A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (Trial H5: MP0420)
Phase: PHASE3
Conditions: COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 A Multicenter, Adaptive, 
Randomized, Blinded Controlled 
Trial of the Safety and Efficacy of 
Investigational Therapeutics for 
Hospitalized Patients With 
COVID-19 (Trial H5: MP0420)
 Version 2.0 
09 April 2021
  NCT05780463

Appendix H5: MP0420 – version 2.0 (09 April 2021) 
The content of this appendix is confidential and should only be viewed 
by persons covered by the CDA entered between Molecular Partners/ 
Novartis and NIAID in relation to the TICO / ACTIV-3 study.   
This appendix provides detailed information pertaining to the study of this investigational 
agent. If not stated otherwise, the text in the master protocol gives the approach that will be 
taken to study this agent.    
H.5.1. Introduction and rationale for studying the agent
MP0420 (INN ensovibep) is a multi-valent DARPin® molecule (designed ankyrin repeat
protein), consisting of 5 DARPin® domains[1]. MP0420 simultaneously and specifically 
binds to 3 epitopes in the receptor-binding domain (RBD) of the SARS-CoV-2 spike 
protein with three different domains and two domains that bind to human serum albumin. 
This multi-valent binding leads to potent neutralization of SARS-CoV-2 in live virus 
assays, preventing subsequent viral entry into human cells and viral replication[1]. The
multi-valent, cooperative binding leads to extremely high potencies with affinity in the 
picomolar range and is expected to be effective against mutational escape. The two 
DARPin® domains which bind to human serum albumin (HSA) increase the half-life to 
that of a human antibody in the range of two-three weeks[2, 3]with no anticipated change
of DARPin® concentration even in case of significant variation of body weight or albumin 
levels. 
MP0420 is produced in E.coli-based fermentation, which decreases cost and complexity 
compared to antibody production. DARPin® molecules, including MP0420, do not 
require glycosylation or extensive post-translational modification by producer cells, 
making simple, highly scalable bacterial fermentation feasible[4]. No ingredients of
animal origin are used in the fermentation of MP0420. E.coli-based fermentation is also 
used extensively when manufacturing other proteins including Neulasta, Lantus, and 
Lucentis. 
Whereas one antiviral agent (remdesivir), a polymerase inhibitor, has been 
demonstrated to have clinical benefit in hospitalized patients with mild to moderate 
disease and is now part of standard-of-care (see Appendix I), treatment options for 
hospitalized COVID-19 patients are still limited. It is plausible that additional antiviral 
effects could be produced by the combination of MP0420 with remdesivir and hence, 
contribute to improvement in time to sustained recovery.  
Study MP0420-CP101, a Phase I, randomized, double blind, placebo-controlled, single 
ascending dose study of MP0420 in 24 (8 per cohort) healthy volunteers is underway. 
The first two dosing cohorts were completed (3 mg/kg, 9 mg/kg) at the end of 2020 with 
a third cohort of 20 mg/kg planned to commence in Q1 of 2021. The primary objectives 
include safety and tolerability and secondary objectives include characterization of 
pharmacokinetics and the development of anti-drug antibodies. Please refer to the 
I I 
I I 
I I I 
I I 

Investigator Brochure (IB) for preliminary safety and efficacy data from the first two 
cohorts (3 mg/Kg and 9 mg/Kg).  
 
H5.1.1 Potential benefits and risks from MP0420 
Potential benefits 
The potent antiviral activity of MP0420 has the potential to reduce the viral load of SARS-
CoV-2, which could translate into beneficial clinical effects. This statement is supported 
by preclinical studies summarized below. MP0420 demonstrated high affinity binding to 
its target, the RBD in the spike protein of SARS-CoV-2, with no observed off-target 
binding as measured in Retrogenix assay and GLP TCR study [5]. MP0420 has been 
shown to potently neutralize SARS-CoV-2 in live virus assays. In addition, several known 
spike mutations did not affect the antiviral activity of MP0420 in neutralization assays 
using VSVG-pseudotypes [5, 6]. MP0420 was shown to neutralize variants of the UK 
originated lineage B.1.1.7 (del69-70, del145, N501Y, A570D, D614G, P681H, T716I, 
S982A, D1118H) and the South African originated lineage B.1.351 (D80A, D215G, 
E484K, N501Y, A701V) as efficiently as the wild-type Wuhan virus with IC50 values in 
the low single-digit ng/mL range. MP0420 also gave potent protection against individual 
mutations reported in currently circulating SARS-CoV-2 strains: N501Y, E484K, K417E, 
Y453F, D614G, S477N, A222V, G446V, G476S, T478I, P479S, V483A, Q493K and 
F490S. 
   
