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| Names | |
|---|---|
| Preferred IUPAC name (6R)-N6-Propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider | |
| KEGG | |
PubChem CID | |
| UNII | |
CompTox Dashboard (EPA) | |
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| Properties | |
| C10H17N3S | |
| Molar mass | 211.33 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
Dexpramipexole is a first-in-class oral investigational medicine that lowers blood and tissue eosinophils before they can cause damage in the target organ. Dexpramipexole is being developed by Areteia Therapeutics and has the potential to be the first oral treatment ever approved for eosinophilic asthma.
The eosinophil-targeting effects of oral dexpramipexole were discovered during its clinical development. [1] Across five clinical trials, dexpramipexole has consistently been shown to significantly reduce blood eosinophil counts. [1] [2] [3] [4]
The most recently completed dexpramipexole clinical trial was EXHALE-1 (AS201), a Phase II clinical trial in participants with moderate-to-severe eosinophilic asthma. [4] Dexpramipexole demonstrated highly significant, dose dependent eosinophil lowering during the primary assessment phase and was maximal at Week 12. Dexpramipexole produced clinically relevant changes in FEV1 across study arms and time points and the magnitude of FEV1 improvement was comparable to currently approved biologics. Dexpramipexole was well tolerated in the trial, with adverse events balanced across treatment and placebo groups, no serious adverse events, and no adverse events leading to discontinuation.
Areteia Therapeutics is currently conducting three global Phase III clinical trials of dexpramipexole in eosinophil-associated asthma as listed below.
EXHALE-2: [5] a global Phase III clinical trial to evaluate the efficacy and safety of dexpramipexole as an add-on oral therapy in participants with inadequately controlled eosinophilic asthma, is currently recruiting people ≥12 years old with a documented physician diagnosis of asthma who require medium to high dose inhaled corticosteroids with at least one other controller medicine and a history of asthma exacerbations. The study will assess the effects of two different doses of dexpramipexole on exacerbation rates and lung function.
EXHALE-3: [6] a global Phase III clinical trial to evaluate the efficacy and safety of dexpramipexole as an add-on oral therapy in participants with inadequately controlled eosinophilic asthma, is currently recruiting people ≥12 years old with a documented physician diagnosis of asthma who require medium to high dose inhaled corticosteroids with at least one other controller medicine and a history of asthma exacerbations. The study will assess the effects of two different doses of dexpramipexole on exacerbation rates and lung function.
EXHALE-4: [7] a global Phase III clinical trial to evaluate dexpramipexole as an add-on oral therapy in participants with inadequately controlled eosinophilic asthma, is currently recruiting people ≥12 years old with a documented physician diagnosis of asthma who require treatment with at least low-dose inhaled corticosteroids and one other controller medicine. The study will assess improvements in lung function, asthma control, and quality of life.
Dexpramipexole was originally identified as a candidate therapy for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease by James Bennett, M.D., Ph.D., then of the University of Virginia.
The drug was initially investigated in ALS by Knopp Biosciences and Biogen Idec. A 2010 Phase II clinical trial showed a slowing of ALS disease progression and mortality benefits. [8] In January 2013, Biogen Idec discontinued its development of dexpramipexole in ALS due to lack of efficacy in the Phase III study. [9]
As a result of observing eosinophil lowering in the ALS trials, [1] Knopp pivoted dexpramipexole clinical development to eosinophil associated diseases. In subsequent clinical trials, dexpramipexole significantly reduced eosinophil counts and glucocorticoid requirements in patients with hypereosinophilic syndrome [2] and significantly reduced blood and tissue eosinophil counts in patients with chronic rhinosinusitis with nasal polyps. [3]
Dexpramipexole is the (D)-enantiomer of pramipexole. Enantiopure dexpramipexole has essentially no dopamine agonist activity and shares no other pharmacologic similarity to pramipexole. [10] In contrast, pramipexole the (S)-enantiomer is a dopamine agonist and is an approved drug (Mirapex) used in Parkinson’s disease.
Dexpramipexole is a low molecular weight, orally bioavailable, water-soluble small molecule with linear pharmacokinetics and linear dose proportionality.
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of white blood cells in the body.
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.
Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous system, or bone marrow.
Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis, is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy).
Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (NERD/N-ERD) or historically aspirin-induced asthma and Samter's Triad, refers to the triad of asthma, chronic rhinosinusitis with nasal polyps, and intolerance of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). AERD most commonly begins in early- to mid-adulthood and is a chronic disease that has no known cure. The cause of the disease is a dysregulation of the arachidonic acid metabolic pathway and of various innate immune cells, though the initial cause of this dysregulation is not currently known. While NSAID intolerance is a defining feature of AERD, simple avoidance does not prevent the onset, development or perennial nature of the disease.
