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AASLD 2012: REP9AC'
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AASLD 2012: REP9AC'

CONTROL ID: 1420385
PRESENTATION TYPE: Poster Only
CURRENT CATEGORY: Hepatitis B CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
TITLE: REP 9AC’: A second generation HBsAg release inhibitor with improved tolerability.
AUTHORS (FIRST NAME, LAST NAME): Mamun A. Mahtab2, Michel Bazinet1, Andrew Vaillant1
Institutional Author(s): INSTITUTIONS (ALL): 1. REPLICor Inc., Montreal, QC, Canada.
2. Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.

ABSTRACT BODY: BACKGROUND: HBsAg mediated suppression of the immune system and permits the chronicity of HBV infection. NAPs inhibit HBsAg release from infected hepatocytes. The first generation NAP, REP 9AC, rapidly cleared serum HBsAg in infected patients and allowed recovery of durable immunological control over HBV infection. REP 9AC’ is a second generation nucleic acid-based amphipathic polymer (NAP) with improved tolerability. An updated progress report of the ongoing phase I/II study on the safety and efficacy of REP 9AC’ in combination with the immunotherapeutic agents Zadaxin ™ and Pegasys ™ in patients with chronic HBV infection is presented.
METHODS: All patients were, HBsAg+ with pre-treatment HBV DNA titers between 10^6 and 10^9 copies/ml. Patients recieved parenteral REP 9AC’ therapy with addon therapy of either thymosin α1 (Zadaxin™) or pegylated interferon 2α (Pegasys™) after effective clearance of serum HBsAg. Safety and virologic response (HBV DNA [Roche Cobas™], HBsAg, anti-HBs [Architect™]) were assessed regularily during treatment.
RESULTS: At the time of abstract submission, 10 out of 12 patients treated have effectively cleared serum HBsAg and anti-HBsAg antibodies have been observed in all these patients. Immunological recovery is evidenced in these patients by a 2.5 to 7 log reduction in their HBV DNA titers from pre-treatment levels after 20-30 weeks of treatment (see figure). Co-treatment with either Zadaxin ™ or Pegasys ™ has been initiated to monitor how the absence of HBsAg may potentiate the effectiveness of these cytokines in human patients.
CONCLUSIONS: REP 9AC’ can rapidly and effectively clear HBsAg from the serum of infected patients and allow the restoration of an effective immune response, as evidenced by substantial reductions in serum HBV DNA. Combination treatment with immunotheraptic cytokines may enhance the immunological recovery in these patients and lead to a permanent control of HBV infection.

Tags: REP9AC, Replicor
18 Comments Post a Comment
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Avatar_m_tn
What phase number is this stephen? Are we going to see results of larger trials or not? And final thing i dont understand why when a drug like REP 9AC shows this high efficacy in clearing hbsag does not enter the market without going through never ending phase 2 and 3??
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Avatar_m_tn
It is phase I/II.  I wish I know the answers to your other questions. Please bear in mind, it costs a lot of money to conduct phase 2 and 2 trials, and the outcomes are not predictable.
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Avatar_m_tn
25 September 2012, Oxford, England.



Montreal, Quebec – Tuesday , September 25, 2012 – REPLICor is currently undertaking a proof of concept trial in patients with chronic hepatitis B (HBV) undergoing treatment with its nucleic acid polymer (NAP) REP 9AC’ in combination with Zadaxin™ or Pegasys™.  The hepatitis B surface antigen protein (HBsAg) is produced in large excess by the HBV infection as subviral particles (SVPs) which act to block the immune response to HBV infection.  NAPs act to block the release of SVPs from infected hepatocytes, providing an effective method for clearing HBsAg from the blood.  The elimination of HBsAg in the blood of HBV-infected patients is well known to be the best indicator of a curative response to treatment.