Significant reduction in viral load and pathogenesis was observed in five studies 
conducted using two hamster models. MP0420 dose-dependently reduced virus titers in 
the lung, throat and nasal turbinates. Disease-related body weight loss was reduced and 
a protective effect on lung tissues was observed. Please refer to the IB for details [5].  
 
Potential risks 
Anticipated risks are predicted to be low based on preclinical data, clinical data from 
four other DARPin® molecules (highlighted below) and initial safety and PK data from a 
Phase 1 First in Human dose-escalation study support this prediction. The Study 
Review Committee from the Phase 1 study reported that the overall tolerability was 
acceptable in both of the first two cohorts with no Serious Adverse Events and 
permission was granted to enroll the third cohort.  The first two cohorts were comprised 
of 6 “active” plus 2 placebo subjects treated at 3 mg/kg and 9 mg/kg respectively via a 
single 1-hour i.v. infusion. The study outcomes remain blinded. One participant 
experienced mild ALT-elevation (less than 2x upper-limit of normal) in conjunction with 
an episode of likely unrelated diarrhea, a second reported a headache, and a third 
participant an erythema at the injection site which resolved on same day.  
 
Preliminary PK data from the 3 mg/kg and 9 mg/kg cohorts of MP0420-CP101 indicate 
a half-life of 2-3 weeks in humans, which is consistent with predictions based on 
studies in mice, rats, hamsters and cynomolgus monkeys in which the systemic half-
lives were close to the species’ serum albumin half-lives, reflecting the intended 
binding of MP0420 to serum albumin. Please refer to IB for details.  
 
MP0420 is designed not to interact with the human immune system and binds specifically 
to a foreign viral protein without homology to any human protein. The absence of off-
target binding to 5835 human cell surface and secreted proteins has been obtained with 

the Retrogenix binding platform. In addition, a Good Laboratory Practice (GLP) study to 
characterize cross-reactive binding of MP0420 to a panel of FDA- and EMA-
recommended normal human tissues found that there was no biologically relevant 
binding.  
 
GLP toxicology studies have not been performed as there is no relevant species for such 
studies:  sequence homology studies show no homology between the target bound with 
high specificity by MP0420 on the SARS-CoV-2 virus and any protein of the animal 
species used for GLP safety studies. Nevertheless, limited safety evaluations have been 
made in non-GLP studies in mice, rats and cynomolgus monkeys as well as in SARS-
CoV-2 infected hamsters and MP0420 was well-tolerated in all cases [5]. 
 
Clinical experience is available for four other DARPin® molecules. Abicipar, the first 
DARPin® used in humans, targets VEGF-A and is in late-stage development as a 
treatment by intravitreal injection for age-related macular degeneration[7].  No signal for 
systemic safety concerns was identified in a Phase 3 program where 1258 patients were 
treated with abicipar over 52 weeks. There was an initial high incidence of local 
inflammatory reactions, addressed by improving the purification process. 
 
Three other DARPin® molecules are being developed and have been administered 
intravenously in Phase 1-2 studies to more than 100 cancer patients. Those three 
molecules are identified as MP0250 (which targets VEGF and HGF), MP0274 (which 
targets two HER2 domains) and MP0310 (which targets 4-1BB activation with tumor 
targeting and tumor-localized activation via FAP-binding). For those three molecules, the 
safety profiles in the individual studies pointed to general side-effects as expected from 
other biologics or any “foreign protein” medication, i.e. occurrence of infusion related 
reactions (IRRs). The nature and onset time of IRRs was compound-specific, with 
frequent IRRs at the first infusion observed with MP0274, IRRs typically starting at the 
2nd or 3rd infusion with MP0310 (where occasional IRRs also reported at first infusion), 
and only very infrequent IRRs with MP0250. All IRR events were manageable with 
routine intervention, using antihistamines, NSAIDs and occasionally, corticosteroids. 
Otherwise, the safety profile was driven by the target-related effects rather than the 
DARPin® nature of the compounds. The anti-VEGF MP0250 was associated with a high 
incidence of hypertension and proteinuria, while no treatment-emergent hypertension or 
proteinuria were observed with MP0274 or MP0310, indicating that the events observed 
with MP0250 could not be attributed to the DARPin® chemical structure per se. Exposure 
was mostly limited to a few weeks or months as expected for Phase 1 studies in 
oncology, but no additional safety concerns were identified in individual patients who 
remained on DARPin® therapy for longer periods (longest duration of 60 weeks and a 
median duration of 9.7 weeks ref. IB 7.10.2.3) [5]. 
 
