Tuesday, February 26, 2013

Functional Cure of Chronic Hepatitis B: RNAi Therapeutics May Be the Only Game in Town (Part I)


Today, I wanted to post the first of a two-part series on the hepatitis B virus (HBV) candidate by Arrowhead Research which is set to enter clinical development in the first half of this year.  But as if on cue, the company just announced the publication of extremely potent ('multi-log') reductions in gene expression with their systemic DPC delivery technology.  This thus bodes very well for what is shaping up to be an RNAi Therapeutics pipeline highlight: ARC520 for the treatment of chronic hepatitis B viral (HBV) infection. 

Are you wondering what could be the next HCV-type or maybe even larger drug development opportunity?  HBV may well be the new HCV.  With HCV increasingly curable, the pharmaceutical industry has increased appetite for finally also developing a cure for chronic HBV.  Based on the potent preclinical data with DPC delivery technology and the view of thought leaders in the field that the specific suppression of HBV proteins may be the single most promising mechanism by which this can be achieved,  I am more and more thrilled by the prospect that ARC520 could become a poster child for an RNAi Therapeutics that addresses a major public health burden.

In anticipation of the March webinar by Arrowhead where the company wants to talk more about the concept behind ARC520 and their most recent data on the drug candidate, two blog entries over the coming week will first explain the rationale for why HBV is such an attractive RNAi Therapeutics opportunity and then discuss the features that make ARC520 a particularly promising (including in a commercial sense) RNAi Therapeutics candidate.


Only RNAi Can Suppress HBV Proteins in a Specific, Potent, and Rapid Manner

About 2 billion worldwide are infected with hepatitis B virus (HBV).  300-400 million of these have subsequently developed chronic HBV, meaning that they are at increased risk of prematurely dying from liver-related complications such as cirrhosis and liver cancer.   Every year, more than one million chronic HBV patients die of such complications.  In East Asia and developing countries where mother-to-child transmission is the predominant (and highly effective from a viral point of view) mode of infection, HBV is responsible for more than half of primary liver cancers; in Western countries where transmission largely occurs via body fluids, esp. blood, it still accounts for about one quarter of cases.

This means that the public health burden of chronic HBV infection already surpasses that of HCV and is extending its lead as the new direct antiviral agents against HCV prove quite effective at eliminating HCV.  An important difference between HBV and HCV is that HBV is a DNA virus that will persist for life in hepatocytes.  This explains we can only dream of a ‘functional’ cure, not a cure full-stop.  HCV, by contrast, is an RNA virus which, in the absence of replication, will disappear due to the relative instability of RNA.  

Vaccination works almost 100% well to protect us from HBV infection. but its therapeutic application so far has failed and it also does not address mother-to-child transmission. Interferon and viral polymerase inhibitors (nucs) are currently only recommended for those with active chronic HBV as determined by increased liver enzyme levels in the presence of HBV.  These drugs, however, only work to convert 10-30% of those treated into the inactive carrier state with normalized liver enzymes and very little HBV DNA in the blood.  Nucs have the added benefit of very effectively inhibiting active viral replication, meaning that it does a good job at minimizing the ongoing inflammation in the liver.  Unfortunately, only very few of these patients can be considered to be cured and they are thus still at risk for viral re-emergence.

It is widely accepted that a functional cure for chronic HBV, meaning viral suppression in the absence of drug treatment, can only be achieved by harnessing adaptive immunity.  Here, the name of the game is achieving hepatitis B surface antigen (HBsAg) seroconversion, meaning the development of antibodies to HBsAg.  People who stably carry such antibodies can be considered cured.  Although the exact mechanism by which this is supposed to occur is being debated, it is widely accepted that immune exhaustion due to the presence of abundant HBsAg in the serum in the form of subviral particles and in the liver is the cause of why our immune system tolerates HBV, instead of eradicating it.

