Articles

Efficacy and safety of zapnometinib in hospitalised adult

patients with COVID-19 (RESPIRE): a randomised, double-
blind, placebo-controlled, multicentre, proof-of-concept,
phase 2 trial
Gernot Rohde,a Stephan Stenglein,b,∗ Hans Prozesky,c Ganesh Manudhane,d Oana Sandulescu,e Martin Bauer,b Tim Overend,b Winfried Koch,f
Dennis Neuschwander,g Oliver Planz,h Antoni Torres,i and Martin Witzenrathj
a
Goethe University Frankfurt, University Hospital, Medical Clinic I, Department of Respiratory Medicine, Frankfurt/Main, Germany
b
Atriva Therapeutics GmbH, Tübingen, Germany
c
Division of Infectious Diseases, Department of Medicine, Stellenbosch University and TREAD Research, Tygerberg Hospital, Cape Town,
South Africa
d
Seven Hills Hospital, Mumbai, India
e
National Institute for Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest, Carol Davila University of Medicine and Pharmacy,
Bucharest, Romania
f
BDS Koch, Schwetzingen, Germany
g
Department of Biostatistics, GCP-Service International Ltd. & Co. KG, Bremen, Germany
h
Eberhard Karls University, Tübingen, Germany
i
Hospital Clinic i Provincial de Barcelona, Barcelona, Spain, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Catalan
Institution for Research and Advanced Studies (ICREA), Biomedical Research Networking Centers in Respiratory Diseases (CIBERES),
University of Barcelona, Barcelona, Spain
j
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité - Universitätsmedizin Berlin, Berlin, Germany,
German Center for Lung Research (DZL), Berlin, Germany

Summary eClinicalMedicine
2023;65: 102237
Background Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with
immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in Published Online 4 October
2023
patients with COVID-19. https://doi.org/10.
1016/j.eclinm.2023.
Methods In this randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial, we 102237
recruited hospitalised adults with moderate or severe COVID-19 from 18 hospitals in Germany, India, Romania,
South Africa, and Spain. Those requiring ICU admission or ventilator support at screening or randomisation
were excluded. Patients were randomly assigned (1:1) to receive oral zapnometinib (900 mg on Day 1; 600 mg on
Days 2–6) or matching placebo, on top of standard of care. Randomisation, stratified by baseline clinical severity
status (CSS 3 or 4, measured on a 7-point ordinal scale), was done using Interactive Response Technology.
Patients, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was CSS at
Day 15 and was conducted on the full analysis set (FAS: all patients who were randomised to the study, received
at least one dose of study medication and had at least one post-dose assessment of CSS, as randomised). Safety
analyses were conducted on the safety analysis set (all study participants who received at least one dose of study
medication, as treated). This study is registered at ClinicalTrials.gov (NCT04776044) and EudraCT (2020-004206-59).

Findings The trial was terminated early as the emergence of the Omicron variant impacted recruitment. Between
12th April 2021 and 9th August 2022, 104 of the planned 220 patients were enrolled and randomly assigned, 103
were treated, and 101 were included in the FAS (zapnometinib: n = 50; placebo: n = 51). The primary outcome
was not significantly different between the two groups, but patients on zapnometinib had higher odds of
improved CSS versus placebo (odds ratio [OR] 1.54 [95% CI 0.72–3.33]; p = 0.26). Predefined subgroup analyses
identified trends for improved CSS in patients with severe disease at baseline (OR 2.57 [0.76–8.88]; p = 0.13) and
non-Omicron variants (OR 2.36 [0.85–6.71]; p = 0.10); the p value of the CSS subgroup by Treatment interaction
term in the model was p = 0.28. The frequency and intensity of adverse events was low and similar between arms.
Twenty (39.2%) patients treated with zapnometinib experienced adverse events compared with eighteen (34.6%)

*Corresponding author. Atriva Therapeutics GmbH, Eisenbahnstr. 1, Tübingen 72072, Germany.

E-mail address: [email protected] (S. Stenglein).

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patients treated with placebo. One patient receiving zapnometinib and two patients receiving placebo died during
the study. None of the deaths were considered related to study medication.

Interpretation These results provide proof-of-concept for the innovative approach of targeting the Raf/MEK/ERK
pathway in patients with hospitalised moderate/severe COVID-19. Further clinical studies will be required to
evaluate the clinical benefit of zapnometinib in this and other indications.

Funding Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.

Copyright © 2023 Atriva Therapeutics GmbH, Martinsried, Germany. Published by Elsevier Ltd. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: COVID-19; Anti-viral; Immunomodulator