As with other proteins and as has been seen with the DARPin class, potential risks for 
infusion of MP0420 are mostly associated with infusion-related reactions. Signs and 
symptoms of infusion-related immediate hypersensitivity reactions may include, but are 
not limited to: anaphylaxis, angioedema, bronchospasm, chills, diarrhea, hypotension, 
itching, skin rash, shortness of breath, urticarial, tachycardia, and throat irritation or chest 
tightness. Such reactions can be managed through enhanced clinical monitoring and 
symptomatic treatment using established clinical practices. None of these have been 
-

reported to date from the ongoing Phase 1 study of MP0420. DARPin related IRRs have 
been managed with the standard interventions including antihistamines, NSAIDs, and 
occasional corticosteroids. The proposed single dose use of MP0420 will avert potential 
reactions associated with multiple doses.  
 
In conclusion, the available clinical experience with DARPins® indicates a general safety 
profile in line with other biologic drugs, and the absence of safety concerns that could be 
attributed to the DARPin® chemical structure. 
 
A potential risk is the production of anti-drug antibodies (ADA) which might reduce 
exposure to MP0420 after two to three weeks. Analysis of PK and ADA are included in 
the Ph1 CP101 study as well as other planned Ph2 CP204 and Ph2-3 CP302 studies as 
described in the investigational plan described in the IND held by Molecular Partners. 
However, as MP0420 treatment is expected to achieve its full therapeutic potential when 
applied as a single administration, this risk is anticipated to be of little or no clinical 
significance.   
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of MP0420 may be found in the Investigator’s 
Brochure(s) [5] and Participant Information Leaflet. 
Given the data on MP0420 from the ongoing Phase 1 study, the preclinical toxicology 
profile, non-clinical and clinical data from 3 other DARPin® molecules, and the limited 
disease directed therapeutic options for patients with COVID-19 illness, the overall 
benefit-risk assessment of MP0420 in this study is considered favorable. 
 
H5.1.2 Motivation for agent selection by the ACTIV Trial Oversight Committee (TOC) 
The ACTIV-2/3 Agent Selection Committee (ASC) reviewed the Molecular Partners 
agent (MP0420), which contains 3 different DARPins blocking the RBD (like a mAb 
mixture in one) for highest potency & to prevent viral escape against the SARS-CoV-2 
virus and voted in favor of the agent proceeding into ACTIV-3, and the TOC endorsed 
that recommendation.  MP0420 was supported because Molecular Partners presented 
strong preclinical data for viral neutralization, including the intention to conduct studies 
on the emerging viral variants of concern with the USG Therapeutics Research labs. 
Given where the current mutations are, they should not affect the potency of MP0420.  
Live virus neutralization using MP0420 exceeded the minimum criteria for trial entry, 
which are IC50 <100 ng/ml and IC90 <1000 ng/ml.  While there was some concern about 
safety and toxicity with this being a new class of agents, Molecular Partners’ early safety 
and toxicity showed no issues and they plan to complete full FDA-compliant GLP TCR 
study by early January 2021 [5].  In addition, single dose PK studies in mouse (50 mg/kg), 
hamster (10 mg/kg) and cynomolgus monkey (10 mg/kg) showed MP0420 to be well 
tolerated with no clinical signs of adverse effects. 
Molecular Partners also provided a strong rationale for their choice of dosing for their 
agent which was strongly supported by their preclinical dose finding studies in hamsters.  
MP0420 at 20 mg/kg i.p. at same time as infection resulted in no weight loss and no 

