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.

23 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...
This comment has been removed by a blog administrator.
Candy Wilson said...
This comment has been removed by a blog administrator.
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

wellnaa said...

It took so many years to discovered that i have being living all my life unknowingly to myself that i have hepatitis b virus one of the most deadly disease in the world, i kept experiencing server pains all over my joint and constant headache .it takes me three years if not more than to discovered the true only when i went for a checkup and my doctor told me the most Shockley news i have ever heard in my life that it is incurable and he can't help me . i came across a magazine written baby center when i and my wife visited the clinic for ant natal care where a person testified of being cured by a clinic called medication clinic. i immediately contact the clinic and they were so nice and understanding and they told me that i will get cured within the shortest space of time and God so kind i got cure within two months of drinking the medication with the doctor direction and instruction . am so happy that i came across that magazine. if you are experiencing this kind of problem hurry up to medication clinic , contact medicationclinic@gmail.com

Patricia Witwort said...

Special thanks to God almighty for using Dr, Okhadigbo for curing my Hepatitis B disease, I was having a Hepatitis B and doctor told me that I have seven months to live, that news brought sadness into my life,
I was depressed, don’t know what to do. One faithful day I saw a testimony
on how a Powerful spell caster that is also known as a Herbal man cured
that cure a lady, who is called Liliana Campos, due to her testimony the
man is a great Herbal man , quickly I copied his email:(dr.okhadigboherbalhome@gmail.com) then I contacted him and he asked me not to bother myself that all my problems are over. I was happy to hear such words, he told
me to buy some items, though I couldn’t find the items myself he asked
me to send down the money to buy the items for me,
faithfully I sent him the money he bought the items and prepared a cure
for me. He told me that he is going to send the cure through courier
delivery service, I paid to the courier delivery service, then, I got
the cure, he instructed me on how I will take the cure. I took the cure
and I was freed from the Hepatitis disease, I went for scanning, the
Hepatitis was no longer there. I am very grateful for what he did for
me. If you have any disease you can contact him via email:
dr.okhadigboherbalhome@gmail.com. or call him +2348 1599 21615,
you will also get healed with your illness,

Thanks
Good Luck...

Monica Brown clement said...

Have been suffering from (HERPES SIMPLEX VIRUS) disease for the past four years and had constant pain, especially in my knees. During the first year,I had faith in God that i would be healed someday.This disease started circulating all over my body and i have been taking treatment from my doctor, few weeks ago i came on search on the internet if i could get any information concerning the prevention of this disease, on my search i saw a testimony of someone who has been healed from (Hepatitis B and Cancer) by this Man Dr ehizele and she also gave the email address of this man and advise we should contact him for any sickness that he would be of help, so i wrote to Dr Ehizele telling him about my (HERPES Virus) he told me not to worry that i was going to be cured!! hmm i never believed it,well after all the procedures and remedy given to me by this man few weeks later i started experiencing changes all over me as the Dr assured me that i have cured,after some time i went to my doctor to confirmed if i have be finally healed behold it was TRUE, So friends my advise is if you have such sickness or any other at all you can email: drehizeleherbalhomeofsolution@gmail.com or call him +2347063715104 or call me or whattsapp me to hear from me +16625721737. He told me that he also help people to cure HIV VIRUS and also help people to bring their ex lover back. contact dr Ehizele if you have any problem. email: drehizeleherbalhomeofsolution@gmail.com

morgan said...

Am Clara Raymond from USA I was in trouble when doctor told
me that I have been diagnosed with HIV/AIDS… I
thought about my Family, I know my Family will face a
serious problem when I’m gone, I lost hope and I wept
all day, but one day I was going the internet I found
Dr Idahosa email. I emailed him and he guided me. I
asked him for solutions and he started the remedies for
my health. Thank God, now everything is fine, I’m cured
by Dr Idahosa herbal medicine, I’m very thankful to Dr.
Idahosa and very happy with my hubby and family.
email him on hsvnaturalremedyclinic@gmail.com or
what_sapp him Tel- +2347033330164

DOCTOR IDAHOSA CAN AS WELL CURE THE
FOLLOWING DISEASE:-
1. HIV/AIDS
2. HERPES
3. CANCER
4. SINGLES
5.HEPATITIS
6.E.T.C

Blessing David said...

OMG, here I am to share a good testimony to myself how I have contacted a real herbalist who helped me. I value everything to give their precious time to read my testimony, 9 months ago I was diagnosed with Hepatitis B, which means I was 9 months ago positive to Hepatitis B when I told one of my good friends about it, he thanked me and then said that he would help me, he told me that we should do research on the Internet, we find Dr. OBOH, and my friend said he has a lot about him and said that he was a true herbalist remedy for all illnesses, I was really surprised at this and also confused, I was speechless and quickly contacted him to help me and he prepared some herbs for me and send it to me and he told me how to take the medicine I did, and for the next 2 weeks I went to the hospital and said that I am now Hepatitis B n egative, I'm very happy about it, when I contacted Dr. OBOH again to tell him the good results, I asked him how he helped me, and he said he was a gift and that he could cure the pain just like. PM to me so I can give you her information

His Email; drobohsolutioncenter25@gmail.com
His WhatsApp; +2348155714344
His Facebook Page; https://web.facebook.com/Dr.Oboh.solution.center/


He can also heal ......