Research in context
Evidence before this study both inhibit viral replication and prevent a hyperinflammatory
We searched PubMed up to March 2022, for English-language immune response disease pathway. The dual effect of
articles on phase 2 randomised clinical trials and meta- zapnometinib is a promising and innovative therapeutic
analyses regarding the use of MEK inhibitors in the treatment principle to be evaluated in future clinical trials in severe
of moderate/severe COVID-19. We searched using the terms respiratory disease, including seasonal influenza.
“COVID-19”, “SARS-CoV-2 infection”, “MEK inhibitors”,
Implications of all the available evidence
“trametinib”, “cobimetinib”, “selumetinib”, “phase 2”,
With the availability of effective vaccines for COVID-19 and
“randomised”. This search revealed no evidence for the use of
the increasing prevalence of variants of lower pathogenicity
zapnometinib or other MEK inhibitors in the treatment of
such as Omicron, the numbers of patients with COVID-19
moderate/severe COVID-19.
requiring hospitalisation are currently considerably lower than
Added value of this study was seen at the height of the pandemic. With this positive
Data obtained from the RESPIRE study indicate the potential outlook, it is important not to lose sight of the fact that a
of the oral MEK-inhibitor zapnometinib as a safe short-term considerable number of COVID-19 patients still end up
treatment option for hospitalised patients with moderate/ requiring hospital treatment. It also remains possible that
severe COVID-19. Data indicate that patients treated with SARS-CoV-2 variants of concern with increased pathogenicity
zapnometinib have a higher probability (odds ratio) of and immune signatures conferring resistance to vaccines may
improved clinical severity status (CSS) than patients treated yet emerge. Zapnometinib with its mechanism of action
with placebo. The safety profile of zapnometinib was found to agnostic to variant type therefore remains relevant in the
be similar to placebo. These data must be put in the context development of the armamentarium for the treatment of
of the study being terminated early and therefore COVID-19 and is therefore a strong candidate for further
underpowered due to the emergence of the omicron variant clinical development.
of COVID-19 leading to a significant reduction in the number Since MEK inhibition has the potential to target multiple RNA
of COVID-19 patients being hospitalized. While several agents virus types beyond SARS-CoV-2 e.g., influenza and respiratory
have demonstrated clinical value in patients with moderate/ syncytial virus (RSV) this further underlines zapnometinib as
severe COVID-19, and are now included in treatment being a potential candidate for development as a broad-
guidelines, therapeutic options are still limited. The principle spectrum therapeutic to treat patients with moderate/severe
of inhibiting the Raf/MEK/ERK pathway with non-ATP- viral respiratory infections.
competitive drugs like zapnometinib offers the potential to

Introduction vaccination programmes introduced. The high levels of

The rapid emergence of SARS-CoV-2 and global spread morbidity and mortality in the early days of the COVID-
of COVID-19 highlighted the need for broad-acting 19 pandemic, coupled with the lack of treatment op-
therapeutics that are effective against severe viral dis- tions, highlight the pressing need for broad-acting
eases. At the onset of the COVID-19 pandemic there agents to treat moderate/severe viral respiratory
were no effective treatments available. Initial therapeutic infections.
attempts involved repurposing existing agents such as Zapnometinib (ATR-002) is a highly specific small-
antivirals (e.g., remdesivir) and immunomodulators molecule inhibitor of MEK1 and MEK2 (both protein
(e.g., corticosteroids).1–3 Over time, specific therapies kinases and members of the Ras/Raf/MEK/ERK sig-
targeting SARS-CoV-2 were developed and effective nalling cascade). MEK inhibition by zapnometinib