deaths (5/6 placebo animals died on Days 2/3).  In addition, MP0420 showed a 7-log 
reduction of lung virus load at Day 3 and an 8-log reduction at Day 5. Molecular Partners 
showed a solid plan for Phase 1 development of their agent and strong FDA support 
based on their pre-IND meeting.  Finally, the ASC found the manufacturing and 
scalability strategy for Molecular Partners sufficient for the full trial and beyond now that 
they have partnered with Novartis to scale up the manufacturing.  The agent can be 
rapidly manufactured in bacteria with high yield production. 
Molecular Partners/Novartis’ statement regarding plans for licensure: Molecular Partners 
and Novartis are biopharmaceutical companies whose goal is to bring important medical 
breakthroughs to as many patients in as many countries as possible. It would therefore 
be Molecular Partners/Novartis’ general intent to pursue licensure in countries where the 
trial occurs. In the case of the COVID-19 pandemic, the actual decision to pursue 
licensure will be impacted by other factors which may include: status of the COVID-19 
pandemic in the country and unmet medical need, availability of other therapies including 
vaccines, available drug supply and other supply feasibility issues, and regulatory 
considerations.  
H5.1.3 Justification for dose chosen for MP0420  
The dosing regimen of MP0420 for the ACTIV-3 study was selected by considering a 
range of data that together predict a single intravenous dose of 600 mg will be safe and 
efficacious in COVID-19 patients. Factors considered for dose selection included: 
preclinical safety data, available clinical safety and tolerability results from the ongoing 
Phase 1 dose escalation FIH study (MP0420-CP101), in vitro and in vivo pharmacology 
results, observed clinical PK for MP0420 in the FIH study, clinical PK for a structurally 
similar DARPin (MP0250) and PK/PD modeling. Each of the considered elements is 
briefly summarized below. 
Preclinical and clinical safety for MP0420 
The safety-focused NOAEL approach was used to determine first-in-human doses of 3, 
9 and 20 mg/kg and a summary of the relevant preclinical safety data can be found in 
the IB. Dosing of healthy volunteers with single i.v. infusions of 3 and 9 mg/kg (9 mg/kg 
would equate to a flat dose of 720 mg in an 80 kg person) has been completed and these 
doses were assessed as safe and well tolerated with no serious adverse effects reported. 
The 20 mg/kg cohort will be enrolled in Q1 2021. Based on this, the proposed dose of 
600 mg (7.5 mg/kg in an 80 kg person) is expected to be safe in ACTIV-3 patients. 
 
Preclinical pharmacology for MP0420 
In vitro pharmacology studies demonstrated that MP0420 displays sub-pM binding 
affinities to the SARS-CoV-2 RBD (SPR assessment) and has IC50 values in the range 
of 10-50 pM (1–5 ng/ml) in SARS-CoV-2 neutralizing assays against wild-type, 
pathogenic, and pseudo-type viruses. Furthermore, IC50 values in the same range for 
the neutralization of pseudo-type viruses with different spike serotypes suggest 
MP0420 could be effective against mutational escape. Based on non-clinical 
pharmacology assessment in SARS-CoV-2 infected hamsters, therapeutic dosing 
regimen for MP0420 have been identified between 3 and 20 mg/kg. When dosed 

during infection (acute) rather than prior to infection (prophylactic) efficacious doses are 
observed at 9 mg/kg and higher with significant improvement in mortality that was 
generally associated with a reduction in SARS-CoV-2 viral load 
 
