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Replicors presentation at the aasld2015
Update on the safety and efficacy of REP 2139 mono-therapy and subsequent combination therapy with pegylated interferon alpha-2a in chronic HBV / HDV co-infection in Caucasian patients
Michel Bazinet1, Victor Pantea2, Valentin Cebotarescu2, Lilia Cojuhari3, Paulina Jimbei3, Jeffrey Albrecht4, Peter Schmid4, Hadi Karimzadeh5, Michael Roggendorf5, Andrew Vaillant1;
1Replicor Inc., Montreal, QC, Canada; 2N. Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova (the Republic of); 3Toma Ciorba Infectious Clinical Hospital, Chisinau, Moldova (the Republic of); 4National Genetics Institute, Los Angeles, CA; 5Institure of Virololgy, Technische Universität München, Munich, Germany
Introduction: HBV / HDV co-infection causes rapid progression of liver disease and with no approved therapy, presents a significant unmet medical need. Nucleic acid polymers (NAPs) block HBV subviral particle assembly and release from infected hepatocytes and can eliminate serum HBsAg. As the NAP REP 2139 was previously been shown to clear serum HBsAg and improve the ability of immunotherapy to elicit SVR in Asian patients with HBV, its activity in combination with Pegasys® in HBV / HDV co-infected Caucasian patients is currently being examined. Methods: In a phase II proof of concept trial (REP 301; NCT02233075), patients with chronic HBV / HDV co-infection received once weekly dosing of 500mg REP 2139-Ca (calcium chelate complex) by 2h IV infusion for 15 weeks, followed by 15 weeks of combined therapy with 250mg REP 2139-Ca and 1 80ug Pegasys® and then 33 weeks with Pegasys® monotherapy. Viremia (HDV RNA and HBV DNA), HBsAg and anti-HBs are followed every two weeks (Robogene RT-PCR, Abbott RealTime HBV, Abbott Architect) performed at the Institute of Virology, University of Duisburg-Essen (Essen, Germany). HDV RNA is validated on separate test platforms at the National Genetics Institute (Los Angeles, USA) and the Institute of Virology, Technische Universität München (Munich, Germany). Results: REP 2139-Ca treatment is well tolerated with mild and quickly resolving IV infusion reactions. Serum HBsAg is currently reduced 1-6 log in 11/12 patients (5 with serum HBsAg < 1 IU / ml) and HDV RNA is currently reduced 1.5-7 log in 12/12 patients (undetectable in 6 patients). Anti-HBs is detected in 10/12 patients, with 6 patients 800 mIU / ml. In all patients with pre-treatment HBV DNA < 10 IU / ml, de-repression of serum HBV DNA is observed. Conclusions: Updated interim data from the REP 301 protocol assessing the safety and antiviral efficacy of REP 2139 (first in monotherapy and then with add on Pegasys® at week 1 6) in 12 Caucasian patients with chronic HBV / HDV co-infection demonstrated substantial reductions in serum HBsAg and HDV RNA as well as appearance of anti-HBs. HDV RNA reductions appear stronger than HBsAg reductions, suggesting an additional antiviral mechanism other than the inhibition of subviral particle assembly may affect HDV directly. REP 2139-Ca may become an important new therapeutic option for patients with chronic HBV / HDV infection.
Michel Bazinet1, Victor Pantea2, Valentin Cebotarescu2, Lilia Cojuhari3, Paulina Jimbei3, Jeffrey Albrecht4, Peter Schmid4, Hadi Karimzadeh5, Michael Roggendorf5, Andrew Vaillant1;
1Replicor Inc., Montreal, QC, Canada; 2N. Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova (the Republic of); 3Toma Ciorba Infectious Clinical Hospital, Chisinau, Moldova (the Republic of); 4National Genetics Institute, Los Angeles, CA; 5Institure of Virololgy, Technische Universität München, Munich, Germany
Introduction: HBV / HDV co-infection causes rapid progression of liver disease and with no approved therapy, presents a significant unmet medical need. Nucleic acid polymers (NAPs) block HBV subviral particle assembly and release from infected hepatocytes and can eliminate serum HBsAg. As the NAP REP 2139 was previously been shown to clear serum HBsAg and improve the ability of immunotherapy to elicit SVR in Asian patients with HBV, its activity in combination with Pegasys® in HBV / HDV co-infected Caucasian patients is currently being examined. Methods: In a phase II proof of concept trial (REP 301; NCT02233075), patients with chronic HBV / HDV co-infection received once weekly dosing of 500mg REP 2139-Ca (calcium chelate complex) by 2h IV infusion for 15 weeks, followed by 15 weeks of combined therapy with 250mg REP 2139-Ca and 1 80ug Pegasys® and then 33 weeks with Pegasys® monotherapy. Viremia (HDV RNA and HBV DNA), HBsAg and anti-HBs are followed every two weeks (Robogene RT-PCR, Abbott RealTime HBV, Abbott Architect) performed at the Institute of Virology, University of Duisburg-Essen (Essen, Germany). HDV RNA is validated on separate test platforms at the National Genetics Institute (Los Angeles, USA) and the Institute of Virology, Technische Universität München (Munich, Germany). Results: REP 2139-Ca treatment is well tolerated with mild and quickly resolving IV infusion reactions. Serum HBsAg is currently reduced 1-6 log in 11/12 patients (5 with serum HBsAg < 1 IU / ml) and HDV RNA is currently reduced 1.5-7 log in 12/12 patients (undetectable in 6 patients). Anti-HBs is detected in 10/12 patients, with 6 patients 800 mIU / ml. In all patients with pre-treatment HBV DNA < 10 IU / ml, de-repression of serum HBV DNA is observed. Conclusions: Updated interim data from the REP 301 protocol assessing the safety and antiviral efficacy of REP 2139 (first in monotherapy and then with add on Pegasys® at week 1 6) in 12 Caucasian patients with chronic HBV / HDV co-infection demonstrated substantial reductions in serum HBsAg and HDV RNA as well as appearance of anti-HBs. HDV RNA reductions appear stronger than HBsAg reductions, suggesting an additional antiviral mechanism other than the inhibition of subviral particle assembly may affect HDV directly. REP 2139-Ca may become an important new therapeutic option for patients with chronic HBV / HDV infection.
