Article Type : Case Report
Authors : Weimer LE1, Cattari G, Binelli A, Fanales-Belasio E, Piras S and Sensi F
Keywords : Sars-Cov-2; Bamlanivimab - etesevimab
In December 2019, the sudden arrival and devastating spread
of the SARS-COV-2 pandemic has stimulated an accelerated programme of
international research to identify effective ways to limit the spread of
infection and to reduce the morbidity and mortality associated with SARS-COV-2
the novel coronavirus disease-19 (COVID-19). The SARS-CoV-2 pandemic has
already infected more than 141 million people worldwide and resulted in 3.01
million deaths. Due to the limited number of vaccine for the general population
in most countries, the combination of monoclonal antibody (mAb) remains an
important Therapeutic Opportunity to change the Clinical History in the
Sars-Cov-2 Era and the multiorgan involviment, especially in the elderly
individuals. More than 50 monoclonal antibody-related clinical trials are being
conducted in different countries around the world, with few of them nearing the
completion of the third and fourth phase clinical trial. Recently the FDA (Food
AND Drug Administration) approved the emergence use authorization of
combination therapy of monoclonal antibody including REGEN-COV (casirivimab and
imdevimab, administered together), the combination bamlanivimab - etesevimab
and revoked the authorization (EUA) that allowed bamlanivimab therapy alone. This minireview
explain the importance of Combination Therapy with Monoclonal Antibodies as The
First Major Therapeutic Opportunity to change the Clinical History in the
Sars-Cov-2 Era.
In December 2019, the
sudden arrival and devastating spread of the SARS-COV-2 pandemic has stimulated
an accelerated programme of international research to identify effective ways
to limit the spread of infection and to reduce the morbidity and mortality associated
with SARS-COV-2 the novel coronavirus disease-19 (COVID-19) [1]. The SARS-CoV-2
pandemic has already infected more than 201 million people worldwide and
resulted in 4,27 million deaths [2]. Due to the limited number of vaccine for
the general population in most countries, the combination of monoclonal
antibody (mAb) remains an important Therapeutic Opportunity to change the
Clinical History in the Sars-Cov-2 Era and the multiorgan involviment,
especially in the elderly individuals. More than 50 monoclonal antibody-related
clinical trials are being conducted in different countries around the world,
with few of them nearing the completion of the third and fourth phase clinical
trial. Recently the FDA (Food AND Drug Administration) approved the emergence
use authorization of combination therapy of monoclonal antibody including
REGEN-COV (casirivimab and imdevimab, administered together), the combination
bamlanivimab - etesevimab and revoked the authorization (EUA) that allowed bamlanivimab therapy alone. This minireview
explain the importance of Combination Therapy with Monoclonal Antibodies as The
First Major Therapeutic Opportunity to change the Clinical History in the
Sars-Cov-2 Era.
Combination
with Monoclonal Antibodies in Sars-Cov-2 persons as Cocktail with
Antiretroviral Drugs in HIV Infection
The mAbs are likely to
aid in reducing viral load by interfering with virus entry into a cell by
binding to viral spikes and thus inhibiting virus attachment to cell surface
receptors or by targeting host cell receptors or co-receptors, thereby making
the binding sites of host cells unavailable for SARS-CoV-2. Actually
Bamlanivimab - etesevimab and casirivimab - imdevimab decrease viral load when
given early on in the course of SARS-CoV-2 infection and favourably impact
clinical outcomes for patients with mild-to-moderate COVID-19. Although full
clinical trial data are pending, top-line and interim results from multiple
trials suggest that the therapies may also function as prophylaxis in at-risk
patients recently exposed to SARS-CoV-2.
