Welcome to Biotechr


Biotechr is written by Dr. Robert Kruse (@RobertLKruse), who holds a PhD and is currently completing his MD. His research work focused on infectious disease and immunology. This blog is focused on analyzing the latest developments in biotechnologies being developed in academia and industry, with a particular focus on biomedical therapeutics. I hope that the posts are interesting and useful, and hope you join in the discussion with guest posts on the site!

Disclaimer: The thoughts on this blog are not intended as any investment advice regarding any companies that might be discussed, and represent my opinion and not the opinions of my employer. This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual.

Thursday, April 23, 2015

How low must HBsAg levels go?

by Robert Kruse


I wanted to write some commentary on HBsAg levels and the therapeutic goal for knockdown that must be achieved in order to have clinical responses. This is in response to some speculation from the current ILC 2015 meeting. I wanted to say as a disclaimer that I believe that siRNA and antisense drugs (Tekmira, Isis, Arrowhead, Analym) could very well work against HBV and mediate clinical response; I am just more apprehensive about the certainty of its clinical success. I also do not own any stock in the companies referenced here, and this is not meant to be investment advice, but a scientific discussion.

My fellow HBV commentator at the RNAi Therapeutics Blog suggests that if levels of HBsAg under 500 IU/mL are achieved, that a synergy between interferon and siRNA could be achieved and cure could happen. He suggested that a month treatment of siRNA could get this low level, and then interferon could finish the job.

Let's assume that theory is right. It makes me nervous that even in patients under this magical threshold, they only had 9% cure rate after an entire year of interferon treatment, which most patients can't even tolerate. Does that mean the siRNA combo plus interferon will only have a 9% cure rate? I would hope not, otherwise the therapy would not be very efficacious. Since siRNA knocks down all viral genes, there is the hope that other mechanisms could be at play that would increase this cure rate.  (edit: @RNAianalyst clarified reported data was for all patients with different HBsAg levels, so 9% cure rate was for combined group. In the link below though, HBeAg negative patients with HBsAg levels of ~200 IU/mL and pegasys and adefovir treatment had 17% cure rate (defined as HBsAg loss) at 2 years after 48 weeks of treatment. Definite improvement over non-responders with higher levels of HBsAg, but not still not a home run like HCV blockbuster medications)

I also want to comment on applying a retrospective clinical cohort analysis to prognostications about the potential of this therapy. The study by Dr. Joerg Petersen is likely true and is similar to other clinical reports I've read on pubmed before, that patients with baseline HBsAg that is lower will respond to treatment better. The problem is that if you compare a patient with 5000 IU/mL vs 500 IU/mL, there are likely a host of differences in their baseline status, namely different levels of ongoing immune responses and/or viral genotype.

The lower HBsAg patient possibly has a more vigorous ongoing polyclonal T cell response against HBV that is keeping the levels of HBsAg low - there must be a reason for the difference in the first place after all. It is likely then that adding interferon to this patient can help push that person's immune system over the top. In the example above, the HBeAg negative patients are negative for that antigen because of a more active immune response against HBV, which lent themselves for a 17% cure rate with IFN added versus HBeAg+ patients who had an 11% cure rate (differing levels of HBsAg modified this as well). Indeed, the type of immune response a person has greatly influences the effect of IFN on the course of HBV.

This situation is analogous to how checkpoint inhibitors for certain tumors are very efficacious, likely because the tumors are more immunogenic, so there is a better immune system at the site ready to fight the tumor. The checkpoint inhibitors can easily push the anti-tumor T cells over the top. On the other hand, the patient with the 5000 IU/mL baseline, even if artificially induced to have lower HBsAg levels to 500 IU/mL, still has a poor ongoing immune response that might not be boosted well by interferon. It's certainly possible that the HBsAg drop could help DC presentation and augment T cell polyclonality, but I don't know how long that might take and I'm not sure if anyone in the field does either. It's possible that their viral antigen specific T cells are already exhausted against the given epitopes and are beyond recovery. The siRNA is analogous to holding the target still, interferon could be bullets, but if the patient doesn't have a gun, ie effective adaptive immunity, it all might be a waste.

