Evaluating Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in Subjects With Moderate COVID-19

Senhwa Biosciences, Inc.20 enrolled

Overview

This single-center, open-label, 2 arm parallel-group, randomized, interventional prospective exploratory study in 20 subjects aimed to evaluate safety and explore putative clinical benefits of Silmitasertib 1000 mg BID dose in patients with moderate COVID-19. Two-arm trial comparing the SOC/supportive care alone to the SOC/supportive care with addition of Silmitasertib (allocation ratio 1:1).

Silmitasertib is a first-in-class small molecule drug that targets Casein Kinase 2 (CK2). Protein kinase CK2 phosphorylates key proteins required to trigger mechanisms vital for viral replication and also is involved in development of host anti-viral immune response. SARS-CoV-2 viral proteins interacting with many human host proteins affect multiple innate immune pathways. One of these key proteins dysregulated by SARS-CoV-2 is the protein kinase CK2. SARS-COV-2 upregulates CK2 to support viral replication, avoid innate immune response and spread virus to nearby cells. Overactivation of CK2 indirectly contribute to successful viral replication and development of cytokine storm.SARs-Cov-2-induced overexpression of CK2, while pharmacological inhibition of CK2 suppresses virus proliferation. CK2 signaling appears to be an important pathway hijacked by SARS-CoV-2. Emerging pre-clinical and clinical data and results of independent efficacy evaluation conducted by Utah State University and UCSF COVID-19 research group and Senhwa Biosciences hypothesize that Silmitasertib (CX-4945) could potentially quell virus-provoked aberrant hyperactivation of the innate immune system by inhibition of upregulated CK2 protein kinase, preferentially restoring normal host cell cytokine regulation, and attenuating viral replication in patients with moderate to severe COVID-19, thereby preventing disease progression and improving clinical outcomes. Intended target patient population for treatment with Silmitasertib (CX-4945) are SARS-COV-2 positive patients with moderate to severe COVID-19, since in the moderate to severe stage of the disease infected cells actively produce viral proteins that dysregulate signaling pathways to allow viruses to manipulate host immune responses to create an environment more favorable for infection, that may not be observed in the initial or mild stage of the disease. CX-4945 demonstrated remarkable clinical benefits under emergency IND authorization in a patient with COVID-19 pneumonia not responsive to remdesivir, dexamethasone and antibiotics and requiring supplemental oxygen. The patient recovered and was discharged from the hospital in five days of treatment with CX-4945. The purpose of this open-label, randomized, 2 arm parallel-group controlled, interventional prospective exploratory study in 20 subjects is to evaluate safety, tolerability and pharmacokinetics of Silmitasertib (CX-4945) 1000 mg BID dose, to compare time to clinical recovery, and putative clinical benefit across treatment groups, and to evaluate anti-viral activities in COVID-19 patients. Silmitasertib is a generally well-tolerated medication. Most adverse events reported were mild to moderate in severity. The most common toxicities associated with CX-4945 were gastrointestinal disorders, manageable with drug discontinuation or use of anti-diarrheal medication. Based on the currently available data, the identified or potential risks of the product do not outweigh its identified or potential benefits.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Covid19

