Chimerix Announces Initiation of a Phase 2/3 Study of DSTAT in Acute Lung Injury for Patients with Severe COVID-19
April 29 2020 - 07:00AM
Chimerix (NASDAQ:CMRX), a biopharmaceutical company focused on
accelerating the development of medicines to treat cancer and other
serious diseases, today 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.1
“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).2,3
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-19.1,4-6
- Infiltration of monocytes and other immune cells into inflamed
lung tissue is a key pathogenic driver of ALI.7 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.1,8
- 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-19.9,10 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.11 HMGB1
promotes NETs which may drive hypercoagulation by providing a
substrate for platelet aggregation and upregulating tissue factor
on endothelial cells.12 Activated platelets in turn release
PF4, which further exacerbates inflammation.13 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-19.1,14,15
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.
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.
About Chimerix
Chimerix is a development-stage biopharmaceutical company
dedicated to accelerating the advancement of innovative medicines
that make a meaningful impact in the lives of patients living with
cancer and other serious diseases. Its two clinical-stage
development programs are dociparstat sodium (DSTAT) and
brincidofovir (BCV).
Dociparstat sodium is a potential first-in-class
glycosaminoglycan compound derived from porcine heparin that has
low anticoagulant activity In vitro and in vivo animal model data
support DSTAT’s potential to reduce the inflammation and cellular
infiltration associated with acute lung injury and address
coagulation disorders associated with COVID-19 pathology.
Separately, DSTAT inhibits the activities of several key proteins
implicated in the viability of AML blasts and leukemic stem cells
in the bone marrow during chemotherapy (e.g., CXCL12, selectins,
HMGB1, elastase). Randomized Phase 2 data suggest that
DSTAT may also accelerate platelet recovery post-chemotherapy via
inhibition of PF4, a negative regulator of platelet production that
impairs platelet recovery following chemotherapy. BCV is an
antiviral drug candidate in development as a medical countermeasure
for smallpox. For further information, please visit the Chimerix
website, www.chimerix.com.
Forward Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of 1995
that are subject to risks and uncertainties that could cause actual
results to differ materially from those projected. Forward-looking
statements include those relating to, among other things, the
mechanism of action of DSTAT and its potential in ALI patients with
COVID-19; Chimerix’s ability to develop DSTAT, including the
initiation of a Phase 2/3 clinical trial for DSTAT as a potential
treatment for ALI associated with COVID-19; and Chimerix’s ability
to submit and/or obtain regulatory approvals for DSTAT. Among the
factors and risks that could cause actual results to differ
materially from those indicated in the forward-looking statements
are risks that DSTAT may not achieve the endpoints of the Phase 2/3
clinical trial; risks that DSTAT may not obtain regulatory approval
from the FDA or such approval may be delayed or
conditioned; risks that development activities related to DSTAT may
not be completed on time or at all; Chimerix’s reliance on a sole
source third-party manufacturer for drug supply; risks that ongoing
or future trials may not be successful or replicate previous trial
results, or may not be predictive of real-world results or of
results in subsequent trials; risks and uncertainties relating to
competitive products and technological changes that may limit
demand for our drugs; risks that our drugs may be precluded from
commercialization by the proprietary rights of third parties; and
additional risks set forth in the Company's filings with
the Securities and Exchange Commission. These forward-looking
statements represent the Company's judgment as of the date of this
release. The Company disclaims, however, any intent or obligation
to update these forward-looking statements.
CONTACT:Investor
Relations:
Michelle LaSpaluto 919 972-7115 ir@chimerix.com Will O’Connor Stern
Investor Relations will@sternir.com 212-362-1200
Media:David SchullRusso
Partners858-717-2310david.schull@russopartnersllc.com
note: DSTAT may be referred to as 2-O,3-O desulfated heparin,
ODSH or CX-01 in these references.
- Rao, Narayanam V., et al. “Low Anticoagulant Heparin Targets
Multiple Sites of Inflammation, Suppresses Heparin-Induced
Thrombocytopenia, and Inhibits Interaction of RAGE with Its
Ligands.” American Journal of Physiology - Cell Physiology, vol.
299, no. 1, July 2010, doi:10.1152/ajpcell.00009.2010.
- Zhou, Fei, et al. “Clinical Course and Risk Factors for
Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A
Retrospective Cohort Study.” The Lancet, vol. 6736, no. 20,
Elsevier Ltd, 2020, pp. 1–9,
doi:10.1016/s0140-6736(20)30566-3.
