Official Title
Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Antiviral Activity of BLD-2660 in Hospitalized Subjects With Recently Diagnosed COVID-19 Compared to Standard of Care Treatment
Brief Summary

BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9 that is selective over the cathepsins as well as other protease families, displays good metabolic stability and permeability, oral bioavailability and low cytochrome P450 (CYP) inhibition. It is under development for the treatment of coronavirus disease-19 (COVID-19) resulting from infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2), where there is significant unmet medical need.

Detailed Description

Interleukin 6 (IL-6), a proinflammatory cytokine, is a key driver of a cytokine storm that
plays a significant role in clinical complications and acute lung injury. Emerging data
indicate that serum levels of IL-6 are elevated in COVID-19 patients and are predictive of
respiratory failure and mortality. IL-6 has been shown to contribute to lung damage during
SARS-CoV infection and the virus itself is capable of directly inducing its expression.
Suppression of pro-inflammatory IL-6 have been shown to have a therapeutic effect in many
inflammatory diseases, including viral infections.

In a mouse model of lung injury employing bleomycin, BLD-2660, at therapeutic doses of 30 and
100 mg/kg twice per day (BID), reduced IL-6 levels in bronchoalveolar lavage (BAL) fluid.
BLD-2660 also attenuated fibrosis damage as measured by significant reductions in the alpha
smooth muscle actin and collagen 1 in lung tissue. BLD-2660 also demonstrated target
engagement by inhibiting cleavage of one of its substrates, spectrin, in bronchoalveolar
cells.

BLD-2660 was also evaluated in a mouse model of NASH fibrosis, demonstrating an anti-fibrotic
effect. A significant decrease in IL-6 transcription was also observed. This suggests that
the effect of BLD-2660 on IL-6 is independent of the injury, or the affected organ.

It has been shown that the receptor for SARS-CoV-1 and -2 entry into the cell is
angiotensin-converting enzyme 2 (ACE-2). ACE-2 and the dimeric calpains (data on file) are
co-expressed in respiratory epithelial cells, the site of both viral entry and predominant
early lung injury in COVID-19. Inhibition of dimeric calpain activity has not been associated
with impairment of normal immune function. The safety and tolerability of BLD-2660 has been
demonstrated in the recently completed Phase 1 single ascending dose (SAD)/multiple ascending
dose (MAD) B-2660-101 study.

As BLD-2660 has been demonstrated to (1) reduce tissue IL-6 levels and (2) attenuate lung
fibrosis damage, it could therefore, potentially reduce the nonproductive IL-6 mediated
host-response to infection, which contribute to morbidity and mortality in COVID-19. In
addition, data suggest that survivors of SARS-CoV-2 infection are at risk for chronic
impairment of pulmonary function, likely attributable to pulmonary fibrosis secondary to lung
injury and inflammation. Although there is not yet available data documenting numbers of
patients infected with SARS CoV2 pneumonia who progress to pulmonary fibrosis, epidemiology,
viral immunology, and current clinical evidence support that pulmonary fibrosis may become
one of the serious long-term complications of survivors of COVID-19 related pneumonia.

Thus, BLD-2660 could not only potentially downregulate the nonproductive host-response to
infection, which contributes to morbidity and mortality in COVID-19 but also could reduce
potential long-term fibrosis and loss of pulmonary function resulting from SARS-CoV
pneumonia. This study will evaluate BLD-2660 as an add-on therapy to standard of care (SOC)
in hospitalized subjects with recent diagnosis of COVID-19.

Completed
SARS-CoV-2
COVID19

Drug: BLD-2660

BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.

Eligibility Criteria

Inclusion Criteria:

At least 18 years of age at the time of signing the ICF.

Hospitalized for COVID-19.

Diagnosed with COVID-19 as defined by having at least 2 of the following signs or symptoms
within the past 2 days:

- Fever defined as a body temperature of ≥ 38.0 °C oral, or ≥ 38.3 °C rectal, ≥37.7 °C
forehead or ≥38.7°C aural (axillary temperatures are not allowable);

- Cough;

- Fatigue;

- Shortness of breath.

Radiographic evidence (chest x-ray or CT scan) of one the following:

- Ground-glass opacities, or

- Local or bilateral patchy infiltrates, or

- Interstitial pulmonary infiltrates.

Oxygen requirements:

- SpO2 ≤ 94% on ambient air OR

- Requires supplemental oxygen administration by nasal cannula, simple face mask, or
other similar oxygen delivery device.

Male and/or female subjects.

- Contraception use by men or women should be consistent with local regulations regarding
the methods of contraception for those participating in clinical studies.

