Future drug/cure prospects for next year and beyond

[itac]

Hi guys! Wish you a happy new year with minimal issues.

Wanted to discuss what are the future drugs/cures we should be looking forward to.

The hbv foundation released this article in their blog, back in May this year:
http://www.hepb.org/blog/is-a-cure-for-hepatitis-b-coming-experts-say-yes/

Does it sound too optimistic?

The biggest disappointment for this year was that Arrowhead ARC-521 drug was discounted because of toxicity. That's probably was the closet candidate to be released to the market. What's the next best potential candidate? Replicor are still having the phase 2b trial in Moldova, which will they release the results for it in September 2018. Given they will need phase 3 after that, so I'm guessing the earliest they might release their drug would be 2020? Assuming they will prove to be efficient and safe. Is there any other potential drug candidate that we should be expecting to be released by 2020 or earliest or that's our currently only hope? There is the Arbutus company (with the CTO who invented the Hep c cure) that's developing the RNAi drug also, but is their direction correct or will they flop like Arrowhead did in terms of toxicity, etc? Anyhow, I don't think they are too close to release a drug to the market either before 2020. Are you aware of any other drugs we should keep an eye on?

That's in the short term for the functional cure potential.
In the long term, can we expect a full sterilization cure using CRISPR/CAS9 given that science article proved it possible to target CCCDNA? I don't think there is any company that's utilizing this technology as of now, so I guess we shouldn't expect something like this before 2025?

So here are my bets: 2022 - functional cure
2027 - full sterilization cure

I know it's a long wait, but I'm trying to be realistic.
What's your take on this and guesstimate?

[Jatashankar]

By this delay soon 1-2decades will pass away and then these drug research delay will go into crap because by that time the hbvers count worldwide will perish gradually due to completion of their lifecycles. New babies are getting vaccines extensively so hbv won't be a big headache for future generations. Later it will be a history like smallpox and polio. Delaying the drug release is itself detrimental for these companies.

[itac]

You sound a little pessimistic my friend, as I mentioned:
"So here are my bets: 2022 - functional cure
2027 - full sterilization cure"

2022, that's 3 more years from 2019, given the progress made with arrowhead drug reaching 99.9% potency with suppressing all viral practices I'm hopefull that a drug will be out by then.

[RobInPA]

I see that J&J (Janssen) has a new drug that they are testing. It's in Phase 1 now but plans for Phase 2 are upcoming. I included some links about the trial and drugs. What does everyone think about this new drug?

https://clinicaltrials.gov/ct2/show/NCT02662712?term=56136379HPB1001&rank=1

http://liverlearning.aasld.org/aasld/2016/thelivermeeting/144773/jeysen.yogaratnam.safety.tolerability.and.pharmacokinetics.of.jnj-56136379.a.html

http://www.natap.org/2016/AASLD/AASLD_81.htm

[itac]

I don't know, Janssen? Don't these make shampoos? Don't think they are very close to a potential cure drug...

[RobInPA]

Janssen is part of Johnson & Johnson. J&J is a HUGE Pharma company. They also have a commercial products part of the company that makes shampoo, baby products, etc. The Pharma part is different. I'm going to keep an eye on there studies and this new drug. Like I said, they only have the Phase 1 study going on but I think the Phase 2 ones start later this year. I'll keep everyone posted.

[Airquake]

http://www.streetinsider.com/dr/news.php?id=12406237&gfv=1

[Royal36]

Bm2016 what was the status of your liver before you started the viread ? Just wanna know how effective is the viread in regressing the liver issues.

[Bm2016]

around 2004 was when the GI dr. told me my viral load spike rapidly, at the time the unit of measurement was in copy/ml, it went up exponentially from thousands to millions. at the time not many treatment choice available, it was either needle injection of interferon, or hepera 10mg, physically the pill was so small, if I were dropped on floor by accident, I may not able to find it, and the drug strength was weak, the only good news was it was so easy to swallow, after failed, then I also tried lamivudine, and later blood report shown my virus mutated, at the time viread was new to market for HIV only, and no other options available, so I tried viread, and the viral load quickly went down in 6 months, the only alarming blood report was my alt was consistently in triple digits, up to 200 to 300 range at one point, and did liver biopsy, ultrasound, result normal, after many years on viread, bloodwork show I lost hbv e-antigen, and then hbv dna undetectable, at the time my GI dr. was smiling and told me about 2% chance of seroconversion, and the entire time, as SORTE mentioned, I never feel sick, or thought it bothered my quality of life. only my GI dr told me I was sick. but I did get seasonal a few colds and fevers every year, and if other family member has cold or fever first, I will catch them too.
thing took a huge leap forward once my hbsag -, I don't recall the last time I have a running nose or fever, and now even other member has cold and fever, I won't catch them with precaution, like washing hands.

only recently I was interested in finding more about this virus, and found out the drs. I've been seeing were co-found/researchers who discovered the hep b virus more than a half century ago.

