VERU-111, an Oral, Next Generation, First-In-Class Small Molecule for the Potential Treatment of COVID-19

SARS-CoV-2

VERU IS ENROLLING PATIENTS

To Evaluate VERU-111 for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

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Scientific Overview

Over the last 20 years, a number of viral epidemics have posed a serious global public health risk including Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2002-2003, H1N1 Influenza in 2009, and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. Around December 2019, a new viral acute severe respiratory illness emerged in Wuhan, China. In February 2020, the World Health Organization (WHO) announced that the illness COVID-19, caused by a coronavirus named SARS-CoV-2, has been declared a global pandemic with over 4,605,338 cases and 307,280 deaths worldwide and counting (May 15, 2020; Worldometers.info) a critical task

A critical task of COVID-19 is to hijack the host’s internal transportation system, the microtubules of the cytoskeleton.1 Given the spatial distances between the point of virion entry at the plasma membrane to the different locations in the cell for viral replication and release of infectious virions out of the cell, a structural network, the cytoskeleton, is required for efficiency. Viruses take control of their host’s cellular machinery to carry out viral replication, assembly and to exit from the cell to spread infectious virion. The principal cytoskeletal networks involved in viral replication and trafficking (transport) are microtubules and actin which are principally involved in cellular transport. Microtubule networks are dynamic and targeting these networks to disrupt intracellular trafficking to impair virus and host interactions may be an effective way to treat coronavirus infections.

VERU-111 is an orally bioavailable bis-indole that binds to the “colchicine binding site” of a and b tubulin and inhibits tubulin polymerization at low nanomolar concentrations. VERU-111 disrupts the microtubule filaments similar to nocodazole and colchicine, the central mechanism that contributes to both their antiviral and anti-inflammatory activities. For example, the effects of VERU-111 treatment on triple negative human breast cancer cells (MDA-MB-321) illustrates how the microtubules intracellular networks are disrupted from spindle shape and organized to globular and disorganized.2 The central mechanism of colchicine clinical anti-inflammatory and anti-viral activities is based on its ability to bind the “colchicine binding” sites on alpha and beta tubulin which when incorporated into microtubule block subsequent microtubule polymerization.2 Inhibition of tubulin polymerization is responsible for the effects of colchicine on cell migration, cytokine release, and intracellular trafficking (antiviral) and disruption of inflammatory cell activities seen for acute gout and familial Mediterranean fever. Colchicine modulates leucocyte mediated inflammatory activities including inhibition of leucocyte production of superoxides and release of various cytokines and pyrogens.3 Colchicine-like agents may therefore be useful in treating the “cytokine storm” seen with SARS-CoV 2. IL-18 is a member of the IL-1 cytokine family and unopposed elevated levels of IL-18 concentrations have been associated with macrophage activation syndrome and poor clinical outcomes in severe inflammatory and septic shock conditions.4 Interestingly, colchicine abrogates IL-1b and IL-18 overexpression by reducing its transcription to reduce severe inflammation and septic shock. Verweyen et al. (2020) also showed that colchicine as well as nocodazole abrogated IL18 expression confirming that microtubule depolymerization is the mechanism.

SARS-CoV-2

Development Plan

Based on VERU-111’s mechanistic similarities to other microtubule depolymerizing agents as well as its preclinical and clinical efficacy and safety experience, VERU-111 may have a two-pronged approach to the treatment of SARS-CoV-2: antiviral and anti-inflammatory agent. As an antiviral, it may have direct effects on S protein-microtubule trafficking with the potential to reduce the production of infectious virions particularly by affecting viral replication and assembly and virion egress. As an anti-inflammatory agent, it may reduce virally induced severe inflammation in the respiratory system and may reduce the incidence of cytokine storm and septic shock that can occur in patients that progress to severe acute respiratory pneumonia.

Veru met with the FDA and under the Coronavirus Treatment Acceleration Program (CTAP), FDA granted IND permission on May 12, 2020. Veru is proceeding with a double-blinded, placebo-controlled, Phase 2 Study of VERU-111 for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in patients at high risk for Acute Respiratory Distress Syndrome (ARDS). Approximately 40 subjects will be randomized 1:1 to either 18 mg VERU-111 oral daily or placebo. Hospitalized subjects with documented evidence of COVID-19 infection with symptoms for less than 8 days and who are at high risk for ARDS will be enrolled. The primary efficacy endpoint of the study will be the proportion of patients that are alive and without respiratory failure at Day 29. Secondary endpoints include measured improvements on the WHO Disease Severity Scale (8 point ordinal scale).5

  1. Ward B Virology 411:244-250, 2011.
  2. Deng S et al. An orally available tubulin inhibitor, VERU-111, suppresses triple negative breast cancer tumor growth and metastasis and bypasses taxane resistance. Mol Cancer Ther 19:348-363, 2020.
  3. Slobodnick A et al. Update on colchicine, 2017. Rheumatology 57:i4-i11, 2018
  4. Verweyen E et al. Synergistic signaling of TLR and IFNalpha/beta facilitates escape of IL-18 expression from endotoxin tolerance. American J Resp and Crit Care Med 201:526-539, 2020.
  5. WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial Synopsis. World Health Organization 2/18/2020 Geneva, Switzerland p 5-6.