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offers a dual effect: immunomodulation and antiviral 18 hospitals in Germany, India, Romania, South Africa,
activity. Zapnometinib has been shown to abate the pro- and Spain (17 hospitals provided randomised patients).
inflammatory cytokine response to viral infection The protocol was approved by the respective regulatory
in vitro and in vivo, and thus may prevent a “cytokine authorities and by the Ethics Committees concerned and
storm”, the hyperinflammatory immune response that is available online in the Supplementary Material. The
can be triggered by particular viral infections.4,5 In pa- trial was registered (ClinicalTrials.gov: NCT04776044/
tients with COVID-19, the cytokine storm is associated EudraCT: 2020-004206-59), was conducted in accordance
with COVID-19 severity and has been described as a with the principles of the Declaration of Helsinki and
significant cause of COVID-19-related death.6,7 This Good Clinical Practice and adhered to the CONSORT
host-targeting effect may mitigate overactive inflamma- reporting guidelines.
tory responses, such as those leading to acute respira-
tory distress syndrome in patients who are severely ill Patients
with COVID-19 or influenza.4,6 Patients aged ≥18 years with a laboratory-confirmed
In addition to immunomodulation of the host diagnosis of SARS-CoV-2 infection presenting as
response, zapnometinib has antiviral activity. Activation COVID-19 requiring hospitalisation were eligible. All
of the MEK pathway is essential for replication of many patients had a clinical severity status (CSS) of either 3
RNA viruses including influenza viruses, hantaviruses, (hospitalised, not requiring supplemental oxygen) or 4
respiratory syncytial virus (RSV), and coronaviruses.8,9 (hospitalised, requiring supplemental oxygen). Patients
Inhibition of the MEK pathway has been shown to with a rapidly worsening clinical condition, or those
reduce virus propagation in vitro and in vivo.4,8,10,11 The requiring ICU admission or ventilator support at
antiviral activity of zapnometinib was primarily estab- screening or at randomisation, were excluded. Other
lished in influenza virus infection models, where it exclusion criteria included suspected infection other
demonstrated broad antiviral activity against different than SARS-CoV-2; history of malignant disease, auto-
influenza virus strains, including strains resistant to immune disease, or severe liver, kidney, blood, cardiac,
other antivirals such as baloxavir marboxil.11,12 Inhibition pulmonary, neurological, or endocrine disease; or un-
of MEK1/2 by zapnometinib or other MEK-inhibitors controlled hypertension. Full eligibility criteria are
blocks the formation of functional influenza virus par- included in the protocol (see Supplementary Materials).
ticles in the host cell, ultimately reducing the viral load All patients provided written informed consent prior to
in mice.10,11 Zapnometinib has also been shown to enrolment.
inhibit MEK1/2 in SARS-CoV-2 infected cells and
significantly reduce virus production.4 To date, the Randomisation and masking
antiviral activity of zapnometinib has been demon- Eligible patients were randomly assigned (1:1) to receive
strated in influenza virus, hantavirus, RSV, SARS-CoV-2 zapnometinib or placebo using interactive response
and other coronaviruses, Borna disease virus, dengue technology (IRT). The randomisation list and allocation
virus, and human metapneumovirus4,10,11 (and Atriva list were provided by a statistician not involved in the
Therapeutics unpublished data). analyses. Patients, investigators, the study team, and the
At the time of the onset of the COVID-19 pandemic, Sponsor remained blinded to treatment allocation
zapnometinib was under investigation as a novel treat- throughout the study. Only the statistician and labora-
ment option for severe influenza. The immunomodula- tory conducting pharmacokinetic analyses had access to
tory properties of zapnometinib and its broad-acting allocation information. Randomisation was stratified by
antiviral activity, combined with preclinical data showing trial site and by CSS at baseline (3 or 4) within trial sites.
that zapnometinib effectively inhibits SARS-CoV-2, sug-
gested that zapnometinib may be an effective treatment Procedures
for patients with COVID-19. Consequently, the RESPIRE Patients received 900 mg (6 tablets) of zapnometinib
trial was initiated to investigate the safety and efficacy of orally on Day 1 followed by 600 mg (4 tablets) once daily
zapnometinib as a treatment for hospitalised patients on Days 2–6, or matching placebo tablets (matched for
with COVID-19. Here we report the findings of this size, colour, and general appearance). No dose modifi-
proof-of-concept trial. cations were permitted. All other care and medication of
the patients was at the investigator’s discretion as per
local standards of care, and could include remdesivir,
Materials and methods dexamethasone, and other therapies as deemed appro-
Study design priate (including approved treatments and those used
RESPIRE was a randomised, double-blind, placebo- off-label). Certain medications known to be metabolised
controlled, proof-of-concept, multi-centre, phase 2 clinical by CYP2C8 and CYP2C9 were prohibited, based on
trial that assessed the safety and efficacy of zapnometinib in vitro data showing that zapnometinib inhibits these
in addition to standard of care for the treatment of adult enzymes at clinically relevant levels of exposure (Atriva
patients hospitalised with COVID-19. It was conducted at Therapeutics, unpublished data on file).

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Patients were assessed up to Day 15 and again on across the 7 categories in the placebo arm at Day 15 was
Days 21, 30, and 90 for CSS, adverse events (AEs), and derived from publications available at the time of study
concomitant medication use. Patient-reported degree of planning. Day 15 was chosen because it was assumed
dyspnoea and vital signs (including Glasgow Coma Scale that the distinction between less and more severe
for level of consciousness) were evaluated daily on Days courses of COVID-19 would have occurred for most
1–15, 21, and 30, and laboratory values on Days 1, 3, 5, 8, patients at this day. To discover a treatment effect on the
11, 15, and 30. Vital signs were evaluated three times 7-point CSS scale quantified by an odds ratio (OR) of
daily on Days 1–7. Assessments on Days 9, 10, and 12–14 2.18 with 85% statistical power using ordinal logistic
were only required if the patient remained hospitalised. regression analysis, 99 evaluable patients were required
CSS was determined using a 7-point ordinal scale for each treatment arm (alpha = 0.05, two-sided). The
(based on the 8-point ordinal scale recommended by the assumed OR of 2.18 for sample size estimation was
World Health Organization [WHO] for measuring accepted as a clinically relevant effect size in pre-trial
illness severity over time in patients with COVID-19).13 discussions with regulatory bodies and ethics
Severity scores were determined at each time point committees.
and ranged from [1] (not hospitalised, no limitations of
activities) to [7] (death). Patient-reported degree of Analysis sets
dyspnoea was measured on a 7-point Likert scale The statistical analyses were conducted according to a
(grading change in current breathing from baseline modified intent-to-treat principle. The Safety Analysis
ranging from markedly worse to markedly better) and a Set (SAS) was used for all safety analyses and comprised
visual analogue scale (from 0 = no shortness of breath at all randomised patients who received at least one dose of
all to 100 = maximum shortness of breath). investigational medicinal product (IMP); all safety ana-
Imaging data results, laboratory data, and use of lyses were conducted as treated. The Full Analysis Set
standard of care treatment (including the need for (FAS) was used for efficacy analyses and included all
supplemental oxygen, ventilator support [invasive, non- patients from the SAS who had at least one post-baseline
invasive, high flow], renal replacement therapy [RRT], assessment of CSS (the primary endpoint). The Per
vasopressor treatment, and use of extracorporeal mem- Protocol Set (PPS) comprised all patients of the FAS
brane oxygenation [ECMO]) were also recorded who followed the study protocol without major protocol
throughout the study period. Nasopharyngeal swabs and violations. All efficacy analyses were conducted as
sputum, and blood and plasma samples, were collected randomised; some analyses of the primary endpoint
for exploratory analysis of SARS-CoV-2 viral load and were additionally conducted as treated.
biomarkers of immune response, respectively. These The study used stratified randomisation by baseline
data will be reported separately. CSS and site. According to EMA Guidelines on inves-
tigation of subgroups in confirmatory clinical trials
(Final Version 2019)14 subgroup analyses by baseline
Outcomes CSS 3 and 4 for the primary and key secondary end-
The primary objective of the trial was to demonstrate the points were conducted.
efficacy of zapnometinib versus placebo, on top of
standard of care, based on the CSS at Day 15 (primary Statistical analysis of the primary endpoint
endpoint). The key secondary endpoint was the time The null hypothesis of no shift across the seven ordered
from randomisation to discharge from hospital. Other categories of the CSS scale at Day 15 when comparing
secondary endpoints comprised the time to discharge the two treatment groups was tested using logistic
from hospital or to score of ≤2 maintained for 24 h in regression analysis for ordered categorical data. A pro-
National Early Warning Score 2 (NEWS2), whichever portional odds model with cumulative logit link was
occurred first; time to resolution of fever [defined as used. The CSS at baseline (3 or 4, categorical) and the
≤36.6 ◦ C (axilla), ≤37.2 ◦ C (oral) or ≤37.8 ◦ C (rectal or 4C Mortality Score for COVID-1915 were included into
tympanic) for at least 24 h without antipyretics for 24 h]; the model as covariates. For subgroup analyses, this
time to SpO2 >94% on room air maintained for 24 h; model was extended with the subgroup terms (if not
CSS over the hospital period calculated as the area un- already included) and a subgroup by treatment interac-
der the curve from the 7-point ordinal scale at Days 3, 5, tion term. The treatment effect was estimated as the
8, 11, 15, and 30, survival time up to Day 30, and time to (proportional) OR of zapnometinib versus placebo with
event/AUC analyses of the various endpoints (see a two-sided 95% profile likelihood confidence interval
Supplementary Materials). (CI). The validity of the proportional odds assumption
was investigated and confirmed for all primary and key-
Statistical analyses secondary FAS based and subgroup analyses at study
Sample size estimation Day 15; violations of the proportional odds assumption
The sample size estimation was based on the primary were found for the Omicron subgroup, CSS analysis
endpoint (CSS at Day 15). The distribution of CSS and for a worst CSS subgroup analysis. Baseline CSS 3

