Fibrinogen x fibrin

The blood protein fibrin plays a key role in stopping bleeding, but in certain circumstance it can also contribute to disease. Therein lies the challenge for developing a fibrin-targeting drug. Scientists need to figure out how to stop the disease-driving activity while also maintaining the protein’s very important role in clotting and coagulation. Therini Bio is developing a drug designed to selectively block fibrin, potentially addressing inflammation behind neurological disorders such as Alzheimer’s disease as well as some eye disorders. The South San Francisco-based biotech’s research has yielded encouraging preclinical data. As the biotech transitions into a clinical-stage company, it has raised $36 million from a syndicate that includes the investment arms of Merck, Sanofi, and Eli Lilly. Therini is based on the research of Katerina Akassoglou, an investigator at the Gladstone Institutes at the University of California San Francisco, and formerly of the University of California San Diego. Her work focuses on the role blood proteins have on nervous system disorders. Research from Akassoglou and her colleagues published in 2018 in Nature Reviews Neuroscience and Nature Immunology described how fibrin is associated with toxic inflammation and neuron damage in Alzheimer’s, multiple sclerosis, and other neurological disorders. In these diseases, disruption to the blood-brain barrier allows fibrin to enter the brain and spark disease-driving inflammatory effects there. How a protein that is helpful can also contribute to disease is a matter of timing, said Therini President and CEO Michael Quigley, who is also a venture partner at SV Health Investors was previously an executive at Gilead Sciences. The formation of fibrin is a normal bodily process, and it happens frequently in people who exercise regularly. For example, runners experience tiny bleeds in tissues that are stopped by clot-forming fibrin, Quigley said. But after fibrin performs its healing role, it goes away. Fibrin clots are broken down by enzymes in the blood. Problems can develop when fibrin doesn’t go away, Quigley said. Low levels of the fibrin-busting enzymes result in the clotting protein staying around longer. In some diseases, there are additional inhibitors to the breakdown process. When blood clots persist, they contribute to inflammation in the body. “In settings of disease, the breakdown of the clot does not happen,” Quigley said. “Persistence is believed to be a driver of disease.” Fibrin’s pro-inflammatory role in a wide variety of diseases has been known for some time, Quigley said. In the 1980s, research efforts included thrombolytics—drugs that break down blood clots. But long-term use of these drugs raised bleeding risks, making them unsuitable as therapeutic interventions, he said. Therini’s proposed solution is THN391, an antibody that blocks disease-driving fibrin without diminishing the protein’s blood clotting properties. Fibrin forms from another protein called fibrinogen. The epitope, the part of the protein to which Therini’s antibody binds, is not exposed in fibrinogen, Quigley said. But this epitope presents itself when fibrinogen converts to fibrin. THN391 targets only this epitope. “What is unique, we can specifically target the chronic inflammatory disease driving aspect of fibrin while sparing the coagulation aspect,” Quigley said. In preclinical research, THN391 was able to cross the blood-brain barrier to block disease-driving fibrin. Results also showed the Therini drug led to reductions in hallmarks of multiple sclerosis, Alzheimer’s, and retinal diseases, Quigley said. Just as important, targeting the particular fibrin epitope did not diminish the protein’s role in clotting and coagulation. Therini scientists believe THN391’s fibrin-targeting approach will apply to retinal diseases characterized by inflammation, such as diabetic macular edema. The company will pursue neurodegeneration and eye disorders in parallel, Quigley said. Additional research includes fibrin tethering, in which an anti-fibrin antibody is used to also deliver a drug payload to disease sites. Delivering a therapeutic agent on top of blocking fibrin could be beneficial in treating disease, though this research is still in the discovery stage, Quigley said. With the new capital, the startup will advance THN391 into Phase 1 testing. Safety and proof of mechanism data are expected by the end of next year. Therini was initially named MedaRed. In 2019, the Gladstone spinout raised $6.5 million in seed financing led by Dementia Discovery Fund and Dolby Family Ventures. The following year, MedaRed changed its name to Therini Bio. In 2021, the startup raised another $17 million in a seed round extension led by SV Health Investors’ Impact Medicine Fund, MRL Ventures, and Sanofi Ventures. The Series A financing was co-led by Dementia Discovery Fund, MRL Ventures Fund, the therapeutics-focused corporate venture fund of Merck, Sanofi Ventures, and Impact Medicine Fund. Eli Lilly joined as a new investor in the new round, which included participation of all earlier investors. Therini says the latest financing brings the total amount raised since inception to $62 million. Image by Therini Bio