr. McFadden earned a B.A. in neuroscience and a Ph.D. in biochemistry from Trinity College Dublin.