Therini Bio reports positive Phase 1a results for THN391, a humanized monoclonal antibody that selectively neutralizes fibrin-induced neuroinflammation without affecting coagulation. Using ascending single and multiple dosing, the drug shows safety, dose-proportional pharmacokinetics, and supports monthly administration. Phase 1b studies will assess efficacy in Alzheimer’s disease and diabetic macular edema.
Key points
THN391 is a humanized monoclonal antibody targeting the inflammatory epitope on fibrin.
Phase 1a trial was randomized, double-blind, placebo-controlled with single and multiple ascending doses.
The treatment showed no serious adverse events, preserved coagulation, and avoided anti-drug antibody responses.
Pharmacokinetic analysis revealed dose-proportional exposure and a half-life supportive of once-monthly dosing.
Phase 1b trials will evaluate clinical efficacy in Alzheimer’s disease and diabetic macular edema cohorts.
Why it matters:
By demonstrating safety and monthly dosing feasibility of THN391, this study substantiates targeting fibrin-mediated neuroinflammation as a novel approach to treating Alzheimer’s and retinal degenerative diseases. This upstream intervention could shift paradigms from symptomatic relief to disease modification in neurodegeneration and vascular dysfunction.
Q&A
What is fibrin’s role in neurodegenerative diseases?
How does THN391 avoid increasing bleeding risk?
What do dose-proportional pharmacokinetics imply?
What endpoints will Phase 1b studies assess?
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Academy
Fibrin and Neuroinflammation in Aging
Introduction: Fibrin is a fibrous protein formed from fibrinogen by the enzyme thrombin during blood clotting. While essential for sealing vascular injuries and preventing blood loss, fibrin’s presence in tissues can trigger immune responses when it escapes the bloodstream. In the aging brain and retina, fibrin deposition can initiate chronic inflammation, contributing to neuronal damage and vascular dysfunction.
Fibrin Formation and Clearance
- Generation: The coagulation cascade converts soluble fibrinogen into insoluble fibrin strands that form the structural matrix of blood clots.
- Clearance: Fibrinolytic enzymes, mainly plasmin, break down fibrin to maintain vascular patency and tissue homeostasis.
- Age-related Dysregulation: Impaired fibrinolysis and blood-brain barrier breakdown allow fibrin to accumulate in the brain and retina.
Fibrin’s Role in Neuroinflammation: When fibrin deposits in neural tissue, innate immune cells like microglia and macrophages bind fibrin via complement receptors and integrins. This engagement triggers a cascade that releases pro-inflammatory cytokines, reactive oxygen species, and matrix-degrading enzymes, leading to chronic inflammation and neuronal damage.
Impact on Neurodegenerative Diseases:
- Alzheimer’s Disease: Fibrin co-localizes with amyloid plaques and accelerates plaque toxicity by activating microglia and promoting tau pathology.
- Diabetic Macular Edema: Fibrin deposits compromise retinal microvasculature, causing leakage, edema, and vision loss.
Therapeutic Targeting Strategies
- Small Molecule Inhibitors: Modulate coagulation factors to reduce fibrin formation but risk systemic bleeding.
- Monoclonal Antibodies: Humanized antibodies like THN391 bind inflammatory epitopes on fibrin, blocking immune activation while preserving clotting functions.
- Gene Therapy: Experimental approaches aim to enhance endogenous fibrinolysis or restore blood-brain barrier integrity.
Advantages of Fibrin-Targeted Antibodies: Their selectivity minimizes bleeding risk. Favorable pharmacokinetics support monthly dosing. By targeting an upstream driver of inflammation, these antibodies address root causes rather than just symptoms.
Challenges and Future Directions: Ensuring adequate central nervous system penetration, avoiding anti-drug antibody development, and identifying biomarkers for target engagement remain key research areas. Ongoing trials will refine dosing, patient selection, and long-term safety profiles.
Conclusion: Understanding fibrin’s dual role as a clotting factor and immune activator reveals novel therapeutic avenues for aging-related neurodegenerative and retinal diseases. Targeted interventions like THN391 hold promise for halting disease progression at its inflammatory roots.