LifeSci

OrPro Therapeutics

OrPro Therapeutics is developing a therapeutic platform based on thioredoxin, a human protein disulfide-reducing enzyme with unique mucus-normalizing, anti-inflammatory and anti-infective properties. OrPro’s lead candidate Theradux (ORP100) is a new inhaled treatment designed to treat cystic fibrosis (CF) and other obstructive diseases characterized by thickened, stiff and adhesive mucus. The company’s research facilities are located on the Torrey Pines mesa at the 40,000 square foot JLABS facility at Janssen Research & Development’s La Jolla-based West Coast Research Center. JLABS is a “no strings attached” model that provides core research labs hosting specialized capital equipment, shared administrative areas and individual bench, wet lab and office modules.

Meet OrPro Therapeutics

OrPro Therapeutics is developing ORP100S, a new type of drug to treat inflammation and obstruction in the lung associated with both chronic airway disorders and progression to severe COVID-19 disease caused by SARS-CoV-2 coronavirus infection. ORP100S is delivered by inhalation and is planned for home use with the objective of reducing COVID-19 severity and the need for hospitalization. Our therapeutic strategy is based on supplementing the activity of the human protein thioredoxin-1 (TXN1), which is normally secreted onto the airway surface where it acts to selectively modify certain types of disulfide bonds between cysteine amino acids. This mechanism targets airway mucus to keep it at a normal viscosity (thickness and stickiness) and able to maintain the essential process of mucus clearance that sweeps the lungs clean of inhaled material and excess fluid. Thioredoxin also targets regulatory (allosteric) disulfide bonds on immune system proteins as part of a natural mechanism to prevent excessive release of cytokines in response to an inflammatory stimulus. Together, impaired airway clearance and abnormally elevated cytokine release comprise key pulmonary manifestations of moderate to severe COVID-19 that can lead to systemic disease and poor outcomes.

Why is your company the best option to solve the problem you're solving?

Published studies have shown that thioredoxin normalizes human mucus viscosity and in animal models can treat pneumonia and prevent progression of viral lung infection to acute respiratory distress syndrome (ARDS). Importantly, the activity of thioredoxin is not specific for just one virus but is anticipated to work as effectively for coronavirus as for influenza. Unfortunately, natural thioredoxin is not suitable for delivery as a drug itself because it has a short half-life in the body, low stability in the active form, and needs to be kept on the lung surface to avoid side effects. ORP100S is an improved thioredoxin (US patent 9,168,290) optimized for safe, targeted delivery to the site of action in the airway by direct inhalation. ORP100S is being developed for the treatment of chronic airway diseases including cystic fibrosis (CF) as well as for the immediate threat posed by COVID-19. Because of the urgent need to respond to the pandemic, there is a potential route to rapid FDA approval, especially for broad-spectrum approaches that overcome many of the limitations of vaccines, antivirals, and antibody-based drugs. ORP100S is at a mid-stage of preclinical development with Good Manufacturing Practice (GMP)-ready formulation and manufacturing advanced to 150L scale fermentation in E. coli with exceptionally high product titer and process yield. In acute toxicology studies funded by the National Institutes of Health and the Cystic Fibrosis Foundation, we have demonstrated a broad safety window with nebulized aerosols using approved inhalation delivery devices. The improvements in ORP100S also result in long-duration time on target and enhanced activity vs. natural thioredoxin as confirmed in studies undertaken at leading respiratory centers National Jewish Health (Denver, CO), The University of North Carolina - Chapel Hill, and the University of Alabama - Birmingham.

What nuggets of info make you interesting? Why do people care about what you're doing?

Many of the most important drugs developed using biotechnology have resulted from the application of secreted proteins as therapeutics. Our technology platform has for the first time enabled thioredoxin to be utilized as a safe, effective therapeutic by separating its extracellular and intracellular activities. Based on the anti-inflammatory and mucus-normalizing properties of secreted thioredoxin we anticipate that ORP100S, our engineered thioredoxin variant, will have high-impact potential across multiple diseases with unmet needs including serious indications affecting the lungs, digestive and reproductive tracts, and the eye.

What else do you want us to know?

We credit UC Berkeley Professor Emeritus Bob Buchanan for inspiring us through his discovery of the role of thioredoxin in reversible redox regulation and establishment of the paradigm that thioredoxin is a selective switch that modulates protein and enzyme activity. This perspective was essential for the breakthrough that led to our target-binding thioredoxin technology. Fun OrPro fact: In between graduate degrees CEO Peter Heifetz once canoed across the East China Sea in an antique Sabani boat, sponsored by Prince Charles of England and pursued by a pair of sake-crazed reporters from the Japanese edition of Sports Illustrated.