Soluble ACE2 shows promise for treating severe Covid19(nature.com)
nature.com
Soluble ACE2 shows promise for treating severe Covid19
https://www.nature.com/articles/s41392-020-00374-6
25 comments
I too tried to follow the progress of Apeiron's APN01 which started to get news coverage at the end of February due to a University of British Columbia press release [1]. This pre-existing therapeutic was created out of SARS-CoV-1 research and I expected a SARS-CoV-2 trial to be accelerated. It never happened.
There is a story to be told here. Either a missed opportunity, incompetence, or a complete misunderstanding on my part of what a promising COVID-19 therapeutic looks like.
[1] https://www.med.ubc.ca/news/pilot-clinical-trial-in-china-to...
There is a story to be told here. Either a missed opportunity, incompetence, or a complete misunderstanding on my part of what a promising COVID-19 therapeutic looks like.
[1] https://www.med.ubc.ca/news/pilot-clinical-trial-in-china-to...
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When the first study started for this in February I was always optimistic this would both work and be cheap and easy to mass produce - it was the method I was hoping for and betting on. I've been disappointed to not see more news about this, I wonder what happened.
Similar working of linoleic acid:
https://www.youtube.com/watch?v=EMaKFcpV5wg
https://www.youtube.com/watch?v=VB06uVA97zI
but.. 'linoleic acid is a precursor to arachidonic acid which is involved in inflamation'.
Any news about zinc acetate (losenges) with zinc ionophores as hydroxychloroquine (in small doses, early) or quercetin pythosome (quercenase)?
edit: (to downvoter: would you mind telling me where I'm wrong? https://news.ycombinator.com/item?id=22627167 https://news.ycombinator.com/item?id=22603462 https://news.ycombinator.com/item?id=22631469 , as well quite promising)
https://www.youtube.com/watch?v=EMaKFcpV5wg
https://www.youtube.com/watch?v=VB06uVA97zI
but.. 'linoleic acid is a precursor to arachidonic acid which is involved in inflamation'.
Any news about zinc acetate (losenges) with zinc ionophores as hydroxychloroquine (in small doses, early) or quercetin pythosome (quercenase)?
edit: (to downvoter: would you mind telling me where I'm wrong? https://news.ycombinator.com/item?id=22627167 https://news.ycombinator.com/item?id=22603462 https://news.ycombinator.com/item?id=22631469 , as well quite promising)
Is this technique patentable? Would be quite nice if it were not...
I know it's a gross question but who would invest the money to get FDA approval for it? The better angels of our nature don't have a couple hundred million sitting around to throw at the process. Are there grants or funds for getting approval for development of medicines that aren't patentable?
Are there not charities looking for solutions to address the pandemic? Such as the Gates Foundation?
And does the drug approval process seriously cost $200 million. I imagine it is not cheap, but that number seems very high for such small trial groups and a highly motivated/cooperative regulatory agency.
And does the drug approval process seriously cost $200 million. I imagine it is not cheap, but that number seems very high for such small trial groups and a highly motivated/cooperative regulatory agency.
Sure, it's not impossible to get unencumbered funding.
Are you forgetting about state funding?
What's the history of a state fully funding a drug (not talking about basic research)? Has a government developed, tested, approved, and provided a medicine? genuinely curious, but you can't forget something that hasn't happened yet
I‘m not an expert on this, but it seems that penicillin was discovered and developed into a drug with public funding.
No. You may not have seen it but I edited my comment a few minutes after posting to mention grants.
The FDA does have an orphan drug program that would seem to apply (if non-patentable) and could help fund clinical trials but I don’t know how much else of the process it will pay for.
The FDA does have an orphan drug program that would seem to apply (if non-patentable) and could help fund clinical trials but I don’t know how much else of the process it will pay for.
US constituent states cannot print money. This only makes sense at the federal level.
If it is not, it will encounter hurdles at every step, and probably never make it past initial trials. Nobody wants patent-free medicine except the public, and the public doesn't make decisions about drug safety...
> Nobody wants patent-free medicine except
Except literally every single country on this planet because they all want to go out of lockdown and restart their economy
Except literally every single country on this planet because they all want to go out of lockdown and restart their economy
I know it seems hard to believe, but (IMHO) the existence of a patent will in no way encumber (and will actually help) the production, distribution, and administration of this drug if it works.
Entities that actually have expertise and capability in clinical development of such complicated biologics get through this process by burning billions of dollars. These billions are provided by investors who must have some reasonable chance at making a profit (or at least not losing a lot of money). Non-profit enterprises simply don't have the money or the expertise. The government has no expertise in the development path. The U.S. gov't (through the FDA) has vast amounts of expertise in analyzing clinical trial proposals and data, but not actually running them.
Entities that actually have expertise and capability in clinical development of such complicated biologics get through this process by burning billions of dollars. These billions are provided by investors who must have some reasonable chance at making a profit (or at least not losing a lot of money). Non-profit enterprises simply don't have the money or the expertise. The government has no expertise in the development path. The U.S. gov't (through the FDA) has vast amounts of expertise in analyzing clinical trial proposals and data, but not actually running them.
Problem is that the benefits of license free medicine to society are diffuse, while the benefits of a licensing fee are concentrated. That makes lobbying and organization/cooperation much easier for the entity that is developing the medicine.
The public is not as likely to organize their interests and establish a competent lobbying strategy. Just not enough in it for a single person for them to pay attention.
The public is not as likely to organize their interests and establish a competent lobbying strategy. Just not enough in it for a single person for them to pay attention.
> we must be mindful that this represents a single observation.
I wonder if this would theoretically work just as well on the new Mink mutated version as well.