DIABETES,
HIV & AIDS,
INFECTION OF URINARY TRACT,
CANCER,
WHY,
BARENESS / INFERTILITY
DIARRHEA
ASTHMA ... ETC ...._____
His Email; drobohsolutioncenter25@gmail.com
His WhatsApp; +2348155714344
His Facebook Page; https://web.facebook.com/Dr.Oboh.solution.center/

morgan said...

I am from New York. I was in trouble when doctor told me that I have been diagnosed with Genital herpes… I though about my Family, I know my Family will face a serious problem when I’m gone, I lost hope and I wept all day, but one day I was surfing the internet I found Dr. idahosa email. I emailed him and he guided me. I asked him for solutions and he started the remedies for my health. Thank God, now everything is fine, I’m cured by Dr. idahosa herbal medicine, I’m very thankful to Dr. idahosa and very happy with my hubby and family. email him on hsvnaturalremedyclinic@gmail.com or whatsapp Tel- +2347033330164

DOCTOR IDAHOSA CAN AS WELL CURE THE FOLLOWING DISEASE:-

1. HIV/AIDS
2. HERPES
3. CANCER
4. ALS
5. Arthritis
6. Shingles

Unknown said...

WHAT A GREAT MIRACLE THAT I HAVE EVER SEE IN MY LIFE. My names are David
Clara I’m a citizen of United Kingdom, My younger sister was sicking of
breast cancer and her name is David Sandra I and my family have taking her
to all kind of hospital in UK still yet no good result. I decided to go to
the internet and search for cancer cure so that was how I find a lady
called peter Lizzy she was testifies to the world about the goodness of a
herbal man who has the root and half to cure all kind of disease and the
herbal man email was there. So I decided to contact the herbal man for my
younger sister help to cure her breast cancer. I contacted him and told him
my problem he told me that I should not worry that my sister cancer will be
cure, he told me that there is a medicine that he is going to give me that
I will cook it and give it to my sister to drink for one week, so I ask how
can I receive the cure that I am in UK, he told me

That I will pay for the delivery service. The courier service can
transport it to me so he told me the amount I will pay, so my dad paid for
the delivery fee. two days later I receive the cure from the courier
service so I used it as the herbal man instructed me to, before the week
complete my sister cancer was healed and it was like a dream to me not
knowing that it was physical I and my family were very happy about the
miracle of Doctor so my dad wanted to pay him 5 million us dollars the
herbal man did not accept the offer from my dad, but I don't know why he
didn't accept the offer, he only say that I should tell the world about him
and his miracle he perform so am now here to tell the world about him if
you or your relative is having any kind of disease that you can't get from
the hospital please contact dr.sakuraspellalter@gmail.com or whatsapp him
+2348110114739 for the cure, he will help you out with the
problem. And if you need more information about the doctor you can mail me
davidclara223@gmail.com or whatsApp me +1845-652-1151

Milad Koehler said...

I am here to give a testimony about Dr. Uyi regarding HPV who cure me from it, i want to inform the general public how i was cured from (HUMAN PAPILLOMA VIRUS) by Dr. Uyi, i visited different hospital but they gave me different type of drugs but never cured me. I was browsing through the Internet searching for remedy on HPV and i saw comment of people talking about how Dr. Uyi cure herpes virus. When i contacted him he gave me hope and said not to worry that he can totally cure me, after little discussion he proceed with the preparation of the medicine and send it to me. Today, I am so happy as i am sharing this testimony. My advice to you all who thinks that there is no cure for HPV/HSV that is Not true just contact him and get cure by Dr. Uyi, He has different type of cure to so many disease/virus. You can contact him on his Email: uyiherbalmedicationcenter@gmail.com or WhatsApp him on +2348077199766.

Milad Koehler said...

Hello!!

I was diagnosed of HPV few months ago after i came back from the hospital i decided to search online for answer and solution, I saw someone introduce Dr. Uyi online that he can cure HPV and HIV and I decided contact him after a few discussion with him and we reach an agreement, he prepared the herbal medicine and ship it to me and I used it according to his prescription after 2 week I went to the hospital to check my status again because I was feeling differently from the way I tested POSITIVE before, to my greatest surprise the status was HPV NEGATIVE the medical doctors there was surprise and I have decided to tell the whole world about this if you are having this similar problem I recommend you to Dr. Uyi and his email: uyiherbalmedicationcenter@gmail.com

You can call Dr. Uyi directly with his mobile number or contact him through whatsApp on, +2348077199766

Smith Burkhard said...

