– Romark is conducting clinical trials and seeking worldwide marketing and emergency use authorizations for a novel host-directed antiviral therapeutic for COVID-19 to address emerging variants and play an important role in returning to normal functioning of society.
TAMPA, Fla. – March 9, 2022 – Romark announced today that results of its Vanguard Co-V clinical trial of NT-300 (nitazoxanide extended-release tablets, 300 mg) for treatment of mild or moderate COVID-19 have been published in Lancet’s eClinicalMedicine.1
NT-300 is an oral host-directed antiviral therapeutic undergoing late-stage clinical development for treating mild or moderate COVID-19. NT-300 does not target the virus directly but denies the virus access to energy and cellular machinery needed to replicate. The advantage of this mechanism is broad-spectrum activity against SARS-CoV-2 variants and low potential for viral resistance.
Important findings from the randomized double-blind placebo-controlled clinical trial conducted in 36 outpatient medical centers in the United States and Puerto Rico and published in eClinicalMedicine included an 85% reduction in risk of severe illness for patients treated with NT-300 compared to placebo (1/184 [0.5%] vs. 7/195 [3.6%] for placebo, p=0.07) and 5.2-day reduction in median time to return to usual health for patients with mild illness treated with NT-300 (p<0.01). Romark is preparing to initiate two additional clinical trials to support worldwide marketing authorizations for NT-300 as a treatment of mild or moderate COVID-19 – one in patients at high risk of severe illness (NCT05157243) and another in patients at standard risk (NCT05157269).
“In the context of emerging variants and the limitations associated with existing monoclonal antibody and oral direct-acting antiviral therapeutics, there is an important need for new treatments,” said Jean-François Rossignol, MD, PhD., Chief Medical and Scientific Officer of Romark. “We believe NT-300 can play an important role in protecting against emerging variants and facilitating the return to normal functioning of society.”
Romark is also seeking emergency use authorizations for NT-300 to treat mild or moderate COVID-19 in the United States and Europe.
“From a public health perspective, it is crucial that we prepare for emerging variants,” added Rossignol, “variants that are more transmissible, produce more severe disease, escape immunity provided by vaccines, and are less susceptible to monoclonal antibody and direct-acting antiviral therapeutics.”
Other new research2 recently published online in advance of publication provides important insight into the mechanisms responsible for the clinical observations reported in the eClinicalMedicine article. The preprint paper, authored by thirty-five scientists from the Icahn School of Medicine at Mount Sinai, Harvard Medical School, Harvard T.C. Chan School of Public Health, Boston University School of Medicine, and University of Texas Medical Branch, reported that nitazoxanide inhibits SARS-CoV-2 viral replication and infection in multiple non-human primate and human cell lines including human alveolar epithelial type 2 cells, acts synergistically with remdesivir, and inhibits a broad range of SARS-CoV-2 variants and viral syncytia formation. Oral treatment of Syrian hamsters infected with SARS-CoV-2 with extended-release nitazoxanide reduced weight loss, inflammation, and viral dissemination and syncytia formation in the lungs.
Nitazoxanide, the active ingredient of NT-300, was originally developed for treating intestinal protozoan infections caused by Cryptosporidium parvum and Giardia lamblia. Laboratory studies demonstrating broad-spectrum antiviral activity led to the development of nitazoxanide as a broad-spectrum, host-directed antiviral drug.
In cell cultures, the active ingredient in NT-300, nitazoxanide, inhibits maturation of the SARS-CoV-2 spike protein, which in turn blocks SARS-CoV-2 syncytia formation. Nitazoxanide has also been shown to inhibit replication of SARS, MERS, and other coronaviruses as well as influenza viruses, rhinoviruses, parainfluenza viruses, RSV, and other respiratory viruses in cell culture studies.2-7
Laboratory studies to evaluate the potential for resistance of influenza A virus to tizoxanide, the active circulating metabolite of nitazoxanide, have been unable to select for resistant viruses, suggesting a low potential for viral resistance. Other studies have shown tizoxanide suppresses secretion of pro-inflammatory cytokines that are upregulated by viral respiratory infections including IL-6.8 The broad-spectrum antiviral and anti-cytokine activities of nitazoxanide are attributed to modulation of mitochondrial function and consequential effects on human cell signaling pathways.
Because the nitazoxanide active ingredient is repurposed for the treatment of COVID-19, its safety is supported by an extensive clinical and postmarketing safety database. However, marketed formulations of nitazoxanide are inappropriate for treatment of viral respiratory illnesses because drug is not continuously present in the body at high enough concentrations to stop the virus from replicating. An extended-release formulation, NT-300, was developed to address this problem.
NT-300 (nitazoxanide extended-release tablets, 300 mg) is an investigational broad-spectrum antiviral drug undergoing Phase 3 clinical development for treating acute respiratory illnesses caused by a broad range of seasonal, emerging or drug-resistant respiratory viruses, including influenza viruses, rhinoviruses, other enteroviruses, coronaviruses, parainfluenza viruses, respiratory syncytial viruses (RSV), human metapneumovirus or bocavirus.
