CP-COV03, a niclosamide-based oral antiviral drug, under study as possible cure for COVID-19 variants

SUMMARY
CP-COV03, a niclosamide-based oral antiviral drug, to cure COVID-19 variants
CP-COV03 is a broad-spectrum antiviral drug candidate, developed by Hyundai Bioscience to treat COVID-19. Its active pharmaceutical ingredient is niclosamide, an anthelmintic drug, and is expected to work on various viral diseases including COVID-19 and its mutations as well as influenza.
CP-COV03 was originally developed with the advanced drug delivery system (DDS) technology by CNPharm, a major shareholder of Hyundai Bioscience. It is a 'host-directed' drug that focuses on the host cell, unlike existing vaccines and antiviral drugs that target the virus. Niclosamide received international attention after COVID-19 broke out, since its efficacy against mutations of COVID-19 has been proven through multiple researches.
Hyundai Bioscience, emphasizing on multi-target capability of niclosamide that may cure COVID-19 variants, plans to expand the use of CP-COV03 to treat even other viral diseases such as the flu.
If successfully approved, CP-COV03 is expected to be a game-changer drug in the war against virus of the century as it is inexpensive and easy to mass-produce. It can be administered to patients with dual or multiple viral diseases such as COVID-19 and influenza at an affordable price.

• An antiviral drug to be combined with dexamethasone is finally found
• An oral antiviral drug that may substitute remdesivir
• CP-COV03 raises efficacy up 2.1 times when combined with dexamethasone

SEOUL, South Korea, Dec. 7, 2021 /PRNewswire/ -- Experimental results have been published for the first time showing that an antiviral drug containing niclosamide, an anthelmintic, in combination with dexamethasone, an anti-inflammatory drug, produces a 'synergistic effect' for severe COVID-19 patients. There is a growing possibility that a combination therapy for severe COVID-19 patients, for which there is currently no suitable treatment, may be developed for the first time in Korea.

Hyundai Bioscience (KOSDAQ symbol 048410) recently conducted an efficacy testing at KRIBB (Korea Research Institute of Bioscience and Biotechnology) on COVID-19-infected hamsters. It was announced on December 7^th that as a result of oral administration of CP-COV03, an oral treatment for COVID-19, combined with dexamethasone, the therapeutic effect was found to be 2.1 times higher than that of dexamethasone alone.

At a press conference held at the Korea Press Center on the 7^th, Hyundai Bioscience announced the results of these experiments and decided to provide related data to the medical community. This is the first study result that confirmed the synergistic effect of an oral antiviral drug with dexamethasone as COVID-19 combo treatment.

Dexamethasone, a steroid drug, is prescribed for patients with severe cases of COVID-19, and was administered together with remdesivir to former US President Donald Trump when he was diagnosed with COVID-19.

If the niclosamide-based CP-COV03 is approved for emergency use in the clinical stage, this combination therapy may be applicable to severe-case patients. It may help reduce the number of severe-case patients and death rates, and then consequently solving the shortage crisis of hospital beds.

Currently, there are virtually no effective antiviral drugs for severe COVID-19 patients. As a temporary measure, doctors are prescribing a limited number of drugs such as remdesivir, the only approved antiviral agent for COVID-19, and Dexamethasone. However remdesivir's efficacy was questioned by WHO, and COVID mutation due to drug resistance was reported from Yale University research ^[1].

In the meantime, medical and scientific communities have been raising voices for the need to find an antiviral drug that will best combine with Dexamethasone, which is known to weaken immunity, in order to safely and effectively treat severe COVID-19 patients.

In June 2020, Dr. Martin Landray of Oxford University emphasized, "Dexamethasone is a 'good first step' to finding a cocktail of drugs that can effectively treat Covid-19. ^[2] " In October 2020, researchers at the University of Geneva in Switzerland reported in the LANCET that Dexamethasone is an essential drug for the treatment of COVID-19, but 'searches for magic bullets should continue; we lack drugs specifically designed to target SARS-CoV-2' ^[3] .

Dr. Geun-Woo Jin, Director of Hyundai Bioscience Research Center, stated, "Dexamethasone, being a steroid drug, has a side effect of weakening immunity, and we need to find a combination treatment that will give antiviral efficacy instead of weakened immunity. CP-COV03 is the best partner for combination with Dexamethasone."

• Host-directed niclosamide is effective against COVID-19 variants
• Existing virus-directed paradigm can't handle variants

Hyundai Bioscience, having started developing a COVID-19 treatment last year, announced that, to overcome its drawback as a latecomer, it developed CP-COV03 with COVID-19 variants in mind from the beginning. In order to solve the COVID-19 crisis triggered by a readily mutating RNA virus, Hyundai Bioscience said that a 'shift in thought' was needed and it had to go beyond existing approaches or practices in the pharmaceutical industry.

Accordingly, Hyundai Bioscience decided to improve existing drugs and develop an orally administered 'host-directed' antiviral drug that acts on host cells rather than the virus. They selected niclosamide among many other candidates and developed CP-COV03 by incorporating their own advanced drug delivery system (DDS) technology.

Dr. Jin said, "As a latecomer in the COVID-19 drug competition, we recognized that the biggest challenge was to be mutations and it cannot be solved by existing methods. Through a shift in thinking, we concluded that host-targeted therapy was the answer and that niclosamide was the best drug to fit it."

