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Arrowhead Begins Phase 1 Trial of RNAi ARC-520 for Treatment of Chronic HBV

Arrowhead Begins Phase 1 Trial of RNAi Therapeutic ARC-520 for Treatment of Chronic Hepatitis B Infection

PASADENA, Calif. - July 23, 2013 - Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that it has initiated dosing in a Phase 1 clinical trial of ARC-520, the Company's candidate for the treatment of chronic hepatitis B virus infection. Trial initiation followed successful completion of the Clinical Trial Notification (CTN) regulatory process in Australia. The objectives of the study are to characterize the safety profile of ARC-520, determine maximum tolerated dose, and evaluate pharmacokinetics in healthy volunteers. ARC-520 is the first candidate to use Arrowhead's proprietary Dynamic Polyconjugate (DPC) delivery platform and includes two distinct siRNA sequences that have pan-genotypic coverage for 99.6% HBV GenBank sequences.  

The Phase 1 trial is a single-center, randomized, double-blind, placebo-controlled, single dose-escalation, first-in-human study of ARC-520 administered intravenously to healthy adult volunteers and is being conducted in Melbourne, Australia. Each dose cohort includes 6 subjects randomized at ratio of 1:2 (placebo: active) to receive a single intravenous injection of either placebo or ARC-520. Arrowhead expects to complete this Phase 1 trial in the fourth quarter of 2013 and begin a Phase 2a trial in chronic HBV patients in 2014.

"This Phase 1 study will establish a safety profile for ARC-520 as well as provide the first human data for our DPC delivery platform. This is an important step forward as we seek to advance ARC-520 into HBV patients and build additional RNAi therapeutics based on what we believe is the most potent delivery system in the industry," said Dr. Christopher Anzalone, President and Chief Executive Officer.

Hepatitis B is the world's most common serious liver infection. It is estimated that 350 million people worldwide are chronically infected with HBV, representing approximately 1 in 20 people on the planet. No currently available treatment methods can reliably achieve meaningful cure rates. ARC-520 is designed to reduce the production of new viral particles and viral proteins. Many experts believe that reducing key viral proteins can revive patients' adaptive immune response and potentially lead to a functional cure of chronic HBV infection with a finite treatment regimen. Arrowhead previously presented data generated in rodent models and in a chimpanzee chronically infected with HBV, showing that ARC-520 induces rapid, deep, and durable knockdown of both circulating HBV DNA and key viral proteins, including hepatitis B s-antigen, e-antigen, and the core protein that forms the capsid.
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Avatar universal
Single Dose of ARC520 Unlikely to Produce Functional Cure Due to Long HBsAg Half-Life

The chimpanzee HBV data on ARC520 showed that while HBV viral DNA and the HBeAg were greatly reduced almost immediately following onset of gene silencing, HBsAg elimination lagged behind: a 50% reduction following ~8 days and another 50% reduction following 15-20 days.  This raised questions in the minds of some readers here about the potency of ARC520 in real patients.

My response was that this most likely reflects a slow HBsAg elimination even in the absence of new HBsAg production.  This was also speculated on in the ARC520 analyst day webcast by Arrowhead Research.

Thanks to the patent application by GSK which I discussed here last night, I was finally able to find a good reference on HBV elimination in real patients (not mice and woodchucks).  In this paper by Chulanov et al., the kinetics of viral components were followed in patients with acute hepatitis caused by HBV.  In this setting, it is assumed that almost no new viral production occurs thus facilitating the determination of half-lives.

Strikingly, the observations were entirely consistent with the chimpanzee data: whereas the HBV DNA and HBeAg half-lives were on the order of 1-2 days, the half-life of HBsAg was ~8 days. What is more, in patients with high viral titers (remember, the chimpanzee had exceptionally high titers) to start with, the half-life increased.  This means that even if there was almost complete knockdown of HBsAg with ARC520 in the chimpanzee, HBsAg after 8 days would still be predicted to be ~50% of the starting value…exactly what was observed.  The fact that a 75% reduction (i.e. another halving) was observed after 15-20 days suggest that RNAi gene silencing was still near its peak even 2 weeks following ARC520 administration.  Thus, the chimpanzee data are entirely consistent with a high potency of ARC520 ‘in the real world’.

