Issue: July 25, 2020
Disclosures: Patel reports no relevant financial disclosures.
July 24, 2020
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Cancer drugs’ targeted, anti-inflammatory effects support repurposing for COVID-19

Issue: July 25, 2020
Disclosures: Patel reports no relevant financial disclosures.
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Since the COVID-19 pandemic began, researchers around the world have joined the effort to develop a vaccine and test potential treatments.

The Global Coronavirus COVID-19 Clinical Trial Tracker — a dashboard developed by Cytel — identified 1,570 clinical trials as of late June. About 60% of those were recruiting or had been completed.

The most commonly investigated treatments include hydroxychloroquine, plasma-based therapies, lopinavir-ritonavir and azithromycin. The FDA also granted emergency use authorization to remdesivir (GS-5734, Gilead) for treatment of patients with suspected or laboratory-confirmed COVID-19, based on its ability to shorten time to recovery.

Jai N. Patel, PharmD, BCOP, CPP
Jai N. Patel

Drug repurposing — the use of approved or investigational drugs to treat or prevent diseases outside the scope of their original medical indication — has been an effective strategy against rare diseases and is an active area of investigation during the COVID-19 pandemic.

Repurposing requires shorter timelines and less cost, resulting in a less risky and more rapid return on investment.

There are three critical steps: identification of a candidate molecule for a given indication; preclinical evaluation of drug mechanism and effect; and investigation in phase 2 or phase 3 clinical trials, assuming sufficient safety data exist from prior phase 1 trials.

Efforts to repurpose drugs to treat COVID-19 will focus on three key stages of infection: preventing the virus from entering healthy cells, halting replication if it does get inside the cells and reducing damage to affected tissues.

Many anticancer drugs are being investigated as potential molecules for drug repurposing against COVID-19 given their targeted and anti-inflammatory effects. An overview of those investigations follows.

BTK inhibitors

Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib (Imbruvica; Janssen, Pharmacyclics) and acalabrutinib (Calquence, AstraZeneca), are used to treat certain B-cell malignancies.

The cytokine storm that occurs in pneumonia is partly mediated by BTK. BTK inhibition also has been shown to abrogate pulmonary inflammatory cytokines, regulate macrophage signaling and rescue mice from lethal influenza-induced acute lung injury, sparking interest in its potential to treat COVID-19.

Studies suggest BTK and hematopoietic cell kinase (HCK) — its upstream activator — drive inflammatory cytokine production initiated by alveolar type II cells in the lung, levels of which are reduced after treatment with ibrutinib monotherapy.

Treon and colleagues reported results of a case series of six patients with Waldenström macroglobulinemia and COVID-19. The five patients who received a full ibrutinib dose — 420 mg daily — did not experience dyspnea and did not require hospitalization.

Roschewski and colleagues administered off-label acalabrutinib to 19 hospitalized patients with severe COVID-19. Eleven of these patients were on supplemental oxygen and eight were on mechanical ventilation.

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Results showed improved oxygenation among a majority of patients over a 10- to 14-day treatment course, and measures of inflammation — C-reactive protein and interleukin-6 — rapidly normalized.

Several ongoing trials are evaluating ibrutinib (NCT04375397), acalabrutinib (NCT04380688) and zanubrutinib (BGB-3111, BeiGene [NCT04382586]) to mitigate COVID-19-related symptoms, with a focus on pulmonary distress and reducing time on a ventilator.

JAK inhibitors

Angiotensin-converting enzyme II (ACE2) — highly expressed in many organs, including the heart and lung — has been identified as critical for entry of SARS-CoV-2, the novel coronavirus that causes COVID-19, into target cells with assistance from the cellular protease TMPRSS2.

ACE2 also inactivates the potent vasoconstrictive peptide angiotensin II (Ang II).

Upon binding of ACE2 to the SARS-CoV-2 spike protein and internalization of the virus, ACE2 subsequently sheds from the cell surface, producing locally increased Ang II and hyaluronan levels. This results in development of acute respiratory distress syndrome (ARDS).

Ang II mediates its actions through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway.

Ang II increases immune cell infiltration, enhancing proinflammatory cytokine production. Because Ang II, its receptor (AT1-R) and cytokine receptors utilize JAK-STAT, inhibition of this pathway may prove useful for treating ARDS associated with COVID-19.

Multiple trials are testing the efficacy and safety of ruxolitinib (Jakafi, Incyte) — the most commonly used JAK inhibitor in oncology — against the virus, as well as for prevention and treatment of ARDS (NCT04348071, NCT04355793, NCT04362137, NCT04377620, NCT04334044, NCT04337359, NCT04331665, NCT04366232, NCT04361903).

Tofacitinib (Xeljanz, Pfizer [NCT04332042]) and baricitinib (Olumiant, Eli Lilly [NCT04358614]) — which are approved to treat rheumatoid arthritis — are being investigated for their inhibitory effects on the JAK-STAT pathway among individuals with COVID-19.

