Newest Repac Abstract

[Aduiski]

HBsAg and HDV RNA reduction with REP 2139-Ca and peg-INF alpha 2a in chronic HBV/HDV infection.

Nucleic acid polymers (NAPs) inhibit the release of HBsAg and the NAP REP 2139 can efficiently clear HBsAg from the blood of patients with HBV mono-infection. REP 2139-Ca therapy combined with pegylated interferon alpha-2a is being evaluated in Caucasian patients with HBV/HDV co-infection (NCT02233075).
Patients received REP 2139-Ca once weekly for 15 weeks (500 mg) by 2 h IV infusion, followed by combined therapy for 15 weeks with pegylated interferon alpha-2a (180ug SC qW) with 250 mg REP 2139-Ca. Patients then transition to 33 weeks of pegylated interferon alpha-2a monotherapy. HDV RNA, HBV DNA, HBsAg and anti-HBs are followed every two weeks using standard assays (Robogene RT- PCR, Abbott RealTime HBV, Abbott Architect).
On treatment, observed HBsAg reductions are currently *5 logs in 6 patients (all \1 IU / ml), *3 logs in three patients and *0.5 to 1.5 logs in three patients. HDV RNA is currently undetectable in ten patients (*5 to 8 log reduction from baseline) with *3 and *5 log reductions observed in the other two patients. Substantial elevation (389–15,408 mIU/ml) of serum anti-HBs and the development of liver flares were only observed with the onset of exposure to pegy- lated interferon alpha-2a and was only evident in patients with serum HBsAg \1 IU / ml at the start of immunotherapy.
REP 2139-Ca is able to achieve rapid reductions in serum HBsAg and HDV RNA in Caucasian patients with HBV/HDV infection. REP 2139-Ca may become an important new therapeutic option for patients with chronic HBV/HDV infection.

[stef2011]

Avaz and thise websites may easily push all their members to join the petition if you put it like this: hdv has no cure and people die from this (this cannot be said about hbv of course),this drug has shown it can cure hdv and mild sides effects, this drug must be approved!

the small private drug company needs orphan drug approval for hdv

Off label use then is allowed for hbv too

[cure4life]

Im in, and will find donations from many non hbv people as well.  

[stef2011]

Yes it is and the difference between germany/italy or moldavia was only to save money while blood tests are made in labs in germany and us thats why i was thinking petition to get it approved

If you add hdv has no cure at all (hbv actually has a cure to block it) we may push all the public to join us.
For hbv they can say there are drugs to block it but this cannot be said about hdv, plus there are laws in some european countries that allows use of experimental drugs when there s no cure

[Royal36]

I know there is a Facebook group its Admin most of the time in here with us, i believe about 5000 HBV members in that group so this ppl they 'll definitely do a difference in the petition. Good luck!

[Aduiski]

The third and last one:

Antiviral effect of therapy with REP 2139-Ca and nucleos(t)ide analogues against HBV in vivo

Treatment of human patients with chronic HBV infection with the nucleic acid polymer (NAP) REP 2139 results in the elimination of circulating HBsAg. In this preclinical study we evaluated a novel combination therapy associating REP 2139-Ca with tenofovir diso- proxil fumarate (TDF) and entecavir (ETV), in vivo, in the DHBV infection model.
DHBV-carrier ducks were treated for 4 weeks with normal saline (IP), REP 2139-Ca (10 mg/kg IP QD), TDF (15 mg PO QD), REP 2139-Ca + TDF or REP 2139-Ca + TDF + ETV (1 mg PO QD). Serum DHBsAg was monitored by ELISA and DHBV DNA by qPCR. After therapy cessation all animals were followed during additional 8 weeks. Total DHBV DNA and cccDNA were analyzed in autopsy liver samples by qPCR.
On-treatment antiviral responses were more marked when REP 2139 was combined with TDF or TDF and ETV. Sustained virologic responses (SVR) during 2 months off-therapy were only observed in the groups receiving REP 2139 alone or in combination with TDF or TDF and ETV but not in TDF-monotherapy. SVR consisted of stably suppressed serum DHBsAg and DHBV DNA and significant decrease in liver DHBV DNA and cccDNA that were more marked in com- bination-therapy groups. Importantly, SVR animals had undetectable liver DHBsAg as assessed by immunostaining analysis.
Antiviral performance of REP 2139 was sustained and enhanced by combination with TDF or ETV. Thus an interferon-free regimen of REP 2139 with TDF or ETV could improve antiviral response and shorten treatment regimens in HBV infected patients.

