Revive Therapeutics Ltd (RVVTF)

[Jama87]

NEW DD - NAC WORKS IN COVID - Mods Please Sticky

I don't mean to spam the board but I'm pretty pumped about what I've just read and want to summarize it all together in a single post. Hopefully it can be stickied for visibility.

I've dug up some extremely interesting scientific publications this morning that are both pretty new that everyone on here needs to read ASAP.

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine

Published 20th July 2020 (Less than two weeks before the Phase 3 announcement of Bucillamine!)

https://www.sciencedirect.com/science/article/pii/S1521661620306513

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

Deeper in the article:

Eight of the nine patients required VV ECMO. We have observed a significant overall reduction in inflammatory markers (CRP and ferritin) during IV NAC administration. A rebound of inflammation was noted in six patients following discontinuation of NAC (Supplementary Figs. S1-S6)

When they stopped NAC the patients got worse... this is very convincing.

But wait, there's more.

Why do we think Bucillamine will work for Covid just because NAC works?

Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients

Published May 28th, 2020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263077/#:~:text=Endogenous%20glutathione%20deficiency%20appears%20to,death%20in%20COVID%2D19%20patients.

This article gives a great explanation of how NAC works. The exact same mechanism should apply to Bucillamine in theory.

To put this into really simple terms (if I understand correctly):
People with Glutathione deficiency had worse Covid.
Glutathione deficiency makes the inflammation worse.
NAC helps resolve glutathione deficiency by donating thiols.
Bucillamine donates thiols with 16x potency.

Since the antiviral effect of glutathione is nonspecific, there is reason to believe that glutathione is also active against SARS-CoV-2. Therefore, restoration of glutathione levels in COVID-19 patients would be a promising approach for the management of the novel coronavirus SARS-CoV-2. Notably, long-term oral administration of N-acetylcysteine has already been tested as an effective preventive measure against respiratory viral infections.

The timing of the first article coming before the bump from phase 2 to phase 3 makes me think the FDA based the phase 3 bump on this data. I can't believe it hasn't been posted yet to this board.

I don't see how Bucillamine won't get approved for mild to moderate if NAC is reducing inflammation in severe cases.

And one final bonus that is not purely NAC but also seems to give some evidence that NAC may work:

Application of methylene blue -vitamin C –N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial

Published August 20th, 2020.

https://www.sciencedirect.com/science/article/pii/S0014299920305860?via%3Dihub

An NAC/vitamin compound seemed to help Covid patients.

As the last therapeutic option, five patients were administered methylene blue-vitamin C–N-acetyl Cysteine (MCN). Nitrite, nitrate, methemoglobin, and oxidative stress were significantly increased in patients in comparison to healthy individuals. Four of the five patients responded well to treatment. In conclusion, NO, methemoglobin and oxidative stress may play a central role in the pathogenesis of critical COVID-19 disease. MCN treatment seems to increase the survival rate of these patients.