BRINGING ATP TECHNOLOGY TO PATIENT CARE
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FOCUSING ON NOVEL THERAPEUTICS BASED ON P2 RECEPTORS' SIGNAL TRANSDUCTIONS
We're an emerging biopharmaceutical company focusing on novel therapeutic approaches based on the pharmacologic manipulations of P2 receptors' signal transductions activated by extracellular adenosine 5'-triphosphate (ATP). Our lead drug-candidate DT-0111 is a small, water soluble, selective P2X2/3R antagonist that is being developed for the treatment of chronic obstructive pulmonary disease (COPD) and chronic cough.
COPD & CHRONIC COUGH
Chronic obstructive pulmonary disease (COPD) is characterized by a slow, progressive narrowing of the airways and the resulting impediment of air movement in and out of the lungs, impaired oxygenation of blood, mucous hypersecretion and cough. It is expected that by 2020, COPD will become the third leading cause of death in the U.S. and an increasing cause of morbidity and mortality worldwide. In the U.S., about 16 million patients have received a diagnosis of symptomatic COPD, and the direct and indirect costs of COPD are currently estimated at about 32 billion dollars. At present time, there is no drug therapy that can prevent the relentless progression of the disease. COPD is commonly treated with short and long acting bronchodilators long-acting muscarinic antagonists (LAMA) and long-acting beta agonists (LABA), and corticosteroids with LAMA or LABA or without, and phosphodiesterase-4 inhibitor. The use of these drugs is associated with serious side effects. Recognition of global importance and rising prevalence of COPD, and the absence of optimal therapies emphasize the critical need for new drugs for the treatment of this disease. The global COPD market is currently estimated to be worth $11.3 billion and it is forecast to increase to $15.6 billion by 2019.
Chronic cough (cough lasting longer than eight weeks), which is manifested by 3-40% of adult patients, can be associated with several pulmonary disorders. It is an important cause of morbidity and mortality and significantly reduces quality of life. It is estimated that chronic cough affects approximately 10% of the adult population in the US. No new prescription or over-the-counter drugs for the treatment of cough have been approved for a generation. The world market for cough is estimated to be >$3 billion.
ATP IN THE LUNGS
Adenosine 5'-triphosphate (ATP), the molecular structure of which is shown in the upper panel on the right, is a ubiquitous molecule found in every cell of the human body where it plays a major role in cellular energetics and metabolism. ATP is released from cells under physiologic and pathophysiologic conditions. Extracellular ATP acts an autocrine and paracrine agent exerting its effects on target cells by activation P2 Purinergic receptors (P2R). There are two families of P2R: P2YR, G-protein couples receptors, and P2XR, trans-cell membrane cationic channels. ATP is released from infected or injured cells to activate inflammatory or reparatory processes. As depicted in the lower panel on the right, ATP stimulates vagal sensory nerve terminals in the lungs thereby triggering a pulmonary-pulmonary central reflex resulting in bronchoconstriction and cough. In addition, it causes local release of pro-inflammatory neuropeptides via an axon reflex. These actions are mediated by P2X2/3R localized on vagal nerve terminals. DT-0111 is a selective antagonist of P2X2/3R; it inhibits these deleterious effects of ATP.