All subjects (male or female) who are of childbearing potential must agree to use highly
effective contraception during the study. Female subjects and male partners of female
subjects must continue to use highly effective contraception for 30 days after the last
dose of study drug. Female subjects should not donate oocytes during this time. Male
subjects and female partners of male subjects must continue to use highly effective
contraception for 90 days. Male subjects must agree not to donate sperm during this time.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

Note: Ethinyl estradiol is the primary estrogen used in hormonal contraceptives. The
progestin component consists of norethindrone, levonorgestrel, norgestrel, norethindrone
acetate, ethynodiol diacetate, norgestimate, desogestrel, and drospirenone. As BLD-2660 is
a weak CYP3A4 inducer, exposure to both the estrogen and progestin components in hormonal
contraceptives may be decreased, resulting in an increased risk of pregnancy. As such, it
is recommended that subjects who are on hormonal contraceptives for birth control should
use an alternate means of contraception (condoms, diaphragms, intrauterine device (IUD),
other barrier methods, sexual abstinence, etc.) during participation in the study.

Women of childbearing potential must have a negative serum pregnancy test at Screening
within 72 hours prior to first administration of study drug.

Women not of childbearing potential must be postmenopausal (defined as cessation of regular
menstrual periods for at least 1 year

Capable of giving signed informed consent which includes compliance with the requirements
and restrictions listed in the ICF and in this protocol

Exclusion Criteria:

Active bacterial pneumonia infection

Known active tuberculosis (TB).

History of Child-Pugh B or C cirrhosis.

History of ischemic heart disease or myocardial infarction or acute coronary syndrome.

Subjects requiring supplemental oxygen ≥0.75 FiO2.

It is not in the best interest of the subjects to participate, in the opinion of the
treating Investigator.

Female subjects who are pregnant or breastfeeding or expecting to conceive within the
projected duration of the study, starting with the screening visit through 90 days after
the last dose of study drug.

The following laboratory parameters are excluded:

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of
normal (ULN);

- Creatinine clearance < 50 mL/min.

Requiring, or expected to require mechanical ventilation at screening.

Treatment with chloroquine or hydroxychloroquine at study entry.

Treatment with anti-IL 6, anti-IL-6 receptor antagonists, or with Janus kinase inhibitors
(JAKi) in the past 30 days or plans to receive during the study period.

Participation in any other clinical study of an experimental drug treatment for COVID-19
within 6 half-lives of the experimental treatment.

Note: Subjects participating in an observational study are an exception to this criterion
and may qualify for the study with Sponsor approval.

Note: Subjects who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.

- Unable to swallow solid oral medication or known malabsorption disorder.

- Subjects who have allergy to BLD-2660 or inactive components of BLD-2660.

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years ~ Maximum: N/A
Countries
Brazil
United States
Locations

Blade Research Site
Irvine, California, United States

Blade Research Site
Los Angeles, California, United States

Blade Reseach Site
San Jose, California, United States

Blade Research Site
Washington, District of Columbia, United States

Blade Research Site
Washington, District of Columbia, United States

Blade Research Site
Brandon, Florida, United States

Blade Research Site
Fort Pierce, Florida, United States

Blade Research Site
Panama City, Florida, United States

Blade Research Site
Tampa, Florida, United States

Blade Research Site
Idaho Falls, Idaho, United States

Blade Research Site
Peoria, Illinois, United States

Blade Research Site
Ames, Iowa, United States

Blade Research Site
Lexington, Kentucky, United States

Blade Research Site
Louisville, Kentucky, United States

Blade Research Site
Baltimore, Maryland, United States

Blade Research Site
Detroit, Michigan, United States

Blade Research Site
Farmington Hills, Michigan, United States

Blade Research Site
Omaha, Nebraska, United States

Blade Research Site
Ridgewood, New Jersey, United States

Blade Research Site
Charleston, North Carolina, United States

Blade Research Site
Durham, North Carolina, United States

Blade Research Site
Fayetteville, North Carolina, United States

Blade Research Site
Philadelphia, Pennsylvania, United States

Blade Research Site
Charleston, South Carolina, United States

Vanderbilt University Medical Center
Nashville, Tennessee, United States

Blade Research Site
Dallas, Texas, United States

Blade Research Site
Spokane, Washington, United States

Blade Research Site
Campinas, Sao Paulo, Brazil

Blade Research Site
Bahia, Brazil

Blade Research Site
Belo Horizonte, Brazil

Blade Research Site
Botucatu, Brazil

Blade Research Site
Porto Velho, Brazil

Blade Research Site
Ribeirão Preto, Brazil

Blade Research Site
São José Do Rio Preto, Brazil

Blade Research Site
Vitória, Brazil

Clinipace Worldwide
NCT Number
MeSH Terms
COVID-19