One signal emerging from early data is that patients with persistently
higher viral load progress more frequently and this effect is most pronounced
for patients with pre-existing risk factors for disease progression [3]. The
cocktail therapy comprising casirivimab and imdevimab (REGN-COV2), block virus
binding to the human ACE2 receptor, has been developed by Regeneron
Pharmaceuticals and approved for EUA by the FDA on November 21, 2020. The
recommended dose is 1200 mg for both mAbs as a single intravenous infusion dose
for the treatment of adults and pediatric patients suffering from mild to
moderate COVID-19, as well as those who are at high risk of progressing to
severe COVID-19. But patients who are hospitalized due to COVID-19 or who
require oxygen therapy due to COVID-19 or any other underlying non-COVID-19
related comorbidity were excluded from receiving the cocktail therapy as study
findings demonstrated limited benefits of the drug in patients suffering from
severe diseases. The authorization is based on positive phase-2 data announced
in September and October from 799 adults in an ongoing randomized,
double-blind, placebo-controlled trial of non-hospitalized patients
(“outpatients”) with COVID-19, in which significant reductions were observed in
the level of the virus along with significantly fewer medical visits within 28
days of receiving the combination treatment . On further analysis, interim
results from phase 1–2 trials in 275 patients published in December corroborated
previous findings and demonstrated improved results in patients in whom
endogenous immune response had not been initiated and patients who had high
viral load at the start of mAb therapy [4]. The absence of co-morbidities does
not completely eliminate the risk of severe disease and sequalae, and there is
an urgent need for additional insight into a more personalized predictive
algorithm to unlock as-yet-unidentified risk factors. The way to classify
candidate patients for neutralizing mAbs would be to select patients who are
expected to have poor antiviral responses (for example, elderly or immune
compromised patients) or to identify patients with poor T cell and/or B cell
function via experimental techniques (such as by serology or flow cytometry). Regarding
the latter, there is a lack of published evidence on humoral immune response
dynamics and correlation with clinical outcomes. Finally, antiviral and antimicrobial
therapies are traditionally plagued by their promoting escape variants, and
sometimes combination therapy can mitigate this risk. As a first-generation
approach for neutralizing mAbs, monotherapies have been developed and have been
demonstrated to be efficacious, but it is expected that a greater number of
combination therapies will follow. For example, in phase II/III trials
involving patients with COVID-19, bamlanivimab and the bamlanivimab and
etesevimab combination had similarly improved magnitudes and timings of symptom
relief relative to the placebo25. However, to date, the bamlanivimab and
etesevimab combination does not appear to lead to the emergence of
drug-resistant variants of SARS-CoV-2. This is similar to what has been
observed for the other authorized neutralizing mAb combination (casirivimab and
imdevimab), as already described herein [5].
Benefits of Monoclonal Antibodies Therapy: Does their use as a prophylactic
or treatment potentially affect natural long-term immunity?
Considering
the large doses used and the relative half-life of antibodies (~3 weeks for IgG
molecules), there is a pertinent consideration whether the presence of
circulating neutralizing mAbs could impact active immunity, whether through
memory from infection or vaccination. From the collective clinical data with
MAb114, REGN-EB3 and palivizumab, the general benefits and risks associated
with neutralizing mAbs are similar to those observed with traditional passive
immunization against infectious agents. The agents themselves are relatively
tolerable for patients, efficacious during the early onset of disease symptoms
and in certain cases as a prophylactic, but with limited efficacy once
infections are severe. The distinctions between these therapies are largely
logistical; CPT is more rapidly implemented during an emerging pandemic when
few therapeutic options are yet available, while neutralizing mAbs take time to
discover and it takes time for regulatory approval for their use to be obtained
as well as to scale up manufacturing capacity. The use and promise of passive
immunization during the coronavirus outbreaks of the twenty-first century (that
is, with SARS-CoV, Middle East respiratory syndrome-related coronavirus and
SARS-CoV-2) have re-emphasized these past lessons while also highlighting
additional insights, as we discuss next [6]. Fortunately today, the process to
mass-produce recombinant mAbs has become scalable to meet demand and is
cost-competitive with other treatments. Neutralizing mAbs overcome limitations
intrinsic (for example, the risk of blood-borne diseases, time to development
of detectable high-affinity antibodies and risk of low antibody titres, as well
as variable epitope specificity. Furthermore, a high titre of neutralizing
antibodies — which current evidence indicates is necessary for the efficacy-is
inherent with neutralizing mAbs. As of April 2021, at least 20 neutralizing mAb
therapies were being tested in late-stage clinical trials or had already been
approved for use in nine infectious diseases, including RSV infection and
Ebola.