Eosinophilic pneumonia is a disease in which an eosinophil, a type of white blood cell, accumulates in the lungs. These cells cause disruption of the normal air spaces (alveoli) where oxygen is extracted from the atmosphere. Several different kinds of eosinophilic pneumonia exist and can occur in any age group. The most common symptoms include cough, fever, difficulty breathing, and sweating at night. Eosinophilic pneumonia is diagnosed by a combination of characteristic symptoms, findings on a physical examination by a health provider, and the results of blood tests and X-rays. Prognosis is excellent once most eosinophilic pneumonia is recognized and treatment with corticosteroids is begun.
Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn.
Loeffler endocarditis is a form of heart disease characterized by a stiffened, poorly-functioning heart caused by infiltration of the heart by white blood cells known as eosinophils. Restrictive cardiomyopathy is a disease of the heart muscle which results in impaired diastolic filling of the heart ventricles, i.e. the large heart chambers which pump blood into the pulmonary or systemic circulation. Diastole is the part of the cardiac contraction-relaxation cycle in which the heart fills with venous blood after the emptying done during its previous systole.
Reslizumab is a humanized monoclonal antibody against human interleukin-5 (IL-5). Reslizumab binds specifically to IL-5, a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. By binding to human IL-5, it blocks its biological function; consequently survival and activity of eosinophils are reduced. The benefits with reslizumab are its ability to reduce the exacerbation rate and improve lung function and asthma-related quality of life in patients with severe eosinophilic asthma and with at least one previous asthma exacerbation in the preceding year. The most common side effects are increased blood creatine phosphokinase, myalgia and anaphylactic reactions.
Mepolizumab, sold under the brand name Nucala by GlaxoSmithKline, is a humanized monoclonal antibody used for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis, and hypereosinophilic syndrome (HES). It recognizes and blocks interleukin-5 (IL-5), a signalling protein of the immune system.
Eosinophilic gastroenteritis is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal (GI) tissue, first described by Kaijser in 1937. Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement. Any part of the GI tract can be affected, and isolated biliary tract involvement has also been reported. The stomach is the organ most commonly affected, followed by the small intestine and the colon.
Ciclosporin is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant. It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis, rheumatoid arthritis, dry eye and other auto-immune related conditions. A variety of pre-clinical and clinical studies have been and are investigating its use to treat lung-related disorders via inhalation.
Eosinophilic bronchitis (EB) is a type of airway inflammation due to excessive mast cell recruitment and activation in the superficial airways as opposed to the smooth muscles of the airways as seen in asthma. It often results in a chronic cough. Lung function tests are usually normal. Inhaled corticosteroids are often an effective treatment.
Dupilumab, sold under the brand name Dupixent, is a monoclonal antibody blocking interleukin 4 and interleukin 13, used for allergic diseases such as eczema, asthma and nasal polyps which result in chronic sinusitis. It is also used for the treatment of eosinophilic esophagitis and prurigo nodularis.
Setipiprant (INN; developmental code names ACT-129968, KYTH-105) is an investigational drug developed for the treatment of asthma and scalp hair loss. It was originally developed by Actelion and acts as a selective, orally available antagonist of the prostaglandin D2 receptor 2 (DP2). The drug is being developed as a novel treatment for male pattern baldness by Allergan.
Eosinophilic myocarditis is inflammation in the heart muscle that is caused by the infiltration and destructive activity of a type of white blood cell, the eosinophil. Typically, the disorder is associated with hypereosinophilia, i.e. an eosinophil blood cell count greater than 1,500 per microliter. It is distinguished from non-eosinophilic myocarditis, which is heart inflammation caused by other types of white blood cells, i.e. lymphocytes and monocytes, as well as the respective descendants of these cells, NK cells and macrophages. This distinction is important because the eosinophil-based disorder is due to a particular set of underlying diseases and its preferred treatments differ from those for non-eosinophilic myocarditis.
Fevipiprant (INN; code name QAW039) is a drug that was being developed by Novartis. It is a selective, orally available antagonist of the prostaglandin D2 receptor 2 (DP2 or CRTh2).
Lymphocyte-variant hypereosinophilia is a rare disorder in which eosinophilia or hypereosinophilia is caused by an aberrant population of lymphocytes. These aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells termed colony forming unit-Eosinophils or CFU-Eos.
Familial eosinophilia is a rare congenital disorder characterized by the presence of sustained elevations in blood eosinophil levels that reach ranges diagnostic of eosinophilia or, far more commonly, hypereosinophilia. Although high eosinophil levels are associated with certain diseases and thought to contribute to the tissue destruction found in many other eosinophilia-related diseases, clinical manifestations and tissue destruction related to the eosinophilia in familial eosinophilia is uncommon: this genetic disease typically has a benign phenotype and course compared to other congenital and acquired eosinophilic diseases.
Toreforant (JNJ-38518168) is an orally-dosed selective antagonist of the histamine H4 receptor that has been studied for various health conditions. It is the successor of a number of H4-selective compounds developed by Johnson & Johnson. Phase IIa clinical trials completed as recently as November 2018 continue to suggest that toreforant is safe.
