This is a very insightful post @msn81 and you have identified the key question. How do you prove BIT225 is doing something useful in patients?
Yes you are right you can't sample macrophages from around the body, really the only accessible ones are the ones in the blood. When you give a new treatment like BIT225 you don't really know what is happening in the macrophages in the liver, in the skin, in the brain, bone marrow, etc. The only way around this problem is to give patients your drug for a long time and see if they stay healthy and measure various blood based markers to see if you can find a marker that predicts clinical benefit.
This is exactly what the early HIV drug developers did. The gave patients drugs that stopped HIV replicating in the lab and watched what happened when they gave it to patients. They discovered that if you give enough different drugs at once (3 or 4) that the virus is prevented from replicating so much that it can't be detected in the blood and the patients stays healthy and even recovers to an extent. Over time the marker that correlated best with clinical utility was plasma free viral suppression; the better the drug suppressed the virus in the blood the longer the patient stayed healthy. Today it is accepted if you have a new drug that surpresses viral replication well and doesn't have too many side-effects (especially long term), and where resistance doesn't occur too quickly, you have an approvable drug. This is why BIT had as their primary aim viral supression in the blood.
Where did BIT go wrong? This is just my opinion, and I don't know all the issues BIT faced (especially financial), but I think they chose the wrong population to study. When you look at phase 2 trials for other antiretrovirals the population most companies choose to study are the drug experienced patients. These are the patients that have been infected for decades and who have developed resistance to most or all of the antiretrovirals on the market. These patients don't have good supression of the virus so if you add your new drug to their current treatment mix you will see a measurable effect (i.e. the virus levels in the blood will go down) and the FDA will approve your drug (assuming the side-effects are not too terrible).
Why didn't BIT do their trial in these patients? It is certainly not because MM didn't think to do this (she is no idiot). This is only speculation, but I think it revolves around money. The drug experienced patients are pretty much only found in first world countries like Australia. It is very expensive to run a clinical trial in Australia and if you only have the cash to run a small trial (BIT's trial was small for a phase 2 trial) then you need to go somewhere where it is cheaper. It looks like they hoped that testing in newly infected patients where the virus level is still naturally very high (HIV infections have a U-shaped viral load pattern, lots of virus at the beginning of infection, relatively low virus levels in the middle, and lots of virus at the end when you get AIDS) that they would be able to show a difference. Unfortunately they lucked out and the standard treatment knocked down the virus to such an extent that they couldn't see any effect of adding BIT225. Such is life.
They did have the backup plan of measuring sCD163 which they new from previous studies should show an effect. The problem they now have is showing that this is clinically useful. I suspect it is, but it will take a lot more work to prove this - at least another longer term phase 2b trial. I don't think BIT has the time or the cash to do such a trial. This is why I am skeptical about the commercial prospects of BIT.
