key: cord-0916069-i9mqoks7
authors: Pogue, Jason M; Lauring, Adam S; Gandhi, Tejal N; Marshall, Vincent D; Eschenauer, Gregory A; Nagel, Jerod L; Baang, Ji Hoon; Zhou, Shiwei; Valesano, Andrew L; Petty, Lindsay A
title: Monoclonal antibodies for early treatment of Covid-19 in a world of evolving SARS CoV-2 mutations and variants
date: 2021-05-23
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab268
sha: bdd6aceef2cacd930607b233bcea479cd4b798ba
doc_id: 916069
cord_uid: i9mqoks7

Monoclonal antibodies targeting the receptor binding domain (RBD) of SARS CoV-2 spike protein are important outpatient treatment options in Covid-19 to mitigate progression of disease and prevent hospitalization. The impact of different RBD mutations on efficacy of available monoclonal antibodies and processes for incorporating this impact into treatment algorithms are ill-defined. Herein, we synthesize the data surrounding the impact of key RBD mutations on efficacy of US FDA emergency use authorized monoclonal antibodies and describe our approach at Michigan Medicine at monitoring mutation frequency in circulating virus and developing an algorithm that incorporates these data into outpatient treatment pathways.

A c c e p t e d M a n u s c r i p t Monoclonal antibodies (bamlanivimab (BAM), bamlanivimab + etesevimab (BAM-ETE), and casirivimab + imdevimab (CAS-IMD)) are available under emergency use authorization (EUA) for early outpatient treatment of mild-moderate Covid-19. [1] [2] [3] They have been shown to reduce the incidence of hospitalization and death in individuals at high risk for progression to severe disease with a number needed to treat (NNT) of roughly 20 patients to prevent one hospitalization. 2 These agents were selected for development based on neutralizing activity against viruses bearing "Wuhan-1-like" or D614G SARS-CoV-2 spike proteins, and their efficacy to date has been assessed in settings where D614G predominated. Numerous variants of concern (VOC) or interest (VOI) with key mutations to the Receptor Binding Domain (RBD) of the Spike protein have since emerged. These mutations may impact the efficacy of these agents, as the RBD is the target site for all currently authorized monoclonal antibodies. [1] [2] [3] Furthermore, these same RBD mutations have also been identified, and may be present, in viruses from lineages distinct from the main VOC/VOI.

It is important that monoclonal antibody programs consider the impact of mutations and local epidemiology of circulating virus when choosing monoclonal antibody products for use in their treatment algorithms. However, this is challenging for many reasons. First, SARS-CoV-2 genomic surveillance is incomplete, varies from state to state, and many data sources are not readily available or easy to understand. Second, while the information provided in the updated FDA EUA fact sheets includes information on the impact of mutations on the neutralizing activity of monoclonal antibodies, 1-3 they do not offer usable guidance that can be applied to treatment decisions. Furthermore, what considerations (i.e., incidence of mutations locally, level of comparative "resistance" across available monoclonal antibodies, and available supply of monoclonal antibodies) should lead to preferential use of one agent over another are unclear. Herein, we describe the approach of the monoclonal antibody program at Michigan Medicine ( Figure 1 ).

In order to develop a rational treatment strategy, the first step is to understand the impact that different variants and individual mutations have on the treatment options. This can be accomplished by assessing the impact of key RBD mutations on the IC 50 (concentration necessary to neutralize 50% of the virus) and IC 80 values for each monoclonal antibody (Table 1) . [4] [5] [6] [7] For some of the variants, the impact on the EUA monoclonals is straightforward. The N501Y mutation, which is the RBD mutation present in the B.1.1.7 strain, does not significantly impact any of the four approved monoclonal antibodies; thus, all products are appropriate treatment options. 4,5 For both B.1.351 and P.1 strains, BAM, ETE, and CAS all lose inhibitory activity against the combination of RBD mutations present (N501Y, E484K, and K417N(T)), and only CAS-IMD would be expected to be effective, due to the retained activity of imdevimab in the setting of these mutations. [4] [5] [6] A c c e p t e d M a n u s c r i p t

The data are less clear for other variants or viruses bearing individual mutations. When E484K is the only RBD mutation present, as in P.2 and B.1.526, BAM loses activity, while CAS-IMD retains activity. ETE, and thus the BAM-ETE combination is more complicated. The ETE IC 50 is 2-3-fold higher against viruses with E484K when compared to the wildtype. 4, 5 While the IC 50 is higher than that of IMD, it still remains relatively low at <0.1 µg/mL, 4 given the mean peak concentration after a 1400 mg dose of ETE is 504 µg/mL. 2 Additionally, the ETE IC 80 against E484K mutants is 1.3 and 3.4fold lower than those for CAS and IMD, respectively. 4 Therefore, it is expected that BAM-ETE would remain a similarly effective option compared to CAS-IMD in the setting of E484K. It is important to note, when assessing BAM-ETE activity against E484K, that N501Y also slightly impacts the activity of ETE, causing a 1-3-fold increase in IC 50 values. 4 4 While a separate publication recently suggested a ~7-fold increase in ETE IC 50 with B.1.427, the IC 50 remained < 0.1 µg/mL, which was similar to that of CAS and lower than that of IMD. 7 Taken together, these studies suggest that both combination products (BAM-ETE and CAS-IMD) will be equally effective against the L452R mutation.