Interventions

SilmitasertibDRUG

Capsules

SOCDRUG

Some therapeutics for COVID-19 are available through EUA. SOC treatment availability is expected to change during the course of this trial.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or non-pregnant female adult ≥ 18 years of age 2. Diagnosed with COVID-19 by standard RT-PCR assay or equivalent testing 3. Outpatient subjects with moderate illness caused by SARS-CoV-2 infection as defined below, * Symptoms of moderate systemic illness/infection with COVID-19: At least two of the key COVID-19-related symptoms with score 2 or higher (0=none, 1=mild, 2=moderate, and 3=severe): cough, sore throat, malaise, headache, muscle pain, fever, neurological symptoms such as brain fog/concentration challenges, gastrointestinal symptoms or shortness of breath with exertion AND * Clinical signs indicative of moderate systemic illness/infection with COVID-19 At least 1 of the following: respiratory rate ≥ 20 breaths per minute, heart rate ≥ 90 beats per minute AND * No clinical signs indicative of Severe or Critical Illness Severity required hospitalization (see exclusion criterion #1) 4. Patient (or legally authorized representative) provides written informed consent prior to initiation of any study procedures. 5. Adequate hematopoietic capacity, as defined by the following: 1. Hemoglobin ≥ 9.0 g/dL and not transfusion dependent 2. Platelets ≥ 100,000/mm3 3. Absolute neutrophil count ≥ 1500 cells/mm3 6. Adequate hepatic function, as defined by the following: 1. AST and ALT ≤ 2.5 times upper limit of normal (ULN) 2. Total bilirubin ≤ 1.5 x ULN 3. Albumin ≥ 3.0 g/dL 7. Adequate renal function, as defined by the following: a. Renal: calculated creatinine clearance \>45 mL/min for patients with abnormal, increased creatinine levels (Cockcroft-Gault formula). 8. Ability to take oral medication and be willing to adhere to drug administration and premedication requirements (see Section 6.3) throughout study duration. Exclusion Criteria: 1. Any signs indicative of Severe or Critical Illness Severity required hospitalization as defined below: * Severe COVID-19: Shortness of breath in rest, or respiratory distress, respiratory rate (RR) \>/= 30 per minute, heart rate (HR) \>/=125 bpm, SpO2\</=93% on room air at sea level or PaO2/FiO2\<300 * Critical COVID-19: respiratory failure required mechanical ventilation, oxygen delivered by high-flow nasal cannula, ESMO; shock or multi-organ dysfunction/failure 2. Pregnant or nursing women. (NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Should a man father a child, or a woman become pregnant or suspect she is pregnant while participating in this study, he or she should inform the treating physician immediately.) 3. Active or uncontrolled infections other than COVID-19 or with serious illnesses or medical conditions which would not permit the patient to receive study treatment 4. Chronic diarrhea (excess of 2-3 stools/day above normal frequency) 5. Concomitant treatment with another investigational drug from Day 1 through Day 28. 6. Current use or anticipated need for drugs that are known strong inhibitors or inducers of major CYP enzymes.

Locations (1)

Center for Advanced Research and Education

Gainesville, Georgia, United States

Outcomes

Primary Outcomes

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]) Within the CX-4945 Treatment Group

To assess adverse events associated with the administration of CX-4945 orally, twice daily to patients with moderate COVID-19. The occurrence of overall AEs in the two treatment groups are summarized.

Time frame: From randomization (Day 1) to Day 60

Secondary Outcomes

Clinical Recovery Associated With COVID-19 Within the CX-4945 Treatment Group

To compare the number of days to clinical recovery specifically associated with COVID-19 in the CX-4945 treatment group as compared to the control arm by Day 14 of the study.

Time frame: First 14 days of the study.

Anti-Viral Activity of CX-4945

To evaluate preliminary evidence of anti-viral activity of CX-4945 as compared to the control arm.

Time frame: Quantitative changes in viral load from Day 1 to Day 28.

Maximum Plasma Concentration [Cmax] of CX-4945

To evaluate the maximum plasma concentration of CX-4945 when given at 1000 mg BID PO (Experimental Arm taking CX-4945 only i.e. Group A).

Time frame: Plasma sample of CX-4945 are collected at the following timepoints: Day 1: pre-dose, 1, 2, 3, 6 and 24 hours post Day 1 morning dose and Day 14: pre-dose, 1, 2, 3, 6, 24, 48 and 72 hours post Day 14 morning dose.

Time to Maximum Observed Plasma Concentration [Tmax] of CX-4945

To evaluate the time to maximum observed plasma concentration of CX-4945 when given at 1000 mg BID PO (Experimental Arm taking CX-4945 only i.e. Group A).

Data from ClinicalTrials.gov

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Area Under the Concentration-Time Curve [AUC0-6] of CX-4945

To evaluate the area under the concentration-time curve \[AUC0-6\] of CX-4945 when given at 1000 mg BID PO (Experimental Arm taking CX-4945 only i.e. Group A).

Clinical Benefit of CX-4945 i.e. All-cause Mortality Status - the Number of Deaths Occurred in Each Treatment Group From Randomization (Day 1) Through Day 60

Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of all-cause mortality. Mortality status and cause will be assessed by study staff and the information will be documented on a Clinical Status questionnaire. The data collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in all-cause mortality between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: From Randomization (Day 1) through Day 60

Clinical Benefit of CX-4945 i.e. Number of Respiratory Failures Occurred in Each Treatment Group From Randomization (Day 1) Through Day 45

Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of the number of respiratory failures. Respiratory failures will be assessed by study staff and the information will be documented on a Clinical Status questionnaire. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in number of respiratory failures between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: From Randomization (Day 1) through Day 45

Clinical Benefit of CX-4945 i.e. Number of Subjects Hospitalized in Each Treatment Group From Randomization (Day 1) to Day 45

Between the experimental arm with CX-4945 and the control arm, patients will be evaluated in terms of the number of subjects hospitalized in each treatment group. The number of subjects hospitalized will be assessed and the information will be documented on a clinical status questionnaire. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in number of subjects hospitalized between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: From Randomization (Day 1) to Day 45

Clinical Benefit of CX-4945 i.e. Number of Days to Normalization of Oxygen Saturation Level Measured by Pulse Oximeter at Randomization (Day 1), Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45 and Categorized as <96% Versus ≥96%.