Dose-related lung distribution of MP0420 was demonstrated in healthy mice following 
single i.v. doses of 1, 10 and 50 mg/kg. Analysis of BAL harvested at 72 h post dose 
provided evidence for distribution of MP0420 into the epithelial lining fluid (ELF) of the 
lung. MP0420 concentrations in ELF of 1.8, 6.1 and 44 nM for the dose levels 1, 10 and 
50 mg/kg were measured, which is respectively 21, 90, and 80 times lower than 
measured in serum samples taken at the same time. However, the estimated ELF 
concentrations are in the range of, or above, the potency of MP0420 against wild-type 
virus in in vitro assays where IC50s of 0.05, 5 and 5 nM were measured against viral 
challenge levels of 104, 105 and 106 TCID respectively. In addition, literature data 
suggests that the vasculature of inflamed respiratory tract epithelium is more permeable 
to plasma proteins, and thus it is conceivable that MP0420 concentrations in the ELF of 
COVID-19 patients could be higher than those determined in healthy mice. 
Initial human PK results from MP0420-CP101 
Ph1 investigation of the safety, tolerability and PK of MP0420 in healthy participants is 
ongoing. Initial assessments of cohort 1 (i.v., 3 mg/kg) and cohort 2 (i.v., 9 mg/kg) are 
available. Cohort 3 will be enrolled in March 2021. Based on initial data analysis, the 
estimated half-life for MP0420 across cohorts is approximately 14.4 days (mean, range: 
11.4-24.0 days). Slightly greater than dose-proportional increases in exposure were 
observed from cohort 1 to cohort 2 (3.8-fold increase in AUC with a 3-fold increase in 
dose).  Cohort 2 exhibited day 14 serum concentrations of 143 ±20.4 ug/mL (mean ±SD), 
which corresponds to 1690 ±241 nM (mean ±SD), and is >1000-fold above the IC50 
determined for MP0420 in infected Vero E6 cells.  
 
Human dose projection by PK/PD modelling 
The PK/PD model was constructed from publicly available data describing viral kinetics 
from SARS-CoV-2 patient throat swabs from untreated COVID19 patients and calibrated 
to describe reported viral load data from patients treated with a neutralizing antibody 
therapeutic (LY-CoV555). The PK/PD model predicts effects in the lung and makes the 
following assumptions: 10% of systemic MP0420 rapidly distributes from blood to lung; 
lung viral kinetics are approximated by throat swab viral kinetics; 60 spike trimers (RBDs) 
are present on the virus’ surface; binding RBD neutralizes interaction with the ACE-2 
receptor, which blocks infection; MP0420 has a Kd = 1 pM (based on SPR binding data); 
clearance of DARPin-bound virus is equal to non-DARPin-bound viral clearance; 
sustained immune response over the duration of viral infection. The model predicts a 
near-maximal effect on reduction of free spike protein with an MP0420 dose of 75 mg 
(>95% reduction in free viral spike protein AUC), which is expected to correlate with 
clinical efficacy. Due to uncertainties in both the modeling predictions and the severity of 
disease at onset of therapy, an 8-fold margin was applied and a dose of 600 mg was 
selected.  
 

Thus, the composite of PK/PD modelling, preclinical pharmacology, and clinical safety, 
tolerability and PK data support the use of 600 mg MP0420 for treatment of COVID-19 
patients.  
H5.2. Agent specific eligibility criteria 
 In addition to the inclusion and exclusion criteria outlined in the master protocol, the 
following patients will be excluded:  
1. pregnant women  
2. nursing mothers  
3. women of child-bearing potential who are unwilling to acknowledge the strong 
advice to abstain from sexual intercourse with men or practice appropriate 
contraception through 11 weeks after receiving MP0420/placebo 
4. men who are unwilling to acknowledge the strong advice to abstain from sexual 
intercourse with women of child-bearing potential or to use barrier contraception 
through 11 weeks after receiving MP0420/placebo. 
H5.3. Description of investigational agent 
H5.3.1. Administration and duration 
See the PIM and Pharmacy Procedures for details. See also section H5.5 below for 
guidance on the clinical management of the infusion, including infusion-related reactions. 
MP0420 will be administered intravenously within one hour in a one-time infusion. 
Specific instructions can be found in the pharmacy procedures.  
 
The recommended infusion rate is ≤5 mL/min to administer the entire content of the 
infusion bag. The infusion rate may be reduced as deemed necessary if an infusion 
reaction is observed.  
 
Participants will be closely monitored during the infusion and for at least 2 hours after 
completion of the infusion. Additional monitoring may be necessary based on clinical 
judgement of the study investigator(s) and/or site staff, and in accordance with the 
master protocol. The site must have resuscitation equipment, emergency drugs and 
appropriately trained staff available during the infusion and for at least 2 hours after the 
completion of the infusion. 
 
If a participant has not already received the relevant dose of remdesivir at the day of 
enrolment, and has no contraindications to start remdesivir, it is recommended (but not 
required) that the relevant dose of remdesivir is infused after the infusion of 
MP0420/placebo is completed. 
 