Niclosamide, the main component of CP-COV03, has a mechanism of targeting host cells, unlike most antiviral agents that target the virus^[4]. As a result, Hyundai Bioscience explains that it will exhibit antiviral efficacy without being affected by the mutations of COVID-19, such as the Omicron and Delta variants ^[5].

"The antiviral drugs for COVID-19 being developed by major global pharmaceutical companies are 'virus-directed' mechanisms that focus on the virus, so there is a limit in responding to virus mutations", said Dr. Kyung-Il Kim, Hyundai Bioscience's CTO (Chief Technology Officer). "CP-COV03 induces autophagy of host-cells to remove viruses that penetrated into the cells, making it effective regardless of mutation."

Dr. Kim also stated, "Because CP-COV03 targets host cells, it will be a broad-spectrum antiviral drug that can treat COVID-19 and its variants."

On December 2^nd, PLOS, a famous American scientific journal, published the results of human cell experiments conducted by Union Pharmaceutical in Denmark and a joint research team from major European universities, stating that niclosamide exerts strong antiviral efficacy against variants of COVID-19, from alpha, beta and delta^[6]. In April, Pasteur Institut Korea also announced its research result that niclosamide exerts antiviral efficacy against alpha and beta variants of COVID-19 ^[7].

In an interview with Science Insider in April 2020, Dr. Nevan Krogan, a molecular biology professor at the University of California San Francisco, said that host-targeted antiviral drugs are less likely to develop resistance and can be used in a wide range of treatments. If such antiviral drug comes out, it will treat "COVID-22 or COVID-24 or whatever virus comes ^[8]."

• A dual antiviral drug that may treat COVID-19 and influenza is expected
• Preemptive prescription may be possible for common symptoms
• CP-COV03 to carry out phase 2 for COVID-19 and influenza together

The ultimate goal of Hyundai Bioscience is to prove step by step that CP-COV03, a host-targeting antiviral agent, is the premiere 'multi-target' antiviral drug that can be used for various viral diseases, leading to victory in the battle against viruses in the 21^st century.

According to Hyundai Bioscience, the decision to use CP-COV03 for both COVID-19 and the flu in phase 2 clinical trials is primarily intended to prove the versatility of the drug. If CP-COV03 completes phase 1 clinical trial for COVID-19, the flu clinical trial may proceed directly at phase 2 skipping phase 1.

If CP-COV03 is approved for emergency use as a treatment for COVID-19, it will be possible to immediately take a preemptive response to patients with similar symptoms of the two diseases in the medical field even before it is separately approved as a flu treatment. This is expected to greatly contribute to resolving the medical crisis as well as concerns about the twindemic caused by the simultaneous outbreak of COVID-19 and the flu.

When CP-COV03 completes the flu clinical trials, the world's first official demonstration of the universal antiviral efficacy of niclosamide in humans will also be established.

Mr. Sang-ki Oh, Hyundai Bioscience's CEO, stated, "CP-COV03 is an antiviral drug with a host-targeting mechanism that is safe and effective against various viral infections. Our goal is to become the game changer that solves the issue of both COVID-19 mutations as well as new viruses in the 21st century's anti-virus war."

• Challenge to become a COVID-19 game changer
• Aiming for emergency use authorization in the first half of 2022
• Affordably priced drug to ease patients' burden

As soon as the phase 1 clinical trial of CP-COV03 is completed, Hyundai Bioscience plans to apply for phase 2 clinical trials to the Korea FDA to complete it and obtain emergency use authorization within the first half of 2022. It has been said that preparations for phase 2 are already underway, such as discussing the plan for phase 2 clinical trials with related organizations.

Hyundai Bioscience is confident that niclosamide-based CP-COV03 would pass clinical trials as the effectiveness of niclosamide for treating COVID-19 was already proven in clinical study conducted on COVID-19 patients by Iraqi-Qatar researchers, including the Baghdad University medical school in September 2021.

In the clinical trial at the Baghdad University medical school, the hospitalization period of patients in the experimental group treated with niclosamide was reduced from 7 days to 5 days, and the patient's healing rate increased by 50% ^[9]. 

Dr. Jin said, "The efficacy of niclosamide on the human body has already been proven in clinical trials from this study, but the need to increase the bioavailability remained a challenge. We are confident that we will pass phase 2 clinical trials because we succeeded in increasing the bioavailability of niclosamide up to 40 times with our proprietary drug delivery technology."

In an efficacy test for CP-COV03 on hamsters, Hyundai Bioscience proved superior efficacy and drug safety than other oral drugs for COVID-19 being developed by global competitors. Based on its excellent price competitiveness, it is expected that CP-COV03 may become a game changer in the COVID-19 pandemic that may also surpasses Tamiflu during the time of the H1N1 flu outbreak.

Hyundai Bioscience anticipates that CP-COV03 may well be priced very reasonably so that it can be prescribed and consumed without financial burden the similar way as Tamiflu did.

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[Glossary]

Host-directed therapy:
Also called host-targeted therapy, therapy that reduces the virus by enhancing the response of the host cell rather than directly acting on the virus. Autophagy is a representative mechanism that improves the function of the host cell.

Autophagy:
A mechanism by which cells decompose their own proteins or decompose and remove unnecessary components within cells to use them as their own energy sources.

RNA virus:
Viruses having RNA as a gene, such as influenza virus, corona virus, reovirus, and retrovirus.

SOURCE Hyundai Bioscience