I do see quite a few members here who were also hbsag seroconverted, mostly talked about the curing process,  but not much discussion on the quality of life after hep b free.
what I really like right now is regular exercise, eat healthy and balance diet, and occasionally eat some exotic greasy food, I really don't miss the hep b after I found what a normally healthy life sick free I have now.

[Liverpatient]

Hi Bm2016,

I wonder why you are acting dishonest in your conflicting comments here in this forum? In one of your replies to studyforhope above you wrote,

"while my hbv dna went undetectable for 5 or 6 years ago, i still experienced joint pain, tiredness, bad breath, blurry vision, headache while taking viread, and the GI told me as long as my hbv dna undetectable or low, my chance of dying from other disease  is higher than from liver cancer. Now as soon as my hbsag-, hbsab+, hbv dna undetectable,
personally i have not experience any more symptom, now i really understood the difference between nasty hep b and hep b free";

While now in your reply to Royal36, you are saying this,

"after many years on viread, bloodwork show I lost hbv e-antigen, and then hbv dna undetectable, at the time my GI dr. was smiling and told me about 2% chance of seroconversion, and the entire time, as SORTE mentioned, I never feel sick, or thought it bothered my quality of life. only my GI dr told me I was sick".

So again I wonder why you're providing such dishonest and inconsistent messages? As someone who is suffering from various bad symptoms of the hepB disease, it makes me angry when people come here and tell conflicting strories; also it makes me angry when people are reserved not to speak about the bad side-effects of living with hepB. I know most hepb patients do not suffer from any symptoms, and that is good for them, but few unfortunate ones like me do suffer from various issues, and in that case it is helpful to get a feedback from other patients in similar situation.

[Bm2016]

Hi, Liverpatient,
i am absolutely telling the truth about my own personal experience, not like dishonest as you described,  and nothing to hide, my symptom was just not botherly noticeable, until now i noticed the changes and learn out about it.

[RobInPA]

What about these?  I found these articles online. Has anyone heard about these?

http://www.ibtimes.co.uk/possible-cure-hepatitis-b-that-100-successful-being-tested-by-australia-scientists-1497540

http://www.chinapost.com.tw/taiwan/national/national-news/2013/06/05/380320/New-hep.htm

[24CN]

The forum search function is your friend. The first is currently a dead end, the second is vague bollocks.

[Aduiski]

thanks for these insights studyforhope. Would you be able to make a rough estimate on when could cmx157 become available on the market?

[studyforhope]

The fastest would be 3 to 4 years from now.  They would need to run a phase iii trial against TAF. The problem is that it's true benefits over TAF are hard to show with lab tests, as I have described above,  thus a sponsor might shy away.

[sorte]

studyforhope: Do you think TAF or cmx157 may have better functional cure rate, in the long term use of course ? For current nucs it's only 3-5%, so not much higher than spontaneous seroconversion.

[Aduiski]

Thx studyforhope

[studyforhope]

All three drugs, viread, TAF and cmx157 basically supply tenofovir diphosphate to the liver cells. TAF and maybe more so cmx157 could achieve a higher intracellular concentration. But the blockage factor of replication will still be in the same range and the de novo virion production will not completely stop. Thus any major difference in the functional cure rate is not likely.

However, if cmx can deliver this suppression without interfering with other organ functions, it would be a big progress. As long as you take the pill you are almost as good as functionally cured, since there should be no more progression of liver disease by hbv and the rest of the body is not touched by the drug to any relevant degree.

One must not forget, that even the "functional cure" relies on ongoing suppressing immune activity, that is in itself not entirely without negative side effects on the body.

[sorte]

studyforhope: can you elaborate that part about functional cure ? What are negative effects on the body after functional cure ?

