Aa
Myrcludex B - Phase 2a clinical trial
Final ID: LB-20
A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B
S. Urban; 2; P. Bogomolov; 4; N. Voronkova; 4; L. Allweiss; 3; M. Dandri; 3; M. Schwab; 6, 7; F. A. Lempp; 2; M.
Haag; 6; H. Wedemeyer; 5; A. Alexandrov; 1;
1. MYR GmbH, Bad Homburg, Germany.
2. University Hospital Heidelberg, Heidelberg, Germany.
3. University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4. Moscow Regional Research Clinical Institute, Moscow, Russian Federation.
5. Hannover Medical School, Hannover, Germany.
6. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
7. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
Abstract Body: Introduction: Current therapies for chronic hepatitis B rarely induce cure. Moreover, no effective treatment for the majority of hepatitis D patients is available. Myrcludex B is a first-in-class entry inhibitor inactivating the HBV/HDV receptor NTCP, thereby addressing a replication step possibly required for curative therapy. We here present findings of the first clinical trials of Myrcludex B in chronic hepatitis B and D.
Aim: To evaluate safety and tolerability, as well as antiviral efficacy of Myrcludex B.
Methodology: Cohort A: 40 chronically HBV infected, HBeAg negative patients (all HBV DNA >2000 IU/ml median HBV DNA 4.7 log10 IU/ml; no cirrhosis) were treated for 12 weeks with once daily sc 0.5mg, 1mg, 2mg, 5mg and 10mg Myrcludex B for 12 weeks (8 patients per dose). Treatment was extended to 24 weeks in patients receiving 10mg. Cohort B: 24 patients with hepatitis delta (compensated liver disease; 12.5% cirrhosis) scheduled for 48 weeks
of pegylated interferon alpha (PEG-IFNα) therapy. 8 hepatitis delta patients are receiving pre-treatment with 2mg Myrcludex B alone for 24 weeks (B1); Myrcludex B was added to (PEG-IFNa) for the first 24 weeks to another 8 patients (B2) while 8 patients are treated with PEG-IFNa alone (B3).
Results:
Myrcludex B was very well tolerated, injection side dermatitis occurred in 3 patients (10mg group) of Myrcludex B, regressed on treatment. A psoriasis exacerbation occurred in one HDV patient (B2) leading to discontinuation.
>1log10 HBV DNA decline at week 12 was observed in 6/8 (75%) patients receiving 10mg Myrcludex B while this occurred less often in the remaining dose groups (7/40; 17%). ALT normalized in 22/40 (55%) patients, median ALT values declined from 76 U/l before therapy to 36 U/l at week 12 (p1log10 HDV RNA decline at week 24 during Myrcludex B monotherapy (B1) or combination therapy (B2) while this response was observed in 7/7 of B3 patients at week 12. HDV RNA became negative in 2 (B1) and 5 (B2) patients at week 24. ALT values declined at week 24 in 6/7 (B1), 4/7 (B2) and 3/7 (B3, week 12) patients. One patient in B1 and one in B2 had negative HDV RNA and normal ALT at week 24. One patient (B2) experienced 1log10 HBsAg decline at week 24. Myrcludex B treatment induced preS-specific antibodies and bile acid elevation at doses >1mg.
Conclusion: Myrcludex B is safe and well tolerated in HBsAg positive patients with or without HDV coinfection. HBV entry inhibition seems to be associated HBV DNA and HDV RNA declines and improvement of biochemical disease activity.
A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B
S. Urban; 2; P. Bogomolov; 4; N. Voronkova; 4; L. Allweiss; 3; M. Dandri; 3; M. Schwab; 6, 7; F. A. Lempp; 2; M.
Haag; 6; H. Wedemeyer; 5; A. Alexandrov; 1;
1. MYR GmbH, Bad Homburg, Germany.
2. University Hospital Heidelberg, Heidelberg, Germany.
3. University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4. Moscow Regional Research Clinical Institute, Moscow, Russian Federation.
5. Hannover Medical School, Hannover, Germany.
6. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
7. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
Abstract Body: Introduction: Current therapies for chronic hepatitis B rarely induce cure. Moreover, no effective treatment for the majority of hepatitis D patients is available. Myrcludex B is a first-in-class entry inhibitor inactivating the HBV/HDV receptor NTCP, thereby addressing a replication step possibly required for curative therapy. We here present findings of the first clinical trials of Myrcludex B in chronic hepatitis B and D.
Aim: To evaluate safety and tolerability, as well as antiviral efficacy of Myrcludex B.