Interim results from REPLICor’s proof of concept trial were disclosed today at the 2012 held at the University of Oxford Christ Church and Examination Schools, Oxford, England.  Patients who had cleared HBsAg from their blood with REP 9AC’ monotherapy were subjected to combination treatment with REP 9AC’ and either Pegasys™ or Zadaxin™.  Profound increases in anti-HBV antibodies or immune function were observed in all patients with as few as 6-10 weeks of combination treatment.  Many patients have achieved HBV antibody levels seen in healthy patients after vaccination with a total of 12 weeks of combination treatment. All patients who have achieved this therapeutic vaccine-like response have been removed from treatment and continue to control their viral infections off treatment. The remainder of patients are expected to achieve full immunological control of their infection in the coming weeks.   REPLICor expects that the profound reactivation of a therapeutically effective immune response with short term Zadaxin™ or Pegasys™ treatment given in combination with its HBsAg release inhibitor REP 9AC’ can achieve durable immunological in most patients, regardless of viral genotype or state of their HBV infection.
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Avatar_m_tn
Lets all hope that this comes to fruition real quick. Does look like a cure for this virus. Heres hoping :-)
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Avatar_m_tn
Was this a press release or a presentation at the meeting on Molecular biology of Hepatitis B viruses?
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Avatar_m_tn
press release

http://www.replicor.com/debut_anglais2.htm

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Avatar_m_tn
Thanks - difficult to find as it is not in the English version of the website.
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Avatar_m_tn
it is :) .. go on the news section and look at the September 25, 2012 news.
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Avatar_m_tn
It was in the French section.
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Avatar_m_tn
This is the abstract directly from the abstract book of the AASLD 2012 in boston, not from the website.:
CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
TITLE: REP 9AC’: A second generation HBsAg release inhibitor with improved tolerability.

AUTHORS (FIRST NAME, LAST NAME): Mamun A. Mahtab2, Michel Bazinet1, Andrew Vaillant1
Institutional Author(s):  
INSTITUTIONS (ALL): 1. REPLICor Inc., Montreal, QC, Canada.
2. Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.

ABSTRACT BODY: BACKGROUND: HBsAg mediated suppression of the immune system and permits the chronicity of HBV infection. NAPs inhibit HBsAg release from infected hepatocytes. The first generation NAP, REP 9AC, rapidly cleared serum HBsAg in infected patients and allowed recovery of durable immunological control over HBV infection. REP 9AC’ is a second generation nucleic acid-based amphipathic polymer (NAP) with improved tolerability. An updated progress report of the ongoing phase I/II study on the safety and efficacy of REP 9AC’ in combination with the immunotherapeutic agents Zadaxin ™ and Pegasys ™ in patients with chronic HBV infection is presented.
METHODS: All patients were, HBsAg+ with pre-treatment HBV DNA titers between 10^6 and 10^9 copies/ml. Patients recieved parenteral REP 9AC’ therapy with addon therapy of either thymosin α1 (Zadaxin™) or pegylated interferon 2α (Pegasys™) after effective clearance of serum HBsAg. Safety and virologic response (HBV DNA [Roche Cobas™], HBsAg, anti-HBs [Architect™]) were assessed regularily during treatment.
RESULTS: At the time of abstract submission, 10 out of 12 patients treated have effectively cleared serum HBsAg and anti-HBsAg antibodies have been observed in all these patients. Immunological recovery is evidenced in these patients by a 2.5 to 7 log reduction in their HBV DNA titers from pre-treatment levels after 20-30 weeks of treatment (see figure). Co-treatment with either Zadaxin ™ or Pegasys ™ has been initiated to monitor how the absence of HBsAg may potentiate the effectiveness of these cytokines in human patients.
CONCLUSIONS: REP 9AC’ can rapidly and effectively clear HBsAg from the serum of infected patients and allow the restoration of an effective immune response, as evidenced by substantial reductions in serum HBV DNA. Combination treatment with immunotheraptic cytokines may enhance the immunological recovery in these patients and lead to a permanent control of HBV infection.
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Avatar_m_tn
So this was exactly the same as Stephencastlecrag has posted in the beginning of this thread . It seems that the abstract presented at the Molecular Biology of hepatitis B meeting in Oxford was slightly later/more up to date  than this one, since it mentions the discontinuation of the drug in antibody positive patients.
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Avatar_m_tn
As regard to REP9AC, have they changed the method of delivering the drug? Is it now by injection or still by infusion? I just wonder because their period of treatment seems to have increased quite significantly?