H5.3.2. Formulation and preparation 
MP0420 is a sterile drug product and is packaged in 20R glass vials.  
A total of 4 vials (concentration: 15 mg/mL, extractable volume: 10.0 mL) provides the 
600 mg dosing of the agent; the (see Table H5.1). Placebo is normal saline. The study 
medication is prepared by an unblinded pharmacist at the local pharmacy. To ensure 

blinding of the participant and clinical staff a colored sleeve will be placed over the 
infusion bags used (see PIM and Pharmacy Procedures). 
MP0420 should be prepared and dispensed as soon as possible after randomization. 
Infusions should be completed within 24 hours after the infusion has been prepared by 
the pharmacist. 
 
Table H5.1. Study medication overview.  
Intervention Name 
Placebo 
MP0420 
Dose Formulation 
0.9% sodium chloride solution 
Biologic – DARPin® molecule (10.0 mL 
extractable volume per vial, 15 mg/ml per 
vial)  
Dosage 
Level(s) 
(mg) 
Not applicable 
600 mg  
Route of 
administration 
IV infusion 
IV infusion 
Use 
Placebo 
Experimental 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Commercially available 0.9% sodium 
chloride solution 
Molecular Partners AG, Zurich-Schlieren. 
Switzerland 
Packaging and 
Labeling 
Commercially available 0.9% sodium 
chloride solution 
Study intervention will be provided in 
20R single-use glass vials individually 
packaged in a carton, and labeled 
appropriately. 
 
H5.3.3 Supply, distribution, and accountability 
Procedures for ordering and accepting drug, for maintaining inventory of MP0420, and 
for breaking the blind in the event of a medical emergency will be described in the 
Pharmacy Procedures. 
H5.3.4. Contraindicated medications 
No medication is known to be contraindicated in patients receiving the investigational 
agent.  
 
H5.3.5. Precautionary medications 
The clinical site should have necessary equipment and medications for the management 
of any infusion reaction (see section H5.5 below).  
 
Premedication for infusions is not planned. 
 
If an infusion reaction occurs during administration or if the participant has a medical 
history suggesting a potential benefit from premedication, the study investigator(s) 
should determine the appropriate premedication. 
 

The investigators and sponsor may decide to recommend premedication, if the frequency 
of infusion reactions among participants warrants it. If minor infusion reactions are 
observed, administration of acetaminophen, 500 mg to 1000 mg, antihistamines and/or 
other appropriately indicated medications may be given prior to the start of infusions for 
subsequent participants. The decision to implement premedication for infusions in 
subsequent participants will be made by the investigator and sponsor and recorded in 
the study documentation. Any premedication(s) given will be documented as a 
concomitant therapy. 
H5.4. Clinical and laboratory evaluations 
 
H5.4.1 Timing of Assessments 
Appendix B outlines the clinical and laboratory monitoring. Assessment and reporting of 
AEs (section 10.1.1), SAEs (section 10.1.2) and unanticipated problems (section 10.1.3) 
and their severity, causality (section 10.1.5) and expectedness (section 10.1.6) is 
performed as outlined in the relevant section of the master protocol.  
 
H5.4.2 Immunogenicity Assessments 
At the visits specified in the master protocol (Days 0, 28, and 90) venous blood samples 
will be collected to determine antibody production against MP0420 – 2 one mL serum 
aliquots. Immunogenicity may be assessed by a validated assay designed to detect 
ADAs in the presence of MP0420. Antibodies may be further characterized for their ability 
to neutralize the activity of MP0420. Remaining volume from the PK sample may also be 
used for immunogenicity assessments as needed.   
 
H5.4.3. Pharmacokinetic Assessments 
At the visits specified in the master protocol (Days 0, 1, 5, 28, and 90) venous blood 
samples will be collected to determine MP0420 serum concentration for pharmacokinetic 
assessment. The PK/Immunogenicity assessment will require 2 mL of the serum 
collected, as described in the Master Protocol Appendix B as “Research Sample 
Storage”.  PK samples may be assessed by a validated assay at a bioanalytical lab. The 
PK assessment will use the same 2 ml serum specified in the Immunogenicity 
assessment section above (H5.4.2). Analysis of samples from placebo-treated subjects 
is not planned for PK analysis as placebo is shared across arms. Using a limited amount 
of placebo samples as negative controls will be possible. Remaining sample used for PK 
may be pooled and used for exploratory metabolism or bioanalytical method experiments 
as deemed appropriate. Samples maybe shipped to the lab for analyses in batches as 
the substudy is unfolding. Results from such analyses will be returned to the trial central 
database. This data and all other data on the participants will remain in the trial central 
database until the trial is unblinded. 
H5.5. Clinical management issues 
All participants should be monitored closely for 2 hours after the infusion, as there is a 
risk of infusion reaction and hypersensitivity (including anaphylaxis) with any biological 
agent. 