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and CSS 4 as well as virus variant were pre-planned for the data and all authors approved the final manuscript
subgroup analyses; baseline CSS was considered as for submission.
mandatory because it was implemented in stratified
randomisation. Results of overall and subgroup analyses
were presented in addition as forest plots. Results
Recruitment to RESPIRE began in April 2021 and it was
Statistical analysis of the key-secondary endpoint planned to randomise 220 patients. In February 2022
The time to discharge from hospital was analysed it was observed that enrolment into the trial had
using the Cox proportional hazards model including decelerated. This was due to recruitment challenges
treatment and clinical severity status at baseline as arising from the lower frequency of hospitalisations for
covariates and 4C Mortality Score as stratum instead COVID-19 as a result of the propagation of vaccination
of covariate because of questionable proportional programmes and the increasing prevalence of the less
hazard assumption. The model provided hazard ratios severe Omicron variant.16,17 The Sponsor decided to
with 95% profile likelihood CIs. As a hazard ratio of >1 conduct an unplanned interim analysis which occurred
is beneficial for time to discharge, the term rate ratio in May 2022. At this analysis, the independent data
was used instead of hazard ratio. Subgroup analyses monitoring committee (iDMC) reviewed unblinded data
were planned and conducted as for the primary from 104 recruited patients. Following the meeting, the
endpoint. iDMC recommended that the trial should continue as
designed; however, the Sponsor decided to terminate
Handling of missing values the trial early, while blinded to the study findings, due to
Missing CSS values were primarily imputed by logical the unfavourable recruitment outlook. Early termination
rules such as last observation carried forward for visits of the trial reduced the planned statistical power
missed as result of premature discontinuation if the last considerably; therefore, statistically significant results
known CSS value of the patient was 1 (i.e., not hospi- could not be expected, however clinical relevance of
talised, no limitations of activities). If a missing CSS estimated trends in favour of zapnometinib was never-
value could not be replaced by one of these logical rules, theless observed.
imputation was done using an ordinal generalised linear As of the date of the database lock following study
mixed model with treatment group, visit, the treatment- termination (12 July 2022), 104 patients had been
by-visit interaction, baseline clinical severity status, and enrolled and randomised. Of these, 103 patients had
4C Mortality Score for COVID-19 as fixed effects, and been treated and comprised the SAS (zapnometinib
with study participant as random effect (longitudinal [n = 51]; placebo [n = 52]; Fig. 1). The FAS included 101
modelling). patients (zapnometinib [n = 50]; placebo [n = 51]). Two
Deaths and other competing events in Cox Propor- treated patients were excluded from the FAS: one pa-
tional hazards modelling were taken into account by tient from the zapnometinib arm had no post-baseline
censoring at the end of the observation period (i.e., value of CSS recorded, and one patient from the pla-
study Day 30). cebo arm was excluded due to major protocol deviation.
Missing covariate values were imputed based on Based on pharmacokinetic data, it was detected that four
prediction from correlated variables using linear patients received the wrong treatment due to a labelling
regression. error (two patients planned to receive placebo were
treated with zapnometinib and two patients planned to
General receive zapnometinib were treated with placebo). To
Statistical tests of the endpoints were planned to be investigate the impact of this error on the primary
done two-sided on an alpha level of 0.05; as the planned endpoint an “as treated” analysis was conducted with
sample size was not reached, p values were interpreted the full analysis set.
in the sense of exploratory data analyses. All statistical The median age of the patients was 56.0 years (IQR
analyses were conducted using SAS version 9.4 (SAS 43.0–69.0 years; Table 1). There was a slight difference
Institute Inc). in the distribution of sex between arms; a higher pro-
portion of patients in the zapnometinib arm were male,
Role of the funding source whereas the placebo arm contained an equal ratio of
The Sponsor/funders (Atriva Therapeutics) were men to women. Baseline CSS was well balanced be-
involved in the trial design, trial management, data tween arms: 40.0% of patients had a CSS score of 4
collection, data analysis, data interpretation, and report (hospitalised, requiring supplemental oxygen) in the
writing. The Federal Ministry of Education and zapnometinib arm and 41.2% of patients in the placebo
Research, Germany (Bundesministerium für Bildung arm. The distribution of Omicron versus non-Omicron
und Forschung; BMBF) had no role in study design, variants was also balanced between arms. None of the
data collection, data analysis, data interpretation, or patients were vaccinated against SARS-CoV-2 before or
writing of the report. All authors had full access to all during their participation in the study. There were no

