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Ramatroban, a Thromboxane A2/TPr and PGD2/DPr2 receptor antagonist for Acute and Long haul COVID-19

Author: Ajay Gupta, MD

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>
Date: Wednesday, July 7, 2021 at 1:10 PM
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Cc: “Dr. Saul Yedgar” <saulye@ekmd.huji.ac.il>
Subject: Ramatroban, a Thromboxane A2/TPr and PGD2/DPr2 receptor antagonist for Acute and Long haul COVID-19

While corticosteroids may have a role in about 5% of hospitalized patients who have the cytokine storm, currently there is no effective treatment for mild or moderate COVID and long haul COVID. Massive increase in respiratory and plasma thromboxane A₂ (TxA₂) plays a key role in thromboinflammation and microvascular thrombosis, while an increase in respiratory and plasma PGD₂ potentially suppresses innate interferon response, and acquired Th1 anti-viral response, while promoting a maladaptive type 2, anti-helminthic like immune response. Ramatroban is a potent dual receptor antagonist of Thromboxane A2/TPr and PGD2/DPr2 that has been used in Japan for the treatment of allergic rhinitis for past 20 years (Baynas®, Bayer Japan). We first disclosed use of ramatroban for COVID in a provisional patent application filed on 31^st March, 2020; followed by the publication Gupta et al, J Mol Genet Med, 2020

Several experts, as outlined below in yellow highlighted text, have supported the idea of using ramatroban as an anti-thrombotic and immunomodulator in COVID-19.

1.     Prof. Louis Flamand, Nicolas Flamand, Eric Boilard Laval Univ. Quebec, Canada: There is a lipid-mediator storm in COVID-19 characterized by massive increases in thromboxane A2 and PGD2 in the lungs and plasma.  “Blocking the deleterious effects of             PGD₂ and TxA₂ with the dual DPr2/TPr antagonist Ramatroban might be beneficial in COVID-19 Archambault et al, FASEB, June 2021, doi: https://doi.org/10.1096/fj.202100540R

2. Prof. Garret A FitzGerald, Univ. Of Pennsylvania, Member National Academy of Sciences.https://en.wikipedia.org/wiki/Garret_A._FitzGerald “In the current pandemic there may be utility in targeting eicosanoids with existing drugs.  These approaches would likely be most effective early in the disease before the development of ARDS, where cytokines and chemokines dominate. Dexamethasone limits COX-2 expression and might diminish COVID-19 severity and mortality at least in part, by diminishing COX metabolites… Dexamethasone might improve severe COVID-19 by diminishing the prostaglandins / thromboxane storm in the lungs”. “Treatment with a PGD2/DPr2 inhibitor decreased viral load and improved morbidity by upregulating IFN-lambda expression. …..  Antagonism of the thromboxane receptor (TPr) prevents ARDS…. Early administration of well-tolerated TPr antagonists may limit progress to severe COVID-19 (Theken and FitzGerald, Science, 2021)

4.     Prof. Simon Phipps, Univ. of Queensland, Brisbane Australia “It has been hypothesized that DP2 antagonists be repurposed as a novel immunotherapy for the treatment of COVID-19, and this may be appropriate in mild to moderate cases where Th1 immunity is impaired.” (Ullah et al, Mucosal Immunology, 2021)

5.     Prof. Bruce D. Hammock, Distinguished Professor, Univ of California Davis, Member US National Academy of Sciences and National Academy of Inventors; April 25, 2021. https://www.entsoc.org/fellows/hammock “I find your idea of blocking specific thromboxane receptors in preventing or reducing some of the devastating co-morbidity of COVID-19 very compelling. … A DPr2 receptor blocker is conceptually attractive in offering the potential of effective therapy and low risk due to a high therapeutic index.” E mail dated April 25, 2021.  (https://ajp.amjpathol.org/action/showPdf?pii=S0002-9440%2820%2930332-1    and http://ucanr.edu/sites/hammocklab/files/328012.pdf)

6. Ann E Eakin, PhD, Senior Scientific Officer, NIH-NIAID “very compelling data supporting potential benefits of ramatroban in both reducing viral load as well as modulating host responses” E Mail dated Nov 20, 2020

7. Prof. James Ritter, MA, DPhil, FRCP, FMedSci, Hon FBPhS https://www.trinhall.cam.ac.uk/contact-us/contact-directory/fellows-and-academics-directory/james-ritter/ “Very impressive, and fascinating” referring to ramatroban for COVID-19 in an e-mail dated Dec 21, 2020

Ramatroban is expected to reduce lung fibrosis in COVID-19 and therefore diminish clinical manifestations of Long haul COVID. Pang et al, 2021 “examined the effect of Ramatroban, a clinical antagonist of both PGD₂ and TXA₂ receptors, on treating silicosis using a mouse model. The results showed that Ramatroban significantly alleviated silica-induced pulmonary inflammation, fibrosis, and cardiopulmonary dysfunction compared with the control group.” https://www.thno.org/v11p2381.htm

Unfortunately, the animal models of COVID-19 are harsh, lack microvascular thrombosis and immune perturbations characteristic of human disease. These models may be good for testing antivirals but not for testing immunomodulators or anti-thrombotics. There is highly positive anecdotal experience with use of ramatroban in moderately severe COVID-19 (https://www.researchsquare.com/article/rs-474882/v1

Additionally, Ramatroban holds great promise in sickle cell disease, cardiovascular disease https://doi.org/10.1111/j.1527-3466.2004.tb00132.x, and community acquired pneumonia.

Best regards,

Ajay

Ajay Gupta, M.B.,B.S., M.D.

Clinical Professor,

Division of Nephrology, Hypertension and Kidney Transplantation

University of California Irvine  

President & CSO, KARE Biosciences (www.karebio.com)

E-mail:     ajayg1@hs.uci.edu

Cell:         1 (562) 412-6259

Office:     1 (562) 419-7029

Please see some of our recent publications in the COVID area.  

https://assets.researchsquare.com/files/rs-474882/v1/6d209040-e94b-4adf-80a9-3a9eddf93def.pdf?c=1619795476

https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/3395

https://www.tandfonline.com/doi/full/10.1080/13543784.2021.1950687

https://www.amjmed.com/article/S0002-9343(20)30872-X/fulltext