HIV and COVID-19 as
Twin’s Pandemics, The Viral Variants and the Limit to the Effectiveness of the
Therapies
The
polyclonal nature of Convalescent Plasma Therapy, in which a spectrum of
differentiated antibodies target multiple epitopes of the pathogen, may help to
reduce this risk. Nevertheless, emerging preclinical data suggest SARS-CoV-2
spike (S) protein mutations escape from polyclonal serum and convalescent
plasma has reduced neutralizing activity against some viral variants [7]. For
mAbs, however, depending on the infectious agent and the epitope targeted,
combinations of mAbs may be necessary to maintain efficacy and prevent
treatment failure. Experience with mAbs targeting human immunodeficiency virus
(HIV), which has a very high mutation rate, suggests that it may be more
effective and durable to use multiple neutralizing antibodies (that is,
combinational mAb therapy) rather than a single one [8]. These particular mAbs
to HIV also need to be broadly neutralizing and target epitopes generally
conserved among viral variants.
REGN-COV2 Therapy as
the HAART Therapy in the HIV Era
REGN-COV2 is a combination of two potent
neutralizing mAbs — namely, casirivimab and imdevimab, which are IgG1 mAbs with
unmodified Fc regions. These two mAbs were chosen from a pool of more than 200
neutralizing mAbs present in the initial isolation of thousands of antibodies
and were derived from parallel efforts using humanized mice and the sera of
patients recovering from COVID-19 [9]. An ongoing phase I/II/III
placebo-controlled trial (NCT04425629) is investigating the safety and efficacy
of a single infusion of casirivimab and imdevimab — 2,400?mg (n?=?266,
interim), 8,000?mg (n?=?267, interim) or matching placebo (n?=?266)-for
symptomatic adults who have not previously been hospitalized within 3 days of a
positive active SARS-COV-2 diagnosis (and within 7 days of the first symptoms)
3. In the modified full analysis set for the phase I/II analysis, the median
age was 42 years (7% aged 65 years or older), 85% of patients were white, 9%
were Black and 34% were considered at high risk (for example, they were
elderly, had obesity or had underlying chronic medical conditions). Pooled
treatment achieved the primary end point of time-weighted average change from
the baseline in viral load (log10 copies per millilitre), collected from a
nasopharyngeal swab, in patients with a positive baseline for viral RNA
(n?=?665). The difference in time-weighted average from day 1 through day 7 for
the pooled doses of casirivimab and imdevimab compared with placebo was ?0.36
log10 copies per millilitre (P?<?0.0001). The combination was reported to
reduce viral load particularly in patients with higher viral loads who were
seronegative at the baseline. On a key clinical end point, a lower proportion
of patients treated with casirivimab and imdevimab had COVID-19-related
medically attended visits (2.8% for pooled doses versus 6.5% for placebo). In
post hoc analyses, a lower proportion of patients treated with casirivimab and
imdevimab had COVID-19-related hospitalizations or emergency department visits
compared with patients who received placebo (2% versus 4%). The absolute risk
reduction for casirivimab and imdevimab compared with placebo was greater for
patients at high risk of progression to severe COVID-19 and/or hospitalization
(3% versus 9%). Collectively, these results supported the EUA of Regeneron’s
casirivimab and imdevimab cocktail in the United States in November 2020.
The
BLAZE-1 trial studied bamlanivimab together with etesevimab (an S
protein-binding IgG1 with a modified Fc region, resulting in null effector
function) 25,72. Bamlanivimab and etesevimab together significantly decreased
viral load (mean changes from the baseline and percentage of patients with
persistent high viral load) compared with placebo at day 3 to day 11.