The slow HBsAg kinetics, however, have important implications for the dosing regimen and expectations for the outcome of the single-dose phase IIa Hong Kong study.  Whereas I had speculated that functional cures may be seen in the results from this study around a year from now, I now have to moderate my expectations.  This is because a 8 day half-life predicts that a 90% reduction of HBsAg, which seems to be a benchmark set by the companies, could theoretically be achieved only 3-4 weeks after drug administration.  At this point, however, the RNAi activity is expected to wane such that at least 2 or 3 doses every 10 to 14 days would be needed to safely achieve the 90%+ knockdowns in most patients.

As a result, it may be worth for the company to seek an extension for the Hong Kong study.  This, however, would likely require a degree flexibility by the Hong Kong authorities since the 9-month chronic tox studies are only beginning.  If seeking such an extension would mean delays in the clinical development timelines, I would do just the single-dose as the multi-dose study should begin in the second half of 2014 anyway.

Update: According to information provided by Arrowhead Research yesterday, following just 2 weeks of study initiation, dosing with ARC520 has already been completed for 2 out of the 6 ascending dose cohorts. Accordingly, the company remains on track to report data in Q4 or even by the end of Q3 and initiate the Hong Kong study soon thereafter.
Avatar universal
I dont know why companies walk very slow toward hbv cure ..

for hepatitis c .. in the last two years .. several drugs have been approved and marketed .. and all give very good results ..  Vicrtelis (boceprevir) ..  Incivek (telaprevir) .. and alot of drug either near to approved or in last phase of trial ..

why the progression in hep c ahead of hepa b??

in spite of the number pf people infected with hepa b is more .. and also .. hepa c can be cured by peginterferon only .. still hepa b tratment with no real support ..
Avatar universal
Almost all the new HCV drugs are developed in the USA where there are more Hep C patients than Hep B. You will also notice much less research on HBV from the USA compared to Asia and Europe. Also, Hep C has no vaccine. So I believe big pharma just target where  money can be made. Very disappointing for hbvers.
Avatar universal
No new HBV drugs since 2008!! Very disappointing!!
Avatar universal
Arrowhead has progressed very quickly on this drug so your statement is somewhat unfounded:

"I dont know why companies walk very slow toward hbv cure .. "
Avatar universal
In the above article .. stated that Arrowhead just started in Phase 1 clinical trial ..

can this be slow or fast? we are in mid of 2013 .. they are moving like turtle .. every year hbv kills million people !!
Avatar universal
More like 600 000 according to WHO.

In my opinion humanity already dealt with HBV with vaccine. we are just a left over that will eventually die out within 2 generations as all gets vaccinated in modern countries. So its not very profitable to put money into as cheapo countries wont pay good money anyway. Vaccine will be eventually cheap as hell and therefore be spread to poorest.

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Avatar universal
unfortunately you seems true we are leftovers of hep b mostly from non usa countries. performance of usa is hopeless on this issue. bill milinda is working on mosquitos research and thi is hopelessly funny.
Avatar universal
they are in phase 1 after four years in very successful phase 2 and it will be available with 'partial antiviral activity on hvb' in 2020 'with side effects'. That will be the result presented by those ugly greedy and dumb hvb researchers in 2020. see "smart hcb researcher", they are hero of their patients  and if you have some time for us hvb people learn some biology from them dumbs hvb researchers.
Avatar universal
only one compound whose progress is seeming good is gileads gs9620, but this too wont be  a cure perhaps will be a 1 month course in every 6 month for indefinite time may be 5-6 years  with tenofovir addd onnnnn......still this will be accepted by our hbvers  community  with pleasure......so gilead move fast hurry we are ready to watch you in 2017 in our hands treating ourselves hopefully.
may god help all those working hard for cure.god bless them all.
Avatar universal
In the USA people with HBV keep quiet, because you can't get a decent health insurance coverage once you disclose your status. That is why the statistics are low.

