3K3A-APC Advanced Drug Monograph

Name: 3K3A-APC Name (English): 3K3A-APC

Description: 3K3A-APC is a genetically engineered variant of activated protein C (APC). APC is a naturally occurring human protein with anticoagulant and cytoprotective properties. 3K3A-APC is modified to significantly reduce its anticoagulant activity while retaining its cytoprotective effects, including anti-apoptotic, anti-inflammatory, and endothelial barrier stabilization properties.

Mechanism of Action: 3K3A-APC's cytoprotective effects are believed to be mediated through the activation of protease-activated receptor 1 (PAR-1). This activation leads to alterations in gene expression profiles, promoting cell survival and reducing inflammation.

Clinical Development:

• Acute Ischemic Stroke: 3K3A-APC has been the primary focus of clinical development for the treatment of acute ischemic stroke. A Phase 2 clinical trial (RHAPSODY) evaluated its safety and tolerability in this population. Exploratory analyses suggested a potential reduction in intracranial hemorrhage rates. However, concerns regarding increased early mortality and potential research misconduct were raised by whistleblowers regarding this trial in November 2023. A Phase 3 trial is reportedly underway.
• Amyotrophic Lateral Sclerosis (ALS): A Phase 2 open-label trial is ongoing to assess the safety and potential efficacy of 3K3A-APC in patients with ALS. The study aims to determine if 3K3A-APC can reduce pathological changes associated with ALS, including microglial activation.
• Alzheimer's Disease: Preclinical studies in mouse models of Alzheimer's disease suggest that 3K3A-APC may have beneficial effects by inhibiting the BACE1 amyloidogenic pathway, reducing amyloid-beta deposits, and improving cognitive and cerebrovascular function.
• Traumatic Brain Injury: Animal studies have shown that 3K3A-APC can reduce lesion volume and improve behavior in a mouse model of traumatic brain injury.

Preclinical Studies:

• In animal models of stroke, 3K3A-APC has demonstrated neuroprotective effects, reducing infarct volume and edema, and improving neurological function. It has also shown potential to enhance the benefits of tissue plasminogen activator (tPA) without increasing bleeding risk.
• Studies in mice with traumatic brain injury and amyotrophic lateral sclerosis have indicated that 3K3A-APC can exert beneficial effects.

Safety and Tolerability:

• Early-phase clinical trials suggest that 3K3A-APC is generally well-tolerated, with mild side effects such as headache, nausea, and vomiting reported at similar frequencies to placebo. However, long-term safety data are not yet available.
• Preclinical toxicology studies in mice and monkeys did not identify significant signs of toxicity.

Pharmacokinetics:

• In monkeys, the elimination half-life of 3K3A-APC has been reported to be approximately 1 hour.

Regulatory Status:

• 3K3A-APC received Fast Track designation from the FDA for the treatment of stroke in 2020.

Investigational Use: 3K3A-APC is currently an investigational drug and is not approved for general clinical use. Its use is limited to clinical trials.