The following is my understanding re: ROT. The
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Posted On: 03/24/2021 10:08:16 AM
The following is my understanding re: ROT.
The initial COMBO trial was at 350mg and there were some responders and others did not.
They increased the dose to 525mg in the MONO trial and again there were some responders and others that did not.
They hypothesized that perhaps it was related to the quantity of CCR5 and thus the occupancy of LL.
So, the increased the dose again to 700mg in the MONO trial. And this time the responders did very well, but there were still others that did not respond. Also, they found that there were a few patients who had some variability in suppression of their viral load. It appeared that this variability was when the patient got sick. The hypothesis was that during illness, the quantity of CCR5 increased in the patient and thus the LL occupancy would decrease.
When they presented the data to the FDA. It was reportedly obvious to the FDA that the efficacy was not a clean, linear relationship between dosing and responder. In some cases the 700mg dosing had slightly lower responder rates than the 525mg, and there was still the issue of the variability.
Additionally, there was the issue of: why do some patients not respond? The hypothesis being that perhaps they just had too much CCR5 and thus occupancy was too low.
My understanding was the FDA, partially based on the arguments CYDY put forth, believed that ROT was the key to unlock these mysteries. CYDY told the FDA that with an accurate ROT, they could precision dose any patient based on their native quantity of CCR5 and also increase dosage whenever there was a spike due to e.g. illness.
From that point forward, the ROT essentially became a validation of CYDY's understanding of the MOA of LL for HIV. If the ROT hypothesis proved out, then all the variables would fall into alignment.
But instead, the ROT has become an albatross and gate keeper.
LL was clinically effective and had a great p-value at 350mg. Had we not even tried to explain the other doses and variability, we would have been approved a long time ago.
Regarding Dr. BP's ROT, my guess is that it worked. NP stated it was only about 50% accurate, but that is hard to believe. As I recall, NP had previously stated that the FDA did not approve the test. My guess is that it is because it is new and not formally approved or widely accepted in the industry.
The other thought I had was that I think Dr. BP was illuminating LL and seeing if it binded to something and thus it would be less luminescent. And then assuming that if there was additional fully bright LL, then dosing wasn't the limiting factor. But that doesn't really address CCR5 occupancy; it is more of LL uptake. Perhaps this was the issue the FDA had with it. (Or perhaps my limited understanding of the test is off base).
Whatever the case, we are now working with two new companies to develop a ROT that we believe the FDA will accept. Hopefully, one of them will prove successful. And soon.
The initial COMBO trial was at 350mg and there were some responders and others did not.
They increased the dose to 525mg in the MONO trial and again there were some responders and others that did not.
They hypothesized that perhaps it was related to the quantity of CCR5 and thus the occupancy of LL.
So, the increased the dose again to 700mg in the MONO trial. And this time the responders did very well, but there were still others that did not respond. Also, they found that there were a few patients who had some variability in suppression of their viral load. It appeared that this variability was when the patient got sick. The hypothesis was that during illness, the quantity of CCR5 increased in the patient and thus the LL occupancy would decrease.
When they presented the data to the FDA. It was reportedly obvious to the FDA that the efficacy was not a clean, linear relationship between dosing and responder. In some cases the 700mg dosing had slightly lower responder rates than the 525mg, and there was still the issue of the variability.
Additionally, there was the issue of: why do some patients not respond? The hypothesis being that perhaps they just had too much CCR5 and thus occupancy was too low.
My understanding was the FDA, partially based on the arguments CYDY put forth, believed that ROT was the key to unlock these mysteries. CYDY told the FDA that with an accurate ROT, they could precision dose any patient based on their native quantity of CCR5 and also increase dosage whenever there was a spike due to e.g. illness.
From that point forward, the ROT essentially became a validation of CYDY's understanding of the MOA of LL for HIV. If the ROT hypothesis proved out, then all the variables would fall into alignment.
But instead, the ROT has become an albatross and gate keeper.
LL was clinically effective and had a great p-value at 350mg. Had we not even tried to explain the other doses and variability, we would have been approved a long time ago.
Regarding Dr. BP's ROT, my guess is that it worked. NP stated it was only about 50% accurate, but that is hard to believe. As I recall, NP had previously stated that the FDA did not approve the test. My guess is that it is because it is new and not formally approved or widely accepted in the industry.
The other thought I had was that I think Dr. BP was illuminating LL and seeing if it binded to something and thus it would be less luminescent. And then assuming that if there was additional fully bright LL, then dosing wasn't the limiting factor. But that doesn't really address CCR5 occupancy; it is more of LL uptake. Perhaps this was the issue the FDA had with it. (Or perhaps my limited understanding of the test is off base).
Whatever the case, we are now working with two new companies to develop a ROT that we believe the FDA will accept. Hopefully, one of them will prove successful. And soon.
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