[studyforhope]

The functional cure is a situation where an effective memory tcell response permanently controls the respreading of the virus from hundreds of thousands of tiny remnant infected cell clusters. A high anti hbsag antibody helps to reduce the speed of viral respreading from these clusters by immuncomplexing de novo released virions, incapacitating them to reinfect.

The tcell response itself waxes and wanes with the size of these clusters, being activated mainly by increased virion immuncomplexes captured by dendritic cells.

Thus the remnant control proceeds as a series of activations and withdrawals, causing often small alt increases and in each case gamma interferon, TNFalpha and other cytokines are produced in the complex interplay of adaptive immunity.

The effectiveness and intensity of thsee periodic internal activation is very variable and depends mainly on the quality and quantity of tcell epitopes available and displayed and the functional capacity of the tcell clones available to react.

Basically the defense reaction continues lifelong in the absence of external drugs and due to the effectiveness of the system, the hbsag stays undetectable or very low, the vl stays low and the surface antibody is visible and measurable, since the true hbsag quantity produced by the hbv remnant genomes is small enough that the antibody will complex with it, rendering it undetectable with standard assays.

But all these immunactivations, despite their high effectiveness, will still send pro inflammatory signals to the rest of the body, causing tiredness,  joint problems and numerous other minor ailments.

[Bm2016]

Hi studyforhope, I've recently transitioned from taking lifelong viread medication to hbsab+ seroconverted, and ended viread a year ago.  while my hbv dna went undetectable for 5 or 6 years ago, i still experienced joint pain, tiredness, bad breath, blurry vision, headache while taking viread, and the GI told me as long as my hbv dna undetectable or low, my chance of dying from other disease  is higher than from liver cancer. Now as soon as my hbsag-, hbsab+, hbv dna undetectable,
personally i have not experience any more symptom, now i really understood the difference between nasty hep b and hep b free.

does functional cured mean immune system able to suppress the hbv, or also include while no immune response, but while taking life medication and hbv is under controlled as well.

[studyforhope]

Functional cure is defined as permanent  immune suppression of viral remnants. This can be borderline effective or very effective and with many intensities of general collateral effects of the chronic mild immune activation still in the liver.

If a medication would suppress viral production to extremely low levels and it would otherwise have no or only minimal side effects it would be as good as a functional cure. The only problem remaining would be ongoing cost and efforts.

[itac]

studyforhope, I don't get this... Are you saying that functional cute is not good enough as its cause long term side effects? I thought that functional cure has good prognosis outcome in terms of fibrosis/liver cancer. But you are saying that even with functional cure you still going to have side effects? I thought it was considered almost same prognosis as someone who never got infected as long as the immune system doesn't get supressed? It's kinda depressing what you say. More like studyfordepress :D I guess sterilization cure is our real hope. 2027? Or earlier?

[Liverpatient]

I was also thinking functional cure to mean undetectable vl and undetectable hbsag with or wihout development of anti-hbsag. This would mean, according to my little knowledge, almost equivalent to a complete cure. A complete cure meaning total eradication of the virus and its proteins from the body, though i don't know whether this is possible.

[studyforhope]

The prognosis of highly effective permanent  tcell control of viral remnants is indeed excellent. What i tried to explain was that the constant effort to suppress these slowly regrowing remnants will sometimes have some price of collateral immune activation, which you probably can feel. This does not lead to a reduction of life expectancy but it might lead to some reduction of quality of life from time to time, without you even knowing what is going on.

[itac]

But you can say that on other retroviruses in your body like hpv, herpes, Bar Epstein,gut bacteria plus with aging there are bunch of problems coming anyway... Also those side effects, it doesn't mean that it's going to affect all people, it probably depends how many cluster remnants remain in your body when you get functionally cured. Also, wouldn't it be possible to access those remnants in the future and destroy these cells? using DRACO or whatever technology will be out there?

[Bm2016]

during my latest and last visit to GI office before the dr sent me home for good, the dr told me my condition will be almost as good as someone who has been vaccinated for hbv, based on my latest blood report, but with the exception if i have to go through immune suppression therapy, which then i will have to restart viread again. it seem like the dr only care about as long as my hbsag negative and hbv dna undetectable (alt 25) for over a year,  taking the hbsab+ out of the equation, and don't want to see me anymore.

although my hbsag went negative only for 2 years, now i really enjoy my quality of life, so much more energetic, enjoy all the foods i can eat without worry about bone and muscle pain later, a huge step forward, even though you may suggest a reduction of quality of life with the functional cured, but whatever the reduction of quality of life will be, i would imagine it will be still better than what i used to have.