They pretreat with tenofovir for 6 month, then 12 month triple combo. If recruiting takes about 6 month you have a completed start date mid 2016. Then the treatment phase will be ending 2017, in the fall. After that, a waiting period of 12 month is required to see if the seroconversions that were achieved, will be stable for at least 12 month. Thus the real important trial results will be available towards the end of 2018.Or mid 2018 if recruitment is really fast.
Remember a non stable seroconversion is worthless in the end. Many factors will determine if it will be stable in a particular patient. Viral resurgence after stopping tdf, hbsag suppression and immune stimulation will take some time and more permanent internal mechanisms will have to take over to permanently keep the remnant infection at a very small level.
Remember a non stable seroconversion is worthless in the end. Many factors will determine if it will be stable in a particular patient. Viral resurgence after stopping tdf, hbsag suppression and immune stimulation will take some time and more permanent internal mechanisms will have to take over to permanently keep the remnant infection at a very small level.
found it https://clinicaltrials.gov/ct2/show/NCT02565719?term=Replicor&rank=1
Looks very good, they attack HBV from many directions and 60 people is a decent group. But why est primary completion date is so late, apr 2018 ?
Looks very good, they attack HBV from many directions and 60 people is a decent group. But why est primary completion date is so late, apr 2018 ?
It is an fda registered phase II trial, you can find the details on the fda.gov website. 60 patients are planned.
do you think they will start again from Phase I and small group or it will be Phase II and some more people ?
The start of the next trial was announced to be very soon. It will involve new and some old nap together with peg or thymosin alpha and tenofovir from the start and for a full year.
Thank you so much for the explanation so basically we still years behind a functional cure
These results are already many weeks old, due to the abstract submission deadline. The treatment is continuing for several month and it can be expected that the results will further improve.
the design of this stydy was obviously not optimized for therapeutic effect, but to demonstrate first the power of 2139 independent from interferon.
while it has quite dramatic effects on hbsag secretion and shows the resulting improvement in immunological balance as a result of that, it became also clear that the lasting effects of monotherapy are very limited. Interferon or thymosin alpha combo is needed to drive the antibody production up, lead to a much greater reduction of infected cells and lead to a long term stabilization after ending drug dosing.
This combo in itself needs to be further optimized, and for the more immunadapted portion of patients a therapeutic vaccine or even birinapant might be necessary to achieve a lasting result.
the next trials will most likely use a full year of combo therapy from the start. They will also use tenofovir as third drug from the beginning, however it is unclear if this is beneficial or rather harmful for the long term svr rates.
In summary it can be said that any serious cure attempt will need the naps as a component.All the other attempts to reduce hbsag like the interfering RNA companies are pursuing pale in comparison to the naps. It also shows that the mere reduction of hbsag to close to und is not sufficient to achieve the famous functional cure and a powerful immune enhancement is needed in addition and in many cases even more will be required.
the design of this stydy was obviously not optimized for therapeutic effect, but to demonstrate first the power of 2139 independent from interferon.
while it has quite dramatic effects on hbsag secretion and shows the resulting improvement in immunological balance as a result of that, it became also clear that the lasting effects of monotherapy are very limited. Interferon or thymosin alpha combo is needed to drive the antibody production up, lead to a much greater reduction of infected cells and lead to a long term stabilization after ending drug dosing.
This combo in itself needs to be further optimized, and for the more immunadapted portion of patients a therapeutic vaccine or even birinapant might be necessary to achieve a lasting result.
the next trials will most likely use a full year of combo therapy from the start. They will also use tenofovir as third drug from the beginning, however it is unclear if this is beneficial or rather harmful for the long term svr rates.
In summary it can be said that any serious cure attempt will need the naps as a component.All the other attempts to reduce hbsag like the interfering RNA companies are pursuing pale in comparison to the naps. It also shows that the mere reduction of hbsag to close to und is not sufficient to achieve the famous functional cure and a powerful immune enhancement is needed in addition and in many cases even more will be required.
hbv+hdv study is made on HBe- patients.
It looks like 6 patiens obtained seroconversion, hbs < 1IU and some antibodies, but I suppose we need to wait at least 6 month to see if it will be sustained.
It looks like 6 patiens obtained seroconversion, hbs < 1IU and some antibodies, but I suppose we need to wait at least 6 month to see if it will be sustained.
Please give us your brilliant minds view on Relicor. Any thoughts vs HbeAg positive or negative, or are they only testing HbeAg negative for now? Thank you.
So studyforhope does that mean that rep 2139 will not cure hbv? Interesting as they say "hdv rna reduction appear stronger than hbsag reductions". Then they say "rep 2139 may become an important new therapeutic option ..." So just another medication like tenefovir etc... But not cure?
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"as well as appearance of anti-HBs" y u omited this line?
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