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Fig. 1: CONSORT flow diagram. a Two patients randomised to the zapnometinib arm received placebo, two patients randomised to the placebo
arm received zapnometinib. The assignment of these patients to treatment groups depends on the analysis sets, namely, as treated for the SAS
but as randomised for the FAS. b Patient excluded from FAS as the PCR test for confirmation of COVID-19 infection was not done. c Includes
patients who died during the trial (zapnometinib arm: n = 1; placebo arm: n = 2). BL, baseline; FAS, full analysis set; LTFU, lost to follow-up; PK,
pharmacokinetic; PPS, per protocol set; SAS, safety analysis set.

notable differences between treatment arms in medical zapnometinib arm and 97.9% in the placebo arm. Mean
history, concomitant diseases, or prior medication use duration of treatment was 5.8 (±0.7) and 5.7 (±1.0) days,
(Table 1). respectively. Fourteen patients discontinued the trial
Treatment adherence was high in both arms: The early (seven in each arm), mainly due to withdrawal of
mean proportion of tablets taken was 97.8% in the consent (Fig. 1).

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Zapnometinib arm (n = 50) Placebo arm (n = 51) Total (n = 101)

Sex, n (%)
Female 17 (34.0) 26 (51.0) 43 (42.6)
Male 33 (66.0) 25 (49.0) 58 (57.4)
Age, years
Mean (SD) 54.1 (18.6) 56.8 (15.6) 55.4 (17.1)
Median (IQR) 54.5 (38.0–70.0) 57.0 (44.0–68.0) 56.0 (43.0–69.0)
Race, n (%)
Asian 21 (42.0) 22 (43.1) 43 (42.6)
Black/African American 3 (6.0) 2 (3.9) 5 (5.0)
White 26 (52.0) 27 (52.9) 53 (52.5)
CSS, n (%)
3 (hospitalised, not requiring supplemental oxygen) 30 (60.0) 30 (58.8) 60 (59.4)
4 (hospitalised, requiring supplemental oxygen) 20 (40.0) 21 (41.2) 41 (40.6)
SARS-CoV-2 variant
Non-Omicron 27 (54.0) 29 (56.9) 56 (55.4)
Omicron 23 (46.0) 22 (43.1) 45 (44.6)
Median time since hospitalisation, days (IQR) 2.0 (2.0–3.0) 2.0 (2.0–3.0) 2.0 (2.0–3.0)
Median time since onset of symptoms, days (IQR) 7.0 (4.0–10.0) 7.0 (5.0–10.0) 7.0 (5.0–10.0)
COVID-19 symptoms, n (%)
Cough 46 (92.0) 48 (94.1) 94 (93.1)
Dyspnoea 28 (56.0) 33 (64.7) 61 (60.4)
Fever 41 (82.0) 36 (70.6) 77 (76.2)
4C Mortality score
Median (IQR) 5.0 (2.0–8.0) 5.0 (2.0–8.0) 5.0 (2.0–8.0)
<9 points, n (%) 41 (82.0) 40 (78.4) 81 (80.2)
≥9 points, n (%) 9 (18.0) 11 (21.6) 20 (19.8)

Note: the majority of patients received systemic steroids as local SOC and per investigator discretion (not prespecified in study protocol). CSS, clinical severity status; FAS,
full analysis set; IQR, interquartile range; SD, standard deviation.

Table 1: Baseline demographics and disease characteristics (FAS).

