I decided to make this post now, because I recon someone was going to make it sooner or later in any case and it seems CP-COV03 could receive emergency use authorization in Korea within the next month after their Phase 2 trial has been a success http://www.hyundaibioscience.com/page/news.php?mode=view&no=55&page=4. If that should really be the case an a priori discussion could be interesting. Hyundai Biosciences has also applied for emergency use authorization with the FDA and the EMA as well as applied for the patent in 23 countries including Korea, the United States, Europe, China and Japan.
CP-COV03 also known as Xafty is an antiviral based on Niclosamide. Niclosamide has long been identified as a multifunctional drug, via drug repurposing screens (Anti-EBV, Anti-MERS, Anti-SARS-CoV etc.) https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00052. The problem is Niclosamide has poor bioavailability and low concentration in target organs. What Hyundai Biosciences has developed is a new drug delivery system that delivers sufficient Niclosamide into the cell to overcome the low bioavailability problem, as such they have shown to achieve a 5-fold increase in bioavailability (see here for some more info: https://www.mdpi.com/2073-4360/13/7/1044). This in turn turns on the cell’s autophagy mechanism that the cell would normally use to eliminate the virus on its own, i.e in this process, cells identify the virus as a foreign substance and remove it themselves.
Herpes viruses hijack and control autophagy, a method which was supposed to be the body's strongest defence mechanism to clear the virus naturally by degradation. Having the ability to override this in an infected person's body by use of a drug-induced autophagy could be helpful in defeating herpes and other viruses that inhibit or hijack autophagy in the body https://www.nature.com/articles/srep09730.
For EBV we know that “Huang et al. demonstrated that niclosamide inhibits EBV lytic replication in lymphoma cells and epithelial cells and causes irreversible cell cycle arrest in lytic EBV-infected cells via disrupting mTOR activation, offering the potential to treat acute EBV-associated infectious diseases.”.
If it were to be successfully approved or with a successful Phase 3 trial, CP-COV03 is expected to be a game-changer drug in the war against viruses as it is inexpensive, easy to mass-produce and has a ‘viral removal’ mechanism that is in principle applicable to all viral infections.
The pharmacokinetic (PK) data of CP-COV03 from their clinical trial is noteworthy. As a result of analysis based on the blood collection results of 60 clinical participants, the highest blood concentration of the top 10 patients with the highest blood drug concentration of CP-COV03 was 660ng/mL on average. This is a value that far exceeds the drug concentration (IC100) that inhibits the proliferation of the Corona 19 virus by 100%. The IC50 (inhibits 50% viral replication) of Niclosamide is 0.28uM and IC100 is 1uM. The researchers claim that CP-COV03 can maintain IC100 for 12h. As an example: Paxlovid is modeled to maintain IC90 in 90% of the population. However as Siebe (https://twitter.com/PatientPersists) points out on Twitter things are a bit more complicated than that: Siebe_status.
Furthermore, Hyundai Biosciences has announced that it has been running a Long-Covid study with this drug for quite some time (https://www.archyde.com/hyundai-bio-cp-cov03-long-covid-researcher-clinical-trial-started/, https://www.newsdirectory3.com/hyun...inical-trial-begins-cp-cov03-very-long-covid/), but the results are still outstanding and no references or official information on this trial can be found. A Twitter user has said he is participating in the trial: lokeolliji.
The great news:
Professor Woo Heungjeong of Hallym University, who served as vice president of the Korean Society of Infectious Diseases, will be presenting the results of the COVID-19 phase 2 clinical trial at the upcoming conference of the American society of Microbiology in Texas (https://asm.org/Events/ASM-Microbe/). The presentation is titled “Clinical And Virological Efficacy Of A Potential Pan-antiviral Agent, Cp-cov03 In Covid-19 Infection” and the abstract of the presentation can be found here: https://www.abstractsonline.com/pp8/#!/10789/presentation/6711.
CNPharm/ Hyundai Biosciences aren't the only company that has been trying to repurpose niclosamide as a Covid-19 treatment.
Daewoong Pharmaceutical is also repurposing niclosamide as a Covid-19 treatment called DWRX2003. However, after inital success in Phase 1 studies the company was not able to recruit enough patients in their Phase 2 study https://www.koreabiomed.com/news/articleView.html?idxno=12385 and the information on clinicaltrials.gov isn't very informative https://clinicaltrials.gov/ct2/results?cond=&term=DWRX2003&cntry=&state=&city=&dist=. Did their drug fail?
CP-COV03 also known as Xafty is an antiviral based on Niclosamide. Niclosamide has long been identified as a multifunctional drug, via drug repurposing screens (Anti-EBV, Anti-MERS, Anti-SARS-CoV etc.) https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00052. The problem is Niclosamide has poor bioavailability and low concentration in target organs. What Hyundai Biosciences has developed is a new drug delivery system that delivers sufficient Niclosamide into the cell to overcome the low bioavailability problem, as such they have shown to achieve a 5-fold increase in bioavailability (see here for some more info: https://www.mdpi.com/2073-4360/13/7/1044). This in turn turns on the cell’s autophagy mechanism that the cell would normally use to eliminate the virus on its own, i.e in this process, cells identify the virus as a foreign substance and remove it themselves.