[studyforhope]

The situation is indeed similar to other lifelong chronic infections like herpes, CMV, EBV. They can cause occasional problems also and need a functional tcell system to maintain the suppression.

And BM2016 you are a case of excellent trouble free suppression and that is a big step forward from the more intense pro inflammatory conditions of chronic hepatitis b. Not everybody is the same, however and as itac said, it will also depend on the amount of remnant virus left at the time of hbsag loss. This amount will however change up and down as explained before, because this is still a dynamic process.

What started this discussion was however the question if an extremely effective antiviral or combo with minor side effect could be at least equivalent to this type of inner immune control in terms of life quality and health maintenance.

Some patients might not have the capacity to permanent immune control due to adaptive alterations in hbv epitopes and a lack of high quality tcell clones. For those this would be an important solution.

[sorte]

I never had any quality of life problems despite of my chronic hbv infection, always good energy levels, doing lots of hard sport trainings. So I hope some day after functional cure I will also stay on the same level :)
I guess level of inflammation is uncomparable much higher during chronic hbv infection than during functional cure phase ? correct ?

[Liverpatient]

Hello Community, and Happy New Year to you all,
Regarding the ongoing research on finding a cure to Hepb, one could follow the Hepatitis B Organization's drug watch here:
http://www.hepb.org/treatment-and-management/drug-watch/

[itac]

Thanks. That list is a mess though - too many things, some are obsolete or not too promising and not much info exist about it. Rather have a shorter list that's focusing on actual things that's half way to be practical and something we can all hope for.

[24CN]

For insights of value you need more data, i.e completion of current phase 2 trials and commencement of phase 2 for those currently in phase 1 / preclinical. As it stands, the list is probably just Replicor. I'm sure studyforhope will contribute when there's something worth looking at.

In the meantime I found the recent (Oct?) interview with Contravir CEO James Sapirstein and webinar with Timothy Block interesting. Both on  YouTube (though you've probably seen these).

[itac]

Contravir also seem like a failed company - their drug candidate try to have better efficiency than TDF? but Gilead just released TAF a month ago! it's over for them. They tried to increase the trial phase 2 dose probably after not achieving the efficiency goal and their share dropped. I guess we only have replicor to relay on for now - the hbv foundation cure webinar seem to be informative but nothing specific really, seem like a corrupted organization that try to promote their partners for a cure, but other than making promises it dosent seen like they are competent enough to come up with a cure and they just mislead reader on their website with that long list of drugs.

[StephenCastlecrag]

Contravir is not a failed company, actually I have a lot of hope on Contravir. CMX157, like TAF, is a prodrug of Tenofovir. TAF has been reported to act faster and better than TDF. Unfortunately, these aspects were not fully investigated during the clinical trials of TAF and has been lamented as lost opportunities A more potent NUC is a necessary condition, but it may also be a sufficient condition for a functional cure of HBV. Now we have to learn from clinical experience. CMX157 is reported to be even more potent than TAF and the investigation of an optimal dosage will be most welcome. At the very least, its success will bring down the cost of TAF and break the Gilead monopoly. But an added excitement is that Contravir is reporting very good results with its cyclophilin inhibitor CRV431, "showing that it effectively blocks a critical interaction between HBV X protein (HBx) and host cyclophilin A".
"Importantly, HBx is required early in the viral life cycle and works "upstream" of other classes of anti-HBV drugs.  CRV431 therefore could potentially interrupt several essential pathways enabling development of a curative combination with other HBV treatments.  CRV431 has demonstrated synergistic activity in vitro with ContraVir's tenofovir prodrug CMX157, currently in Phase 2 clinical trials."
We can be hopeful.

[StephenCastlecrag]

I also dispute your description of HBF, the Hepatitis B Foundation. It is the only non-profit organization dedicated to finding a cure for HBV, not just by words, but also through research. Arbutus, the pharma touted by many to be the first to develop a cure for HBV based many of their products from the research work of HBF and its scientists. It would not surprise me if HBF would develop a cure for HBV. Their effort in raising awareness of HBV, their lobbying for greater funding for HBF research, and their fight against the discrimination and stigma of HBV through dissemination of knowledge benefit us all.

