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.
Drug: Silmitasertib
Capsules
Other Name: CX-4945
Drug: SOC
Some therapeutics for COVID-19 are available through EUA. SOC treatment availability is expected to change during the course of this trial.
Other Name: SOC/ Best Supportive Care
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
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.
Center for Advanced Research and Education
Gainesville, Georgia, United States
Chris P. Recknor, MD, Principal Investigator
Center for Advanced Research and Education