MY HERPES SIMPLEX CURE BY HERBAL MEDICINE..
It's Good for herpes patient to please read my testimony,my name is James i am from California USA, I caught genital herpes from my ex girlfriend who never had any symptoms. I have had it for 1 year now, and it has affected my life. I have told my boyfriends who I trusted about it and I have never had a bad reaction, it has affected my new relationships with Damon People think herpes is really a minor skin irritation,herpes has a long term effects on health.The stigma attached to this virus by ignorant people is ridiculous. Most people have herpes in one form or another. I would like to advise people on how i got rid of my herpes.i was reading a comment on the internet,and i saw a testimony posted by a woman from island that she got rid of her herpes with the help of dr. boadi .so i was so happy when i saw that post,that his herbal medication is free.i quickly collected the herbal doctor email: drgodstimeboadi@gmail.com
call or whatsapp him on his mobile number +2348144964531
visit website http://drgostimeboadiherbalcentre.blogspot.com.ng/
He also have the herb to cure
(1) CANCER,
(2) DIABETES,
(3) HIV&AIDS,
(4) URINARY TRACT INFECTION,
(5) CANCER,
(6) HERPES,
(7) BARENESS/INFERTILITY
(8) DIARRHEA
(9) ASTHMA...

Crystal Robin said...

Hello Dr Suku is real and he's powerful herbal treatment..After been in pain and sorrow for over 7years it was Dr.SUKU that cured me from Hepatitis B Virus, I got infected with Hepatitis B Disease in 2010 and I have visited several herbalists, spiritualists and pastors for cure me but all was in avail, my world was gradually coming to an end until i saw a post in a health forum about a herbal medicine from Africa who have and herbal medicine to cure all kinds of deadly diseases including HERPES ,WALTER,HIV AIDS, ALS, HPV, MND, Epilepsy, Leukemia, Asthma, Cancer, Ghonorhea,Hepatitis B etc, at first i doubted if it was real but decided to give it a try, when i contact this herbalist via his email, drsukuherbalhome@gmail.com he prepared a herbal medicine portion and sent it to me via DHL Delivery when i received this herbal medicine portion, he gave me step by step instructions on how to apply it, when i applied it as instructed, i was cured of this deadly disease within 2 weeks, I am now Hepatitis B Negative. all thanks to Dr.SUKU Contact this great herbalist called Dr.SUKU his email: drsukuherbalhome@gmail.com or
Text/Call cell number +1(325) 701-3934 Dr.Suku

Unknown said...

This is real take it serious, who will believe that a herb can cure ten
years HIV in my body, i navel believe that this will work i have spend a
lot when getting drugs from the hospital to keep me healthy, what i was
waiting for is death because i was broke, one day i hard about this great
man who is well know of HIV and cancer cure, i decided to email him,
unknowingly to me that this will be the end of the HIV aids in my body, he
prepare the herb for me, and give me instruction on how to take it, at the
end of the two week, he told me to go to the hospital for a check up, and i
went, surprisingly after the test the doctor confirm me negative, i thought
it was a joke, i went to other hospital was also negative, then i took my
friend who was also HIV positive to the Dr, after the treatment she was
also confirm negative . He also have the herbs to cure cancer please i want
every one with this virus to be free, that is why am dropping his email
address, solutioncenterhome@gmail.com email or call +2347087771434 and
he is
a great man.thank you for saving my life, and is also good in saving you
from any kind of diseases like Herpes Hepatitis B .,Gonorrhea,Cardiac problem,Fibroid
Cancer
Watering sperm
Womb fertilization
Penis erection
Witch craft attack
S T D diseases
Internal heat
Rashes
Low sperm count
Dairy. Diabetes
long time sickness I promise I will always testify for your good work.

Unknown said...

WHAT A GREAT MIRACLE THAT I HAVE EVER SEE IN MY LIFE. My names are David
Clara I’m a citizen of United Kingdom, My younger sister was sicking of
breast cancer and her name is David Sandra I and my family have taking her
to all kind of hospital in UK still yet no good result. I decided to go to
the internet and search for cancer cure so that was how I find a lady
called peter Lizzy she was testifies to the world about the goodness of a
herbal man who has the root and half to cure all kind of disease and the
herbal man email was there. So I decided to contact the herbal man for my
younger sister help to cure her breast cancer. I contacted him and told him
my problem he told me that I should not worry that my sister cancer will be
cure, he told me that there is a medicine that he is going to give me that
I will cook it and give it to my sister to drink for one week, so I ask how
can I receive the cure that I am in UK, he told me

That I will pay for the delivery service. The courier service can
transport it to me so he told me the amount I will pay, so my dad paid for
the delivery fee. two days later I receive the cure from the courier
service so I used it as the herbal man instructed me to, before the week
complete my sister cancer was healed and it was like a dream to me not
knowing that it was physical I and my family were very happy about the
miracle of Doctor so my dad wanted to pay him 5 million us dollars the
herbal man did not accept the offer from my dad, but I don't know why he
didn't accept the offer, he only say that I should tell the world about him
and his miracle he perform so am now here to tell the world about him if
you or your relative is having any kind of disease that you can't get from
the hospital please contact dr.sakuraspellalter@gmail.com or whatsapp him
+2348110114739 for the cure, he will help you out with the
problem. And if you need more information about the doctor you can mail me
davidclara223@gmail.com or whatsApp me +1845-652-1151

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.