Potential of FX06 to prevent disease progression in hospitalised nonintubated COVID-19 patients (Ixion)

The emergence of a novel coronavirus, officially known as Severe Acute
Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), has presented an unprecedented
challenge for the healthcare community across the world. High infectivity,
ability to get transmitted even during the asymptomatic phase and relatively
low virulence have resulted in a rapid transmission of SARS-CoV-2 beyond
geographic regions, leading to a pandemic. The first case of this diseases,
known as coronavirus disease 2019 (COVID-19), occurred on December 8,2019 in
the Hubei province of China. Since then, the infection has spread worldwide,
with nearly 194 million confirmed cases and over 4 million deaths (World Health
organization situation report from July 27th, 2021). Respiratory involvement,
presenting with mild flulike illness to potentially lethal acute respiratory
distress syndrome or fulminant pneumonia, are the dominant clinical
manifestations of COVID-19. Like other coronavirus, SARS-CoV-2 is characterized
by a spherical morphology with spike projections on the surface. It was
demonstrated that SARS-CoV-2 shared high sequence identity with that of
SARS-CoV and SARS-like coronavirus (SL-CoV). Notably, SARS-CoV-2 has lower
pathogenicity but higher transmissibility from human to human compared with
SARS-CoV. Cell entry is the first step of cross-species transmission.
SARS-CoV-2 is more likely to infect lung type II alveolar cells, which may
explain the severe alveolar damage after infection.

FX06 is a naturally occurring peptide, Bβ15-42, derived from the E1 fragment of
fibrin. The mechanism of action of FX06 is an important new discovery in
understanding acute inflammation and edema formation. FX06 competes with E1
fragments of fibrin for binding to an endothelial specific molecule,
VE-cadherin, thereby acting as an anti-inflammatory, and it signals through
VE-cadherin, thereby reducing plasma
leakage into tissues. Based on animal models of vascular leakage and systemic
inflammation, FX06 has considerable therapeutic potential for all diseases and
pathological conditions associated with increased vascular permeability. FX06
binds to vascular endothelial (VE)-cadherin, preventing VE-cadherindependent
transmigration of leukocytes. Besides many different animal models of shock
(septic, hemorrhagic, hypovolemic), FX06 was also tested in acute and chronic
models of myocardial ischemia and reperfusion in rats, mice and pigs. FX06
reduced relative infarct size by more than 40%; this effect size is comparable
to ischemic preconditioning. The peptide is synthetically produced for
exogenous human administration.

FX06 was found to have a benign safety profile in safety pharmacology and
toxicology studies. The only
findings representing potential risks to humans were mild platelet activation
in response to shear stress in an in vitro study and mild transient hypotension
observed in telemetered dogs. Preliminary data suggest that initial clearance
of FX06 is mainly via the kidneys. FX06 is also partially degraded by plasma
carboxypeptidases.

Escalating doses of FX06 were evaluated in a single Phase I study in 30 healthy
volunteers using a pioneer dose design. PK analysis demonstrated a broadly
linear relationship between dose and AUC. Clearance was independent of dose.
The calculated plasma elimination half-life was between 11 and 17 minutes. FX06
was well tolerated in the Phase I study.

FX06 has been evaluated in a Phase IIa clinical trial of first-time acute STEMI
(ST-segment elevation myocardial infarction) patients undergoing primary
percutaneous coronary intervention. In this proof-of concept trial, FX06
reduced the necrotic core zone as one measure of infarct size on magnetic
resonance imaging and appeared safe and well tolerated.

Preliminary data from an investigator-initiated trial (IIT) in critically ill
COVID-19 patients revealed a trend to improved survival in FX06-treated
patients. However, no statistically significant difference could be observed in
this 50-patient randomized, placebo-controlled study. Importantly, no safety
concern was raised. Furthermore, FX06 has been applied in a severe case of an
Ebola virus infected patient under compassionate
use. The patient recovered after critical illness and no drug related safety
concerns were raised

The primary objective is to demonstrate a difference in the proportion of
patients with progressed/worsened disease state in patients receiving FX06
compared to patients receiving placebo until day 28.

Assessment and treatment comparison of the objectives at all available visits
and time points between the FX06 and placebo group

This will be a multicentre, placebo-controlled, double-blinded, parallel,
randomized (2:1), phase II clinical study to investigate the potential of FX06
to prevent disease progression in hospitalised non-intubated COVID-19 patients.

Patients fulfilling inclusion criteria will be stratified according their WHO
severity group (moderate: score 4-5 or severe: score 6) and by country and
randomized 2:1 to either one of the two treatment groups (FX06 or placebo).

Patients will be treated for 5 consecutive days and will be observed until day
28 and followed up at day 60. They will receive FX06 or placebo i.v. as a
two-time (2x 200 mg) bolus injection per day. The interval between the two
injections should be 10 ± 5 min. IMP administration will start at BL.

Patients will be assessed according to Table 1 until day 28 (and followed up
until day 60). After BL, day 1-6, 10 and 28 are planned as personal visits
(visit at the study centre or home visitation; the latter only if patients have
been released from the hospital). If this will not be feasible (e.g., because
patients have been released and are not able to come to the study centre and
the study centre is not able to perform home
visitations) visits can be performed remotely (at least the WHO score,
concomitant medication and adverse events need to be assessed).

Once patients leave the hospital, the necessary information for days 7-9 and
11-27 can be retrieved remotely to assess safety and main efficacy endpoints
(patients can be contacted every 2-3 days to retrieve the information
retrospectively in order not to demotivate patients to participate). A
follow-up visit will be performed as a telephone/video-call at day 60.

If patients leave the hospital before day 6 they will continue the study as
planned (they will not be considered drop-outs as far as at least IMP dose was
administered). Day 6 should still be performed as a personal visit (if
feasible, see above); the days beforehand could be performed remotely for these
patients if personal visits are not feasible. All other visits after day 6
should be performed as planned. If patients leave the hospital with a better
WHO score than at BL before day 5, IMP/placebo administration will not be
continued. IMP/placebo will only be given during their hospital stay. Number of
IMP/placebo administrations will be documented.

There will be 2 study treatments: 1 active FX06) and 1 placebo.

FX06/placebo will be administered over a 5-day period in two-bolus
administration per day. The patients will then be further observed until day
28. The study duration for individual patients will be maximally 28 days (plus
up to 5 days Screening period) for the main study period plus a FU telephone
call at day 60).

The burden and risk mainly consist of extra time spent compared to standard
treatment.