[studyforhope]

I have analyzed and compared all available data from cmx157 and TAF in the finest detail. From this it seems that cmx is still a major step froward from TAF.

Both will have no more relevant kidney toxicity and the dose can be easily adjusted to achieve the same final intrahepatocellular Tenofovir diphosphate concentration. TDFPP is the real drug, the real polymerase inhibitor, all the other precursors are just pharmacokinetic intermediates, and most importantly the ester prodrugs of tenofovir itself like TDF, TAF or CMX are basically smart tricks to achieve intestinal absorption of an otherwise very polar substance ie "naked " tenofovir, and then  the  transmembrane crossing into the hepatocyte.

It strongly appears that the percentage of orally provided tenofovir that ends up in the liver is substantially higher with cmx than TAF.

This means that the amount that goes to the organ where it is needed vs the amount that goes to the rest of the body is a much higher percentage with CMX.

There is an 86% first pass extraction of CMX and then a strong second pass extraction after that, leaving only very small amounts of the drug to go to other tissues, where it basically causes side effects.

The ideal antiviral would go solely to the liver and leave the other organs alone.

CMX has a chance to come quite close to that. TAF not so much.

Regardless, contravir has a long and expensive road ahead and will encounter resistance from Gilead as much as they can all the way.

It is true that with respect to the kidney toxicity both TAF and CMX are very safely positioned, that being the most obvious and "official' side effect of Viread.

But there are effects on other organs as well and CMX will have the clear upper hand. Except it is very hard to show or quantitate these types of side effects. But most Viread users know about these side effects, although they tend to be mild in general.

[studyforhope]

With regard to CRV431 the sparse data show that the effect of this cyclophilin inhibitors on HBv does not seem to very strong. I doubt that the combo with cmx would give such a powerful enhancement, that the viral spreading can dry out. And of course there is all the unknown with respect of side effects.

For Conravir this is of course a nice argument to show strength and appeal in the field. One must realize that Contravir will have to be aquisitioned to pursue CMX to a marketable drug, there is just too much expense.

[Airquake]

EDISON, N.J., Jan. 3, 2017 /PRNewswire/ -- ContraVir Pharmaceuticals, Inc. (CTRV), a biopharmaceutical company focused on the development and commercialization of targeted antiviral therapies, today announced that the company was awarded a $297,875 CAD research grant from the National Research Council in Canada through the Council's Industrial Research Assistance Program (IRAP). Proceeds from the grant will fund a substantial portion of personnel expenses, including the hiring of additional laboratory staff, which is expected to advance preclinical development of ContraVir's potent cyclophilin inhibitor CRV431 for the Treatment of Hepatitis B (HBV).
"We are very grateful to NRC-IRAP for this generous contribution to our CRV431 program in hepatitis B," said Robert Foster, Pharm.D., Ph.D., Chief Scientific Officer of ContraVir. "The fact that we can now expand the team dedicated to advancing this promising new molecule will have a positive impact on our ability to gain critical insights into its mechanism of action and explore new combination regimens capable of potentially eradicating HBV."

"We're proud of our team for continuing to leverage every available opportunity to advance development of our antiviral drug candidates," said James Sapirstein, Chief Executive Officer of ContraVir. "Determining the specific molecules and processes inhibited by CRV431, such as the exciting HBV X pathway, will help us further validate this compound and drive potential interest among commercial development partners working toward curative anti-HBV combination therapies."

[Royal36]

Right itac our only hope is from Replicor i guess and how about the cuban NASVAC ? I think the trial is in progress in Bangladish.

[itac]

NASVAC (ABX203) has failed too this past year.

http://labiotech.eu/abivax-interview-antiviral-hiv-hepatitis/

"“We will be able to do the complete analysis to understand what has been going on there“, but “it is certainly premature to draw conclusions on how we are moving forward“. If there’s a future for ABX-203, Ehrlich estimates that the setback will of at least a couple of years.

Abivax’s stock price fell by over 50% upon this announcement"

[landloper]

That failed in the context of some weird parameters. They were only testing it on people who had previously had antivirals, and the antivirals had failed to take effect. They never tested it on regular hepatitis b patients. It's still unknown in that sense whether NASVAC will be helpful or not.