Brolucizumab ─ termination of 4 weekly trials ─ rebalancing the immunogenicity risk

Brolucizumab (Beovu™) has been the most talked about anti-VEGF molecule since its launch due to the various twists and turns caused by drug-induced intraocular inflammation (IOI). The drug received approval by the United States Food and Drug Administration (US-FDA) for its use in neovascular-age-related macular degeneration (n-AMD) on the basis of the phase 3 trial results of HAWK and HARRIER [1]. After a few months of US-FDA approval, the American Society of Retina Specialists (ASRS) flagged an alert on its safety due to unusual adverse events in the form of retinal vasculitis and retinal vascular occlusion. A safety review committee (SRC) was formed and it reported that the incidence of IOI was similar (4.6%) to HAWK and HARRIER (4.4%), but the proportion of cases with retinal vasculitis (3.3%) and retinal vascular occlusion (2.1%) were more compared to what was revealed in the HAWK and HARRIER trial (1%) [2,3]. The US-FDA approval continued inspite of the SRC report with increased incidence of retinal vasculitis and retinal vascular occlusion predominantly due to the criteria mentioning that moderate vision loss was similar to aflibercept. HAWK and HARRIER trial results revealed that approximately half of the patients could be kept on the 12-week regime [2]. However, there were still a significant proportion of patients who might need more frequent, probably a monthly, injection regime. To assess the safety and efficacy of monthly injection in cases of n-AMD, MERLIN trial was initiated in 2018 [4]. The purpose of the trial was to study of safety and efficacy of brolucizumab 6 mg dosed every 4 weeks compared to aflibercept 2 mg dosed every 4 weeks in patients with retinal fluid, despite frequent anti-vascular endothelium-derived growth factor (VEGF) injections.

Novartis released the results of the 1-year MERLIN study, and it was found that IOI was higher with brolucizumab (9.3%) compared to aflibercept (4.5%). Furthermore, proportion of patients with visual loss was also significantly higher with brolucizumab having 4.8% compared to aflibercept’s 1.7%. Brolucizumab arm had 2% retinal vascular occlusion and 0.8% retinal vasculitis. These results led Novartis to terminate the other trials in which brolucizumab was dosed at 4 weekly interval, such as RAPTOR for branch retinal vein occlusion (BRVO) and RAVEN for central retinal vein occlusion (CRVO). In the interest of patient safety, Novartis has emphasized that after three loading doses given at 4 weekly intervals, the subsequent doses of brolucizumab should not be given with less than 8 weeks interval. [5]

Immunogenicity with brolucizumab has been poorly understood till date due to the lack of evidence to make it fit into a clear hypothesis. Multiple authors including our group have tried to propose various mechanisms to understand this phenomenon. The overall understanding revolves around type 3, type 4, or mixed immunogenic mechanism and formation of anti-drug antibodies (ADA) [6–8]. Infectious and toxic etiologies have been ruled out in brolucizumab induced IOI. The only evidence with histopathological data is by Iyer et al. in which it was probably thought to be due to delayed hypersensitivity on the basis of vitreous sample analysis [6]. However, we are not sure whether vitreous sample alone would be sufficient to give us the right answer as there is involvement of vessels also. In this manuscript, we will revisit the mechanism of immunogenicity in the light of results obtained from the MERLIN trial.

It is clear from the MERLIN data that frequent exposure leads to higher immunogenicity. This could be explained on the basis of the findings in relation to free brolucizumab concentration revealed during the non-clinical data analysis of the brolucizumab development program. It was found that after 43 days of the 2nd injection, concentration of free brolucizumab goes down below the detection limit of quantification. However, it was shown that free brolucizumab concentration increased in the vitreous humor 21 days after the 3rd injection [9]. We hypothesize that if the injection frequency is within a month, then the chances of accumulation of free brolucizumab molecules in the vitreous are high, and a significant amount can escape into the systemic circulation leading to more ADA formation and hence enhanced immunogenicity.

The above hypothesis would have been more robust if we had access to drug concentration and ADA levels at the same time as post injection which is not available in the public domain yet. If the above hypothesis is true, then it will be interesting to see whether loading doses should also be extended to reduce immunogenicity which Novartis has not yet recommended. The above hypothesis goes in sync with the data by the American society of retinal specialist (ASRS) that 58% of patients had more than one brolucizumab injection before they developed inflammation [10]. Furthermore, T cell proliferation assay during the development process did not find a high immunogenic alert [9]. If that is true, then the pathogenesis again points to ADA as a major factor. Preexisting ADA were detected even during non-clinical testing, in the range of 27–47% with animals, and we were aware that it was 43.7% in HAWK and HARRIER [9]. Pre-injection antibodies refers to the molecular mimicry of monoclonal antibody protein in testing (brolucizumab) with some of the nonspecific protein fragments which are already present in human sera and are immunogenic. For the companies that are involved in the development of biologics for retinal diseases, probably the brolucizumab experience demonstrated that more caution and analysis are required if pre injection antibodies are high. The structure of such molecules should be modified early during the research and development process to make sure they do not throw a surprise later.

We hope that the FALCON study which is assessing the safety and efficacy of brolucizumab injection with two arms, one 3x loading doses 4 weekly followed by 12 weekly regime and other arm first injection followed by 12 weekly regime, should be able to give us more clues to understand the pathogenesis in view of free brolucizumab and ADA formation, and should also be able to guide clinicians regarding the safe usage of this drug [11]. The FALCON trial results may take a long time to be available. Meanwhile, final phase 3 data of KITE and KESTREL can also shed some light on this as both trials had loading doses given at 6 weekly intervals rather than 4 weekly. Interim data of KITE showed IOI rates with brolucizumab similar to aflibercept [12], which shows that 2 weeks extension in the loading dose is either not enough or not the right strategy to mitigate the risk of this complex immunogenicity. Many of the studies published from Japanese population demonstrated higher incidence of inflammation compared to the on label risk [13–15]. This raises another possibility of genetic variability. However, these are studies with very small sample size; hence, relying on the rate of inflammation may not be accurate. Immunogenicity has been a complex phenomenon and so are the mitigating strategies. We will know in future whether extension could be a possible tool to mitigate the immunogenicity risk with brolucizumab.

Expert Opinion

Brolucizumab related immunogenicity is a complex phenomenon and yet to be understood. As the drug is US-FDA and EMA approved and available for clinical use, many ways are being explored to use its efficacy and reduce immunogenicity. Termination of all the trials with the monthly regime after the result of MERLIN trial is an effort towards the same. FALCON trial results should be the key to watch as it will help us to understand whether a 12-week extension from the initiation will be of some help in reducing the immunogenic potential of this efficacious molecule.

Declaration of interests

Ashish Sharma: CONSULTANT: for Novartis, Allergan, Bayer and Intas. BD Kuppermann: CLINICAL RESEARCH: Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GSK, Ionis, jCyte, Novartis, Regeneron, ThromboGenics; CONSULTANT: Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana, Theravance Biopharma. Francesco Bandello: CONSULTANT: Allergan, Bayer, Boehringer- Ingelheim, Fidia Sooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One of the peer reviewers of this manuscript acts as a Consultant to Molecular Partners, developer of an anti-VEGF agent, and is a member of Advisory Boards of Roche and Bayer. Three additional peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Dr Kuppermann acknowledges an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute at the University of California, Irvine.