On July 19th, 2018, a joint press release by Allergan and Molecular Partners announced the top-line results for the SEQUOIA and CEDAR phase 3 trials for abicipar pegol, a DARPin drug. Here were the highlighted bullet points:

• Abicipar, the first and only anti-VEGF to maintain stable vision in greater than 91% of patients on a fixed 12-week regimen, achieved the primary endpoint of noninferiority to monthly ranibizumab at week 52.
• Two pivotal head-to-head trials demonstrate the efficacy of abicipar 12-week fixed dosing regimen with 50% fewer injections vs ranibizumab.

However, the inflammation rate was alarmingly high: greater than 15% in both trials. Perhaps most disturbing is that this rate occurred after several modifications to the drug to combat inflammation.

Will the benefits of this drug outweigh the side effects? Where might abicipar fit in our treatment strategy with other upcoming drugs? We asked several world-renowned experts for their initial, gut reaction to the press release and asked Allergan to respond.

Rishi Singh, MD, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio

The Allergan DARPin molecule represents a significant technological step forward at engineering a molecule for a specific target. While the results from these pivotal trials are interesting, future targets for neovascular AMD and diabetic retinopathy can be developed with this platform to attack multiple pathways with the same molecule.

Certainly the inflammation rates seen within the clinical trial are of concern and will need to be managed, likely with a different formulation. That ultimately might delay its potential release date as another trial may need to be completed to assure a lower rate of inflammation.

In light of other drugs, the drug is a “me too” drug, yet the platform itself is promising, especially when attacking multiple modalities like placental growth factor or angiopoietin-2, or other mechanisms of action in the pathological condition.

Charles Wykoff, MD, PhD, Retina Consultants of Houston, Houston, Texas

While the concept of quarterly dosing is not new, and in fact many patients can be successfully managed with quarterly ranibizumab, aflibercept, or bevacizumab dosing, the ability to maintain a large majority of patients on quarterly dosing would be a substantial step forward for the field. For the benefit of our patients, I hope abicipar can get us closer to that target.

Upon seeing the publicly released data, I have 2 concerns. First, while the report that “greater than 91%” of patients maintained stable vision on quarterly abicipar dosing is attractive, I would like clarity on what “stable” means, and I would also like to know the fluid status of these patients. In clinical practice, clinicians typically use SD-OCT to guide management decisions; if a patient has persistent or recurrent intraretinal or subretinal fluid at quarterly dosing, then they are not by definition stable at quarterly dosing within our current standard of care even if they have not specifically lost visual acuity. It will be important to understand if these “greater than 91%” of patients had persistent or recurrent fluid at their 12-week intervals.

Second, every procedure we do has a built-in risk/benefit ratio that must be considered for each eye. The apparent substantial risk of an inflammatory event with abicipar at more than 15% in each of 4 arms compared to less than 1% in both of the ranibizumab arms, is a reason for pause. I would like more clinical information about the severity of these events, when they occurred relative to abicipar dosing, as well as how they were managed, and what the ultimate outcomes were following these events.

Carl D. Regillo, MD, FACS, Wills Eye Hospital, Philadelphia, Pennsylvania

Having more durable anti-VEGF effect is a large unmet need in treating neovascular AMD and other retinal conditions. The phase 3 CEDAR and SEQUOIA studies showed that abicipar performed very well in terms of durability with the fixed q12-week maintenance regimen achieving noninferiority to the gold standard of monthly ranibizumab with the primary endpoint being the proportion of patients with relative vision stability, meaning losing less than 3 lines over 1 year.

There were, however, relatively high rates of inflammation in the abicipar arms. Such inflammation has the potential to adversely affect the adoption of the drug in practice to treat neovascular AMD, depending on the severity and outcomes of affected eyes, and whether or not the rates can be lowered through refinements in formulation before commercialization.

Mayssa Attar, PhD, DABT, Vice President of Non-Clinical and Translational Sciences, Allergan, and Yehia Hashad, MD, Vice President and Global Head Clinical Development Ophthalmology, Dermatology and Medical Aesthetics, Allergan

We agree that the platform is promising; in fact, the DARPin platform continues to be a key part of our strategy to develop highly differentiated drugs in ophthalmology. We believe that abicipar addresses an important unmet medical need for AMD patients, which is both treatment burden and visit burden. The q12 fixed treatment regimen decreases these burdens with assurance to patients and physicians that they can achieve results noninferior to monthly ranibizumab through bringing their patients back every 3 months without the need for visits in between.

We disagree that abicipar is a “me too” anti-VEGF product because the design of SEQUOIA and CEDAR trials has been attempted before and the studies failed with other anti-VEGF drugs. In fact, if other anti-VEGF drugs administered on a fixed q12 dosing regimen for all patients demonstrate noninferiority to monthly ranibizumab in future trials, they will be “me too” to abicipar.

With regard to OCT and all other secondary endpoints, we agree with the KOLs about their importance and we look forward to presenting our data with abicipar at an upcoming conference.

With regard to inflammation, we agree that it has to be examined in the context of abicipar’s benefit/risk profile. CEDAR and SEQUOIA studies demonstrated a favorable benefit/risk profile for abicipar, importantly, being the only anti-VEGF drug to demonstrate noninferiority to monthly ranibizumab with a fixed 12-week dosing regimen. We plan to present further data on inflammation together with the other efficacy data.

It is normal for any biologic drug to undergo continuous improvement to its manufacturing process. In the case of intravitreally administered drugs, this can improve intraocular inflammation rates. A good example is ranibizumab, which in pivotal AMD studies, per the prescribing label, had intraocular inflammation of 13% in year 1 and 18% in year 2. We agree that a 15% inflammation rate is considered high when compared to the control arm ranibizumab which reported <1% in CEDAR and SEQUOIA studies.

Abicipar is at the same stage of development as ranibizumab when results from the original pivotal AMD trials were reported for ranibizumab. We continue to improve our manufacturing process to make a good proposition even better.

Our colleagues in Chemistry, Manufacturing, and Controls have made significant advancements to develop sophisticated analytical methods that can detect very low levels of host cell proteins combined with purification methods to remove these host cell proteins, which we believe could reduce inflammation. This further optimized manufacturing process, which aims to produce the same abicipar molecule, is being evaluated in the ongoing MAPLE study, for internal assurance, and will report results in 2019. RP