On May 11, 2020, we announced that we have entered into a research collaboration agreement with the National Center for Advancing Translational Sciences (NCATS), one of the National Institutes of Health (NIH), to develop emetine hydrochloride as a potential treatment for patients with COVID-19, the disease caused by infection with the SARS-CoV-2 virus. Emetine is an active pharmaceutical ingredient of syrup of ipecac, given orally to induce emesis, and has also been formulated as an injectable to treat thousands of individuals with amebiasis. Several independent in vitro studies have demonstrated nanomolar potency against both DNA and RNA-replicating viruses, including Zika virus, Ebola virus1, Rabies Lyssavirus, human cytomegalovirus, human immunodeficiency virus 1, influenza A virus, Rift Valley fever virus, echovirus 1, human metapneumovirus, and herpes simplex virus type 22. Clinically, emetine has been used to treat approximately 700 patients (including pediatrics) with viral hepatitis3 and varicella-zoster virus4. Additionally, emetine is a potent inhibitor of multiple genetically-distinct Coronaviruses and demonstrated in vitro the strongest anti-coronavirus activity in one study that screened and identified approved compounds with broad-spectrum efficacy against the replication of four Coronaviruses5 and specifically against SARS-CoV-2.6
Figure: In high-density infected cells (A) emetine induces (1) nuclear translocation of RPS14 (2) followed by RPS14 binding to MDM2 (3 & 4) resulting in disruption of the interaction between MDM2-p53 (6) and MDM2- viral IE2 (5 & 7), and by RPS14 ubiquitination and degradation (8). In low-density infected cells (B) although emetine induces (1) nuclear translocation of RPS14 (2), it is unable to interact with MDM2 (4) which is already bound to p53 to facilitate virus replication (3). Source: Source: PLoS Pathogens 12(6):e1005717, June 2016
We are working toward submission of an Investigational New Drug Application (IND) and targeting potential initiation of a Phase 2/3 clinical trial evaluating emetine in high-risk COVID-19 outpatients in the first half of 2021, subject to ongoing discussions with the FDA and additional capital. Any additional FDA requirements may delay our clinical trial start date. If our IND is accepted and if our clinical trial is successful, we intend to initially seek FDA approval to market emetine in the U.S. for the treatment of patients with COVID-19. We intend to conduct an adaptive design Phase 2/3 randomized, double-blind, placebo-controlled multi-center trial to evaluate the safety and antiviral activity of emetine in high-risk symptomatic adult patients with confirmed COVID-19 infection not requiring hospitalization. Based on the FDA pre-IND advice received to-date, we do not anticipate that a Phase 1 clinical trial in healthy volunteers will be required prior to initiating the proposed Phase 2/3 clinical trial although there can be no assurance that FDA will not require a Phase 1 trial or other IND-enabling activities. The potential for cardiotoxicity, in cumulative doses of emetine above 650 mg, has been cited in literature as a reason for its restricted clinical use in most recent years. Patients treated with a subcutaneous injection of emetine at a cumulative dose of 650 mg did not experience any notable toxicity7. As a potential antiviral treatment for COVID-19 patients, we propose to administer emetine as a subcutaneous injection at a cumulative dose of approximately 120 mg. If the Phase 2/3 trial is completed successfully, we anticipate submitting a New Drug Application (NDA) for emetine to the FDA for the treatment of COVID-19. Additional information on the emetine program can be found in our current corporate presentation.
The initiation of the Phase 2/3 trial, its conduct and completion, and NDA submission are subject to our ability to generate sufficient capital resources to fund this program. There can be no assurance that we will be able to obtain funding in an amount and upon terms which would allow us to continue our emetine program. Emetine is an investigational drug for COVID-19 and is not currently FDA approved for any indication.
- Yang S, et al. Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry. Cell Discov (2018) 4:31. doi:10.1038/s41421-018-0034-1.
- Andersen, P.I., et al. Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine. Viruses 2019, 11, 964.
- Del Puerto et al. Pren. méd. argent., 55: 818, 1968
- Annamalai et al. Emetine Hydrochloride in the Treatment of Herpes Zoster. 1968
- Shen L, et al. High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses. J Virol. 2019 May 29;93(12).
- Choy et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020 Jun; 178: 104786
- Mastrangelo, et al. Cancer 31:1170-1175.