Given the impact that various mutations and variants have on monoclonal antibody activity, the next step is to understand circulating virus locally. Given the time-sensitive nature of treatment with monoclonal antibodies it is not possible to perform real time sequencing of infecting virus to inform patient level monoclonal antibody decisions, and therefore focus needs to be shifted to local genomic surveillance. At the University of Michigan, our research laboratory receives an aliquot of all positive patient samples from the health system's clinical microbiology laboratory. All isolates with RT-qPCR cycle threshold values < 30 are then sequenced. These data are then used to create rolling 14-day averages of key RBD mutations, both individually and in combination. Both are important, since these mutations will impact the efficacy of monoclonal antibody treatments regardless of whether or not they are present on a specific VOC.

Next, the monoclonal antibody team must utilize these data, in combination with current supply of BAM, BAM-ETE, and CAS-IMD to determine appropriate monoclonal antibody allocation and usage. While it may seem attractive to simply use CAS-IMD due to activity against all major As both E484K and L452R will render BAM ineffective and there is adequate supply of both BAM-ETE and CAS-IMD, we have discontinued BAM monotherapy. As for combination therapy, the in vitro evidence supports both BAM-ETE and CAS-IMD as appropriate treatment options based on the aforementioned activity of ETE against both E484K and L452R. Therefore, our current process is to preferentially utilize BAM-ETE as supplies are available to "reserve" CAS-IMD should the situation change. However, we also utilize CAS-IMD as needed based on the number of patients requiring treatment.

An important consideration for monoclonal antibody programs is to determine at what threshold percentage of circulating "resistance" to BAM-ETE would there be a need to switch to preferential use of CAS-IMD. As supply issues make it impossible for an early switch to CAS-IMD for all patients (e.g. at the first signs of local B.1.351/P.1 circulation), it is informative to consider the impact that resistance would have on the NNT. The phase III trials report a decrease in the need for hospitalization in the high-risk population for which the EUAs were granted with treatment from roughly 7% to 2% (NNT 20). 2 A c c e p t e d M a n u s c r i p t At Michigan Medicine the cutoff for discontinuation of BAM-ETE has arbitrarily been set at a 10% increase in the NNT (or to an NNT of 22 or higher) for two main reasons. First, it represents a significant decrease in the efficacy of the treatment. Secondly, the NNT begins to rise exponentially once exceeding this threshold and therefore, the impact of further degrees of inactivity become more pronounced. This 10% increase could be a 10% incidence of B.1.351 circulating locally, or a 20% incidence of some yet undefined mutation that decreases the efficacy of BAM-ETE by 50%. This cutoff point is dynamic and subject to change based on local supply of both products as well as variant rates nationally, which may lead to the need to prioritize CAS-IMD for a part of the country where problematic variant rates are higher. Additional considerations for scenarios where supply cannot meet demand include prioritizing CAS-IMD for the highest risk patients currently authorized under the EUA. A recent, real world study of BAM found the highest hospitalization rate in untreated patients ≥ 65 years of age (19%), with an NNT of 8 to prevent a hospitalization in this subset of patients. 8 Given that percentage decreases in efficacy would impact more patients in this group it would be sensible to treat these patients with CAS-IMD, while utilizing BAM-ETE in other patients. If infection rates and the severity of presentation continue to decrease in this population due to successful vaccination campaigns, prioritization could focus on other groups with the highest risk for poor outcomes such as the immunocompromised, morbidly obese, or minoritized patient populations.

Importantly, not all sites have the ability and/or resources to sequence all, or even some of the viruses present locally. In this setting, it is reasonable to use publicly available statewide data to inform these decisions. This can be performed by downloading all statewide sequence data that is uploaded into GISAID, an open access database of viral sequences. The data downloaded from this website can then be uploaded into Nextclade, which translates sequencing data into amino acid substitutions to allow the assessment of the frequency of key RBD mutations in the statewide samples. The above processes for assessment of the impact of mutation rates on treatment options can then be applied to the statewide data set in order to inform monoclonal antibody treatment decisions. One important caveat to statewide surveillance data is that the sample of viruses sequenced can include a combination of routine surveillance and more targeted sequencing. As samples in these data sets will include outbreak investigations and targeted surveillance of high-risk populations for VOC, these data should be interpreted cautiously as they may be less reflective of overall local epidemiology. M a n u s c r i p t A c c e p t e d M a n u s c r i p t * to determine the impact of mutation frequency/effect on monoclonal antibodies the following process was followed. The 5% absolute difference between treatment and no treatment was multiplied by the mutation frequency (e.g. 0.1 for 10%) and the impact the mutation has on efficacy (e.g. 0.5 for 50% decrease in efficacy). The sum of these numbers was then subtracted from the 5% absolute difference to determine the new absolute difference (e.g. 5 x 0.1 x 0.5 = 0.25; 5 -0.25 = 4.75) and then subtracted from the untreated event rate to determine the new event rate for treated patients (e.g. 7 -4.75 = 2.25%). The new absolute difference was then used to calculate the NNT (e.g. 100/4.75 = NNT 21)

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