Safety and Antiviral Activity of BLD-2660 in COVID-19 Hospitalized Subjects

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19; Sars-CoV-2
• Intervention / Treatment: Drug: BLD-2660

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Bahia, Brazil, 41810
    • Blade Research Site
  • Belo Horizonte, Brazil, 30150
    • Blade Research Site
  • Botucatu, Brazil, 18618
    • Blade Research Site
  • Porto Velho, Brazil, 76801
    • Blade Research Site
  • Ribeirão Preto, Brazil, 65470
    • Blade Research Site
  • São José Do Rio Preto, Brazil, 15090
    • Blade Research Site
  • Vitória, Brazil, 29041
    • Blade Research Site
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13034
      • Blade Research Site
• United States
  • California
    • Irvine, California, United States, 92697
      • Blade Research Site
    • Los Angeles, California, United States, 90048
      • Blade Research Site
    • San Jose, California, United States, 95128
      • Blade Reseach Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Blade Research Site
    • Washington, District of Columbia, United States, 20010
      • Blade Research Site
  • Florida
    • Brandon, Florida, United States, 33511
      • Blade Research Site
    • Fort Pierce, Florida, United States, 34982
      • Blade Research Site
    • Panama City, Florida, United States, 32405
      • Blade Research Site
    • Tampa, Florida, United States, 33620
      • Blade Research Site
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Blade Research Site
  • Illinois
    • Peoria, Illinois, United States, 61603
      • Blade Research Site
  • Iowa
    • Ames, Iowa, United States, 50010
      • Blade Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Blade Research Site
    • Louisville, Kentucky, United States, 40207
      • Blade Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Blade Research Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Blade Research Site
    • Farmington Hills, Michigan, United States, 48334
      • Blade Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Blade Research Site
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • Blade Research Site
  • North Carolina
    • Charleston, North Carolina, United States, 29414
      • Blade Research Site
    • Durham, North Carolina, United States, 27708
      • Blade Research Site
    • Fayetteville, North Carolina, United States, 28304
      • Blade Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Blade Research Site
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Blade Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75203
      • Blade Research Site
  • Washington
    • Spokane, Washington, United States, 99204
      • Blade Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Group	Drug: BLD-2660; BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.
Active Comparator: Active (BLD-2660) Group	Drug: BLD-2660; BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Recovery	To evaluate time to recovery as defined by no longer requiring oxygen support or hospital discharge, whichever occurs first.	Course of study; 28 days
Change in Oxygenation	To evaluate change in oxygenation in hospitalized adults with COVID-19 treated with BLD-2660. Measured by change from baseline to Day 10 or hospital discharge, if sooner, in the ratio of peripheral hemoglobin oxygen saturation to fraction of inspired oxygen (SpO2/FiO2)	10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety & Tolerability: Incidence of TEAEs and Serious Adverse Events (SAEs)	To evaluate the safety and tolerability of BLD-2660 in the same population. Measured by incidence of TEAEs and serious adverse events (SAEs)	Course of study; 28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Discharge Readiness	Measured by time to discharge readiness	Course of study; 28 days
Proportion of Subjects Discharged During Study	Measured by proportion of subjects ready to be discharged from the hospital during the 28-day study period following enrollment.	Course of study; 28 days
Time to Resolution of Fever	Measured by time to resolution of fever below entry criteria for 24 hours in subjects with fever at baseline	Course of study; 28 days
Duration of Remdesivir Use	Measured by duration (in days) of remdesivir use in subjects starting remdesivir within 24 hours of first dose of BLD-2660	Course of study; 28 days
Change in Clinical Status	Measured by change from baseline to Days 10, 14, 21 and 28 in clinical status outcome using a 6-point ordinal scale	Course of study; 28 days
Percentage of Subjects in Each Category of the 6-point Ordinal Scale	Measured by percentage of subjects reporting each 6-point ordinal scale of the clinical status outcome assessment.	Course of study; 28 days
Change in IL-6	Measured by change from baseline to Days 10, 14, 21 and 28 in IL-6 in ng/mL measured by analytical assay	Course of study; 28 days
Change in D-dimer	Measured by change from baseline to Days 10, 14, 21 and 28 in D-dimer in ng/mL measured by analytical assay	Course of study; 28 days

Collaborators and Investigators

• Sponsor: Blade Therapeutics
• Collaborators: Clinipace Worldwide

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2020
• Primary Completion (Actual): November 11, 2020
• Study Completion (Actual): June 21, 2021

Study Registration Dates

• First Submitted: April 2, 2020
• First Submitted That Met QC Criteria: April 3, 2020
• First Posted (Actual): April 6, 2020

Study Record Updates

• Last Update Posted (Actual): April 6, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: B-2660-204

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No