We have had the density talk before in meeting the fda

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I found the CC comments/questions posted below and also I quoted from the linked article posted below.


If I am interpreting this correct the CCR5 density varies person to person, but for an individual, it stays fairly constant and does not change with HIV. The CCR5 density also correlated to viral load and has a "threshold of ~10,000 CCR5 molecules per cell, below which infectability dropped drastically."


So, I am guessing there will be a positive correlation between rebounders in the mono trial and CCR5 density, hence some patients needing a higher dose.

If the higher dose does not change that correlation significantly, then would the not also mean that if they want the 70% efficacy, they may look at CCR5 density and say--as an example--efficacy is 70% with patients below ~12,000 CCR5 density and just limit to that population.



January 5th, 2017 CC
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Part of Nader's Opening Statement

Now I must discuss an interesting and potentially very positive new development pertaining to the non-responders to PRO 140 by some patients with R5 strain in our Phase 2 monotherapy trial that could have implication for our Phase 3 monotherapy trial. So just to remind you, some patient did not respond more than few weeks to monotherapy in our previous Phase 2b trial, while others did, and as you know some are now have passed two years of treatment.

At the FDA’s suggestion we reviewed published data indicating that HIV patients can have widely varying density of CCR5 under cell surface. According to this data that number could exceed the previous acknowledged level of CCR5 by factor exceeding 100 folds.
What does this mean? Well, as we all know, PRO 140 works by blocking the CCR5 receptor that allows HIV to infect cells. This means that those patients who didn't respond to PRO 140 in Phase 2 monotherapy trial might have had a high density of CCR5, which means they could have had more CCR5 under surface of their cell than others, which could indicate that they needed more PRO 140 than others.
We know that only 21 of 39 of the original enrolled patient completed 12-week monotherapy trial. Among the 18 non-responders, eight were treated for infection, which is a non-response issue that could be independent of PRO 140. By excluding these patients 21 of 31 patients or about 70% were responders.
So to put this in a simple language, the lack of response to PRO 140 monotherapy by the other 10 patients in the trial may have been due to an insufficient dose of PRO 140 to address the high CCR5 density. This is encouraging as it may provide insights into why some patients with R5 strain responded, while others did not, like this is not the case.

From our 300 patients monotherapy Phase 3 trial, we should at least get a number of responded that would be statistically more significant than previous 39 patients trial. Now this we believe is important to seek second approval for monotherapy for PRO 140 after we hopefully get our first approval for combination therapy.

Question & Answer

Yi Chen

Okay. Thank you. And currently what you just said about why -- the reason that some of the CCR5 patients did not response to [inaudible] (25:43), one is because of the dosing of PRO 140 was not sufficient. So what kind of increase dosing we expect to see for going forward?

Dr. Nader Pourhassan

Yeah. Very good question. So the half life of this product is 3.5 days becomes four days I should say. So in our protocol we have the option available to us to change the injection from every seven days to every four days. So if any patient start having peek in their viral load of -- even let say 100 or anything more than target not detectable which is less than 40 copies per meal we will definitely switch them to every four days and hopefully that would give them enough PRO 140 to be able to respond.





April 17, 2017 CC

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Question & Answer
Matt Mikeska

Hi, guys. Thanks for the update on everything today. My question is about in the Phase 2b studies, some of the past patients you mentioned had higher density HIV situation where the viral load started to increase slightly from being drastically lower. And that you guys felt in last conference call that it might be simply a dosing amount of PRO 140 for those patients that might address that, there is any further studying to determine if that is the case and that the dosing of PRO 140 will take care of these higher density HIV patients, I know there is really nothing to worry about or anything?

Anthony Caracciolo

Well, that’s a great question. Nader, you probably have a little bit more detail on that. Could you provide some of the background you have?

Nader Pourhassan

Sure, Tony. So, in past we did not say that the failure was due to having some patients having higher density of CCR5. What we said in our last conference call is that’s one of the things that we will be looking for, 300 patients it’s a monotherapy-investigative trial which means we will be looking at those situations. We never reported that the failures was due to that but as this trial goes forward, we will be looking at that and other factors. Tony?

Anthony Caracciolo

Yes. So, just to add, I think the right answer to that question is we just don’t know yet. There is going to be a lot of analysis particularly in the monotherapy trial that we are unable to perform in the combination trial because of the fact that it’s more of a salvage study than an ongoing chronic study. So, I think as we start to see some of the data coming in on the monotherapy, those are key points of interest for us to more specifically look at patients that are more receptive to the treatment than those that have not been. So, the right answer is we are hopeful that, that type of data will be forthcoming.




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When we compared virus load and CCR5 expression for the 14 infected subjects, we observed a strong correlation between virus load and CCR5 density (r = .666, P = .009; figure 2A) and a nearly significant correlation between virus load and percentage of CCR5+CD4+ T cells (r = .525, P = .054; data not shown).




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There was a strong correlation between HIV RNA plasma level and CCR5 density (P = .009) that was independent of cell activation and was not due to an HIV-induced CCR5 up-regulation



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To test this possibility, we compared CCR5 density between infected and uninfected subjects. If HIV up-regulates CCR5 expression in vivo, CCR5 density at the surface of CD4+ T cells from infected persons should be high; however, we found no difference in CCR5 density in the 2 groups analyzed (geometric means, 11,206 [95% CI, 10,018–12,395] vs. 11,124 [95% CI, 8520–13,727] in HIV-uninfected and -infected persons, respectively; P = .824; data not shown). We also followed the effect of highly active antiretroviral therapy (HAART) on CCR5 expression. If high CCR5 density is a consequence of HIV productive infection, the reduction of this production should down-regulate the expression of this coreceptor. Six of the patients in this study were followed up during HAART After 4 months of treatment, their virus load dropped drastically (figure 4A); however, CCR5 density at the surface of their DR CD4+ T cells remained constant (figure 4B), arguing against an HIV-induced CCR5 up-modulation.




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These researchers stably transfected CCR5 into CD4 HeLa cells and found a strong correlation between cell infectability and CCR5 density. Of interest, they found a threshold of ~10,000 CCR5 molecules per cell, below which infectability dropped drastically.