Pacritinib (CTI BioPharma), a JAK inhibitor in development for myelofibrosis treatment, also is being evaluated for COVID-19 treatment (NCT04404361).

These candidates have similar JAK inhibitor potencies. However, baricitinib has a higher affinity for AAK1, which is involved with clathrin-mediated endocytosis, suggesting it may be more effective.

Cantini and colleagues conducted a pilot study in which 12 patients from Italy with COVID-19 and moderate symptoms received baricitinib combined with lopinavir-ritonavir. No serious adverse events occurred, and researchers reported significant improvement in respiratory function at week 1 and week 2 compared with baseline.

Immunomodulatory drugs

Thalidomide (Thalomid, Celgene) and lenalidomide (Revlimid, Celgene) exert their antitumor effects using a range of cellular mechanisms. These include induction of oxidative stress, inhibition of angiogenesis and immune modulation, such as enhanced production of cytokine interleukin-2, inhibition of tumor necrosis factor and stimulation of natural killer cells.

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Their anti-inflammatory properties and ability to speed up degradation of messenger RNA in blood cells — thus reducing tumor necrosis factor, increasing interleukin secretion and activating natural killer cells — have made them an attractive option for drug repurposing.

Low-dose lenalidomide is being evaluated to treat nonsevere COVID-19 (NCT04361643), and thalidomide is being investigated for treatment of patients with moderate (NCT04273529) or severe (NCT04273581) forms.

Bromodomain inhibitors

Bromodomains (BRDs) bind acetylated lysines in histone tails. Recognition of acetyl groups is required for recruitment of other chromatin factors and transcriptional machinery.

BRD inhibitors prevent interaction between BRD and acetyl groups, causing downregulation of certain genes.

A SARS-CoV-2 protein interaction map identified BRD2/4 as a binding partner of viral protein E in SARS-CoV-2.

Apabetalone (Resverlogix) inhibited bromodomain and extraterminal domain proteins from interacting with SARS-CoV-2 viral protein, potentially limiting viral reproduction. The manufacturer initiated a phase 3 trial to assess whether harnessing epigenetic modulation may slow COVID-19 spread and severity.

PI3K and mTOR inhibitors

The PI3K/AKT/mTOR pathway, a growth stimulatory pathway in cancer, is critical for development of influenza and modulates antibody response to the virus.

Rapamycin can inhibit the mTOR pathway. Prior studies showed treatment of severe H1N1 influenza-related pneumonia with rapamycin and steroids significantly improved response and recovery. Alternatively, some studies suggested increased immunosuppression from steroids and rapamycin may lead to greater morbidity or mortality and prolong viral replication.

Locally acting inhaled biguanides that inhibit mTOR have been proposed to overcome systemic adverse effects and may represent a novel drug target to combat COVID-19.

Further, kinase inhibitors that target the ERK/MAPK and PI3K/AKT/mTOR pathways significantly inhibited Middle East Respiratory Syndrome coronavirus replication in vitro, whether they were added before or after viral infection.

Duvelisib (Copiktra, Verastem), a PI3K inhibitor approved to treat relapsed or refractory chronic lymphocytic leukemia and follicular lymphoma, is being evaluated to treat COVID-19 (NCT04372602).

Antiandrogen/hormonal agents

Degarelix (Firmagon, Ferring Pharmaceuticals) is a gonadotropin-releasing hormone receptor antagonist that results in reduced luteinizing hormone and follicle-stimulating hormone production, as well as testosterone suppression.

Male hormones may trigger production of TMPRSS2 on lung tissue.

Degarelix is being evaluated in a trial of veterans with COVID-19 who require hospitalization (NCT04397718).

Another study is assessing whether bicalutamide, an antiandrogen, promotes recovery from COVID-19 (NCT04374279).

Other agents under investigation

Several other agents are under investigation for potential repurposing.

  • Isotretinoin can affect both inflammation and SARS-CoV-2 viral entry by inhibiting the overproduction of early response proinflammatory cytokines (eg, interleukin-6 and tumor necrosis factors alpha) that are overexpressed in COVID-19.

It also has been shown to inhibit androgenic factors, which induce TMPRSS2 expression and downregulate ACE2 receptors.

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Several studies are evaluating whether isotretinoin is effective against COVID-19 (NCT04361422, NCT04353180, NCT04389580, NCT04396067).

  • Selinexor (Xpovio, Karyopharm Therapeutics) — approved to treat relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma — is a selective inhibitor of nuclear export that blocks the cellular protein XPO1 and reactivates tumor suppressor proteins, inducing tumor cell apoptosis.

XPO1 is involved in the replication of SARS-CoV-2 and inflammatory response to the virus.

Ongoing studies are evaluating the activity and safety of low-dose oral selinexor among those with moderate or severe COVID-19 (NCT04355676, NCT04349098).

  • Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody that targets circulating VEGF. In cancer, VEGF is critical for cell proliferation, survival, permeability and nitric oxide production.

Researchers evaluating bevacizumab for COVID-19 hypothesize that the agent may reduce levels of VEGF caused by hypoxia, severe inflammation and upregulation of the infected respiratory tract epithelium.

Multiple trials are evaluating bevacizumab for COVID-19-positive patients, particularly those with severe disease (NCT04305106, NCT04344782, NCT04275414).

  • Melphalan, an alkylating agent, is commonly used to treat multiple myeloma. It also is used prior to autologous hematopoietic cell transplantation for patients with plasma cell disorders.

Prior studies showed ultra-low-dose melphalan promotes local and systemic anti-inflammatory effects (eg, interleukin-2 and tumor necrosis factor blockade) but does not exhibit cytotoxic properties. Thus, it is effective for certain lung complications, such as steroid-resistant bronchial asthma.

A trial is evaluating low-dose melphalan for patients with COVID-19 pneumonia (NCT04380376).

Meeting a ‘dire need’

The list of drugs and investigational therapies discussed in this column is not comprehensive but shows how therapeutics that target cancer can be repurposed to combat a virus that has led to nearly a half-million deaths in less than 6 months.

Therapeutics under development but not yet approved to treat cancer also are being investigated to treat COVID-19.

SignalRx Pharmaceuticals, for example, has developed a dual inhibitor that targets BRD2/4 and PI3K/mTOR. Although demonstrated to be effective for promoting adaptive immune responses in cancer, induction of autophagy by PI3K/mTOR and PI3K/mTOR/BRD4 inhibitors also suppresses HIV-1 replication.

Gordon and colleagues used a proteomic approach to describe the interactions of COVID-19 proteins with cellular targets in human cells and identified more than 60 potential targets for drug development. Two key targets were BRD2/4 and mTOR, both inhibited by the dual inhibitor SF2523.

A combinatorial approach that targets multiple steps in viral spread — viral entry, replication and damage to affected tissues — likely will be most effective in mitigating the disease.

BTK and JAK inhibitors have shown the most promising early clinical data so far. However, compounds that inhibit multiple critical pathways — such as BRD2/4 and PI3K/mTOR — may prevent replication and induce adaptive immune response, providing a multipronged approach to combating the disease.

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Novel approaches to drug development, such as use of proteomics to identify targets and repurposing of drugs — whether under investigation or already FDA approved — will accelerate timely delivery of effective therapeutics to patients in dire need of treatments.

References:

Beigel JH, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2007764.

Campbell GR, et al. J Biol Chem. 2018;doi:10.1074/jbc.RA118.002353.

Cantini F, et al. J Infect. 2020;doi:10.1016/j.jinf.2020.04.017.

Cytel. The Global Coronavirus COVID-19 Clinical Trial Tracker. Available at covid-trials.org. Accessed June 24, 2020.

Florence JM, et al. Am J Physiol Lung Cell Mol Physiol. 2018;doi:10.1152/ajplung.00047.2018.

Gordon DE, et al. Nature. 2020;doi:10.1038/s41586-020-2286-9.

Joshi S, et al. Mol Cancer Ther. 2019;doi:10.1158/1535-7163.MCT-18-1206.

Kindrachuk J, et al. Antimicrob Agents Chemother. 2015;doi:10.1128/AAC.03659-14.

Lehrer S. World Acad Sci J. 2020;doi:10.3892/wasj.2020.42.

Pushpakom S, et al. Nat Rev Drug Discov. 2019;doi:10.1038/nrd.2018.168.

Resverlogix. Resverlogix clinical candidate apabetalone featured as a potential COVID-19 treatment in recent publication. Available at: www.resverlogix.com/investors/news?article=662. Accessed June 24, 2020.

Roschewski M, et al. Sci Immunol. 2020;doi:10.1126/sciimmunol.abd0110.

Seif F, et al. Int Arch Allergy Immunol. 2020;doi:10.1159/000508247.

Stebbing J, et al. Lancet Infect Dis. 2020;doi:10.1016/S1473-3099(20)30132-8.

Treon SP, et al. Blood. 2020;doi:10.1182/blood.2020006288.

TrialSiteNews. U.S. Department of Veterans Affairs launches clinical trial investigating degarelix as COVID-19 treatment for hospitalized males. Available at: www.trialsitenews.com/u-s-department-of-veterans-affairs-launches-clinical-trial-investigating-degarelix-as-covid-19-treatment-for-hospitalized-males. Accessed June 24, 2020.

For more information:

Jai N. Patel, PharmD, BCOP, CPP, is chair of cancer pharmacology and associate professor in the division of hematology/oncology at Levine Cancer Institute at Atrium Health. He also is a HemOnc Today Editorial Board Member. He can be reached at jai.patel@atriumhealth.org.