Have you had a chance to read the abstract from the Australian research team on TDF and QHbsAg? It seems to report that qHBsAg continues to decline with continued use of TDF! Your thoughts on this observation, please.
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Avatar_m_tn
Rep9ac' is still delivered by infusion. It seems from discussions at the conference that they ultimately aim at developing an infusion free regimen to make the treatment available in a more practical and less expensive way.

The reductions in quant surface antigen with ongoing TDf treatment are interesting, but overall  still of disappointing magnitude. A continuation downwards after several more years in most patients towards seroconversion is IMO unlikely.

there was a second abstract relating to the same TDF/surface antigen question. here are both of them:

TITLE: Quantitative HBsAg Titers in a Multi-Drug Resistance Chronic Hepatitis B cohort on Tenofovir Disoproxil Fumarate Rescue Therapy

AUTHORS (FIRST NAME, LAST NAME): Lucy Y. Lim1, 2, Scott Patterson1, Rachel Hammond2, James M. Trauer1, Nadia Warner2, Jacob George3, Simone I. Strasser4, Alice U. Lee5, William Sievert6, Amanda J. Nicoll7, Stuart K. Roberts8, Paul V. Desmond9, Scott Bowden2, Alexander J. Thompson2, 9, Stephen Locarnini2, Peter W. Angus1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Gastroenterology and Liver Transplant Unit, Austin Hospital, Melbourne, VIC, Australia.
2. Molecular Research and Development, VIDRL, Melbourne, VIC, Australia.
3. Gastroenterology and Hepatology, Westmeade, Sydney, NSW, Australia.
4. AW Morrow Gastroenterology and Liver Centre, RPA, Sydney, NSW, Australia.
5. Gastroenterology, Concord, Sydney, NSW, Australia.
6. Gastroenterology, Monash Medical Centre, Melbourne, VIC, Australia.
7. Gastroenterology, RMH, Melbourne, VIC, Australia.
8. Gastroenterology, The Alfred, Melbourne, VIC, Australia.
9. Gastroenterology, St Vincent's, Melbourne, VIC, Australia.
ABSTRACT BODY: Background: In CHB patients, quantitative hepatitis B surface antigen (QHBsAg) have recently been associated with predicting response to peg-interferon-alfa, including HBsAg seroconversion (SC) & loss or decline. Long-term nucleos(t)ide analogues (NA) suppresses HBV replication in the majority of patients, however very few actually undergo HBsAg SC. The utility of QHBsAg analysis in these patients is poorly understood & the impact of multi-drug resistant (MDR) variants has not been explored.
Aim: To evaluate the QHBsAg decline in a well-characterized cohort of patients with MDR (rtA181T/V) HBV who were treated with >7years with multiple NA, including at least 3 years of tenofovir (TDF).
Methods: TDF109 was an investigator-initiated, prospective, multi-centre, open-label study of the efficacy of TDF rescue therapy in 60 patients who had previously failed lamivudine (LAM) & subsequent adefovir (ADV) add-on or switch therapy. We have previously presented virological outcome at 2 years (Patterson, Gut 2011). All patients have been maintained on TDF in long-term follow-up, now out to 4 years. QHBsAg titers were retrospectively quantified at baseline & every 6 months, expressed as IU/ml (Roche Elecsys). Sub-analysis according to baseline viral load & the type of HBV resistance-associated substitutions present at baseline was then performed.
Results: At baseline, median QHBsAg titer was 5226IU/ml. Baseline QHBsAg positively correlated with HBV DNA levels at baseline, (R = 0.33, p=0.0168). There was a trend for higher baseline QHBsAg levels in HBeAg positive patients (p=0.13). The median HBsAg titers were 2772IU/ml, 2284IU/ml &1819IU/ml at year 1, 2&3 respectively (P<0.0001 for comparison of baseline to year 3). Patients with detectable rtA181T/V variants have a lower QHBsAg at baseline, but more gradual decline in QHBsAg (p=0.002). There was a trend for patients with no detectable resistance changes or LAM resistance HBV Pol at baseline, to have higher baseline QHBsAg, but higher rate of decline in QHBsAg (table).
Conclusion: QHBsAg significantly declined over time achieving QHBsAg <1500 IU/ml in the majority of patients by 3 years, nearing that of the key viral biomarkers of non-replicative CHB. Due to the high genetic barrier of TDF, ongoing therapy would be expected to achieve even lower levels of QHBsAg.
Variables Number %
(Total n=59) Median QHBsAg at Baseline Median QHBsAg at Year 1 Median QHBsAg at Year 2 Median QHBsAg at Year 3 P-value (baseline – year 3)
HBeAg Positive 66% (39/59) 8759
Note n = 35 3032 3450 3138 0.0027
HBeAg Negative 34%
20/59 3893
Note n = 17 1900 1730 1289 0.0008
Resistance Changes None Detected 25% (15) 15855 7768 5632 4400 0.0027 (n=12)
L-Nucleoside (LAM/LdT)
M204I/V 35% (21) 7462 2225 3450 2433 0.0531 (n=14)
Acyclic phosphonate (ADV)
N236T 8% (5) 3912 1530 862 1140 0.5468 (n=2)
181 Containing (LAM/LdT/ADV/TFV)
A181T/V +/-N236T 30% (18) 2992 2344 1664 1537 0.0020 (n=16)