H5.5.1. Symptoms and Signs 
Symptoms and signs that may occur as part of an infusion reaction, include, but are not 
limited to, fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, 
throat irritation, rash including urticaria, pruritus, myalgia, and dizziness.  
Infusion-related reactions’ severity will be assessed and reported using the Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected version 2.1 [8]. 
H5.5.2. Site Needs 
The clinical site should have necessary equipment, medications, adequately qualified 
and experienced staff with appropriate medical cover for the management of any infusion 
reaction, which may include, but is not limited to, oxygen, IV fluid, epinephrine 
(adrenaline), acetaminophen (paracetamol) and antihistamine. 
The pharmacy procedures and the PIM outline needs of the study site pharmacy and/or 
local site pharmacy. 
H5.5.3. Management of Infusion Reactions including Discontinuation 
Investigators will use their clinical judgement and standard of care to evaluate and 
manage all infusion reactions. If an infusion reaction occurs, then supportive care should 
be used in accordance with the signs and symptoms. If a severe and potentially life-
threatening infusion reaction occurs with MP0420/placebo, its use should be 
permanently discontinued. 
If a participant is not infused with MP0420/placebo or the complete infusion is not given, 
all follow-up procedures and reporting’s outlined in the master protocol (Appendix B for 
overview), should be adhered to as indicated. 
H5.5.4. Adverse Events of Special Interest (AESI) 
The following are AESIs for the agent MP0420 or placebo:  
• Infusion-related reactions 
• Allergic/hypersensitivity reactions 
 
H5.5.5. Incident Pregnancy in Participants or Their Partners 
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study.   
The participant will continue follow-up in the protocol.  The outcome of the pregnancy 
and reported on the Pregnancy Outcome eCRF.  
If an investigator learns that a male participant’s partner has become pregnant while 
the male participant is in this study, the investigator is asked to attempt to obtain 
information on the pregnancy, including its outcome, after obtaining consent from the 
pregnant partner.  The outcome of the pregnancy will be reported on the Pregnancy 
Outcome eCRF. 
 
I I 

H5.6. References 
1. 
Walser, M., et al., Highly potent anti-SARS-CoV-2 multivalent DARPin therapeutic 
candidates. bioRxiv, 2020. 
2. 
Steiner, D., et al., Half-life extension using serum albumin-binding DARPin(R) domains. 
Protein Eng Des Sel, 2017. 30(9): p. 583-591. 
3. 
Baird, R.D., et al., First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug 
Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors. J Clin Oncol, 
2020. in press. 
4. 
Stumpp, M.T., K.M. Dawson, and H.K. Binz, Beyond Antibodies: The DARPin((R)) Drug 
Platform. BioDrugs, 2020. 34(4): p. 423-433. 
5. 
MolecularPartnersAG, Investigator's Brochure: Ensovibep (previously MP0420); Antiviral 
DARPin® drug candidate targeting the receptor binding domain of the SARS-CoV-2 corona 
virus; edition 1.1; 10 Feb 2021 
6. 
Rothenberger, S. and M. Walser, Multi-specific DARPin® therapeutics demonstrate very high 
potency against mutated SARS-CoV-2 variants in vitro. bioRxiv. 
7. 
Callanan, D., et al., Double-Masked, Randomized, Phase 2 Evaluation of Abicipar Pegol (an Anti-VEGF 
DARPin Therapeutic) in Neovascular Age-Related Macular Degeneration. J Ocul Pharmacol Ther, 
2018. 34(10): p. 700-709. 
8. 
NIAID Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse 
Events 
Corrected 
Version 
2.1, 
July 
2017. 
2017; 
Available 
from: 
https://rsc.niaid.nih.gov/clinical-research-sites/grading-severity-adult-pediatric-adverse-events-
corrected-version-two-one.