Randomized, double blind, mutlicenter, multinational, placebo controlled, single parallel escalating dose safety and efficacy study of ACT017 used as an add-on therapy on top of standard of care of acute ischemic stroke

Thrombolysis with alteplase is the only approved pharmacological therapy for
acute ischemic stroke (AIS). Nevertheless, the benefit of this therapy, (a)
extremely time sensitive and the eligibility criteria are limited to a very
short time window not exceeding 4.5 hrs after symptom onset, (b) limited in its
effects with an overall recanalization rate of 46% overall. Altogether, only 7
to 15% of patients are deemed eligible for thrombolysis treatment with
alteplase and 14 to 34% of them will suffer from a secondary re-occlusion after
initial recanalization, associated with clinical deterioration and poor
outcome. Re-occlusion has been attributed to increased platelet aggregation
caused by local thrombus, endothelial injury and probably the thrombolytic
treatment itself.
Combining alteplase with a treatment that has a potential to inhibit secondary
platelet aggregation seems to be therefore obvious. Nevertheless, as previously
stated the currently available molecules are not recommended at the acute phase
(0 to 12 hrs) due to an associated over-risk of hemorrhagic
conversion in tPA-treated patients.
Due to its specific mechanism of action showing no evidence of any additional
bleeding risk both in animals or in healthy subjects, glenzocimab candidate
drug seems to be a promising agent administrable at the acute phase of the
stroke in addition to the best standard of care with the following medical
management objectives:
1) Reduce the size of the clot,
2) Favor cerebral reperfusion, thus decreasing the infarct volume
3) Decrease the occurrence of ischemia-reperfusion injury, thereby increasing
the percentage of salvageable brain tissue and improving neurological recovery

The study primary objective will consist of assessing the safety and
tolerability of single IV (bolus + infusion) doses of glenzocimab in patients
with an acute ischemic stroke administered on top of the best emergency
standard of care (including fibrinolysis by recombinant tissue plasminogen
(tPA), administered within 4h30, with or without added mechanical
thrombectomy). This entails with a specific focus on Intra-Cranial Hemorrhage
(ICH), whether clinically symptomatic, or seen only on 24-hr CT scan (after
exclusion of other diagnoses), serious adverse events (SAEs), suspected
unexpected serious adverse reactions (SUSARs), and medically important events,
bleeding-related events and other safety parameters including biological and
immunological tolerability.

For each given patient, whatever the study phase, the schedule will include:
* A screening assessment at admission including imaging
* A randomization procedure,
* A treatment phase,
* A post-treatment visit evaluation 24 hrs (+/- 3 hrs) after the initiation of
treatment, including a CT-scan (and an MRI evaluation if possible).
* A 7-day (+/- 3 days) post-treatment infarct zone evaluation by MRI. This
examination can be performed before Day 7 if the patient is discharged earlier
than Day 4 from hospital, he/she needs to perform a MRI the day of discharge.
* A 30-day (+/- 3 days) post-treatment evaluation,
* Finally, a 90-day (+/- 3 days) post treatment evaluation corresponding to the
EOS (End Of Study) visit,
* Additional follow-up visit or phone call may be required notably in the case
of emerging adverse events

Dose Escalation (Phase 1b):
During this phase, patients are unevenly randomized between groups, to obtain a
total of 60 patients, 12 at each dose level, providing escalation is complete.
This phase is complete.

Consolidation Phase with Final Dose (Phase 2a):
During this phase, randomization will be 1:1.
In addition, patients in each treatment arm will be stratified by type of
Standard of Care (SOC) administered:
* Thrombolysis with tPA only;
* Thrombolysis with tPA AND mechanical thrombectomy.
A total of 100 new patients should be recruited, 50 under active treatment and
50 under placebo to complete up to 160 patients. Each treatment arm will
contain 25 patients with one SOC, and 25 with the other SOC.
The active glenzocimab dose will be that recommended after the last safety
analysis has been performed: 1000mg.

Glenzocimab is a humanized fragment of monoclonal antibody and therefore risks
generally associated with protein-based medicinal including anaphylactic
reactions and hypersensitivity also apply for glenzocimab. However, such
reactions have not been observed in the non-clinical studies. Because
glenzocimab is a humanized Fab, ADA assessment was not considered to be useful
in the non-clinical studies. Nevertheless, immunogenicity of glenzocimab was
assessed in silico using the EpiMatrix Protein Immunogenicity Scale from
EpiVax. EpiMatrix predicted excess and shortfall in aggregate immunogenicity
relative to a random protein standard. All scores are adjusted for the presence
of Tregitopes. The submitted glenzocimab sequence scored on the low end of
EpiMatrix scale. The regression analysis of licensed monoclonal antibodies
predicted ADA response in ~2% of exposed patients.

Risks associated with the route-of-administration via IV infusion were assessed
in the toxicology studies in cynomolgus monkeys. Results showed that
glenzocimab infusion were well tolerated. However, the occurrence of local
reactions related to the intended IV route-of-administration cannot be
generally excluded in humans.

Antiplatelet drugs currently marketed present a higher risk of bleeding. Such
effect is not expected with glenzocimab because of its unique mechanism of
action. In non-clinical studies, no signs of bleeding were observed at doses up
to 80 mg/kg in cynomolgus monkeys.

Glenzocimab represents a novel therapeutic approach for the emergency treatment
of ischemic stroke. Based on its unique mechanism of action and non-clinical
data demonstrating inhibition of collagen-induced platelet aggregation with no
impact on bleeding time, glenzocimab displays promising efficacy and a high
safety profile and is anticipated to have the potential to address the unmet
medical need for this life-threatening condition.