Constant Therapeutics LLC is a clinical stage company developing Mas receptor agonists for treatment of COVID-19, CNS, and rare disorders. Its lead drug candidate, TXA127, is a pharmaceutical formulation of the natural human peptide, angiotensin-(1-7) [Ang-(1-7)].
TXA127 is uniquely positioned at the intersection of two current views of COVID-19:
- The disease is characterized by a diffuse vasculopathy and
- The disease is an ACE2/Ang-(1-7) deficiency.
TXA127’s mechanism of action addresses much of the pathophysiology of COVID-19 by replacing the lost Ang-(1-7) caused by SARS-CoV-2 binding to ACE2.
The availability of a TREATMENT like TXA127 could transform COVID-19 from an international crisis to a manageable illness. An effective treatment would reduce disease severity, morbidity, mortality and decrease the need for scarce hospital and ICU resources, taking pressure off the development timelines for vaccinesand anti-virals. The disease process in COVID-19 is closely related to the mechanism of action of Constant’s drug. TXA127 may be uniquely positioned as an important therapy, independent of the availability of vaccines, and synergistic with anti-viral medications such as Remdesivir.
Recent data shows that the level of Ang-(1-7) is inversely correlated with the severity of COVID-19 disease (Henry, et al., unpublished):
The disease pathophysiology of SARS-CoV-2 infection is unique and very complex. The binding of SARS-CoV-2 to the membrane bound enzyme ACE2 results in a decrease in enzymatic activity and subsequent reduction in the peptide Ang-(1-7), the principal product of the action of ACE2 on angiotensin II (Ang II). This results in a loss of Ang-(1-7)’s intrinsically protective effects.
Ang-(1-7), the active ingredient in Constant’s product, TXA127, has been shown to have multiple biologic effects that are relevant to the treatment of COVID-19. These effects include:
- reducing oxidative stress and ROS,
- restoring the integrity of epithelial and endothelial surfaces,
- reducing inflammation by reversing the increased permeability of the blood vessels caused by the virus; thereby preventing movement of inflammatory cells into tissue leading to the “cytokine storm,”
- reducing apoptosis,
- inhibiting coagulopathy, and
- reducing fibrosis through down-regulation of the TGF beta pathway.
Ang-(1-7) has been shown to have positive outcomes in a number of animal models of lung injury, stroke and heart disease. In addition, in several disease models it has become clear that blocking the effect of Ang-(1-7) is detrimental.
In response to requests from multiple medical centers around the world, Constant now plans three investigator-initiated clinical trials at Columbia University Irving Medical Center in New York City, Rambam Health Care Campus in Israel, and Policlinico S. Orsola-Malpighi in Bologna, Italy. They will recruit around 280 patients, with Columbia and Israel designed as randomized, placebo- controlled trials with 100 and 120 patients respectively. The trial in Bologna will be open-label and will recruit up to 60 patients. The first two of these trials, in New York and Israel, are expected to begin recruitment in August 2020.
In parallel with these IITs, Constant is planning a definitive multi-center company-sponsored Phase 2/3 trial, with the lead site at the Brigham and Women’s Hospital in Boston, one of the major Harvard teaching hospitals. The trial is expected to recruit approximately 200 patients and will involve 10-15 sites across the US.