For more details see: Pelleg A, Schulman ES, Barnes PJ. Extracellular Adenosine 5'-triphosphate in Obstructive Airway Diseases. Chest 2016; 150:908-15
Pelleg A, Barnes, PJ, Schulman ES. Targeting ATP-axis in lungs as a new therapeutic modality in COPD. Med Res Arch 2023; doi.org/10.18103/mra.v11i10.4487
Pelleg A. DT-0111: a novel P2X3 receptor antagonist. Purin Signal 2023; 19:467-79. doi.org/10.1007/s11302-023-09930-5
KEY PERSONNEL
Amir Pelleg, Ph.D., FACC, FAHA
CEO and CSO
Dr. Pelleg founded the company in 2008. From 1992 to 2004 he was a Professor of Medicine at Hahnemann University School of Medicine and currently is an Adjunct Professor of Medicine at Drexel University College of Medicine. He is an internationally recognized expert on ATP and adenosine and has published more than 100 peer reviewed scientific papers and co-edited and co-authored three books. In 2002, he and Prof. Ed Schulman were the first to propose that ATP plays a mechanistic role in chronic obstructive pulmonary diseases and his lab was the first to demonstrate that extracellular ATP stimulates vagal sensory nerve terminals in the heart and lungs by activating P2X receptors. He has more than thirty years of experience in drug development. He was the founder and CEO and CSO of Duska Therapeutics, Inc., a publicly traded company. While there, he has obtained from the FDA the SPA status for the drug-candidate ATPace™ for the acute treatment of paroxysmal supraventricular tachycardia. He was on the team of MEDCO Research, Inc. that put the first two adenosine drugs Adenoscan® and Adenocard® on the market. He holds B.Sc. degree in biology from Tel-Aviv University, M.S. degree in bioengineering from the Polytechnic Institute of Brooklyn, NY and a Ph.D. degree in physiology from LSU Medical Center in New Orleans, LA. He completed his postdoctoral training as a NIH fellow at the University of Virginia in Charlottesville, VA.
James Ku, M.D., MBA
Vice President
Dr. Kuo has experience in the life science industry as a Chief Executive Officer, business development executive, and venture capitalist. Most recently, he served as Chairman and Chief Executive Officer of Synthetic Biologics, a publicly-traded biotech company. While there, two financings and a collaboration with a European pharmaceutical company were completed. Synthetic’s stock went from $0.82 to $2.30 during his tenure as CEO. Dr. Kuo has also served as Chairman and Chief Executive Officer of BioMicro Systems. The company received several rounds of venture financing, achieved several million dollars in sales of an internally developed instrument for microarray research, and was eventually sold to a major European pharmaceutical company. Dr. Kuo has further served as the Chief Executive Officer of Discovery Laboratories, a publicly-traded company developing surfactant-based respiratory therapeutics. Dr. Kuo has been Associate Director of Licensing and Development at Pfizer and Vice President of Business Development at Myriad Genetics. He has also been Managing Director of HealthCare Ventures, a $378 million venture capital fund. He received his MD from the University of Pennsylvania School of Medicine and his MBA from the Wharton School of Business. He received his BA in molecular biology from Haverford College.
Anu Mahadaven, Ph.D.
Chairwoman
Dr. Mahadevan is a medicinal chemist with extensive experience in molecular structure and activity relationship and drug development. She is currently the CEO of Organix, Inc., a privately-owned company that is a minority shareholder of Danmir. Anu has co-authored more than fifty peer-reviewed papers dealing with medicinal chemistry in general and molecular structure function in particular. She holds a M.S. degree in chemistry from the Indian Institute of Technology, and a Ph.D. in organic chemistry from Purdue University.
Prof. Peter J. Barnes, D.M., FRS
Chairman, Advisory Board
Peter Barnes is Professor of Thoracic Medicine and Head of Respiratory Medicine at the National Heart and Lung Institute and Honorary Consultant Physician at Royal Brompton Hospital, London. He qualified at Cambridge and Oxford Universities (first class honours) and was appointed to his present post in 1987. He has published over 1000 peer-review papers on asthma, COPD and related topics and has edited over 40 books (h-index = 153). He is also amongst the top 50 most highly cited researchers in the world and has been the most highly cited clinical scientist in the UK and the most highly cited respiratory researcher in the world over the last 20 years. He was elected a Fellow of the Royal Society in 2007, the first respiratory researcher for over 150 years.
He has been a member of the Scientific Committee of global guidelines on asthma (GINA) and COPD (GOLD). He also serves on the Editorial Board of over 30 journals and is currently an Associate Editor of Chest, Journal of COPD Foundation, Respiratory Editor of PLoS Medicine and Editor in Chief of Up-to-Date Pulmonary Diseases. He has given several prestigious lectures, including the Amberson Lecture at the American Thoracic Society, the Sadoul Lecture at the European Respiratory Society and the Croonian Lecture at the Royal College of Physicians. He has received honorary MD degrees from the Universities of Ferrara (Italy), Athens (Greece), Tampere (Finland) and Leuven (Belgium).
