Wednesday, May 29, 2013

Potential Breakthrough Cure for Chronic Hepatitis B Enters Clinical Development

Arrowhead Research announced yesterday that it had filed with Australian authorities to commence clinical development for ARC520.  ARC520 is the RNAi Therapeutics candidate for chronic Hepatitis B that aims at suppressing both viral load and the immune-suppressive Hepatitis B surface antigen (HBsAg).  This is thought to be one of the most attractive ways to achieve a (functional) cure for chronic HepB infection, and I believe that ARC520 has what it takes to be a serious contender.  

The first study will test how much of ARC520 can be safely given to volunteers.  While this may not sound all that exciting, safety with the unproven DPC delivery technology is probably the biggest risk factor with the program.  Based on the pre-clinical, rodent and chimpanzee, efficacy data, I would like to see at least 1mg/kg, ideally up to 3mg/kg ARC520-siRNA being safe and well tolerated.  With expected 95% and more HBsAg knockdown at these doses in many patients, it would all seem to come down to the validity of the HBsAg hypothesis.

Formal proof of knockdown potency will come soon thereafter in the form of the Hong Kong trial in which ARC520 will be given to chronic HepB carriers.  That study should get rolling in late 2013/early 2014.   

One nice thing about trials in HepB, just as in HepC, is that drug potency can be readily determined very early on by looking at viral titers in the blood.  Although this in itself is no proof of cure, in most viral infections, a rapid reduction is a good predictor of eventual outcome.  For ARC520, this should be no different. 

An advantage for Arrowhead Research in being early in aiming for a functional cure for chronic HepB is that the current treatment landscape is fairly simple (interferons and nukes).  This should greatly simplify pivotal phase III trial design and allow it to be positioned well on the market.

For biotech investors and traders, having frequent catalysts on a company’s lead candidate is obviously also very attractive.  This should keep the market entertained until 2017/8 when a potential approval could happen.

With 200-300 million chronically infected, ARC520 is definitely the popular choice in today’s drug development.   I will obviously be rooting for it, partly because I am invested in ARC520, but also for a number of other reasons.  

One of them is that I have worked for 3 post-doc years on identifying and characterizing small RNAs derived from the Hepatitis D virus, a virus that only exist in the presence of HepB.  By the way, HepD, basically HepB on steroids, is an orphan disease that I would like to see addressed with an RNAi Therapeutic.  If you are looking for potential targets, check out this paper by Dan Cao, myself and other colleagues at Stanford for potential gene targets.

And lastly, it reminds me of Professor Sir Kenneth Murray who just passed away following a quiet and productive life in which, among many other accomplishments, he was responsible for the first recombinant DNA vaccine.  The indication, of course, was for preventing HepB, and through this millions of lives were saved by his work.  Professor Murray was a co-founder of Biogen and the vaccine was eventually approved by the FDA in 1989 (licensed to GSK).  

With the money he made from his involvement with Biogen and the vaccine, he founded the Darwin Trust of Edinburgh and through this my undergrad and postgrad studies on RNA(i) molecular biology.  If you are still reading this, he shared with you enjoying both fundamental science and its industrial applications.  I also know that he liked to invest in biotech stocks. R.I.P.

60 comments:

Anonymous said...

"Formal proof of knockdown potency will come soon thereafter in the form of the Hong Kong trial in which ARC520 will be given to chronic HepB carriers. That study should get rolling in late 2013/early 2014."

That seems an overly aggressive time frame for the Hong Kong Trial. With the IND just submitted for the first trial, patient enrollment is still a ways ahead. Even with ample patients available, safety concerns will dictate the pace as each dose level is evaluated. Some things can't be rushed and overly optimistic time lines may hurt credibility. Dirk, is management’s early 2014 for the second P1 trial realistic?

Dirk Haussecker said...

Why not? They pretty much already have the data for the Hong Kong study. Both this first one and the Hong Kong study will be single-dose trials (it's completely new chemistry) and the animal tox data should cover them equally. Just a matter of making the Hong Kong authorities feel at ease with seeing the progress in the Australian study.

sanjoy lourembam said...