Keep watching these statistics to change next year, when Health Insurance companies will be banned to abuse us.

In Europe they have free health care, so the numbers of HBV infected seeking treatment are real.
Avatar universal
Cure for HBV?

Well Replicor has it? What is stopping them from using it?

It is an economic issue. Insurance companies don't want to pay for treatments, and frankly they only care about cost

Drug companies are not interested in eradicating the disease not to loose the market. We are a market!

HCV btw is a much harder virus then HBV. But because that community is more active they have better treatments.
Avatar universal
HCV is now considered curable.  HCV is easier to cure because there is no stable ccdna hiding in the cell nucleus like hepatitis B.  
Avatar universal
Speaking of unfounded statements....

But How about trading surface antigen quant for 700ml of plasma every time? This is the company Scantibodies in San Diego that you recommended.  That plasma they collect  is worth a lot btw. So there is just one example of taking advantage of people. People that are sick.

So lets not shy away from real problems how corrupt the medical system is... Why it is like that? because it is a business. Which it cannot be.. So it is a social problem really.

If they were honest they would treat people with interferon first. They would do immune therapies, remove oxidative stress to free the body from toxins, optimize the vitamin intake levels, so the body can fight HBV better.

Instead they give us drugs that slow down cell growth (nucs) thus virus lives longer and has no need to make copies to survive,that is why VL goes down eventually while on these drugs. But adding more toxins in the process to the body. And fatty liver development as a side of nucs is just one example. That is why it is written as a side effect of nucleoside analogs

So it is a wrong treatment strategy.

And with technology available today dont you think they know it? proof of it in what happens when medicine is stopped. VL goes through the roof in most cases when nucs are stopped.

So why giving it in the first place? For HIV it makes sense, because the virus enters every cell of humant body and damages it. So you have to slow it down, just like they wanted cancer that these drugs were originally developed for.

Hep B treatment is not a problem even now with available drugs. Problem is to find a doctor who is honest and that will do what is best for the patient. Finding a doctor that will not first call health insurance to see what they say, but the one that will do what is right.

Do they other there in UCSD in their brand new antiviral center use Alinia with Interferon? Alinia plus Zadaxin? Which is more affective then what is available today. No, it is only nucs. Why is that? Same thing  in UCLA is happening. TDF or ETV and forget about it! You call this options?

Or why doing clinical trials on only what that the drug company has paid for? So there you go an example of a steered  research in one direction.

Public funds must be available for this. Then there would be HBV cure already. Because what we have now an indefinite maintenance therapy is really what is driving the cost of health care.

Only now in these past couple  of years big pharma is starting to move towards immune enhancer therapies. Towards gene therapy, because people all over HBV web are waking up to  how worthless these drugs are that we take.

Why won't these Drug companies ever come to these forums, and talk to us, how can things be done better?

You don't see anybody here from Replicor or Gilead. Why is that? In every industry if we call it that, the manufacturers engage their audience for feedback. Here is just dead silence.  With promises for better tomorrow of 2020.
Avatar universal
Repeated interferon treatments of HBV patients produce results, In the 80s they did that with good success.

So has there really been any real progress since then in terms of HBV treatment? NO..

It only went backwards, they have fazed out interferon use, and replaced it with anti hiv drugs that were originally developed to treat cancer.

So there you have it..

I say if more treating centers would use Alinia plus Interferon with high dozes of Vitamin D3 and C.. with UBI with ozone therapy and or Plasmapheresis - we would have very good results in hbv treatment in 6-12 months.

But all this is being disregarded, till they come up with a quick fix solution for hbv. And that will most likely be gene therapy.

But again, based on what is shown Repicor has the cure already. Why not use it?