On Day 15, the OR for an improved CSS score with reduction was observed with zapnometinib versus pla-
zapnometinib versus placebo (primary endpoint) was cebo among patients with a CSS of 4 at baseline. The
1.54 (95% CI: 0.72–3.33; p = 0.26; Fig. 2) in the pre- median time to discharge from hospital was 8.5 days
planned analysis, as randomised. In the FAS-based as- (95% CI: 7.0–12.0) for patients treated with zapnometinib
treated analysis, the estimated OR was 1.76 (95% CI compared with 10.0 days (95% CI: 8.0–15.0) for patients
0.82–3.81, p = 0.15). Data were similar in the PPS as treated with placebo (rate ratio 1.59 [95% CI 0.73–3.57];
randomised (OR 1.45 [95% CI 0.67–3.17]; p = 0.35). In a p = 0.25; Fig. 3), equivalent to ∼1.5 days shorter. In the
pre-defined subgroup analysis, a trend for improvement overall population, the rate ratio was only moderately
in CSS with zapnometinib versus placebo was observed different between arms (1.31 [95% CI: 0.81–2.13];
for patients with more severe disease (CSS 4) at baseline p = 0.27; Fig. 3). The p value of the CSS subgroup by
(OR 2.57 [95% CI 0.76–8.88]; p = 0.13). The p value of Treatment interaction term was p = 0.53.
the CSS subgroup by Treatment interaction term in the The results of other secondary endpoints evaluated
model was p = 0.28. For the as-treated analysis, ORs of in this study generally demonstrated benefits of zap-
1.37 (95% CI 0.51–3.70; p = 0.53) and 2.56 (95% CI nometinib over placebo. These findings also supported
0.76–8.87; p = 0.13) were estimated for the patients with the observation of a greater clinical benefit being
CSS 3 or CSS 4 at baseline, respectively. observed in patients with more severe disease (CSS 4),
There was also a trend for higher efficacy of zapno- consistent with the subgroup analyses conducted on
metinib in patients with non-Omicron variants the primary endpoint discussed above (Supplementary
compared to Omicron SARS-CoV-2 (OR 2.36 [95% CI Tables S1–S13).
0.85–6.71]; p = 0.10). The p value of the interaction term There was no apparent difference in the use of
was p = 0.25. concomitant medications between study arms. Systemic
For the key secondary endpoint (the time from ran- corticosteroids were used by 29 (56.9%) and 32 (61.5%)
domisation to hospital discharge), a trend to greater patients in the zapnometinib arm and placebo arm,

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Fig. 2: Forest plot of odds ratios for clinical severity status at Day 15, overall and in subgroups (FAS). CI, confidence interval; CSS, clinical severity
status; PPS, per protocol set.

Fig. 3: Forest plot of rate ratios for time to hospital discharge, overall and in subgroups (FAS). CI, confidence interval; CSS, clinical severity status;
PPS, per protocol set.

respectively, and direct acting antivirals by 26 (51.0%) (49.0%) patients in the placebo arm were treated with
and 23 (44.2%), respectively. Overall, 26/49 (53.1%) dexamethasone, remdesivir, baricitinib or tocilizumab
evaluable patients in the zapnometinib arm and 25/51 during the study.

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Protocol deviations and all were judged by the investigators to be unrelated

Major protocol deviations were identified in three (5.9%) to study drug.
of patients treated with zapnometinib and six (11.3%) of
patients treated with placebo. The majority of these de-
viations reflected enrolment of patients who did not Discussion
satisfy the study inclusion/exclusion criteria. Patients The data presented here suggest the potential clinical
with major protocol deviations were excluded from the benefit of zapnometinib as a treatment for COVID-19,
per protocol population. particularly in hospitalised patients requiring supple-
mental oxygen. A clinically relevant trend for improve-
Safety and tolerability ment was observed for the primary endpoint of CSS at
The frequency of AEs was low and similar between Day 15. In patients with more severe disease activity, an
arms (Table 2). Increased alanine aminotransferase OR exceeding 2 was observed. The effect on the key
and diarrhoea were the most common treatment- secondary endpoint was also stronger in patients with
emergent AEs (TEAEs), albeit at low frequencies in more severe disease at baseline. Consistent with this,
both arms. Overall, no apparent effect on parameters of zapnometinib was shown to be more efficacious in pa-
liver function was seen in either arm. Most TEAEs tients infected with non-Omicron variants of SARS-
were mild or moderate in intensity; 7/103 (6.8%) pa- CoV-2, which typically lead to more severe disease
tients experienced a severe event, more frequently in compared to the Omicron variant.18 While these treat-
the placebo arm (5/52 [9.6%] versus 2/51 [3.9%] in the ment differences were not statistically significant, most
zapnometinib arm). The only severe TEAE to occur in likely due to the small sample size caused by the early
more than 5% of patients in either arm was severe termination of the trial, they do indicate a possible
dyspnoea (reported only in the placebo arm [3/52 clinical benefit of zapnometinib. Also, the p values of
[5.8%]). No serious TEAEs were reported in more than the interaction terms of the three models discussed
5% of patients in either arm. Three patients died dur- above were all p > 0.2 which was expected because of the
ing the trial (two in the placebo arm [one due to small sample sizes of the subgroups: baseline CSS 3 and
cardiorespiratory arrest and one due to acute respira- CSS 4. Our conclusion of a better zapnometinib treat-
tory failure] and one in the zapnometinib arm [due to ment effect in more severe patients is mainly based on
respiratory arrest]). All deaths occurred before Day 30, the size of the effect estimates in the CSS 4 subgroup of

n, % Zapnometinib arm (n = 51) Placebo arm (n = 52) Total (n = 103)