Please make it faster, so many people are waiting for this. I wish you every success and I will pray to God for this. Thank you

Anonymous said...

Sounds promising ...
So are you saying that hep B virus can be complete removed from body ? What is timeline for launching tablet form of ARC520 in market after FDA approval ?
I wish you every success for your effort which is for mankind.
Thanks

Dirk Haussecker said...

If all goes well...intravenous form launched in 2016/7, subcutaneous form 2020/22, tablet...more uncertain, but there are oral delivery strategies that should be possible for DPC tech.

Anonymous said...

Thanks dirk for answer. Looks like still people will have to 3/4 years down the line of IV. I was expecting something in 2014. How soon can it be launched ? As I heard in Hong Kong trial is late in 2013.Is this therapy helping to boost immune system to create antibodies of HBsAg?
I can only request you to expedite the process as by then i.e. 2016/17 number of chronic HepB may increase !
Wishing again good luck to your efforts...May god give you success in this experiment!
How is this different from GS290 by Texas Biomed?

Anonymous said...

Yes, how is this different from GS 9620 by Texas Biomed? Oh I'm happy for the good news our researcher are trying may God see you guys through

asd said...

Make it fast! The future of HepB depends on you! Save lives

Anonymous said...

May the good Lord help you guys (the researchers) to make this cure for Hepatitis B available soon... God Bless...

Anonymous said...

Hopefully this is it!!!!the answers to our prayers who have the said virus. To the researches or to the people behind this study may god help you to reach the peak of cure and the peak of success. So many people depends on you guys and I am one of millions/billions who looking forward for the said cure. I am trying to live healthy to live longer so that i could still have a chance to take these med. I wanted to live longer for my family especially for the son, wanted to see him growing up. So please guys make this cure possible..............god bless us all

Anonymous said...

What is a 'functional' cure? Is that a medical term for a full cure?

Thanks

Dirk Haussecker said...

A functional cure is that your immune system has learned to control viral proliferation, but that there is still viral DNA inside your liver (cccDNA especially).

neanderthaler said...
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neanderthaler said...
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Anonymous said...

That's great news for sufferers. Does a functional cure mean that the person will no longer be a carrier, that is he will no longer be infectious to others?

Dirk Haussecker said...

It's correct that this would be one benefit of a functional cure.

Anonymous said...

I'll pray for your success. I just saw a doctor and I am afraid I infected my family. I still have young boys and also my wife I am very concerned about them. I hope this is it.

God answers. Prayers from the Philippines.

Anonymous said...

I thank God so much for the lives of the people(researchers) behind the med..millions/billions of people's lives depends on u..i cant wait to see the medicine outdoored to cure...thanks so muck...wish u success..God bless u

Anonymous said...

hope its true...they can earn m0re money in curing chronic hepa b than preventing it..millions of people worldwide are inactive carriers.

Anonymous said...

some conspiracy regarding pharmaceutical companies is that for a lifetime treatment means a lifetime profit to earn money also synthetic products do not cure rather than worsening the illness because of many side effects. people now a days turn to herbal products although it has a long process of curing but it gives a 100% safe to used.GOD who made it for us to use it..

Anonymous said...

well i just hope this medicine just cure all these people with hepatitus

passang bhutia said...

good news. I pray to god for proper test and lunched soon in the market at reasonable price so every normal people who are suffering may be benefitted. may the gods power always be with the team. please god. om mani padme hung ray.

Anonymous said...

How can I be a patient at the clinical.

Anonymous said...

plz launch arc 520


i cant get any job because of hep b crriers

Anonymous said...

When will there be results from Hong Kong trials?

Anonymous said...

Yes, so many millions of people depending on this breakthrough. Does ARC520 acts on the cccDNA in order to result "a functional cure?"

Dirk Haussecker said...

The goal of ARC520 is a functional cure which means HBsAg seroconversion in most cases. You are therefore asking whether seroconversion (once seroconverted, you stop giving ARC52) can reduce/eliminate cccDNA. We know that seroconversion greatly reduces cccDNA levels, so over time (given enough rounds of cell divisions), ARC520 theoretically should also essentially eliminate cccDNA if you live long enough.

Anonymous said...

