DSTAT

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.

Chimerix is investigating smarter ways to treat acute myeloid leukemia (AML), and potentially other hematologic indications. With more than 21,000 new cases of AML diagnosed annually in the U.S. and a five-year survival rate in elderly patients of less than 30%, there is a clear and urgent need for life-extending and life-saving treatment options.1

What is AML?

AML is a type of cancer in the blood and bone marrow that rapidly progresses and interferes with the production of normal white blood cells, red blood cells and platelets.

How is AML treated?

Currently, most patients receive chemotherapy, sometimes in combination with a targeted therapy, as treatment for AML. The goal is to eradicate as many AML cancer cells and leukemic stem cells as possible. If patients respond well, they may go on to receive a stem cell transplant.

What is the prognosis of AML with treatment?

Patients with AML receiving chemotherapy treatment may experience up to a 70% mortality rate within the first year of treatment, depending on age and comorbidities.1 Even patients who respond well to chemotherapy are likely to relapse in 12 months or less.1

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-protein binding interactions may reverse quiescence of LSCs by inducing cell division which reverses resistance to chemotherapies like “7+3” (cytarabine plus anthracycline).2

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

Treatment with DSTAT in chemotherapy

Phase 3 Study of DSTAT in Combination With Standard Chemotherapy for the Treatment of Acute Myeloid Leukemia (AML)

Chimerix is planning to enroll a Phase 3 in early 2021 to evaluate the efficacy and safety of DSTAT in adults with newly diagnosed adults with AML, fit for intensive chemotherapy

Learn more about the study here.

How does DSTAT work in COVID-19?

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.

Disease and mortality in COVID-19 is often associated with breathing difficulties that progress to Acute Respiratory Distress Syndrome (ARDS) and blood clotting disorders, both of which may be attributed to dysregulated inflammatory responses.  As the mechanistic understanding of COVID-19 pathogenesis has evolved, potential treatments which address the presumptive mechanisms have been identified and prioritized for clinical evaluation.  DSTAT is one such treatment with potential to decrease systemic and pulmonary inflammation, reduce clotting problems and improve clinical outcomes for patients hospitalized with COVID-19.3

Specifically, DSTAT has the potential to:

  • Decrease inflammation and lung immune cell infiltration via inhibition of HMGB1 and P-selectin:   In pre-clinical models, a primary anti-inflammatory effect of DSTAT is mediated through HMGB1, a protein which  increases expression of proinflammatory cytokines including 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 elevated in severe COVID-19.  Infiltration of monocytes and other immune cells into inflamed lung tissue is also key pathogenic driver of respiratory problems. In vivo disease models have demonstrated that DSTAT can reduce HMGB1 in lung fluid, decrease immune cell infiltration in lungs and improve survival.   Molecular drivers of these effects likely include DSTAT inhibition of HMGB1 binding to RAGE, inhibition of leukocyte lung infiltration via decreases in MCP-1 expression, and direct blocking of the cell adhesion molecule P-selectin.  Overall, inhibition of HMGB1 is an attractive target as it may modulate multiple pro-inflammatory factors, reduce immune cell migration and attenuate cytokine-associated lung injury.
  • Improve COVID coagulopathy: Severe COVID-19 infection is associated with a significant risk of blood clotting disorders that can lead to multi-organ failure and death.  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). While NETs are often beneficial in trapping and eliminating pathogens, they can also promote clotting and are correlated with intubation and death in COVID-19.  HMGB1 and PF4 are proteins that can induce formation of NETS and regulate NET degradation; both are significantly elevated in COVID-19 patients and both are inhibited by binding to DSTAT.   DSTAT inhibition of these two proteins may reduce formation of NETs and promote their clearance, thereby potentially preventing and treating coagulation disorders.
COVID treatment
Moderate to severe COVID-19 manifests with excessive inflammation, infiltration of activated immune cells into the lungs and coagulation disorders (e.g., clot formation) in the blood and tissues. DSTAT has the potential to prevent and mitigate these severe effects of SARS-CoV-2 infection by inhibiting several pathogenic pathways.

DSTAT inhibits several apparently key molecular drivers of COVID-19 pathology, including HMGB1, PF4 and P-selectin. DSTAT may effectively reduce excessive inflammation and coagulation disorders observed in COVID-19 via multiple mechanisms without the risk of severe bleeding events presented by fully anticoagulant forms of heparin. DSTAT is an investigational agent which is not currently FDA-approved.

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: 

  1. NIH National Cancer Institute. Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML) Retrieved from https://seer.cancer.gov/statfacts/html/amyl.html; Meyers 2013. Appl Health Econ Health Policy. 11(3):275-286; Walter 2015 Leukemia 29(2):312-320.
  2. Zhang 2012 JBC 287(8):5542-53; Kovacsovics 2018 Blood Adv 2(4):381-389; Yasinska 2018 Oncoimmunology 7:6; Rao 2010 Am J Physiol Cell Physiol 299(1):C97-110; Zheng 2017 Am J Respir Cell Mol Bio 56(1):90-98; Griffin 2014 Am J Resp Cell and Mol Bio 50(4):684-9; Lakshmi 2010 J Biomed Mat Res 95(1):118-28; Yu 2005 Blood 105(9):3545-51;  Lapierre 1996 Glycobiology 6(3):355-66; Tavor 2005 Blood 106(6):2120-7; Kummarapurugu 2018 J Biol Chem 293(32):12480-12490.  
  3. Rao 2010 Am J Physiol Cell Phsiol 299(1):C97-110; Zhou 2020 Lancet 395(10229):1054-1062; Tang 2020 J Thrombosis and Haemostasis 18(9):2428-2430; Kim 2013 Mol Medicine, 19(1):88-98; Huang 2020 The Lancet 395(10223):497–506; Herold 2020 J Allergy Clin Immunol 146(1):128-136; Thompson 2017 N Engl J Med 377(6):562-572; Sharma 2014 J of Immunotoxicol 11(3):260–267; Liu 2020 J Transl Med. 202018(1):206; Lippi 2020 Clin Chim Acta 506:145-148.; Porto 2016 Front Immunol 7:311; Tadie 2013 Am J Physiol 304(5):L342-9; Bdeir 2017 Am J Resp Cell Mol Bio 56(2):261-270; Kowalska 2014 Artioscler Thromb Vasc Biol 34(1):120-6; Krauel 2012 Blood 119(5):1248-1255.

Note: DSTAT is commonly referred to in the citations above as 2-O, 3-O desulfated heparin, ODSH or CX-01