There is also the black box of how different viral genotypes secrete HBsAg at different levels, and different viral genotypes respond to interferon differently. This has been reported in several papers on pubmed, and I wonder how this might influence the goal biomarker levels of any siRNA treatment. I would guess in Dr. Peterson's previous study that the patients were all controlled for the same genotype (typically these studies are at centers in a certain area, so the geography dictates similar genotypes), but this is one confounder to look at in any future clinical reports.

In summary, I believe siRNA and ASO drugs are definitely exciting therapeutic modalities and potential game changers for HBV treatment, since they offer a new mechanism to fight the virus. I just want to add caution, though, to benchmarking certain data points and prognosticating success. HBV is one virus, but with a heterogeneous course across patients, the natural history of which is still being learned. The key immunological studies being discussed above have been limited since we can only really gain relevant data from chimpanzees and humans. It will be fascinating as an HBV researcher to see if knockdown could truly reactivate the immune system in all patients. Even if it doesn't in all, there could be a treatment cohort where a 100% cure rate is achieved, like the patients with better baseline status (<500IU/mL) discussed above. However this goes, it will at least be interesting from a basic science perspective.











26 comments:

  1. I find your blogs interesting and information.
    Even though sRNAi can be used to knock down all viral genes, it seems effort is concentrated on the s-antigen, for good reason. Replicor had demonstrated in several small human clinical trials with REP9AC that sustained svr, including loss of the s-antigen can be achieved in combination of with Interferon. The results have been confirmed with their recent HBV/HDV clinical trial with Rep2139ca.
    It would be interesting to investigate the effect of knock down of the e-antigen in HBeAg positive patients - will it lead to break down of immune tolerance and e-seroconversion?
    Finally, would like to hear your comments on Birinaapant, the 100% cure for HBV in animal models.

    ReplyDelete
  2. Thanks for your comment, Stephen. The effort is concentrated on HBsAg, because it is the most overexpressed protein that seems to act in a number of immunomodulatory roles. It's mRNA transcript levels are also the highest, and therefore a good target for siRNAs.

    The Replicor results do appear to be much more potent than siRNA's in knocking down HBsAg levels, and we will have a blog entry on Replicor later this week.

    You have an interesting idea on e-antigen. I wonder if siRNA treatment could make HBeAg seroconverstion to go much faster, even if HBsAg levels aren't eradicated. The data appears to show that HBeAg is readily knocked down by siRNAs but not sure if people have looked for that yet. HBeAg seroconversion is a good clinical outcome alone, so it could be worth something to Arrowhead, for example.

    For your last question, I think I will explore SMAC mimetics in a later blog post. I can only go off the data on Tetralogic's website, which appears to be good, but the HBV models they are using are unclear, so I don't want to speculate too much at this time.

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    Replies
    1. For Birinapant, you will find two papers published by the Walter Eliza Hall Institute team investigating its potential to treat HBV on behalf of Tetralogic in the recent editions of PNAS.
      Looking forward to reading your comments on REP2139 and Birinipant.

      Delete
  3. Thanks for the tip on Tetralogic. I was literally on their site a few weeks ago and on pubmed and didn't see any publications yet. I'm looking over the paper right now.

    ReplyDelete
  4. BTW, Tetralogic had just "temporarily halted enrollment" of its clinical trial in Melbourne clinical trial.

    ReplyDelete
    Replies


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  5. Thanks for the tip. I'm really surprised by this, considering SMAC mimetics have been tested in other Phase I trials before. I understand theirs might be a different class though. The cranial nerve palsy thing is just kind of bizarre to me, not even liver related.

    ReplyDelete
  6. Bell's Palsy was known and reversible from their cancer clinical trials. Not much information about the present situation.