Pls try and launch d drug many life's depends on it
...so hard revealing u re a carrier...

Nesrin said...

I am 37 .How can i be a voluntary ?i have chronic hep be for 15 years.in first 2 years I took interferon cure then it was negative for about ten years.Now it came back and can't use interferon again .I have a little girl and I'm scared of this illness badly.My doc says there is no cure and no studies about this illness because it is one of the orphan illness.

said tushar said...

how long time it will take to come into the Market ? Please we want to live not die....

Anonymous said...

when specifically are we expecting this medication,and how do we get it in nigeria.i pray that God help your guys in your effort to bring an end to this dreadful disease in Jesus name....

Dirk Haussecker said...

My guess is that it will take ~4 years for ARC520 to get to market if the mechanistic hypothesis underlying it works out).

Anonymous said...

This news gave me a placebo effect.

PASADENA, Calif. - March 3, 2014 - Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that it received regulatory approval to begin a Phase 2a clinical trial of ARC-520, its RNAi-based drug candidate for the treatment of chronic hepatitis B virus (HBV) infection. The Hong Kong Department of Health issued a Certificate for Clinical Trial, allowing the Company to proceed with its planned single-dose study of ARC-520 in two cohorts at two dose levels to be conducted at Queen Mary Hospital and Prince of Wales Hospital in Hong Kong. A site initiation was completed and patient screening will initiate shortly. The Company expects top line study results to be available in the third quarter of 2014.

mudasir bhat said...

Is your drug ARC-520 suitable for inactive carriers also???

Shawn said...

I am terrified to learn that i have hepatitis d. I am a carrier of chronic hepatitis b for the last 20 years. Now it looks like there are no traces of hepatitis b in my blood, but i have markers of D virus. Was told by the doctor that i have cirhosis and most likely will need new liver in 5-10 years. I am terrified, i have young family, 2 year old daughter, mortgage to pay.... and no symptoms of decease, what should i do to get ahead if the decease? I don't smoke, don't drink, what else should i do to improve my condition. The most difficult part of this is that i cannot accept that there is nothing that modern society can do to help people like me. I live in Ottawa, Canada

Dirk Haussecker said...

To the HDV patient: did you seroconvert regarding HBsAg?

Regarding HDV-specific treatment options: There used to be a farnesyl inhibitor discovered by Jeff Glenn from Stanford. Don't know how far that one got.

As part of my research back in the days, I was also interested in RNAi Rx for HDV: an RNAi trigger against HDAg, the only protein encoded by HDV. Another option could be HBsAg knockdown, but if you already cleared HBV, don't know how much that would help you. There are also a bunch of HDV host factors that my colleagues and I at Stanford discovered and which might be targets: http://www.ncbi.nlm.nih.gov/pubmed/19776158

A main reason though why the obvious RNAi approach has not been further developed is apparently small patient numbers. Many HDV patients live in Turkey and that country is actually quite good in terms of reimbursement.

Tekmira, also of Canada, is a company that has the technology that could help you.

Anonymous said...

Thank you so much for bringing this good news to us. I really wish this medicine can be the complete cure for this disease. Looking forward for this day to happen. Thank you!

Anonymous said...

Dirk will this cure also help patients who has only Hbsag positive ?
So called inactive carriers!
Or it works good with patients having hbeag positive?

Latebloomer said...

In the current trial, it is being tested in patients who are e-antigen negative.

From the March 24th News Release:

"...This study will be conducted in adult male and female patients aged 16 to 65 years, with immune active chronic HBV infection, HBV e antigen (HBeAg) negativity, and ongoing entecavir therapy."

Linda

Dirk Haussecker said...

There is no reason why ARC520 and similar candidates wouldn't apply to HBsAg-positive only.

Mohan Natrajan said...

As my wife is suffering from this disease,I would like to see a cure for this disease.I whole heartedly pray to god that this tests should show positive results and I myself will visit you guys once it is confirmed.First of all thank you all

Anonymous said...

can anyone tell me who to contact to be considered for the trials in Australia--thanks

Una River said...