[StephenCastlecrag]

Thanks. Can you please cite the authors. In 2010 APASL in Beijing, Replicor had a poster about REP9AC.........

[Aduiski]

Serum HBV-RNA levels decline significantly in chronic hepatitis B patients dosed with REP2139-CA

Background and aims: The HBsAg release inhibitor REP2139-Ca may be a promising new treatment option for chronic hepatitis B (CHB) patients, however its effect on hepatitis B pregenomic RNA (HBV-RNA) is unknown. HBV-RNA levels during treatment with REP2139-Ca were determined and compared with HBV-DNA and HBsAg levels.
Methods: 12 Patients with HBeAg positive CHB participating in a phase 2 study were dosed with the nucleic-acid based amphipathic polymer REP2139-Ca for 20–38 weeks. Responders to REP2139 (defined as clearance of serum HBsAg) were subsequently treated with an add-on immunomodulatory agent (peginterferon alpha-2a and/or thymosin alpha-1). HBsAg, HBV-DNA, and HBV-RNA levels were determined at baseline, after 20–24 weeks of REP2139-Ca monotherapy, and either during a treatment-free follow-up (for responders) or during entecavir treatment (for non-responders). HBV- RNA was quantified by RT-qPCR using HBV-specific primers. Results: HBV-RNA levels were detectable in all 12 HBeAg-positive patients before treatment [mean 6.70 (SD 0.83) logC/mL], and were significantly associated with HBsAg (r2 0.33, p = 0.049) and HBV- DNA levels (r2 0.74, p \ 0.001). After 20–24 weeks of REP2139-Ca treatment, mean HBV-RNA, HBV-DNA, and HBsAg levels had declined significantly compared to baseline (all p \ 0.001). At week 20–24, HBV-RNA was undetectable in 8/12 patients. In 7 of these 8 patients, HBV-RNA remained undetectable during the treatment-free follow-up period (mean 21.9 weeks, range 7–27). HBsAg sero-con- version was achieved in 4/8 patients during follow-up (anti-HBs range 200–766 U/L).
Conclusions: In patients treated with REP2139-Ca, serum HBV-RNA levels declined significantly compared to baseline. REP2139-Ca may be a promising new treatment option for CHB patients.

[sorte]

Presentations:

http://replicor.com/wp-content/uploads/2016/02/Replicor-REP-301-APASL-2016-O-130web.pdf

http://replicor.com/wp-content/uploads/2016/02/Replicor-APASL-2016-Combo-NAPS-In-vivo-P-0329.pdf

[antistr]

change.org can be used for a petition.

[stef2011]

i open another post on zadaxin, see answer there

[stef2011]

the problem with this drug/company is that we have no info on hbsag quant, they only reported hbvdna.

it would be great to see its effect on low hbsag or combo with cuban vaccine

[OrientS]

Questions ..
first of all hi to everybody and to stef ..

iam here member since 2011 .. when i discovered that iam hbver chronic carrier iwas scared .. i was reading in this forum daily for about two years .. until a i started entecaver 0.5 mg .. now iam (Al7mdulillah) is F0 by fibrosan and und hbvdna .. with almot normal ast ..

i become visiting this forum every 2-3 months ..
it is the best place to get information and exellent advises ..

sorry for the no need introduction ..

is zadaxin is alhpha thmosin?

what is the recommended dose with entecavir?

is there any side effects?

last HBsAg quantitive for me is around 600 iu/ml by roche

less than 1000 iu/ml

from where can i get zadaxin?

thanks for all

[Aduiski]

studyforhope...

Could you please provide your opinion on the most effective long-term approach to  treatment, taking into account the available options such as entecavir/tenofovir, pegasys, zadaxin (thymosin alpha), etc....

Basically, my question is, what would be the advised or seemingly most-effective sequence of the treatment options and when (e.g. at what hbsag level) would each of these medicines be best to be initiated.

Lets say one starts with tenofovir/entecavir...at what time would be the most effective to add pegasys and/or thymosin alpha?

Thanks in advance...

[studyforhope]

This is a thread about rep9ac, so this much more general question would get lost and diluted in this context.

[sorte]

Thanks. Any theories why in that case with naps it's better than interferon and in other cases not ?

[studyforhope]

Thymosin  alpha fosters t cell responses. Direct comparisons with interferon were rarely made.
it might also be that the antibody level is raised more effectively, protecting the svr status better.

