Table of Contents
April 29, 2020: “Chimerix, a biopharmaceutical company focused on accelerating the development of medicines to treat cancer and other serious diseases announced the Company’s initiation of a Phase 2/3 study of dociparstat sodium (DSTAT) in COVID-19 patients with acute lung injury (ALI).
DSTAT is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding complications compared to commercially available forms of heparin.
“Given the severity of the COVID-19 pandemic, we have evaluated many potential targets to address the clinical manifestations associated with severe COVID-19,” said Joseph Lasky, M.D., Professor of Medicine, Pulmonary and Critical Care Section Chief, John W. Deming, M.D. Endowed Chair in Internal Medicine at Tulane University Medical School.
“Based on the literature, we believe DSTAT has the potential to reduce the excessive inflammation, immune cell infiltration and hypercoagulation associated with poor outcomes in patients with severe COVID-19 infection.”
“DSTAT is well-suited to unlock the anti-inflammatory properties of heparin as it may be dosed at much higher levels than any available form of heparin without triggering bleeding complications,” said Mike Sherman, Chief Executive Officer of Chimerix.
“We had planned to evaluate DSTAT in several indications of high unmet need, including ALI from different causes.
The pandemic intensified our focus on ALI associated with COVID-19.
Our team has worked closely with critical care physicians treating COVID-19 patients and with the U.S. Food and Drug Administration (FDA) to develop a Phase 2/3 protocol to determine if DSTAT can reduce the need for mechanical ventilation and improve the rate of survival in patients with severe COVID-19 infection.”
Phase 2/3 Study Design
The study is a 1:1 randomized, double-blind, placebo-controlled, Phase 2/3 trial to determine the safety and efficacy of DSTAT in adults with severe COVID-19 who are at high risk of respiratory failure.
Eligible subjects will be those with confirmed COVID-19 who require hospitalization and supplemental oxygen therapy.
The primary endpoint of the study is the proportion of subjects who survive and do not require mechanical ventilation through day 28.
Additional endpoints include time to improvement as assessed by the National Institute of Allergy and Infectious Disease ordinal scale, time to hospital discharge, time to resolution of fever, number of ventilator-free days, all-cause mortality, and changes in key biomarkers (e.g. interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high mobility group box 1 (HMGB1), C-reactive protein and d-dimer).
The Phase 2 portion of the study will enroll 24 subjects to confirm the maximum safe dose and will then expand by an additional 50 patients (74 total) at the selected dose.
A formal analysis of all endpoints, including supportive biomarkers will be performed at the conclusion of the phase 2 portion of the study. Contingent upon positive results, the Phase 3 portion of the study will enroll approximately 450 subjects.
Clinical Rationale for DSTAT in COVID-19 Patients with ALI
The clinical manifestations of COVID-19 range from mild, self-limited respiratory tract illness to severe alveolar damage and progressive respiratory failure, multiple organ failure, and death.
Mortality in COVID-19 is associated with severe pulmonary disease and coagulation disorders such as disseminated intravascular coagulation (DIC).
The mechanistic rationale supporting DSTAT’s potential in ALI patients with COVID-19 is two-fold:
- Potential to decrease inflammation/immune cell infiltration in COVID-19 patients with ALI:
- A primary anti-inflammatory effect of DSTAT is mediated by inhibition of HMGB1 activity.
HMGB1 induces downstream proinflammatory cytokines, including but not limited to, IL-6, TNF-α, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), all of which are elevated in COVID-19.
- Infiltration of monocytes and other immune cells into inflamed lung tissue is a key pathogenic driver of ALI.
DSTAT reduces lung infiltration by immune cells in ALI, likely by inhibition of MCP-1 and other ligands involved in migration of monocytes, neutrophils and other effector cells that promote hyperinflammation in the lungs.
- A primary anti-inflammatory effect of DSTAT is mediated by inhibition of HMGB1 activity.
- Potential to alleviate the underlying causes of coagulation disorders by inhibiting HMGB1 and platelet factor 4 (PF4) activities:
- Two recent studies have identified a high neutrophil/lymphocyte ratio and low platelet counts as clinically relevant indicators of disease severity and 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 neutrophils and NET release can be pathogenic.
HMGB1 promotes NETs which may drive hypercoagulation by providing a substrate for platelet aggregation and upregulating tissue factor on endothelial cells.
Activated platelets in turn release PF4, which further exacerbates inflammation.
DSTAT’s inhibition of inflammatory drivers of coagulation (e.g., PF4 and HMGB1) has the potential to prevent and treat coagulation disorders observed in COVID-19.
- In a recent Phase 2 Acute Myeloid Leukemia (AML) study DSTAT was well tolerated with adverse events similar across DSTAT and control groups. DSTAT is an investigational agent, not yet licensed or approved for use.
- Two recent studies have identified a high neutrophil/lymphocyte ratio and low platelet counts as clinically relevant indicators of disease severity and mortality in COVID-19.
Conference Call and Webcast
Chimerix will host a conference call and live audio webcast today at 8:30 a.m. ET. To access the live conference call, please dial 877-354-4056 (domestic) or 678-809-1043 (international) at least five minutes prior to the start time and refer to conference ID 8263766.
A live audio webcast of the call will also be available on the Investors section of Chimerix’s website, www.chimerix.com. An archived webcast will be available on the Chimerix website approximately two hours after the event.“