While nucs, which inhibit viral polymerase, not mRNA transcription of viral mRNA which is performed by our own RNA polymerase II off the viral cccDNA, and interferon can have some suppressive effect on HBsAg levels (on the order of ½ log), it seems that RNAi Therapeutics is the only means to achieve the specific, potent, and rapid inhibition of HBsAg that is considered to be necessary for a successful relief from immune exhaustion. In doing so, an RNAi Therapeutics can do everything that a nuc can do and more.  This means that such an RNAi Therapeutic may also significantly expand the pool of chronic HBV patients on therapy and should become a core component in any combination therapy such as with an interferon.

Look out for the next post on why I think ARC520 is an excellent RNAi Therapeutics candidate to achieve the stated objective.

20 comments:

Anonymous said...

Dirk,

After reading an article in Molecular Therapy, I am not impressed with DPC at all.

First, it seems DPC is an IV and not a SubQ.

Second, it is not as potent as it has been hyped. DPC has two components - NAG-MLP & chol-siRNA. It requires 2 mg/kg of chol-siF7 & 8 mg/kg of NAG-MLP to achieve 99% of knockdown for F7. That is a very high dose. LNP or GalNAc would be better than DPC.

Dirk Haussecker said...

Thanks for the comment. I am planning to read that paper asap. However, keep in mind that there are now subQ versions of DPCs that have been validated in monkeys (OTS 2012), meaning that the transition of ARC520 from i.v. to subQ is an obvious life-cycle, market-expanding opportunity(incl. extended patent life).

Bikerieder said...

Dirk

What do you think, is it possible that ARWR could get some funding for ARC-520 from the Heb B Foundation?

Anonymous said...

'HCV increasingly curable' Tell that to my father who needs a liver transplant you douchebag.

Anonymous said...

i jst read your article and am impressed,but i want to ask you a question. I got to know that i'm HBVpositive last weej. Since then i hv gone for several test which confirmed that my liver is stil in order. I want to know,does it mean that it's at acute stage? I also read that the virus is self limited. Pls advice me asap.

mike said...

I always wondered why though they needed 3 shots to protect you. I also wondered why we focus on immunization and not diet to prevent disease so much.

JOHNSON KATE said...
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Candy Wilson said...
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Candy Wilson said...

Thank to Dr.ZUKU i will forever continuously testify Dr.Zuku for changing my life with your herbs Remedy, i have be Suffering from HEPATITIS B over Three years ago i have battled with this virus and was about to ruin my entire body,I have been living with this virus and it has been giving me challenges,one morning i was browsing through the internet then i saw several testimonies about Dr.Zuku curing people from HEPATITIS B and immediately i contacted Dr.Zuku on his email and he assure me that will prepared herbal medicine and when after drinking for 2 weeks i went back to my doctor and my result came out HEPATITIS B negative.Viewers i am so glad, email Dr.Zuku and get your cure. Email: drzukuspelltemple@gmail.com call or text for more information +16177296273 contact Dr Zuku Blogs https://drzukuspelltemple.blogspot.co.ke/ or contact Web/Site https://drzukuspelltemplewhereallkindsofproblemisbesolve.wordpress.com/contact/

Victoria Williams said...

My Hepatitis B HEALING TESTIMONY My mouth is short of words, i am so so happy because Dr Puma healed me from hepatitis b which i have been suffering from the past 3 years now, i have spend a lot when getting drugs from the hospital to keep me healthy, i have tried all means in life to always i can become free from hepatitis one day, but there was no answer until i found about Dr Puma the greatest herbal doctor who provide me some healing medication and spell that he uses to help me, now i am glad telling everyone that i am now free from hepatitis b , i am very very happy, thank you Dr Puma for helping my life comes back newly without any form of crisis, may the good lord that i serve blessed you Dr Puma and equip you to the higher grade for healing my life. i am so amazed. so i will announced to everyone in this whole world that is hepatitis positive so please follow my advice and get healed on time, because we all knows that hepatitis b disease is a deadly type,contact Dr Puma for your hepatitis b healing spell today He will be always happy to assist you online and ensure you get healed on time, contact Dr Puma immediately at Lalapumaspelltemple@gmail.com or WhatsApp him on +2349060961651

austincalnor said...

