Hey @Davisite Having time to read your response - (thank you for...

Hey @Davisite

Having time to read your response - (thank you for taking the time), here’s my reply, for convenience I’ve copied your post here (highlighting parts in red) and responded with my comments in blue. Green quotes are from BIT ASX announcements.

FYI, I don’t have a PHD, so my comments are IMO of how I interpret what Dr Michelle Miller, BSc, MSc, PhD GCertAppFin (Finsia) has provided.


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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?

Thanks

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. They 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 suppresses 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 suppression in the blood.

I believe this is Not True - that is what the cART drugs do (suppression in the blood).

Quote from ASX Announcement 29-October (ASX Aware Response Letter):

BIT225‐009 trial was designed to measure the antiviral efficacy and safety of a BIT225. Its mode of action is the inhibition of HIV‐1 replication primarily in a subset of HIV‐1 infected cells called macrophages. This is a novel target where no benchmark antiviral agent has been investigated previously. This study was an exploratory study with multiple Objectives and end points measured.

Therefore, my understanding is that BIT had their primary aim of viral suppression in Macrophages reservoir cells.

Further - (from the same announcement), the aim of the trial was:

As set out in that 13 February 2017 announcement, the aim of this Phase 2 trial was to demonstrate:

• Accelerated reduction of HIV‐1 in patients treated with BIT225 in combination with cART, indicating that BIT225 can significantly improve current standard of care anti‐ HIV‐1 treatment;

and

• Reduction in HIV‐1‐induced immune activation, indicating that BIT225 is targeting viral reservoirs not impacted by cART.

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 suppression 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).

That’s a Fair Point. MM gave some reasoning around why they chose Thailand, suggesting it was due to having subjects there not having any exposure to any previous HIV medication that could influence/impact their trials. She mentioned that you don’t generally find subjects in developed countries as most subjects would already be on some form of cART medication.

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.

Not true (IMO):

As disclosed in the announcement of 28 September 2018, no differences were noted in the levels of cell‐free virus (plasma viral load) in the blood. This result was expected because of the effectiveness of current ART, which all trial participants were taking. Plasma viral load was rapidly reduced to undetectable levels in all subjects.

What they actually found was:

…The estimate indicates a statistically larger overall decrease in sCD163 for the BIT225 treated group compared to placebo cohort.
And
sCD163 is a primary biomarker specific for monocyte and macrophage immune activation.
And
Additional reduction of this marker in patients taking BIT225 demonstrates significant immunological benefit.
And
The results showed statistically significant differences in the profiles of two specific T‐cell populations during the BIT225 treatment period. These reflect the significant differences in immunological responses in patients receiving 200 mg BIT225 with ART compared to placebo with ART. This was reported in the 28 September 2018 announcement as “…changes to the immune cells that fight disease.”
And
Biotron has shown that BIT225 attacks HIV‐1 growing in macrophage cells, resulting in the production of replication‐incompetent virus i.e. non‐ infectious, dead virus. The data from the current BIT225‐009 clinical trial reported here shows that the body’s immune system recognises this dead virus, which triggers a range of changes to the immune cells that fight disease.
How I understood the point above is that if they can kill the virus and have a “non-infectious, dead virus”... and the body’s immune system can fight the disease itself... I understand this is the pathway to VACINE (IMO, but I believe MM alluded to this same conclusion in the AGM).

Oh, And...
The immunological changes seen in trial subjects receiving ART + BIT225 treatment (described in responses to Q2) are consistent with the body’s immune system recognising this replication‐ incompetent virus as a source of antigen. This immunological response is not seen in trial subjects who did not take BIT225 (i.e. took ART + placebo).

Further...
The goal of many immune stimulation‐based interventions such as vaccines has been to boost specific T cell responses and the consequent downstream concert approach of the immune system to eliminate viral products including viral load. The addition of BIT225 was found to induce immunological changes, as measured by flow cytometry (see Q2 above). This is consistent with a release of a new antigen source such as replicative incompetent virus from macrophages. These results demonstrate that BIT225 has a unique mechanism of action compared to marketed ART.


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.

LOL...That wasn’t the ‘back-up plan’.