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Fibrolase: trials and tribulations
Francis S Markland1, Steve Swenson
1Department of Biochemistry and Molecular Biology, Cancer Research Laboratory, Keck School of Medicine, University of Southern California, 1303 N. Mission Rd., Los Angeles, CA 90033, USA.
Toxins
|November 10, 2011
Summary
Fibrolase, a snake venom enzyme, effectively dissolves blood clots by directly targeting fibrin. While its recombinant form, alfimeprase, showed promise in early trials, it ultimately failed to meet endpoints in later-stage clinical studies.
Area of Science:
- Biochemistry
- Pharmacology
Background:
- Fibrolase is a fibrinolytic enzyme isolated from southern copperhead snake venom.
- It is a zinc metalloproteinase with a unique amino acid sequence and homology to reprolysin subfamily metalloproteinases.
Purpose of the Study:
- To characterize fibrolase and evaluate its thrombolytic potential.
- To assess the efficacy of its recombinant form, alfimeprase, in preclinical and clinical settings.
Main Methods:
- Purification of fibrolase using three-step HPLC.
- Biochemical characterization including amino acid composition, zinc content, and inhibition studies.
- Evaluation of thrombolytic activity in a canine carotid arterial thrombosis model.
- Development and clinical trial assessment of recombinant alfimeprase.
Main Results:
- Purified fibrolase is a homogeneous zinc metalloproteinase composed of 203 amino acids.
- Fibrolase directly cleaves fibrinogen's A(α) and B(β) chains and demonstrates effective thrombolytic activity in vivo.
- Recombinant alfimeprase showed success in Phase I/II trials for peripheral arterial occlusion (PAO) and central venous access device (CVAD) occlusion.
Conclusions:
- Fibrolase is a potent, direct-acting fibrinolytic enzyme with significant thrombolytic potential.
- Despite promising early results, alfimeprase did not meet primary endpoints in Phase III trials for PAO, CVAD occlusion, or stroke, leading to discontinued development.