I was diagnosed of hepatitis b in 2012,I have tried all possible means to get cure but all my effort proved abortive, until a friend of mine introduced me to a herbal doctor from Africa,Dr Eveoko who prepare herbal medicine to cure all kind of diseases including hepatitis b virus (HBV), CANCER. ALS Hepatitis A,B/C, fertility spell, Herpes HIV and all types of STDs Infections, when i contacted this herbal doctor via his email: eveokoherbalhome@gmail.com he sent me hepatitis b herbal medicine via courier service, when I received the herbal medicine through DHL Postal courier service, he gave me the step by step instructions on how to use it. when i make used of it as instructed by him,i was totally cured from the virus within 10 days of usage. i recomment this great Dr to anyone who is seeking for cure to his\her Ailment Indeed he is a very good man, Contact this great herbal doctor . whats-app him with: +2348022010422. you can also reach me at austincalnor@gmail.com

joy said...


I can’t believe this. A great testimony that i must share to all HERPES SIMPLEX VIRUS patient in the world i never believed that their could be any complete cure for Herpes or any cure for herpes,i saw people’s testimony on blog sites of how Dr.Voodoo prepare herbal medicine that cure and brought them back to life again. i had to try it too and you can,t believe that in just few weeks i started using it all my pains stop gradually and i had to leave without the pills the doctor gave to me. Right now i can tell you that few months now i have not had any pain,delay in treatment leads to death. Here is his email:(voodoospell10@gmail.com) or call (+2348135790702) for more information or WhatsApp with him....

Linda Eggers said...

Greetings to the general public, i want to tell about how i was cured of Hepatitis B disease by a Doctor called Dr Agbebaku. I was browsing through the Internet searching for remedy on Hepatitis B and i saw comment of people talking about how Doctor Agbebaku cured them. I Was scared because i never believed in the Internet but i was convince to give him a try because i having no hope of been cured of Hepatitis B so i decided to contact him with his email that was listed on the comment ( dragbebakuspellsolutiontemple@gmail.com ) when i contacted him he gave me hope and send a Herbal medicine to me that i took and it seriously worked for me, am a free person now without problem, my Hepatitis B result came out negative. I pray for you Dr Agbebaku God will give you everlasting life, you shall not die before your time for being a sincere and grate men. Am so happy, you can also contact him if you have any problem Email: dragbebakuspellsolutiontemple@gmail.com or Add him up on What-sap +2349053099479,.

susan said...

It’s obvious some patient with HIV/CANCER are been enslaved to the
antiviral and other supplementary Orthodox medicine just to help suppress
the virus and not a cure. I have been with the virus since 2012 until I was
introduce by a blogger who also narrated Her story online on how she was
cured of Hepatitis b after using Dr Ajayi Herbal Medicine. This is a year
and 2 weeks since I was delivered from Hepatitis B. All thanks to God for
using this Great herbalist to heal me. I have promise to keep telling good
about this. Please fill free to share Your problems with him and don’t
forget to tell him I did refer you to Him. Thanks. Write him on mail
drajayiherbalhome@gmail.com or Ajayiherbalhome@hotmail.com or whatsapp him
on +234905491434

Dr Ajayi can also cure
HIV..........
Cancer.......
Diabetes......

Christ Raymond said...

I’m indeed very happy for the great help, i and my husband are cured of (HEPATITIS B ) with the herbal medicine of Dr Odioa , i have been suffering from this disease for the past 3 years without solution until i came across the email of this doctors who have cure so many people with his herbal medicine, i also choose to give him a chance to help me and my husband, he told me what to do and i kindly did it, and he gave us his herbal medicine and direct me on how to use it, i also follows his instruction for use and he ask us to go for a check up after 3 weeks and which i did, to my greatest surprise our result came out as negative, we are really happy that there is someone like this DR who is ready to help anytime any day. to all the readers and viewers that is doubting this testimony stop doubting it and contact this Dr and see if he will not actually help you. i am not a stupid woman that i will come out to the public and start saying what someone have not done for me. For more information on how to get cured contact him on his active email: What's app: + 2347059055577 or Email odioaherbalcurehome@gmail.com
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REPLY


Christ Raymond said...