Any TEAEs 20 (39.2) 18 (34.6) 38 (36.9)
TEAEs occurring in >5% of either arm
ALT increased 3 (5.9) 1 (1.9) 4 (3.9)
Diarrhoea 4 (7.8) 3 (5.8) 7 (6.8)
Dyspnoea 1 (2.0) 3 (5.8) 4 (3.9)
Cough 0 3 (5.8) 3 (2.9)
Headache 0 3 (5.8) 3 (2.9)
Any severe TEAE 2 (3.9) 5 (9.6) 7 (6.8)
Severe TEAEs occurring in >5% of either arm
Dyspnoea 0 3 (5.8) 3 (2.9)
Any serious TEAE 3 (5.9) 4 (7.7) 7 (6.8)
Serious TEAEs occurring in >5% of either arm
None 0 0 0
Any TEAE leading to discontinuation of IMP 1 (2.0) 0 1 (1.0)
Any TEAE leading to withdrawal from trial 1 (2.0) 2 (3.8) 3 (2.9)
Any ADR 11 (21.6) 8 (15.4) 19 (18.4)
ADRs occurring in >5% of either am
ALT increased 3 (5.9) 1 (1.9) 4 (3.9)
Diarrhoea 3 (5.9) 1 (1.9) 4 (3.9)
Any severe ADR 1 (2.0) 0 1 (1.0)
Any serious ADR 2 (3.9) 0 2 (1.9)
Death 1 (2.0) 2 (3.8) 3 (2.9)

ADR, adverse drug reaction (an AE judged to be at least possibly related to zapnometinib or placebo); ALT, alanine aminotransferase; SAS, safety analysis set; (TE)AE,
(treatment-emergent) adverse event.

Table 2: Summary of safety data (SAS).

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the primary and key secondary analyses and their in- immunological markers and viral load may shed light
crease compared to the CSS 3 subgroup. These are the on the relative contribution of the dual benefit of MEK
first clinical data for zapnometinib as treatment for pa- inhibition (immunomodulation and inhibition of viral
tients with any type of viral infection. replication) on the clinical efficacy of zapnometinib.
The RESPIRE study was well designed to demonstrate A limitation of the RESPIRE trial was the small
proof-of-concept of zapnometinib treatment. The study sample size due to the early termination of the study:
primary endpoint and key secondary endpoint are only 51 patients were treated with zapnometinib.
consistent with those used in other trials of treatments Furthermore, the population of patients in which the
for severe COVID-19.3,19 The primary endpoint was based largest signs of efficacy were observed (those with more
on the 8-point ordinal scale recommended by the WHO severe disease [CSS 4] at baseline) comprised approxi-
and widely used in COVID-19 trials.13 In the RESPIRE mately 40% of the study population. Thus, it is tempting
trial, two stages on this ordinal scale were combined to speculate that the trial may have been successful in
(“Intubation and mechanical ventilation” [6 points] and showing a statistically significant treatment effect with
“Ventilation + additional organ support – pressors, RRT, zapnometinib if more patients with severe disease had
ECMO” [7 points]) since patients with rapidly worsening been recruited. The RESPIRE trial was designed at the
clinical condition, or those requiring ICU admission or time the Alpha variant of SARS-CoV-2 was dominant,
ventilator support at screening or at randomisation, were but by the time the trial was terminated, Omicron was
excluded and these stages were only necessary to docu- prevalent and effective global vaccination programs had
ment deterioration. reduced the proportion of patients hospitalised with
Zapnometinib had a favourable safety profile more severe COVID-19.
that was like that seen in the placebo arm. The overall Background COVID-19 therapy was not specified by
incidence of TEAEs was low and the events that were the study protocol and was at the investigator’s discre-
reported were predominantly mild/moderate and non- tion as per local standards of care applicable at the time
serious in nature. We did not observe any significant the study was running. This design decision was
levels of class effects associated with MEK inhibition necessary to make the study acceptable from an ethical
(such as rash, inflammatory effects cardiovascular perspective, but did introduce some risk that differences
complications, and ocular effects20–23). This likely reflects in therapeutic approaches between sites and countries
the short duration of treatment in the RESPIRE trial, as could have impacted on study results; the small sample
these MEK class effects are typically observed with long- size did not permit a detailed evaluation of this study
term use in oncology indications. design limitation.
Zapnometinib acts by modulating the host immune A further limitation may be found in the statistical
response, in addition to its antiviral properties. There- approach adopted in the time-to-event analyses; for such
fore, the study protocol aimed to enrol patients that were analyses, including the key-secondary endpoint time to
pathogenetically at the transitional stage from declining hospital discharge, patients who died were censored at
viral replication to beginning immune derailment. The the end of the observation period. This is however
trial protocol did not mandate an exact day of symptom considered to be a minor methodological limitation in
onset for patient enrolment; the population happened to view of only three deaths occurring in the study.
be randomised in the second week post infection It is important to note that none of the patients in the
(approximately between days 8–14). The goal was to RESPIRE study had received vaccination against
prevent further decline into a hyperinflammatory state COVID-19. At the time the RESPIRE study was in
of the immune system, translating into prevention of a development multiple COVID-19 vaccines have either
worsening of clinical symptoms. The overall mortality in been approved or were under Regulatory review.
the study was low compared to other trials in hospital- Despite the effectiveness of vaccination and the
ised patients with COVID-19. This reflected the intent of increasing prevalence of variants of SARS-CoV-2 with
the sponsor to focus on the above patient population, lower pathogenicity, a substantial number of patients
not on more severely affected patients, where the spe- with COVID-19 continue to require hospital treatment.
cific immunomodulatory intervention may have come While the RESPIRE study did not evaluate the effec-
too late to prevent the sepsis-like terminal disease tiveness of zapnometinib in patients who developed
pathway. In addition, to comply with expectations from severe COVID-19 despite vaccination, its indirect
regulatory authorities during the study protocol approval mechanism of action would lead to the expectation that
process, the Sponsor was required to exclude individuals it would continue to be effective in such patients.
with certain severe conditions from study participation, These results obtained support the further develop-
given pre-existing concerns on the safety profile of MEK- ment of zapnometinib as an innovative approach for
inhibitors used in other indications (e.g., oncology). targeting the intracellular Raf/MEK/ERK signalling
Analyses of biomarker data from RESPIRE are pathway in patients with hospitalised moderate/severe
ongoing and include analyses of pharmacodynamic data viral respiratory infections where the disease progress is
collected throughout the trial. The assessment of driven by an inflammatory process. A phase 2 trial