Between the experimental arm with CX-4945 and the control arm, patients will be evaluated in terms of time to oxygen saturation level normalization. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in time to oxygen saturation level normalization between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. Best Case Scenario = Days to first response for responder, = Days to last observation for non-responder (censored); Worst Case Scenario = Days to first response for responder, = Days to planned last observation date (31 for EQ-5D-5L and SARS-COV-2 Viral Clearance at visit 7, 45 for others at visit 8) for non-responder (censored); Days to first response = date of first response - the first treatment date/time + 1 Days to last observation = date of last evaluation - the first treatment date/time + 1 For Arm SOC, the first treatment date is the date of visit 2.

Time frame: Randomization (Day 1), Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45

Clinical Benefit of CX-4945 i.e. Proportion of Subjects With Disease Progression or Improvement in Health Status Occurring From Randomization (Day 1) to Day 28.

Between the experimental arm with CX-4945 and the control arm, proportion of subjects with disease progression or improvement in health status occurring from Randomization (Day 1) to Day 28 will be evaluated. Disease progression is defined as change in subject health status assessment from item 7 to items 1- 6 and health improvement -as change from item 7 to item 8, evaluated by the ordinal NIAID 8- point Clinical Progression Outcomes scale - collected at every visit from randomization (Day 1) through Day 45. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in clinical status between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: From Randomization (Day 1) to Day 28

Clinical Benefit of CX-4945 i.e. Changes in the Total Score for Q1~Q5 of the EQ-D5-5L From Randomization (Day 1) to Day 8, Day 14 and Day 28.

Changes in the total score for Q1\~Q5 of the EQ-D5-5L (used as an indicator of symptom improvement) from Baseline (Day 1) to Day 8, 14, 28 were evaluated. The 5-level EQ-5D version (EQ-5D-5L) was used to assess five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Four times during the study (baseline, Day 8, Day 14 and Day 28) the patients were asked to complete health status survey by answering 6 questions about their health and quality of life. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Patients were also asked to assess their overall health status by selecting a number between 1 and 100 to describe the condition of their health, 100 being the best imaginable.

Time frame: From randomization (Day 1) to Day 8, Day 14 and Day 28.

Clinical Benefit of CX-4945 i.e. Changes in the Imaginable Health Status of the EQ-D5-5L From Randomization (Day 1) to Day 8, Day 14 and Day 28.

Changes in the Imaginable Health Status of the EQ-D5-5L (used as an indicator of symptom improvement) from Baseline (Day 1) to Day 8, 14, 28 were evaluated. The 5-level EQ-5D version (EQ-5D-5L) was used to assess five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Four times during the study (baseline, Day 8, Day 14 and Day 28) the patients were asked to complete health status survey by answering 6 questions about their health and quality of life. Patients were also asked to assess their overall health status by selecting a number between 1 and 100 to describe the condition of their health, 100 being the best imaginable.

Time frame: From randomization (Day 1) to Day 8, Day 14 and Day 28.

CX-4945 Inflammatory Marker Outcomes i.e. Plasma IL-6

Labs to evaluate changes in plasma IL-6 (interleukin-6 in ng/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma IL-6 levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: Changes in plasma IL-6 level from Randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14.

CX-4945 Inflammatory Marker Outcomes i.e. Plasma CRP

Labs to evaluate changes in plasma CRP (C-reactive protein in mg/DL) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma CRP levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: Changes in CRP from randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14.

CX-4945 Inflammatory Marker Outcomes i.e. Plasma LDH

Labs to evaluate changes in plasma LDH (lactic acid dehydrogenase in U/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma LDH levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: Changes in LDH from randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14.

CX-4945 Inflammatory Marker Outcomes i.e. Plasma CPK

Labs to evaluate changes in plasma CPK (creatine phosphokinase in U/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma CPK levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: Changes in CPK from randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14.

CX-4945 Inflammatory Marker Outcomes i.e. Plasma Ferritin

Labs to evaluate changes in plasma ferritin (μg/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma ferritin levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: Changes in ferritin from randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14.

CX-4945 Inflammatory Marker Outcomes i.e. Plasma D-Dimer

Labs to evaluate changes in plasma D-dimer (μg/mL) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma D-dimer levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945.

Time frame: Changes in D-dimer from randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14.