[stef2011]

it worked this way on nap but who knows monotherapy

[sorte]

So basically its good when someone has lost HBsAg but has problems with developing antibodies ?

[studyforhope]

Sci clone is a small company. It did not have the means to initiate trials to tests those other potential uses for thymosin alpha like sequential add on after antiviral therapy. It is approved in many countries for hbv, also cancer and as a vaccine adjuvant in some.

What matters here are the results it achieved in combo with naps in the second Bangladesh trial and the effects on svr stability,  which was better than interferon.

[StephenCastlecrag]

SciClone is a relatively small company but it is listed on Nasdaq. In recent years, it has a strong focus on marketing Zadaxin in China for HBV. Recently it entered a settlement agreement with the  "United States Securities and Exchange Commission (SEC) fully resolving the SEC's investigation into possible violations of the Foreign Corrupt Practices Act (FCPA)."  
It has always been a surprise to me why Zadaxin is used in Replicor's clinical trials.

[studyforhope]

It might have been some outside hepatitis expert. It surely led to surprising success. There is a huge difference between a year on thymosin and a year on peg ifn in terms of side effects. If it were not for the fact that Pegasys is approved in Europe and the USA and projects hope for much easier marketability,  they would use thymosin as their main immunstimulatory component.

[stef2011]

it doesn t work but when hbsag is unde or less than 1iu/ml works

it would be good to know if it can help also for hbsag less than 1000iu/ml when on tdf since 6 years, although very expensive i d use it if there was any data it can help in these cases but all trials i have seen it did n t work

[sorte]

Good to know that thymosin alpha has no sides. I'm on interferon now and I don't worry about temp sides but rather long term ones in case I'd have to repeat it in a few years.
Btw, so why thymosin alpha is not used as monotherapy or with nucs ?

[studyforhope]

6 month of follow up is barely enough to confirm a stable svr.

I do not b think that any agency will give approval based on 12 patients. They will, for hdv, negotiate a registration trial design with replicor.

BTW the current trial in Moldavia was NOT DESIGNED to achieve a functional cure. It's pupose was to show that  the nap component was independently causing a strong, objective positive effect, BEFORE the interferon overlap.

The new trial, starting now is designed to achieve a functional cure in the hope that a full year of naps plus a simultaneous interferon or thymosin alpha treatment, all combined with TDF and  with a TDF pretreatment period of 6 month,  will achieve hbsag seroconversion in a high percentage of patients.

Those will be e neg patients again, but without hdv.

What is most fascinating is the thymosin alpha arm, since this has almost no side effects compared with interferon and seemed more promising in the second Bangladesh trial than interferon.

[sorte]

So it's 15 weeks on peginf left and than 6 months of observation ?

[sorte]

Small trial is for orphan drugs I think, fast track is:

http://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm

I wonder if hdv drug has chance for that procedure ?

[studyforhope]

First one needs to await the stability of the HDV CLEARANCE after stopping the treatment. This can only be judged after at least 6 month of follow up.Currently it seems plausible that 5 out of the 11 fully treated patients might have a true SVR for hdv and hbv. But even in these cases we will need to wait and see.

If it is possible  that the currently hdv neg patients that are not expected to stably seroconvert the hbsag will still have selectively lost hdv remains to be seen. It is unlikely and would represent a true sensation if possible.

[stef2011]

i dont know fast track. is it requiring little money and small trials for approval?

[sorte]

I don't think so cure for hdv may be treated as orphan drug, because it's a lof of people infected to test on. I think we should aim for fast track procedure.

[stef2011]

i am not expert on those website but we just need to put out a text for hdv that  can have orphan drug approval and then mention this drug can cure hbv too

of course they cannot split hdv from hbv and orphan drug can be achieved anyway

we can also mention that this cure will cut many drug makers income from antivirals so it needs to be pushed by us

[needadvicewithhep]

Stef and Stephen What do you think of Mer971 suggestion?

Just to play devils advocate for a moment.

Why do a petition whilst Replicor are clearly moving forward with their trials?

I'll sign your petition if you put one together guys.

[StephenCastlecrag]

One or all of us can draft a petition. I will support any effort and will do my best to channel information to and seek support from the Chinese Hepatitis B forum. It will not be easy but not impossible.

[sorte]

I haven't checked those sites yet, but it would be important feature that petition would have language versions, most of hbv infected people are non english speakers I guess.

[Aduiski]

good point

[mer971]

I think that this petition should start from one of us, people who are doctors or have the knowledge of virus as steff or stephan, they know how to write and explain in medical language.
We all will support it