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(SURVIVE) is currently under development which will provide statistical support during the RESPIRE study. D.N. reports
include patients with severe disease caused by influ- payment, funded by Atriva Therapeutics, as an employee of the con-
tract research organisation that supported the RESPIRE study. O.P.
enza. Zapnometinib has several characteristics that
reports grants to his institution from the Federal Ministry of Educa-
favour its use as an agent of first-line defence in the face tion and Research, Germany (Bundesministerium für Bildung und
of future viral threats. The oral formulation is easy to Forschung; BMBF), personal fees for consulting from Atriva Thera-
administer. The production processes of the drug sub- peutics, receipt of equipment and materials to his institution from
stance as well as of the oral dosage formulation (tablets) Atriva Therapeutics and is a shareholder of Atriva Therapeutics. A.T.
reports consulting fees from Pfizer and Janssen, and payment/hono-
are straightforward and scalable. With its excellent sta- raria for lectures, presentations, speakers’ bureaus, manuscript
bility properties for both the drug substance and the writing or educational events, and participation in a Data Safety
drug product, zapnometinib is particularly suitable for Monitoring Board or Advisory Board, from Pfizer, Janssen, and Bio-
stockpiling. Importantly, as zapnometinib targets the merieux. M.W. reports grants from the Deutsche For-
schungsgemeinschaft, BMBF, Deutsche Gesellschaft für
host Raf/MEK/ERK pathway, there is a low risk of
Pneumologie, European Respiratory Society, Marie Curie Foundation,
inducing viral resistance, thus overcoming a limitation Else Kröner Fresenius Stiftung, Capnetz Stiftung, Bayer Health Care,
of many direct-acting antiviral agents used in a variety of Biotest, and Pantherna, consulting fees from Insmed, Pantherna,
viral infections.24–26 The activity of zapnometinib is un- Pherecydes, Aptarion, Glaxo Smith Kline, Inflarx, and Biotest, and
likely to be affected by variant changes, which have payment or honoraria for lectures, presentations, speakers’ bureaus,
manuscript writing or educational events from Astra Zeneca, Insmed,
resulted in regulatory authorities reversing their rec- Chiesi, Novartis, Teva, Actelion, Boehringer Ingelheim, Glaxo Smith
ommendations for most previously developed direct Kline, Biotest, Bayer Health Care. M.W. also holds relevant patents:
acting monoclonal antibodies against SARS-CoV-2.27–29 EPO 12181535.1: IL-27 for modulation of immune response in acute
In conclusion, the results of the RESPIRE trial pro- lung injury (2012), WO/2010/094491: Means for inhibiting the
expression of Ang-2 (2010), DE 102020116249.9: Camostat/Niclosa-
vide proof-of-concept for the innovative approach of
mide cotreatment in SARS-CoV-2 infected human lung cells (2020/
targeting the intracellular Raf/MEK/ERK signalling 21), and PCT/EP2021/075627: New medical use of cystic fibrosis
pathway in patients with COVID-19. These results also transmembrane conductance regulator (CFTR) modulators (2021).
suggest that zapnometinib may have a role in the
treatment of future variants of COVID-19 with the po- Acknowledgements
tential to cause severe illness in humans and possibly This study was funded by Atriva Therapeutics GmbH with support from
the Bundesministerium für Bildung und Forschung (Federal Ministry
other severe respiratory infections caused by RNA vi- of Education and Research, Germany; BMBF). The authors thank the
ruses. Further clinical studies will be required to participants and their families, and the staff at all the study sites. We
confirm these results in COVID-19 and other serious thank Jamie Ashman of Prism Ideas Ltd., for Editorial support in the
viral infections. preparation of this manuscript which was funded by Atriva Therapeutics
GmbH.
Contributors
Authors G.R., S.S., M.B., W.K., D.N., and M.W. conceived the study and Appendix A. Supplementary data
designed the study protocol. Authors G.R., H.P., G.M., O.S., A.T., and Supplementary data related to this article can be found at https://doi.
M.W. recruited and managed patients in the study and collected data. All org/10.1016/j.eclinm.2023.102237.
authors analysed and interpreted the data. Authors G.R., S.S., M.B.,
T.O., W.K., and M.W. prepared the first draft of the manuscript (based
on an outline drafted and agreed by all authors). O.P. and W.K. had full References
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