I've been parsing through Lalezari's presentation on 11/21/23 because I was a bit thrown by his talk about trialing with Leronlimab to deal with HIV "immune activation".
Of course you would want your immune system activated if you have HIV. But later in his talk he talks about immune activation inflammation. That makes sense. Then I looked again at an article someone on the board recommended -
https://www.mdpi.com/2227-9059/11/1/159
There it is talking about chronic immune activation.
So what I have come to realize is Lalezari is saying that the FDA would have a hard time not being interested in Leronlimab if LL can treat PLWH (People Living With HIV) like it treats people with Cytokine Storm - with immune systems that are way out of homeostasis and inflammation is what will kill them.
Lalezari said, "The consensus with the HIV consultants has been that we circle back to HIV but, instead of looking at leronlimab as an antiviral, we look now at leronlimab as a modulator of immune activation. Is that a relevant endpoint? It is, because immune activation inflammation is the primary driver of mortality in HIV patients. Strokes, heart attacks, liver, kidney."
"It is unfortunately a much more difficult endpoint to assess than simply following an HIV viral load but it is kind of in the wheelhouse of what we're believing leronlimab is capable of. So the proposed next study is to look at leronlimab in HIV positive ambulatory subjects. We know it's safe in that group. In individuals who demonstrate elevations of immune activation markers. So known evidence of immune activation inflammation."
"I think that's a study that the FDA is going to have a hard time not wanting to see done. There is currently no therapy for immune activation in HIV."
What he is saying in this last sentence is there is no therapy for the inflammation that results from an activated immune system that is not going back to homeostasis. Part of the reason for that is that HIV is always with People Living With HIV because HIV is a retrovirus. "So a vaccine, a cold, a herpes outbreak, clinical or subclinical, any sort of illness can turn the virus back on." He says, "blipping occurs with any immune activation event" and that is very bad because the person becomes infectious again.
Funny how no one mentions AIDS - Acquired Immune Deficiency Syndrome. Why is the immune system deficient? Because it can never get back to homeostasis. Homeostasis would mean that the whole compliment of immune system components were present and in the right place.
Inflammation shows that immune system components are not present and in place or are being depleted because they are actively dealing with some infectious agents. AIDS doesn't kill you - a deficient immune system kills you. AIDS means you will have Chronic Immune Activation Inflammation that will result in clots, strokes, heart attacks, liver and kidney failure, gut diseases, etc.
CD4+ and CD8+ cells are especially important to restore to homeostasis. HIV directly destroys CD4+ cells through the CCR5 receptor and CD8+ cells are depleted to exhaustion by RANTES. They work together in a certain ratio/balance. Restoring that balance is one of the most important things that LL does. I don't think inflammation can be stopped without that balance.
So Lalezari says at the end of his talk, "...what I had mentioned earlier was that the FDA, having received the protocol, has asked if they can cross-reference the IND file for NASH, which is exactly the right question to be asking is “what other evidence do we have that leronlimab is mediating inflammation and immune activation?”
His next sentence is a little muddled - he says, "So that we are waiting to hear." Cytodyn must have sent in a reply to the question above, "what other evidence do we have that leronlimab is mediating inflammation and immune activation?" He then says, "...the clock is ticking and that we're expecting to hear one way or another from the FDA in the next two weeks."
Those two weeks have passed. It was unclear from the latest PR whether Cytodyn has received an answer back yet or whether the FDA asked yet another question. I just hope it doesn't take 30 days between each bounce of the ping-pong ball in this back and forth!
Of course you would want your immune system activated if you have HIV. But later in his talk he talks about immune activation inflammation. That makes sense. Then I looked again at an article someone on the board recommended -
https://www.mdpi.com/2227-9059/11/1/159
There it is talking about chronic immune activation.
So what I have come to realize is Lalezari is saying that the FDA would have a hard time not being interested in Leronlimab if LL can treat PLWH (People Living With HIV) like it treats people with Cytokine Storm - with immune systems that are way out of homeostasis and inflammation is what will kill them.
Lalezari said, "The consensus with the HIV consultants has been that we circle back to HIV but, instead of looking at leronlimab as an antiviral, we look now at leronlimab as a modulator of immune activation. Is that a relevant endpoint? It is, because immune activation inflammation is the primary driver of mortality in HIV patients. Strokes, heart attacks, liver, kidney."
"It is unfortunately a much more difficult endpoint to assess than simply following an HIV viral load but it is kind of in the wheelhouse of what we're believing leronlimab is capable of. So the proposed next study is to look at leronlimab in HIV positive ambulatory subjects. We know it's safe in that group. In individuals who demonstrate elevations of immune activation markers. So known evidence of immune activation inflammation."
"I think that's a study that the FDA is going to have a hard time not wanting to see done. There is currently no therapy for immune activation in HIV."
What he is saying in this last sentence is there is no therapy for the inflammation that results from an activated immune system that is not going back to homeostasis. Part of the reason for that is that HIV is always with People Living With HIV because HIV is a retrovirus. "So a vaccine, a cold, a herpes outbreak, clinical or subclinical, any sort of illness can turn the virus back on." He says, "blipping occurs with any immune activation event" and that is very bad because the person becomes infectious again.
Funny how no one mentions AIDS - Acquired Immune Deficiency Syndrome. Why is the immune system deficient? Because it can never get back to homeostasis. Homeostasis would mean that the whole compliment of immune system components were present and in the right place.
Inflammation shows that immune system components are not present and in place or are being depleted because they are actively dealing with some infectious agents. AIDS doesn't kill you - a deficient immune system kills you. AIDS means you will have Chronic Immune Activation Inflammation that will result in clots, strokes, heart attacks, liver and kidney failure, gut diseases, etc.
CD4+ and CD8+ cells are especially important to restore to homeostasis. HIV directly destroys CD4+ cells through the CCR5 receptor and CD8+ cells are depleted to exhaustion by RANTES. They work together in a certain ratio/balance. Restoring that balance is one of the most important things that LL does. I don't think inflammation can be stopped without that balance.
So Lalezari says at the end of his talk, "...what I had mentioned earlier was that the FDA, having received the protocol, has asked if they can cross-reference the IND file for NASH, which is exactly the right question to be asking is “what other evidence do we have that leronlimab is mediating inflammation and immune activation?”
His next sentence is a little muddled - he says, "So that we are waiting to hear." Cytodyn must have sent in a reply to the question above, "what other evidence do we have that leronlimab is mediating inflammation and immune activation?" He then says, "...the clock is ticking and that we're expecting to hear one way or another from the FDA in the next two weeks."
Those two weeks have passed. It was unclear from the latest PR whether Cytodyn has received an answer back yet or whether the FDA asked yet another question. I just hope it doesn't take 30 days between each bounce of the ping-pong ball in this back and forth!
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