Herpes viruses hijack and control autophagy, a method which was supposed to be the body's strongest defence mechanism to clear the virus naturally by degradation. Having the ability to override this in an infected person's body by use of a drug-induced autophagy could be helpful in defeating herpes and other viruses that inhibit or hijack autophagy in the body https://www.nature.com/articles/srep09730.
For EBV we know that “Huang et al. demonstrated that niclosamide inhibits EBV lytic replication in lymphoma cells and epithelial cells and causes irreversible cell cycle arrest in lytic EBV-infected cells via disrupting mTOR activation, offering the potential to treat acute EBV-associated infectious diseases.”.
If it were to be successfully approved or with a successful Phase 3 trial, CP-COV03 is expected to be a game-changer drug in the war against viruses as it is inexpensive, easy to mass-produce and has a ‘viral removal’ mechanism that is in principle applicable to all viral infections.
The pharmacokinetic (PK) data of CP-COV03 from their clinical trial is noteworthy. As a result of analysis based on the blood collection results of 60 clinical participants, the highest blood concentration of the top 10 patients with the highest blood drug concentration of CP-COV03 was 660ng/mL on average. This is a value that far exceeds the drug concentration (IC100) that inhibits the proliferation of the Corona 19 virus by 100%. The IC50 (inhibits 50% viral replication) of Niclosamide is 0.28uM and IC100 is 1uM. The researchers claim that CP-COV03 can maintain IC100 for 12h. As an example: Paxlovid is modeled to maintain IC90 in 90% of the population. However as Siebe (https://twitter.com/PatientPersists) points out on Twitter things are a bit more complicated than that: Siebe_status.
Furthermore, Hyundai Biosciences has announced that it has been running a Long-Covid study with this drug for quite some time (https://www.archyde.com/hyundai-bio-cp-cov03-long-covid-researcher-clinical-trial-started/, https://www.newsdirectory3.com/hyun...inical-trial-begins-cp-cov03-very-long-covid/), but the results are still outstanding and no references or official information on this trial can be found. A Twitter user has said he is participating in the trial: lokeolliji.
The great news:
- An alternative to Paxlovid that can be trialed in combination with other antiviral drugs due to its safety profile
- We have data proving that Niclosamide is safe for long-term use. This should make it a lot easier to receive approval or trials, for instance for LongCovid
- The mechanisms applies to many viruses and not only leads to a halt to viral replication, but could even remove the viral reservoirs
- The company is running multiple trials and has applied for emergency use authorization all over the world
- We don’t have to wait for Phase 3 results is Phase 2 results warrant EUA
- The phase 2 clinical trial showed an extremely effective reduction of viral load for both the high dose, but also the low dose vs. HC, furthermore the high dose was more efficient. Why was the time of resolution of 12 acute Covid symptoms only yield a positive result for the low dose group? Does this mean the drug could still fail in phase 3? Some believe that side effects of magnesium were misinterpreted as Covid symptoms, but that seems rather speculative. (The main raw material of the drug is niclosamide, whilst dds technology was used to increase the absorption rate in the body. The material used as the carrier in this technology is composed of magnesium. There may be side effects such as abdominal pain and diarrhea due to high dose magnesium).
- Could EBV or even Covid be hiding in places that aren’t reached by this mechanism, or can they somehow overcome this type of autophagy as well? Whilst autophagy is an antiviral function it has been shown that this is only one side of the coin as different autophagic pathways complicate the situation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744147/.
- No data for the Long-Covid study has been published yet
- The current majority of information available is in Korean. Whilst news reports are translatable, I do not know how things are looking in forums similar such as these that are happening in Korea. As such it's hard to get local opinions of the drug or even to speak to participants of the trial. Furthermore the standard mode of operation is different to what people in the West are used to and usual things for us like clinicaltrials.gov are often not used.
Professor Woo Heungjeong of Hallym University, who served as vice president of the Korean Society of Infectious Diseases, will be presenting the results of the COVID-19 phase 2 clinical trial at the upcoming conference of the American society of Microbiology in Texas (https://asm.org/Events/ASM-Microbe/). The presentation is titled “Clinical And Virological Efficacy Of A Potential Pan-antiviral Agent, Cp-cov03 In Covid-19 Infection” and the abstract of the presentation can be found here: https://www.abstractsonline.com/pp8/#!/10789/presentation/6711.
CNPharm/ Hyundai Biosciences aren't the only company that has been trying to repurpose niclosamide as a Covid-19 treatment.
Daewoong Pharmaceutical is also repurposing niclosamide as a Covid-19 treatment called DWRX2003. However, after inital success in Phase 1 studies the company was not able to recruit enough patients in their Phase 2 study https://www.koreabiomed.com/news/articleView.html?idxno=12385 and the information on clinicaltrials.gov isn't very informative https://clinicaltrials.gov/ct2/results?cond=&term=DWRX2003&cntry=&state=&city=&dist=. Did their drug fail?
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