Bamlanivimab- and etesevimab-treated patients had fewer COVID-19-related
hospitalizations relative to the placebo group (5.8% for placebo reduced to
0.9% for bamlanivimab together with etesevimab). Recently released
placebo-controlled phase III data from 1,035 patients randomized 1:1 to receive
bamlanivimab together with etesevimab versus placebo demonstrated that in
high-risk ambulatory patients (including patients aged 12–17 years with
specific risk factors and patients aged 18 years or older with specific adult
risk factors) treatment with bamlanivimab and etesevimab together was
associated with a 70% reduction in COVID-19-related hospitalizations and deaths
relative to placebo treatment (7.0% for placebo reduced to 2.1% for
bamlanivimab together with etesevimab) [10].
On the basis of these data, an additional EUA of bamlanivimab together
with etesevimab has been issued.
Monoclonal Antibodies
Therapies in Severe COVID-19
There
are concurrent studies investigating neutralizing mAbs for patients
hospitalized with severe COVID-19. The REGN-COV2 trial in hospitalized patients
enrols patients with or without supplemental oxygen and is ongoing. In
prospectively designed analysis of REGN-COV2, there may be clinical benefit in
patients treated with casirivimab and imdevimab and who were seronegative at
the time of treatment76. In the ACTIV-3 RCT (n?=?326, 1:1 randomization),
bamlanivimab added to standard of care (typically including remdesivir) did not
demonstrate additional clinical benefit in hospitalized patients [11]. In line
with similar studies investigating CPT or neutralizing mAbs for patients with
severe viral disease (including COVID-19), the evidence indicates that rapid
viral clearance, in itself, is insufficient. Rather, additional factors, such
as an excessive immune response, are the primary drivers for continued disease
in this particular patient population. Thus, early disease seen in outpatients
is likely virally driven, whereas the pathophysiology for inpatient advanced
disease is predominantly a postviral or periviral phenomenon, with clinical
status uncoupled from viral load.
Adverse events
associated with monoclonal antibody therapies
In
terms of risk associated with mAb treatment of COVID-19, treatment-associated
adverse events were comparable to those with placebo. The most frequent side
effects observed in RCTs include nausea, diarrhoea, dizziness, headache and
vomiting. One per cent of patients receiving casirivimab and imdevimab reported
a grade 2 or higher infusion-related reaction within 4 days of administration
(comparable to 1% reported for placebo treatment). In the phase II portion of
BLAZE-1, nine patients reported an infusion-related reaction (1.9% (6/309) with
bamlanivimab monotherapy, 1.8% (2/112) with bamlanivimab and etesevimab
together, and 0.6% (1/156) with placebo). Most reactions occurred during
infusion; these were mild in severity and were not dose related. Regarding
evidence of ADE, in vitro data indicate neutralizing mAbs do not enhance
productive infection of immune cells with SARS-CoV-2. From the clinical data
available to date, there is no clear evidence these therapies result in
enhanced immune responses consistent with ADE. Furthermore, the safety profiles
of modified and modified plus unmodified mAbs to treat SARS-CoV-2 infection are
similar, suggesting that ADE may not play a role in clinical outcomes.
Emergence of
drug-resistant SARS-CoV-2 strains as Hiv Therapy
For patients with Sars-Cov-2 who receive
neutralizing mAbs, there is potential for the development of drug-resistant
variants as HIV Antiretroviral Therapy, which become more obvious when
selective pressure is applied in the setting of drug treatment [12]. For
bamlanivimab, non-clinical studies using serial passage of SARS-CoV-2 and
directed evolution of the SARS-CoV-2 S protein identified viral variants
(E484D/K/Q, F490S, Q493R and S494P, amino acid substitutions in the S protein RBD)
that had increased resistance to this drug. In clinical trials of bamlanivimab,
genotypic and phenotypic testing are monitoring SARS-CoV-2 strains for
potential S protein variations that are associated with bamlanivimab
resistance. In the BLAZE-1 RCT, which was limited to US investigative sites,
known bamlanivimab-resistant variants at the baseline were observed at a
frequency of 0.27% to date. In the same trial, treatment-emergent variants were
detected at S protein amino acid positions E484, F490 and S494 (including
E484A/D/G/K/Q/V, F490L/S/V and S494L/P); considering all variants at these
positions, 9.2% and 6.1% of participants in the 700-mg bamlanivimab arm (the
EUA dose) harboured such a variant after the baseline at allele fractions of