Years ago, I was told that I am Hep. B carrier. It sickened me once pretty badly... However, recently, I had my blood test done, and miraculously I was cures. No meds, nothing, just healthy lifestyle as far as I know. I also have to admit that I did not let my self think too much about it. I kept living as if it wasn't there.

Anonymous said...

Hi Doctors,

I am Ravi 33 years old, chronic Hep B (e-antigen negative) positive for last 5 years,

Could you please let me know that can i be a voluntary for yours trails in Arrowhead RNAi (ARC-520) treatment?

I saw many online Presentation about Arrowhead RNAi (ARC-520) it is really very grate news and this treatment looking promising also.
Please let me know whom need contact and how to approach to be voluntary for this treatment.

Thanks in advance.

Dirk Haussecker said...

Ravi...if you are in the US, you'll have to wait half a year or so before volunteering (current trial is in HongKong). In general, for participating in experimental studies such as this, visit the clinicaltrials.gov site for more information on study centers etc.

Anonymous said...

What is the latest on this research? When will the drug be available to the African market? My husband tested positive to hepatitis B and we've been praying to God for divine/human cure.

Anonymous said...

Pls make it available for Nigeria citizen. God bless u. Thanks

Anonymous said...

Time to give it up Dirk.

Anonymous said...

time for the dirk knockers to give it up. Dirk's provided access and insight to an otherwise gated realm of info many of us otherwise have no clue to.

just because he says or doesn't say something about your particular investment us your problem.

i bet you moan loudly whenever you get a speeding ticket. for speeding.

Anonymous said...

Hi everyone, i have alwayz believe there is going to be a cure and that has kept me going. am chronic hep b carrier since 2007. Plase how soon will dis drug be out? my husband is loosing hope, he thinks too much abt it and its affecting him. please we need cure.

Anonymous said...

How real is this? I have diagnosed myself as having Hep B and next week will go for a test. I am afraid that I have passed it to my wife and son at birth. My son is 2 1/2. I have numbness in my body, fatigue and itching. It really keeps me down. Trying to maintain a positive attitude but tough. I hope this is real.

nana said...

Infact I was shock whn my doctor said I hav hep.b.wht shall I do to be save?can it kill?

Anonymous said...

How long we can wait for cure for this chronic disease. If it take a yr, we r d lucky persons in the world n can live as healthy as negative.

Anonymous said...

i hope these drug will be available in Nigeria too.

Ven Ngo said...

I am hep carrier for almost 22 years and maybe longer. I think i got it when I was young. I have been taking Viread 300mg for number of years now.
My blood test(ALT and AST) were good till March 2014. I dont drink at all but with my ultrasound, i have mild fatty in my liver. I notice that i have gained weights. According to my DR, My ALT jumped from 48 to 118 and AST 28 to 56(only 6 months) due to my weight but my B Viral DNa is <20 IU/mL.

Remember dont put on too much weights and Dont drink too much.
I can't wait for ARC-520 too.

Ven Ngo said...

Dear Dirk,

With my 2 previous test results:

October 2013: AST = 28, ALt = 48 and B Viral DNA <20 IU/mL
I was about 72kg

March 2014 : AST = 56, ALt = 118 and B Viral DNA <20 IU/mL
I was about 76kg.

I also had ultrasound check every 6 months and i had abit of fat in my liver but the March 2014 has increased more than before.

I am taking Viread for few years now.

Is my liver test bad? I will have have another blood test end of August.

Thanks Sam

Anonymous said...

i am willing to be a volunter for clinical trial in the philippines if needed.

Anonymous said...

The top drawer shelve results are now out from the second trial. In summary the results were impressive hence next trial is in the pipeline using 3mg per 2kg.

Anonymous said...

Could you please describe what "impressive" means in terms of numbers? Did it so far achieved over 90% of functional cure ? How many subjects were in the trial?
Would this work for all Hep B genotypes and variables immunoprofile? Is the definition of positive seroconversion measured in terms of levels of HBSurfarce Antibody?

Anonymous said...

ARWR: Efficacy of ARC-520 Phase IIa not as Strong as Expected, But the Program Is still Viable

http://finance.yahoo.com/news/arwr-efficacy-arc-520-phase-161500207.html

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