Monarch

[qbeing1010]

Can someone explain in layman's terms what the NUC and IFN part of Monarch will do?  Why those?  What exactly are they?  What do we expect to see?

Thank you.

[mudbug021]

interferon (IFN )
nucleos-(t)ide analogues (NUCs)


Basically what a drug is made of. To get more detail information I recommend google each one. For me, there is just no easy way to explain what they do. (maybe somebody else can do this)

At this point in time IFN and NUC are the most effective against HBV but the issue is they dont always work on everybody. What the Monarh trials are going to do is have multiple trials (Arms) going at one time using INF or NUC at different dosing levels used along with ARC-520. The purpose is to find the best combination that is the most effective against HBV.

What is also important about this trial is it will be an Open Label trial. Meaning, when the data becomes available they can present it immediately instead of having to wait for a scheduled presentation. So its feasible we could see data on a monthly basis instead of every 3 months.

[Think2Succeed]

qbeing1010,

Mud touched on a few good points but let me give you my version as well:

Monarch is designed initially to have two arms (management hinted that more arms might be added):

1. ARC 520 administered alone
2. ARC 520 + Entecavir (which is a NUC) + Peg INF

I'll start by answering your question: "Why those?" (NUCs and Peg INF).

There are only 2 classes of drugs approved for treatment of HBV: NUCs and Interferons. When it comes to HBV, Entecavir is regarded as the most potent NUC while Peg INF alpha 2a the most potent interferon against HBV. Arrowhead's choice to co-administer ARC 520 with other approved treatments offers these benefits:

- if the combo is successful then the chances of approval are bigger since there is only one new unknown (ARC 520), FDA being already familiar with Entecavir and PEG INF
- it's much easier to assess the safety and efficacy profile of ARC 520 if combined with approved treatments vs combining it with other drugs that are not approved yet because there is a wealth of already existing data (efficacy and safety) for both Entecavir and INF. All this cocktail has to achieve is a more efficient treatment than INF alone which only produces a functional cure (FC) in about 10-15% of patients.
- you want your drug compared directly against the standard of care if you plan to replace it once it gains approval

What the NUC and IFN part of Monarch will do? What exactly are they?

HBV is a very complicated virus and an infected liver cell (hepatocyte) becomes like a little faucet that produces viral proteins (the most potent one being HBsAG, other viral proteins being HBcAG, the X protein and the HBV DNA). So what a NUC does very well is to protect healthy cells from becoming infected not allowing the HBV to replicate. However, the infected cells remain infected. Peg INF on the other hand (also called an immunomodulator) is designed to stimulate the immune system to better fight the HBV virus. ARC 520 is an antiviral meaning it attacks the virus directly (the HBV viral proteins mentioned above) and its job is to close the faucet from producing viral proteins AND to clear the infected cells of the HBV.

So, when the company states that ARC 520 induced more than 1 log KD of HBsAG and other viral proteins it means it cleared the HBV virus more than 90% (1 log =90%, 2 log =99%).

What do we expect to see?

By attacking the virus in 3 ways (ARC 520 directly, entecavir stopping replication, INF stimulating the immune system) simultaneously we hope that a significant number of functional cures will be achieved ! So far the best we get is 10-15% with Peg INF so the hope is that this cocktail of drugs will achieve a greater percentage of FC's.

I hope this answered your questions.
T2S

[qbeing1010]

T2S,

Fantastic description (I also thank Mud for his). I have a much better grip on this now.

I think someone somewhere stated that it would take X months of monitoring (after dosing) to declare a FC.  Is that true, and how many months?  Or am I confusing this with a total cure (no more virus at all)?

Thanks again for the help.

Q

[Think2Succeed]

Yes, to declare a FC you need to be virus free (mostly) after you stop the treatment for 6 months. This is called "functional" cure because the virus is still present at the deepest level of the DNA but it is inactive so it can not harm you and replicate anymore because the immune system has taken over and is keeping the virus in check. The ideal cure is called a sterile cure....which would clear the virus completely like you never had HBV.

This might be one of the reasons why management only refers to Mannetta as achieving immune response and not declaring it a FC when in fact technically it is...maybe they want to wait for 6 months to make sure the virus is kept in check for this long.

T2S