He is an Emeritus NIHR Senior Investigator,a Master Fellow of the American College of Chest Physicians and a member of the Academia Europaea. He was President of the European Respiratory Society 2013/14. He co-founded an Imperial spin-out company RespiVert, which was acquired by Johnson & Johnson and has developed novel inhaled treatments for COPD and severe asthma.
His research is focused on cellular and molecular mechanisms of asthma and COPD, understanding and developing therapies and research into biomarkers for these diseases. He is involved in multidisciplinary translational research which integrates basic science with clinical studies, thereby providing novel insights into common airway diseases.
Product Pipeline:
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DT-0111 (Aspirex™): A novel water soluble small molecule that acts as a selective P2X2/3 receptor antagonist that is being developed as an inhalation drug for the treatment of COPD and chronic cough.
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DT-0115 (ATPortect™): A proprietary oral formulation of ATP that is being developed as a drug for the protection from ionizing radiation and reduced side effects of radiation therapy.
DT-0111
For the treatment of COPD an d chronic cough
Extracellular ATP stimulates vagal sensory nerve terminals in the lungs by activating P2X2/3 receptors (P2X2/3R). This action results in bronchoconstriction, cough, and localized release of pro-inflammatory neuro-peptides. The levels of extracellular ATP in the lungs of COPD patients is significantly elevated (x3 normal). Therefore, P2X2/3R has been identified as an important target for drug development. Shown on the left (upper panel) is the effect of inhaled DT-0111 (6 mg/ml; 2 min) on inhaled ATP-induced bronchoconstriction (Ptr Response; Δ% ) in the guinea-pig in vivo. The total amount of DT-0111 administered was ~2.9 mg/kg.
In addition, aerosolized DT-0111 abolished aerosolized ATP-induced bronchoconstriction (middle panel: % Raw response) and cough in conscious free moving guinea-pigs (lower panel: number of coughing bouts, left, and number of coughs, right).
Upper panel: DT-0111 effects on tracheal pressure (Ptr). A: Aerosolized DT-0111 (6 mg/ml for 2 min) failed to change baseline Ptr (p = NS). B: Ptr responses to different ATP doses (Low, L; middle, M; and high, H) were significantly suppressed by pretreatment of aerosolized DT-0111. Ptr responses to middle and high ATP concentration were higher than those induced by low ATP dose. C: The averaged percentage of the inhibition of Ptr responses to the three groups of ATP doses by aerosolized DT-0111 are similar in individual guinea-pigs. n = 7 for L, M, and H ATP dose, respectively. Data are mean ± SE. *p< 0.01, compared to baseline Ptr in B, and to ATP at a given concentration prior to DT-0111 in C; †p< 0.01, compared to L ATP dose; and ‡p< 0.01, compared to before DT-0111 pre-treatment.
Middle panel: The bronchoconstrictive effect of inhaled increasing doses of aerosolized ATP before (Ctrl) and after aerosolized DT-0111 inhalation (DT-0111) in conscious guinea-pigs expressed as % change in airways pressure (sRaw). N = 6; * p < 0.05, vs. ATP 0.0 mg/ml; † p < 0.05, DT-0111 vs. Ctrl at the same ATP dose.
Lower panel: Effects of DT aerosol inhalation on aerosolized ATP-induced cough response in guinea pigs. Upper panel: typical burst of coughs occurred during exposure to aerosolized ATP (48 mg/ml) for 5 min, and immediately after the administration of aerosolized DT-0111 (DT, 12 mg/ml.
DT-0115
For the protection from ionizing radiation and reduced side-effects of radiation therapy
DT-0115 is a proprietary oral formulation of ATP aimed at elevating blood levels of ATP.
Multiple studies in vivo using several animal species have shown that exogenous ATP (injectable solution) protects the organism from damage caused by different types of radiation including X-ray, gamma, neutron and isotopes. In addition, previous studies in animal models as well as in human subjects have shown that intravenous administration of sufficient doses of ATP or its precursors, adenosine and inorganic phosphate eventually results in increased blood levels of ATP. The mechanism behind this phenomenon involves the loading of red blood cells (RBC) with ATP in the liver and the release of ATP from circulating RBC into the blood. Currently, there is no oral formulation of ATP that facilitates efficient absorbance of the compound in the gastro-intestinal tract.
Current developmental status: Proof-of-concept in-vivo
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