15% or greater and 50% or greater, respectively, compared with 8.2% and 4.1%,
respectively, of participants in the placebo arm. Most of these variants were
first detected on day 7 following infusion, and were detected at only a single
time point. The clinical impact of these variants is currently unknown. As with
bamlanivimab, casirivimab and imdevimab therapy has the potential to lead to
the development of resistant viral variants. In non-clinical studies, serial
passage of vesicular stomatitis virus (VSV) encoding the SARS-CoV-2 S protein
in the presence of the drugs identified escape variants with reduced
susceptibility to casirivimab (K417E/N/R, Y453F, L455F, E484K, F486V and Q493K)
or imdevimab (K444N/Q/T and V445A). Each viral variant showing reduced
susceptibility to one mAb remained susceptible to the other mAb; all identified
variants retained susceptibility to the combination. In a separate experiment,
neutralization assays were performed with VSV pseudotyped with 39 variants of
the S protein identified in circulating SARS-CoV-2. The G476S, S494P and Q409E
variants had reduced susceptibility (5-fold, 5-fold, and 4-fold, respectively)
to casirivimab, and the N439K variant had reduced susceptibility (463-fold) to
imdevimab. The casirivimab and imdevimab combination was active against all
individual variants tested. It has been reported that the combination of
mutants at residues 417 and 439 may abrogate the effectiveness of the
casirivimab and imdevimab combination [13]. In the casirivimab and imdevimab
RCT NCT04425629, interim data indicated only one variant (G446V) detected in
4.5% of participants at an allele fraction of 15% or greater. However, not all
variants must be considered clinically relevant mutations associated with
resistance to treatment. During the Ebola outbreak in 2018, a genomic
assessment of 48 viral genomes determined that this outbreak was due to a
distinct viral variant. The sequence information allowed researchers to
evaluate the relevance of the distinct mutations to the available vaccine and therapeutics
and to conclude that the neutralizing antibodies MAb114 and ZMapp would likely
be effective against the currently circulating variant. A similar practice for
SARS-CoV-2 surveillance may be prudent to determine whether emergent S protein
variants pose a threat to the efficacy of neutralizing mAb therapies. Indeed,
three SARS-CoV-2 variants of particular interest have been identified and are
circulating globally. In the United Kingdom, a variant called ‘B.1.1.7’ with a
large number of mutations was identified in the autumn of 2020. In South
Africa, a variant called ‘B.1.351 was identified. Originally detected in early
October 2020, B.1.351 shares some mutations with B.1.1.7. In Brazil, a variant
called ‘P.1’ was identified that contains a set of additional mutations that
may affect its ability to be recognized by first-generation neutralizing mAbs
and by the immune responses generated by first-generation vaccines. Although
these variants have been detected in the United States, according to real-time
data accessed via the GISAID COVID-19 variant tracker82 these COVID-19 variants
do not currently represent a significant proportion of COVID-19 infections in
the United States, while recent California (B.1.427/B.1.429) and New York
(B.1.526) variants do. To date, the effect of these variants on the
neutralizing capacity of vaccines and mAbs is unknown. A recent preprint
suggests that the variants identified in the United Kingdom and South Africa
are more resistant to vaccine. Bamlanivimab and imdevimab maintain full
neutralization activity against the primary SARS-CoV-2 receptor-binding site
variants (69-70del and N501Y) implicated in the strain originating in the
United Kingdom, suggesting that these mAbs should maintain full activity
against the new strain originating in the United Kingdom. From what is known
about the strains that were first identified in South Africa, Brazil as well as
the ones in California and New York, it appears that some of the first
generation of antibody therapies may not be as effective and it will be
important for physicans to refer to the most up to date factsheet.
In
conclusion, monoclonal antibodies are, and will most likely continue to be,
important therapeutic options with potential utility in both prophylactic and
treatment setting, going into the 21st century, not just for SARS-CoV-2 but
also for other infectious pathogens too. Efforts should be directed towards
developing monoclonal antibodies that are highly effective, can be developed by
a fraction of a current cost, and for whom there is a specific beneficiary
group.