I’m indeed very happy for the great help, i and my husband are cured of (HEPATITIS B ) with the herbal medicine of Dr Odioa , i have been suffering from this disease for the past 3 years without solution until i came across the email of this doctors who have cure so many people with his herbal medicine, i also choose to give him a chance to help me and my husband, he told me what to do and i kindly did it, and he gave us his herbal medicine and direct me on how to use it, i also follows his instruction for use and he ask us to go for a check up after 3 weeks and which i did, to my greatest surprise our result came out as negative, we are really happy that there is someone like this DR who is ready to help anytime any day. to all the readers and viewers that is doubting this testimony stop doubting it and contact this Dr and see if he will not actually help you. i am not a stupid woman that i will come out to the public and start saying what someone have not done for me. For more information on how to get cured contact him on his active email: What's app: + 2347059055577 or Email odioaherbalcurehome@gmail.com

mable joshua said...

I am really happy that i have been cured from (HEPATITIS VIRUS) with the herbal medicine of Dr Aba, i have been suffering from this disease without any solution until i came across the email of this doctor who have cure so many people with his herbal medicine, i also choose to give him a chance to help me and my husband, he told me what to do and i kindly did it, and he gave us his herbal medicine and direct me on how to use it, i also follow his instructions for use and he ask us to go for a check up after 1 week and 4days which i did, to my greatest surprise our result came out as negative, we are really happy that there is someone like this doctor who is ready to help anytime any day. To all the readers and viewers that is doubting this testimony stop doubting it and contact this doctor if you really have one and see if he will not actually help you. i am not a stupid woman that i will come out to the public and start saying what someone have not done for me and i know that there are some people out there who are really suffering and hurting just because of these diseases so you can mail him on dr.abaherbalhome@gmail.com or whatsApp his number on +2348107155060

Christ Raymond said...

Thanks to Dr ODIOA for his good work I never believe that Hepatitis B has cure,I
was having Hepatitis B over 3 year now before I came across a comment about how
Dr.ODIOA cure Hepatitis B and herpes disease but when I saw it i have it in mind
that he cant cure HEPATITIS B I just decided to give it a try I contact him that
night luckily to me he replied me, but I don't believe him I thought it was
a scam but I still hold on to see the work of Dr ODIOA if he is saying the
truth he ask for some details about me i gave him all he needed and I
waited to see his reply to my problem after all, he told me to go for check
up and I went for Hepatitis B test I cant believe I was negative,am so happy and
grateful to God for using Dr ODIOA to cure me, that is the reason why i
decided to write this wonderful testimony of our i was cured, i recommend
Dr ODIOA to you all around the world,contact him on his Email odioaherbalcurehome@gmail.com or Whats app +2347059055577. you can also reach him through thanks
Dr.ODIOA for helping me at this young age if you need help contact,
He can also cure so many sickness
{1}HIV And AIDS
{2}Diabetes
{3}Epilepsy
{4} Blood Cancer
{5} HPV
{6} ALS
{7} Hepatitis B and C

deas vearest said...

Am jeremiah, I am testifying about a great hebal man that cured my wife of hepatitis B, and liver cirhosis. his name is Dr oniha. My wife was diagnose of hepatities two years ago, i almost spent all i had then, until i saw dr oniha recommendation online, and i call him, then he told me how to get the herb. You can call him on +2347089275769 or email him at dronihaspell@yahoo.com

Donald LEO said...

Greetings to the general public, I want to tell about how I was cured of Hepatitis B disease by a Doctor called Dr. Alli. I was browsing the Internet searching for remedy on Hepatitis B and I saw a comment of people talking about how Doctor Alli cured them. I was scared because I never believed in the Internet but i was convince to give him a try because i having no hope of been cured of Hepatitis B so I decided to contact him with his email that was listed on the comment (allispellhelp1@gmail.com) when I contacted him he gave me hope and send a Herbal medicine to me that I took and it seriously worked for me, am a free person now without problem, my Hepatitis B result came out negative. I pray for you Dr. Alli God will give you everlasting life, you shall not die before your time for being sincere and great men. Am so happy, you can also contact him if you have any problem Email: Allispellhelp1@gmail.com or Add him up on What-sap +2348100772528

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.