    ReplyDelete


  7. i have heard of him before, but after watching his documentary “healing spell” I was turned on to the full story

    about Dr atinga. He is a man who has the Cure for AIDS,Cancer, Sickle Cell, Herpes,warts,HPV,ALS Diabetes and every kind of

    illness, through a whole foods vegetarian diet and natural herbs, what he calls Electric Foods. He went to herbal school college,

    and has thousands of testimonials of healing people with Herpes, HIV AIDS, and HPV several other

    illnesses. Lisa “Left Eye” Lopes of TLC was cured of Herpes by him and she was so moved by his knowledge that she went on

    to spread the word about him in every way she could. She also opened a Cultural/Healing Center for Children in USA

    before she passed away tragically. This all inspired me that i had to contact Dr atinga, because i was having Herpes

    which could not be cure but was only managed, when i contacted Dr. atinga, he sent me some herbs which i took, and now i can tell you, i have be totally cured of Herpes, My Name is Joy wilson, I am from the South africa, and here is my email address .............joywilson953@gmail.com. Please if you have any form

    of illness especially STD, HPV, Infertility,HIV etc. you can contact him immediately through his Email Address

    dr.atingaspellhome@gmail.com

    dr.atingaspellhome@gmail.com

    ReplyDelete
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    ReplyDelete
  12. All thanks to God, i am now negative of HBsAG, Contact: medlab36@gmail.com

    ReplyDelete
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    ReplyDelete
  14. I was diagnose of hep B for more than 2 years, all the medical doctors said to me there is no cure but it can only be control. Ever since then i have been running heather scepter depressed looking for a solution to my problem, i ran into this online testimony of Mrs Stacey who have been cured of Hep B by this medical center she mention, i immediately contacted them, to God be thy glory i also got my cure am so happy today, please my advice is, if you have been living with Hep B contact them now for any kind of disease,don't waste time and get cured here is also their email healthmedlab@gmail.com

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    ReplyDelete
  21. I was diagnosed with HepB 3 months ago and was devastated by the news. I have been ill and sore for over 10 years, with no one being able to figure out what was wrong with me. It was always written off as a virus or infection. Then 2 years ago the severe muscle cramps started. I had them from scalp to toes, and it was when they ran the full spectrum of tests to figure the cramps out, that they discovered the HepB along with severe Vitamin D deficiency, which I link to the HepB. I was so tired and nauseous and in constant pain. I am just sick and tired of feeling sick and tired!!nothing was really working to help my condition.I went off the Sebivo (with the doctor’s knowledge) and started on hepatitis B herbal formula i ordered from Health Herbal Clinic, my symptoms totally declined over a 5 weeks use of the hepatitis B virus natural herbal formula the disease is totally reversed!! Visit there website www. healthherbalclinic. net

    ReplyDelete
  22. What a great and inspiring story! I was married for seven years without any child, because of this my husband start acting strange, coming home lately and not spending time with me any more and he divorced me. So i became very sad and lost in life because my doctor told me there is no way for me to get pregnant this really make life miserable for me. until i came across a friend who told me about Baba Alika from the Internet, how he has helped a lot of women with this similar problems that i am going through so i contacted him on: (babaalikahealinghome@yahoo.com) and explained to him. he told me all what to provide before he could cast a reunite spell to bring back my husband which i did and he sent a powerful prayer which i had to say at mid night while he cast the love spell. It was a miracle, 24 hours later my one and only husband came back to me and apologize for all he has done and told me he is fully ready to support me in any thing i want,i quickly call Baba Alika and told him what was going on at that moment, and he also prepared and sent me a herbal medicine which he said it will cure every unwanted diseases or infections that has been stopping me from conceiving then instructed me on how to use it before meeting with my husband. Behold after using this native herbs and root, few weeks later i started feeling pregnancy signs all over me, truly i was pregnant i just gave birth to twins (boys) on the 1st of this month. I Vow to let the whole world know about Baba Alika for saving my relationship and for also giving me children i can proudly call my own today. For any woman who think it impossible, here is an opportunity for you to smile and bring happiness to your family kindly contact Baba Alika via Email on: (babaalikahealinghome@yahoo.com). Indeed, he is a God sent to bring back lost lovers and bring you happiness...

    ReplyDelete
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    ReplyDelete


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    ReplyDelete