Yes, this is one reason why an approach using a form of soluble ACE2 is so promising; mutations that would normally cause e.g. monoclonal antibodies to stop working (as detailed with the mink mutation) would in theory not stop the 'decoy receptor' approach.
Despite the fact soluble ACE2 is not looking like it'll be developed in time to impact the pandemic, there is a silver lining:
If you look at the original paper (https://www.thelancet.com/journals/lanres/article/PIIS2213-2...), you'll note they include details on angiotensin peptide levels in the patient.
Interestingly, in this n=1 case report, it looks like the soluble ACE2 is unlikely to have worked as an antiviral; the patient already had a high level of antibodies, as you can see in the Lancet paper above. So /if/ the patient's improvements can be ascribed to the soluble ACE2 treatment, it's likely the improvement was because of the effect the soluble ACE2 had on the person's renin-angiotensin system.
And if this holds, then it's likely many of these same improvements would be possible using a common class of widely-available blood pressure medications called ARBs.
This approach would not neutralize the virus, but instead stop the body from damaging itself. That's the theory, at least.
There are ~20 trials of ARBs for COVID-19 in progress now, though almost all are underdosed.
Despite the fact soluble ACE2 is not looking like it'll be developed in time to impact the pandemic, there is a silver lining:
If you look at the original paper (https://www.thelancet.com/journals/lanres/article/PIIS2213-2...), you'll note they include details on angiotensin peptide levels in the patient.
Interestingly, in this n=1 case report, it looks like the soluble ACE2 is unlikely to have worked as an antiviral; the patient already had a high level of antibodies, as you can see in the Lancet paper above. So /if/ the patient's improvements can be ascribed to the soluble ACE2 treatment, it's likely the improvement was because of the effect the soluble ACE2 had on the person's renin-angiotensin system.
And if this holds, then it's likely many of these same improvements would be possible using a common class of widely-available blood pressure medications called ARBs.
This approach would not neutralize the virus, but instead stop the body from damaging itself. That's the theory, at least.
There are ~20 trials of ARBs for COVID-19 in progress now, though almost all are underdosed.
AFAIK the way soluble ACE2 therapy works is you flood the body with "dummy" targets for SARS-CoV-2 to bind to instead of real cells, to slow down the virus infecting more and more cells.
As long as the spike of the new mink strains still binds to ACE2, it should provide some benefit.
As long as the spike of the new mink strains still binds to ACE2, it should provide some benefit.
(My biology background is incredibly weak.)
How would this work? How much medicine would you need to take to get enough dummy targets in your system to make a difference?
How would this work? How much medicine would you need to take to get enough dummy targets in your system to make a difference?
I don't know the doses, but the procedure and effects are described in the linked article. Previous studies have shown human soluble ACE2 can reduce viral load by a factor of 1,000-5,000.
"Nine days after the onset of symptoms, the patient received hrsACE2 twice daily for 5 min by intravenous infusion. Administration of hrsACE2 was continued as scheduled for 7-days and was well tolerated with no clear drug-related side effects. A marked reduction in serum angiotensin II levels with concomitant increases in angiotensin 1–7, angiotensin 1–9, and their metabolite angiotensin 1–5 was observed after the first dose of hrsACE2. These changes were sustained through the observation period. Significant ACE2 activity was observed 7-days after administration of the last dose of hrsACE2. In addition, marked decreases in the concentrations of critical cytokines implicated in COVID-19 pathology to include interleukin IL-6, chemokine IL-8, as well as the soluble receptor for advanced glycation end product, the inflammation marker ferritin, tumor necrosis factor α, surfactant protein-D, C-reactive protein, and angiopoietin 2 were observed. The copy number of SAR-CoV-2 decreased dramatically from 32,000 copies per mL 2 days before administration of hrsACE2 to 2,500 and 270 copies per mL after the first and second day of hrsACE2 treatment, respectively, with rapid clearance from the patient’s plasma during daily testing until the end of the observation period. Furthermore, hrsACE2 injection did not reduce the generation of anti-SARS-CoV-2 IgA and IgG antibodies"
"Nine days after the onset of symptoms, the patient received hrsACE2 twice daily for 5 min by intravenous infusion. Administration of hrsACE2 was continued as scheduled for 7-days and was well tolerated with no clear drug-related side effects. A marked reduction in serum angiotensin II levels with concomitant increases in angiotensin 1–7, angiotensin 1–9, and their metabolite angiotensin 1–5 was observed after the first dose of hrsACE2. These changes were sustained through the observation period. Significant ACE2 activity was observed 7-days after administration of the last dose of hrsACE2. In addition, marked decreases in the concentrations of critical cytokines implicated in COVID-19 pathology to include interleukin IL-6, chemokine IL-8, as well as the soluble receptor for advanced glycation end product, the inflammation marker ferritin, tumor necrosis factor α, surfactant protein-D, C-reactive protein, and angiopoietin 2 were observed. The copy number of SAR-CoV-2 decreased dramatically from 32,000 copies per mL 2 days before administration of hrsACE2 to 2,500 and 270 copies per mL after the first and second day of hrsACE2 treatment, respectively, with rapid clearance from the patient’s plasma during daily testing until the end of the observation period. Furthermore, hrsACE2 injection did not reduce the generation of anti-SARS-CoV-2 IgA and IgG antibodies"
Here's a great breakdown of how it works by the founder of Apeiron, Dr Joseph Penninger, from March. https://www.youtube.com/watch?v=jAW6VBWTiAA
It has been since discovered that there are other receptors/pathways too for SARS-CoV-2 to enter the cell, but it's still unclear which ones are the main culprits.
https://theconversation.com/a-second-pathway-into-cells-for-...