Piper Jaffray's conclusion on latest ARWR note

[Think2Succeed]

All 6 initial MONARCH cohorts are enrolling nuc treatment-naïve HBV patients:

Cohort 1: HBeAg positive, patients of any genotype administered ARC-520 as monotherapy

Cohort 2: HBeAg positive, Genotype B patients administered ARC-520, entecavir + PEGInterferon

Cohort 3: HBeAg negative, Genotype B patients administered ARC-520, entecavir + PEGInterferon

Cohort 4: HBeAg positive, Genotype C patients administered ARC-520, entecavir + PEGInterferon

Cohort 5: HBeAg negative, Genotype C patients administered ARC-520 + PEG-Interferon

Cohort 6: HBeAg negative, Genotype D patients administered ARC-520, entecavir + PEGInterferon

T2S

[roberto]

I was trying to do some research on the different Genotypes and I came across a journal titled "Hepatitis B virus genotypes: Global distribution and clinical importance." In the journal it said some interesting info about the relationship between PEG-IFN efficacy and Genotype:

"Many studies have indicated the role of HBV genotypes in response to IFN treatment, and response is greater with regard to genotypes A and B than genotypes C and D, with the worst response to IFN being observed with genotype D[3,18,46]. An experimental study investigating the effect of IFN showed that IFN/Peg-IFN was more effective in genotypes A or B than in genotypes C, D and I."

This makes Cohort 2 seem the most promising in regards to a immune system reactivation but I guess I am lacking information on how each Genotype is going to react to ARC-520.

Here is the link to the journal : www.ncbi.nlm.nih.gov/pmc/articles/PMC4017058/

[Think2Succeed]

Good find roberto ,

I've read that study a while ago and yes HBV has a few different genotypes but the initial hope of ARC-520 was that it will be active against all genotypes...from the way these 6 Monarch studies are designed we can see now that the company is trying to determine whether ARC-520 is more potent in a certain genotype (the treatments for HCV are recommended based on genotypes).

Here's also a map that is helpful in seeing the HBV distribution by genotype:



As you can see from this map in the US and Europe the most prevalent genotypes are A and G so I expect these two to be included as well in future Monarch cohorts.

Edit:

This makes Cohort 2 seem the most promising in regards to a immune system reactivation but I guess I am lacking information on how each Genotype is going to react to ARC-520.

That's true...and if we look on the map Genotype B falls right on China and Japan !

T2S

[roberto]

Oh so this is why Monarch is modelled after the Pharmasset study... The open label multi-cohort style is the most effective at finding results across multiple genotypes.

The map is definitely interesting as well because it shows where the market is for the cure of each Genotype. Since Arrowhead is focusing on B, C and D then I can assume that our main target market is in Asia for the moment. I guess that makes sense since the heparc studies began in Australia/Hong Kong and East-Asia has the highest population percentage infected with HBV.

When do you think that management will spread the Monarch studies to western Genotypes?

Maybe after we get top-line results from Germany (heparc-2002/2003) and US studies (heparc-2004)?


Hahaha alright. You answered part of my question in your edit. 

[Think2Succeed]

Oh so this is why Monarch is modelled after the Pharmasset study... The open label multi-cohort style is the most effective at finding results across multiple genotypes.

Exactly...Monarch is the equivalent of the phase 2b study conducted by Pharmasset that was acquired by Gilead after releasing results. Now some might want you to think that Arrowhead is far from Pharmasset's success given the almost 100% cure rate for its HCV drug...but let's not forget that HBV and HCV are two totally different viruses and HBV is much more difficult to cure so any FC rate that's bigger than IFN alone or reduces the treatment regimen/side effects will make ARWR an instant winner...and if you add that ARWR also has a few years market lead... So basically IFN is the benchmark ARWR needs to beat...of course ideally ARWR's drugs will cure most patients but given the history of HBV it's more realistic to assume that an improvement from IFN would still be a huge success.

When do you think that management will spread the Monarch studies to western Genotypes?

Maybe after we get top-line results from Germany (heparc-2002/2003) and US studies (heparc-2004)?

Management stated as goals for 2016 that they'll add new Monarch cohorts...so probably in 2016...I think the faster they can do it the better given the competition...probably due to the relationship (previous trials) ARWR already had with the Asian and Australian authorities/clinical sites, Monarch managed to enroll patients there faster....I don't think they're waiting for the results of the European/US based trials.

T2S

[mudbug021]

It kind of makes me wonder if they will start sub-categorizing the virus. IE. HBV(A-J)e- , HBV(A-J)e+.

This also brings up the question is ARC-521 going to be enough. Are they going to need to start more ARC-52x drugs?

It is quite amazing to me how everybody, the market especially, has tried to pigeon hole this disease and punish ARWR for its research for the past 2 years. IMHO, ARWR should be given the Nobel Science/medical prize if/when they figure everything out in the next 1-2 years... but Im getting ahead of myself.

[Think2Succeed]

Dec 24, 2015 11:45:32 GMT -5 mudbug021 said:

It kind of makes me wonder if they will start sub-categorizing the virus. IE. HBV(A-J)e- , HBV(A-J)e+.

This also brings up the question is ARC-521 going to be enough. Are they going to need to start more ARC-52x drugs?

It is quite amazing to me how everybody, the market especially, has tried to pigeon hole this disease and punish ARWR for its research for the past 2 years. IMHO, ARWR should be given the Nobel Science/medical prize if/when they figure everything out in the next 1-2 years... but Im getting ahead of myself.

It's quite possible they'll start sub-categorizing patients by genotype and the E antigen if we find out that ARC-520 works differently in different sub-populations. That's how ARC-521 was born...an improved version of ARC-520 to target the E- patients (although it will work in E+ as well). However, ARC-520/1 should be enough IF the theory that lowering HBsAg long enough will eventually awaken the immune system holds true...the drug has been tested so far in over 100 patients and I'm sure patients with different genotypes were tested. Let's hope though that the only distinction will remain between E+ and E- and ARC-520/1 will work the same regardless of genotype. HBV genotypes are defined by different mutations of the virus and geography but ALL still have the same HBV antigens (although in different proportions)... so if ARC-520/1 is indeed targeting the right target (all antigens of the HBV genome) then at least in theory it should work well across-different genotypes...

T2S