TITLE: Decline in Serum HBV DNA Levels More Accurately Predict Seroconversion During Tenofovir Therapy Than Hepatitis B Surface Antigen Levels in HBeAg Positive Patients with Chronic Hepatitis B

AUTHORS (FIRST NAME, LAST NAME): Avishek K. Singh1, Manoj Kumar2, Syed Hissar1, Ekta Gupta3, Shiv K. Sarin1, 2
Institutional Author(s):
INSTITUTIONS (ALL): 1. Research, Institute of Liver and Biliary Sciences, New Delhi, India.
2. Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
3. Virology, Institute of Liver and Biliary Sciences, New Delhi, India.
ABSTRACT BODY: BACKGROUND: The role of measuring hepatitis B surface antigen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial. AIM: The aim of this study was to determine the HBsAg and HBV DNA response in chronic hepatitis B patients treated with tenofovir 300 mg daily. PATIENTS AND METHODS: A total of 121 patients were studied. Tests of liver functions, quantitative HBV DNA and HBsAg (qHBsAg) levels were performed at baseline, week 4, 12, 24, 48, 96, 144, 192, and240 after commencing tenofovir. RESULTS: Sixty seven (%) patients were HBeAg positive. The median (range) of follow-up was 144 (24-260) wk. During tenofovir therapy, though there was an overall decline, only 1/3rd patients had a significant decline in qHBsAg levels (i.e. ≤0.5 log from baseline), and this was independent of ALT levels (Fig). HBeAg seroconversion (loss of HBeAg and appearance of anti-HBe) occurred in 20 of 67(29.9%) of HBeAg positive patients. HBsAg level decline from baseline at week 4, 12 or any time subsequently did not correlate with HBeAg seroconversion. Decline in HBV DNA at week 4 and 12 (OR =3.704; 95% CI=1.511-9.076; P=0.006 and OR =1.732; 95% CI=1.032- 2.867; P=0.037, respectively) from baseline were significantly predictive of subsequent seroconversion. In fact, patients who had ≥ 2.5 log decline in HBV DNA at 4 week from baseline had higher chance of achieving seroconversion subsequently, as compared to patients who had lesser decline (OR=11.0). Decline in quantitative HBsAg levels during Tenofovir treatment in patients with normal vs. raised baseline ALT (p=ns). CONCLUSION: In patients treated with tenofovir, majority do not exhibit a significant decline in HBsAg levels and this decline does not correlate with HBeAg seroconversion or DNA negativity in HBeAg negative patients. Reduction in HBV DNA levels at week 4 correlate best with e antigen seroconversion


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Avatar_m_tn
Thanks. I was wondering, in the Australian study, the total number of years of NA treatment is > 7 in the cohort studied, I wonder whether this is an important factor in the different results reported? Also, the Indian study would have mainly consisted of genotype D, I presume. Would that make a difference?
It would be nice to think that if after a prolonged period of NA treatment, qHBsAg can be reduced to the magic level of < 1500 iu/ml.
On the whole, the coming AASLD meeting seems to have no major breakthrough in the treatment of Hepatitis B.
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Avatar_m_tn
If you wonder what long term TDf can do in terms of surface antigen loss, here is the largest and longest cohort study, that contains the answer to this question.

