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

A Phase II, Randomized and Controlled Investigator Initiated Trial Evaluating Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in Outpatient Adult Subjects With Moderate Coronavirus Disease 2019 (COVID-19)

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.

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.