- Tang, Ning, et al. “Anticoagulant Treatment Is Associated with
Decreased Mortality in Severe Coronavirus Disease 2019 Patients
with Coagulopathy.” Journal of Thrombosis and Haemostasis, Wiley,
Mar. 2020, doi:10.1111/jth.14817.
- Kim, Sodam, et al. “Signaling of High Mobility Group Box 1
(HMGB1) through Toll-like Receptor 4 in Macrophages Requires CD14.”
Molecular Medicine, vol. 19, no. 1, Mol Med, 2013, pp. 88–98,
doi:10.2119/molmed.2012.00306.
- Huang, Chaolin, et al. “Clinical Features of Patients Infected
with 2019 Novel Coronavirus in Wuhan, China.” The Lancet, vol. 395,
no. 10223, 2020, pp. 497–506,
doi:10.1016/S0140-6736(20)30183-5.
- Herold, Tobias, et al. “Level of IL-6 Predicts Respiratory
Failure in Hospitalized Symptomatic COVID-19 Patients.” MedRxiv,
Cold Spring Harbor Laboratory Press, Apr. 2020, p.
2020.04.01.20047381, doi:10.1101/2020.04.01.20047381.
- Thompson, B. Taylor, et al. “Acute Respiratory Distress
Syndrome.” New England Journal of Medicine, vol. 377, no. 6,
Massachussetts Medical Society, 10 Aug. 2017, pp. 562–72,
doi:10.1056/NEJMra1608077.
- Sharma, Lokesh, et al. “Partially-Desulfated Heparin Improves
Survival in Pseudomonas Pneumonia by Enhancing Bacterial Clearance
and Ameliorating Lung Injury.” Journal of Immunotoxicology, vol.
11, no. 3, 2014, pp. 260–67, doi:10.3109/1547691X.2013.839587.
- Liu, Jingyuan, et al. “Neutrophil-to-Lymphocyte Ratio Predicts
Severe Illness Patients with 2019 Novel Coronavirus in the Early
Stage.” MedRxiv, vol. 807, Cold Spring Harbor Laboratory Press,
Feb. 2020, p. 2020.02.10.20021584,
doi:10.1101/2020.02.10.20021584.
- Lippi, Giuseppe, et al. “Thrombocytopenia Is Associated with
Severe Coronavirus Disease 2019 (COVID-19) Infections: A
Meta-Analysis.” Clinica Chimica Acta, vol. 2019, Elsevier LTD,
2020, doi:10.1016/j.cca.2020.03.022.
- Porto, Bárbara Nery, and Renato Tetelbom Stein. “Neutrophil
Extracellular Traps in Pulmonary Diseases: Too Much of a Good
Thing?” Frontiers in Immunology, vol. 7, no. Aug, 2016, pp. 1–13,
doi:10.3389/fimmu.2016.00311.
- Tadie, Jean Marc, et al. “HMGB1 Promotes Neutrophil
Extracellular Trap Formation through Interactions with Toll-like
Receptor 4.” American Journal of Physiology - Lung Cellular and
Molecular Physiology, vol. 304, no. 5, Am J Physiol Lung Cell Mol
Physiol, 2013, doi:10.1152/ajplung.00151.2012.
- Bdeir, Khalil, et al. “Platelet-Specific Chemokines Contribute
to the Pathogenesis of Acute Lung Injury.” American Journal of
Respiratory Cell and Molecular Biology, vol. 56, no. 2, 2017, pp.
261–70, doi:10.1165/rcmb.2015-0245OC.
- Kowalska, M. Anna, et al. “Modulation of Protein c Activation
by Histones, Platelet Factor 4, and Heparinoids: New Insights into
Activated Protein C Formation.” Arteriosclerosis, Thrombosis, and
Vascular Biology, vol. 34, no. 1, Arterioscler Thromb Vasc Biol,
Jan. 2014, pp. 120–26, doi:10.1161/ATVBAHA.113.302236.
- Krauel, Krystin, et al. “Heparin-Induced Thrombocytopenia: In
Vitro Studies on the Interaction of Dabigatran, Rivaroxaban, and
Low-Sulfated Heparin, with Platelet Factor 4 and Anti-PF4/Heparin
Antibodies.” Blood, vol. 119, no. 5, 2012, pp. 1248–55,
doi:10.1182/blood-2011-05-353391.
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