DSTAT

Dociparstat sodium, also known as DSTAT, is a glycosaminoglycan derivative of heparin with known anti-inflammatory properties, but with substantially reduced risk of bleeding complications compared to commercially available forms of heparin.

DSTAT is currently in development as a first-line therapy in acute myeloid leukemia (AML). The scientific literature and recent clinical studies suggest that adding DSTAT to standard chemotherapy for AML may improve patient outcomes.

DSTAT is also being developed for acute lung injury (ALI) in COVID-19 patients. DSTAT has demonstrated potential in preclinical studies to address key inflammatory and coagulation disorders observed in patients with severe COVID-19.

How does DSTAT work in AML?

DSTAT may enhance eradication of leukemic blasts and quiescent leukemic stem cells (LSCs) by making them more sensitive to chemotherapy. DSTAT is thought to increase the depth of response to standard chemotherapy, thereby reducing the potential for relapse, and improving long-term outcomes for patients with AML. Specifically, DSTAT inhibits binding and/or interactions of proteins including CXCL12, P-selectin, high mobility group box 1 (HMGB1), platelet factor 4 (PF4) and human leukocyte elastase (HLE) which are involved in leukemic blast adhesion, survival and proliferation. Additionally, these DSTAT binding interactions may reverse quiescence of LSCs by inducing cell division which reverses resistance to chemotherapies like “7+3” (cytarabine plus anthracycline).a

Read more about DSTAT and results from a Phase 2 clinical trial here.

How Does DSTAT Work in Acute Lung Injury (ALI) in COVID-19 patients?

COVID-19 is caused by a newly discovered coronavirus (SARS-CoV-2); clinical manifestations range from mild, self-limited respiratory tract illness to severe alveolar damage which may lead to progressive respiratory failure, multiple organ failure and death.

Mortality in cases of severe COVID-19 is often associated with ALI that progresses to Acute Respiratory Distress Syndrome (ARDS).  Respiratory distress is believed to be compounded by high concentrations of inflammatory cytokines (“cytokine storm”), immune cell aberrations, as well as coagulation disorders such as disseminated intravascular coagulation (DIC) and pulmonary embolisms.

DSTAT has the potential to inhibit the hyperactive immune response and resulting inflammation, as well as address the underlying causes of coagulation disorders seen in COVID-19 patients, but with substantially reduced risk of bleeding complications compared to commercially available forms of heparin.b

Specifically, DSTAT has the potential to:

  • Decrease inflammation/immune cell infiltration in COVID-19 patients with ALI: In pre-clinical models, a primary anti-inflammatory effect of DSTAT is mediated through inhibition of high mobility group box 1 (HMGB1) activity. Inhibition of HMGB1 activity reduces expression of downstream proinflammatory cytokines including, but not limited to, IL-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), all of which are implicated in the overactive immune response seen in COVID-19.Infiltration of monocytes and other immune cells into inflamed lung tissue is a key pathogenic driver of ALI. DSTAT has been shown to reduce this immune cell infiltration of the lung in pre-clinical models, likely through inhibition of MCP-1 and other ligands involved in migration of monocytes, neutrophils and other effector cells that promote hyperinflammation. A recent study found the dominant macrophages in the lungs of patients with severe COVID-19 had a highly inflammatory phenotype. DSTAT may reduce lung infiltration by inflammatory cells in COVID-19 through direct or indirect (e.g., HMGB1-mediated) inhibition of several chemotactic ligands.b

    Figure 1. Infection with SARS-CoV-2 can directly kill lung cells lining the alveoli which are critical for efficient oxygenation of the blood. The virus can set off a cascade of events that leads to excessive inflammation (“cytokine storm”), infiltration of activated immune cells into the lungs and coagulation disorders in the blood and tissues. In severe cases breathing is significantly impaired, as in ARDS, and blood clots can lead to life-threatening tissue damage.

  • Alleviate the underlying causes of coagulation disorders by inhibiting activities of HMGB1 and PF4: Two recent studies have identified high neutrophil/lymphocyte ratios and low platelet counts as clinically relevant indicators of disease severity and risk of mortality in COVID-19. Neutrophils are early responders to infection capable of extruding granular and nuclear contents to produce neutrophil extracellular traps (NETs). NETs may be beneficial (e.g., by trapping pathogens); however, excessive NETs can be pathogenic, particularly in the lungs where damage to the thin layer of cells in the alveoli can result in decreased oxygenation. HMGB1 promotes NETs which may drive hypercoagulation by providing a substrate for platelet aggregation and by upregulating tissue factors on endothelial cells.b Activated platelets, in turn, release PF4, which further increases inflammation, creating a detrimental cycle. DSTAT’s inhibition of two key inflammatory drivers of this process (PF4 and HMGB1) may prevent and treat coagulation disorders observed in COVID-19 patients.b

DSTAT has the potential to improve outcomes in COVID-19 patients by dampening the excessive inflammation, aberrant immune cell responses, and coagulation disorders observed in severe disease. However, DSTAT is an investigational agent which is not currently FDA-approved and the safety and efficacy of DSTAT for treatment of ALI in COVID-19 patients has not been studied in clinical trials to date.

DSTAT has been studied in other indications, and in a recent Phase 2 Acute Myeloid Leukemia (AML) study DSTAT was well tolerated with adverse events similar across DSTAT and control groups. The most common serious adverse event was febrile neutropenia with three cases in each DSTAT-treated group and one case in the control group; this was not associated with an imbalance in infection across treatment groups.

All drug product supplies are being directed to clinical trials to determine the safety and efficacy of DSTAT in the setting of COVID-19.

Phase 2/3 Study of DSTAT in Acute Lung Injury for Patients with Severe COVID-19 Infection

Chimerix is currently enrolling a randomized, double blind, placebo-controlled Phase 2/3 study to evaluate the safety and efficacy of DSTAT in patients with ALI due to COVID-19 who are at high risk of respiratory failure. This study is designed to determine if DSTAT can accelerate recovery and prevent progression to mechanical ventilation in patients severely affected by COVID-19.

Learn more about the study here.

References: a Zhang 2012 JBC 287(8); Kovacsovics 2018 Blood Adv 2(4); Yasinska 2018 Oncoimmunology 7(6); Rao 2010 Am J Physiol Cell Physiol 299; Zheng 2016 Am J Cell and Mol Bio 56(1); Griffin 2014 Am J Resp Cell and Mol Bio 50(4); Lakshmi 2010 J Biomed Mat Res 95(1); Yu 2005 Blood 105(9);  Lapierre 1996 Glycobiology 6(3); Tavor 2005 Blood 106(6); Kummarapurugu 2018 JBC 293(32)

b Rao 2010 Am J Physiol Cell Phsiol 299; Zhou 2020 The Lancet 6736(20); Tang 2020 J Thrombosis and Haemostasis; Kim 2013 Mol Medicine, 19(1); Huang 2020 The Lancet 395(10223); Herold 2020 MedRxiv; Thompson 2017 New End J Medicine 377(6); Sharma 2014 J of Immunotoxicology 11(3); Liu2020 MedRxiv 807; Lippi 2019 Clinica Chimica 2019; Porto 2016 Frontiers in Immunology 7; Tadie 2013 Am J of Physiol 304(5); Bdeir 2017 Am J Resp Cell Mol Bio 56(2); Kowalska 2014 Artiosclerosis, Throm, and Vasc Bio 34(1); Krauel 2012 Blood 119(5).(note: DSTAT is commonly referred to in the citations above as 2-O, 3-O desulfated heparin, ODSH or CX-01)