After six years of TDf treatment 11% of patients lost HbsAg.  This does not automatically mean  that after 12 years 22% will have lost the surface antigen. It is actually rather unlikley, since the critical factors, like adaption of the HBV variants in individual patients to the remnant immune pressure will put a limit to this end point.

See also the abstract on the dependence of surface antigen loss on baseline variation width of HBV.

TITLE: Six Years of Treatment with Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated with Sustained Virological, Biochemical and Serological Responses with no Detectable Resistance

AUTHORS (FIRST NAME, LAST NAME): Patrick Marcellin1, Maria Buti2, Edward J. Gane3, Naoky Tsai4, William Sievert5, Ira M. Jacobson6, George Germanidis7, John F. Flaherty8, Phillip Dinh8, Kathryn M. Kitrinos8, John G. McHutchison8, Nezam Afdhal9
Institutional Author(s):  
INSTITUTIONS (ALL): 1. Hôpital Beaujon, Clichy, France.
2. Hospital General Universitari Vall d’Hebron and Ciberehd, Barcelona, Spain.
3. Auckland City Hospital, Auckland, New Zealand.
4. University of Hawaii at Manoa, Honolulu, CA, United States.
5. Monash University and Monash Medical Centre, Melbourne, VIC, Australia.
6. Weill Cornell Medical College, New York, NY, United States.
7. AHEPA University Hospital, Aristotle University Medical School, Thessaloniki, Greece.
8. Gilead Sciences, Foster City, CA, United States.
9. Beth Israel Deaconess Medical Center, Boston, MA, United States.

ABSTRACT BODY: Background:
We previously reported that 5 years of tenofovir DF (TDF) therapy in mostly treatment naïve patients results in sustained virological suppression with no development of resistance and was associated with either the halting or regression of fibrosis in 96% of patients. Here we present 6 year results from these two ongoing 8 year studies (Studies 102 and 103).
Methods:
After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, all patients undergoing liver biopsy were eligible to continue open-label TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance; annual assessments of bone mineral density (BMD) of the spine and hip by DXA were added starting at year 4.
Results:
In a total 641 patients who were initially randomized and treated, 585 (93%) entered the TDF extension phase, and at Year 6, 466 (73%) remain on study. Efficacy results at Year 6 are shown in the table. TDF was well tolerated over the 6 year evaluation period. Less than 2% of patients discontinued TDF due to an adverse event, and ≤1.5% experienced a confirmed renal event (≥0.5 mg/dL increase in serum creatinine from baseline, phosphorus <2 mg/dL, or CrCL <50 mL/min). BMD (T scores) was stable over 2 years of evaluation. No resistance to TDF has been detected through Year 6.
Conclusions:
In these two trials, TDF remains safe and effective over a 6 year treatment period, with no detectable resistance to TDF; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed.




  HBeAg-negative Patients
(Study 102)
N=375  HBeAg-positive Patients
(Study 103)
N=266  
HBV DNA <400 copies/mLa  81% (281/345)  62% (157/251)  
HBV DNA <400 copies/mLb  99.6% (283/284)  99% (167/169)  
ALT normalizationb  86% (228/265)  78% (127/162)  
HBeAg lossb  -  50% (82/163)  
HBeAg seroconversionb  -  37% (61/163)  
HBsAg lossc  -d  11% (n=24)  
HBsAg seroconversionc  -d  8% (n=18)  
aMissing=Failure (LTE-TDF analysis set); bMissing=Excluded (On treatment analysis set); cKaplan-Meier %;dOne HBeAg-negative patient experienced HBsAg loss/seroconversion at Year 5
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Avatar_m_tn
I missed that one. It is very encouraging for those on TDF. I agree that HBsAg seroconversion will remain low, but achieving truly inactive status with qHbsAg < 1500 iu/ml may still be a possibility for the majority, I hope.
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Avatar_m_tn
We all need to write to Repicor  so they go public with their achievement. And start giving it to people.

We need this drug right there. And it is time to remind the company that the time has come to do something really good for humanity. Just start giving the drug to people.

The results are great and something that we have known.

But the big issue is money now and  bureaucracy that comes around approving cures.  
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Avatar_m_tn
Hi All,

Do we know if this medicine can give us hopes still. For cure or treat?
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