The NT-300 tablets, administered orally, are designed to deliver antiviral concentrations of drug to the respiratory tract throughout twice-daily dosing. The 600 mg dose was selected based upon a dose-range-finding clinical trial conducted in outpatients with influenza.9 To date, clinical trials of NT-300 for treatment of viral respiratory illnesses have included more than 8,000 patients. The NT-300 clinical development program has been designed to provide robust evidence of effectiveness to support use of NT-300 and to ensure maximum benefit to the very large number of patients that experience these illnesses.
Romark owns worldwide intellectual property rights to the NT-300 product and uses of nitazoxanide for treatment of COVID-19 and other viral respiratory illnesses.
Five monoclonal antibodies or monoclonal antibody combinations, one intravenously administered (IV) drug, and two oral therapeutics have been authorized for emergency use in treating mild or moderate COVID-19 in the United States – the IV monoclonal antibodies bamlanivimab (Lilly), bamlanivimab + etesivimab (Lilly), sotrovimab (VIR/GSK), bebtelovimab (Lilly), the IV or subcutaneously administered casirivimab + imdevimab (Regeneron), IV remdesivir (Gilead), and orally administered nirmatrelvir + ritonavir (Pfizer) and molnupiravir (Merck). Of the five monoclonal antibody therapeutics, three are no longer available due to inability to neutralize the Omicron variant in vitro, and the distribution of sotrovimab has recently been limited due to inability to neutralize the Omicron BA.2 subvariant in vitro. Existing data supporting emergency use authorization for NT-300 compares favorably to these therapeutics in the following important areas:
1. Safety experience The safety database for NT-300 includes more patients than used to support emergency use for each of the eight therapeutics.
2. Safety profile NT-300 has not been associated with safety concerns associated with the monoclonal antibodies (anaphylaxis) or oral therapies (e.g., anemia, risks to fetuses and children in the case of molnupiravir and drug-drug interactions for nirmatrelvir + ritonavir).
3. Ease of use NT-300 is administered orally vs. intravenous or subcutaneous administration, does not require refrigeration, and requires fewer pills (20, 2/dose) than for molnupiravir (40, 4/dose)) or nirmatrelvir + ritonavir (30, 3/dose).
4. Observed efficacy The 85% relative reduction in progression to severe illness observed for NT-300 in the Vanguard Co-V clinical trial reported in the article in Lancet’s eClinicalMedicine is among the highest reported for any monoclonal antibody or oral therapeutic (range 30% to 89%).
5. Statistical certainty Statistical certainty (nominal p =0.07) with respect to observed efficacy rate falls behind the data used to support emergency authorization of bamlanivimab + etesivimab, sotrovimab, and nirmatrelvir + ritonavir, ahead of data used to support emergency use authorization for bamlanivimab (nominal p =0.09), IV casirivimab + imdevimab (nominal p =0.18), subcutaneous casirivimab + imdevimab (no data), and bebtelovimab (no data), and either higher or slightly lower than molnupiravir depending upon the molnupiravir study used for comparison.
6. Activity against emerging variants Unlike monoclonal antibodies and direct-acting oral antivirals, NT-300 is expected to be effective against all emerging variants because of its host-directed mechanism.
Romark is a vertically integrated, research-based pharmaceutical company focused on the discovery, development, and delivery of innovative new medicines, primarily in the field of infectious diseases. Romark has operations in the United States, Puerto Rico, and Europe, and it conducts research and development and commercializes its products globally.
Romark is a leader in developing new drugs for treating a broad range of seasonal, emerging and drug-resistant viral respiratory illnesses. Products discovered, developed, and commercialized by Romark have been used to positively impact the lives of more than 500 million people worldwide.
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1. Rossignol JF, Bardin MC, Fulgencio J, et al. A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19. eClinicalMedicine 2022; 45:101310.
2. Miorin L, Mire CE, Ranjbar S, et al. The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters. bioRxiv [preprint]. 2022 Feb 9:2022.02.08.479634. doi: 10.1101/2022.02.08.479634.
3. Riccio A, Santopolo S, Rossi A, et. al. Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence. bioRxiv [preprint]. doi: 10.1101/2021.04.12.439201 [in press with Cell Mol Life Sci]
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7. Rossignol JF, Tijsma ASL, van Baalen C. Mechanism of antiviral activity of nitazoxanide against the influenza virus: effect of tizoxanide on adenosine-triphosphate in influenza-infected Madin-Darby kidney cells. bioRxiv [preprint]. 2021 doi: 10.1101/2021.07.30.454324.
8. Hong SK, Kim HG, Chong CS, Choi IS, Lee JB, Park SY. Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int Immunopharmacol 2012; 13:23-7.
9. Haffizula J, Hartman A, Hoppers M, et al. A randomized, double-blind, placebo controlled clinical trial of nitazoxanide in adults and adolescents with acute uncomplicated influenza. Lancet Infect Dis 2014; 14:609-618.