The more I am sick with HBV the more I learn about it, the more I realize that the problem is made bigger then it really is, regarding treating it..
Avatar universal
I mean just look at this how they do trials.. "Each dose cohort includes 6 subjects randomized at ratio of 1:2"

Only 6 people. That is nothing. Why not Take 100-200 people? And see what the result would be.

anyway, I hope ARC-520 works, but 2020 that is a long 7 years ahead..  
Avatar universal
one thing must be told strongly to these ARC-520 and other  fame wanted people that they must come with really new, good, reliable, sustained, cost effective therapy.....otherwise no need to just make news for their company fame and shares.
whatever you  pharma wants to do..do fast..even go for non traditional-non FDA way....as now there is compitition. use yours hooks and crooks.....good luck pharmas..

the good thing with delay in cure therapy is that we are now more informative and not going to accept any thing less than nearly a cure or complete cure..
Avatar universal
New Therapeutic Approaches to Cure Chronic Hepatitis B Virus Infection

Read more: New Therapeutic Approaches to Cure Chronic Hepatitis B Virus Infection | Medindia http://www.medindia.net/news/new-therapeutic-approaches-to-cure-chronic-hepatitis-b-virus-infection-118135-1.htm#ixzz2aSGog1vF
Avatar universal
may be they are working on how to make therapy only partially effective on hbsag clearance, because thats the fact for being in money making bussiness.
Avatar universal
I think it is really unrealistic to expect a single dose of ARC520 to produce a functional cure.  The blogger seems to raise the expectation himself, but  is now discovering that a simple knock down of antigens does not lead to immediate re-awaking of immune response against the chronic HBV infection.
It is interesting to see what he discovers next.
Avatar universal
Considering this phase I trial in healthy volunteers, the question arises what they can discover in this setting, aside from the absence of detectable toxic short term side effects. They cannot determine if the delivery system to the hepatocytes work, since there is no indicator of such delivery available. I doubt that there are liver biopsies planned to detect the compound after application inside the liver cells.It will be interesting to see alt responses after dosing, that hopefully are absent, considering the bee venom peptide that is used to burst endocytosed drug carrier containing microsomes for final delivery into the cytosol.

Only once they use HBV patients they will be able to assess delivery and inhibition effectiveness, the first being deductible from the second.

In general, we have discussed the outlook, promises and problems with the arrowhead approach in previous posts.

It is useful to ask the question what the expression "functional cure" realistically means.

In a fairly recent post by Stefano, a Taiwan study was presented, that showed that at the lower limit of detection of the quant surface  antigen assay, that is 0.05 IU, there are still 42 million surface antigen particles per ml of plasma present.
At one iu that would mean about one billion per ml.
If a patient with 4000 IU, like Stefano, had a 90% reduction by the arrowhead treatment, then it would be 400 billion of these particles per ml after the treatment.
I would like to point out, that the immunosuppressive effect of the hbsag, in its nonspecific variety, is likely caused by a sheer clogging of macrophages and dendritic  cells processing machinery by this huge amount of trash antigen. No wonder that the half life is eight days, and even more with higher antigen loads.
The specific effect of the huge hbsag burden is sending hbsag specific cd8 tcells cells into tolerance and apoptosis all over the body wide presentation.system.

Thus, not only will repeat dosing be necessary, it also remains to be seen if the reduction achieved has a chance to re activate the effective parts of the immune response, like it was quite convincingly seen with the replicor treatment, which achieved a 99.99% reduction of circulating surface antigen.

The arrowhead approach, if there are no relevant side effects from long term therapy, might well achieve a reduction in immune attack on the liver, if the virion production is also substantially reduced. Virion numbers are the strongest inducers of immune attacks onto the liver cells. Thus the hepatitis and fibrosis progression might be reduced. Thus they hold the potential to replace the never ending antiviral treatment with a permanent interfering RNA treatment, if less side effects can be anticipated and it can be priced for long term treatment.

I assume that is what arrowhead means by a functional cure.
Avatar universal
I do remember the discussion well. Yes, functional cure is a term coined by the American scientists. It has been used to describe the current treatments for HIV/AIDS. I read somewhere that Dr Gish once remarked that for most HBV patients, he can now just prescribe them a daily pill.
I must say, I am a bit surprised by the fairly long(?) half-life of serum HBsAg.
Avatar universal
promising treatment.  They need a subcutaneous form though.  sounds like repeated application may be necessary.  
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