Methodology: Cohort A: 40 chronically HBV infected, HBeAg negative patients (all HBV DNA >2000 IU/ml median HBV DNA 4.7 log10 IU/ml; no cirrhosis) were treated for 12 weeks with once daily sc 0.5mg, 1mg, 2mg, 5mg and 10mg Myrcludex B for 12 weeks (8 patients per dose). Treatment was extended to 24 weeks in patients receiving 10mg. Cohort B: 24 patients with hepatitis delta (compensated liver disease; 12.5% cirrhosis) scheduled for 48 weeks
of pegylated interferon alpha (PEG-IFNα) therapy. 8 hepatitis delta patients are receiving pre-treatment with 2mg Myrcludex B alone for 24 weeks (B1); Myrcludex B was added to (PEG-IFNa) for the first 24 weeks to another 8 patients (B2) while 8 patients are treated with PEG-IFNa alone (B3).
Results:
Myrcludex B was very well tolerated, injection side dermatitis occurred in 3 patients (10mg group) of Myrcludex B, regressed on treatment. A psoriasis exacerbation occurred in one HDV patient (B2) leading to discontinuation.
>1log10 HBV DNA decline at week 12 was observed in 6/8 (75%) patients receiving 10mg Myrcludex B while this occurred less often in the remaining dose groups (7/40; 17%). ALT normalized in 22/40 (55%) patients, median ALT values declined from 76 U/l before therapy to 36 U/l at week 12 (p1log10 HDV RNA decline at week 24 during Myrcludex B monotherapy (B1) or combination therapy (B2) while this response was observed in 7/7 of B3 patients at week 12. HDV RNA became negative in 2 (B1) and 5 (B2) patients at week 24. ALT values declined at week 24 in 6/7 (B1), 4/7 (B2) and 3/7 (B3, week 12) patients. One patient in B1 and one in B2 had negative HDV RNA and normal ALT at week 24. One patient (B2) experienced 1log10 HBsAg decline at week 24. Myrcludex B treatment induced preS-specific antibodies and bile acid elevation at doses >1mg.
Conclusion: Myrcludex B is safe and well tolerated in HBsAg positive patients with or without HDV coinfection. HBV entry inhibition seems to be associated HBV DNA and HDV RNA declines and improvement of biochemical disease activity.
Best Answer
The degree of entry inhibition, that one might define as the reduction of successful entry /infection per say 100 virions trying yo infect, is not known as a quantifiable number by anyone. It is however easy to see that a very small success rate of sent out virions to infection is needed to spread the infection, like one per week per infected sendout cell. Thus the block has to be extremely effective to yield slow clearance of infected cells.
The rate of replenishment of cccDNA as far as I know, is also not known.
What needs to be done therefore is to measure the infected cell mass indirectly by quant hbsag. It shows that Myrcludex at the doses used did not reduce the dynamic in favor of infected cell loss. And higher doses over longer time are not feasible as I outlined above.
ARC520 would have to improve its efficacy more than just dramatically to achieve a hbsag reduction that will be effective in inducing the enhancement of immunity required to clear, even in combo with immunotherapy as replicor is doing now. How frequently injections can be repeated is currently unclear, the 3mg/kg dose is unlikely to generate huge improvements over the 2mg/kg dose now reported. Replicors reduction factor is currently over ten thousand times better than the arc520, still needing immunotherapy for stable clearance. Antivirals won't make much of a difference, and arc520 already has a baseline entecavir treatment ongoing.
The rate of replenishment of cccDNA as far as I know, is also not known.
What needs to be done therefore is to measure the infected cell mass indirectly by quant hbsag. It shows that Myrcludex at the doses used did not reduce the dynamic in favor of infected cell loss. And higher doses over longer time are not feasible as I outlined above.
ARC520 would have to improve its efficacy more than just dramatically to achieve a hbsag reduction that will be effective in inducing the enhancement of immunity required to clear, even in combo with immunotherapy as replicor is doing now. How frequently injections can be repeated is currently unclear, the 3mg/kg dose is unlikely to generate huge improvements over the 2mg/kg dose now reported. Replicors reduction factor is currently over ten thousand times better than the arc520, still needing immunotherapy for stable clearance. Antivirals won't make much of a difference, and arc520 already has a baseline entecavir treatment ongoing.
Thank you for the comments. It is a puzzle to me as to how they can determine 1) the degree of entry inhibition; and 2) the effect of that degree of entry inhibition?
I read a paper by Stephan Urban in which he stated from his research, the mechanism of intrahepatic replenishment of the cccDNA pool and the mechanism of re-infection are dependent on the existing cccDNA in the nucleus. Against the replenishing of the cccDNA pool, we have the loss of cccDNA due to liver cells turnover. I have no idea about the rates of these events. Hence my questions.
With ARC520, it is now clear from observation by REPLICor regarding its REP9AC that a deep reduction of serum HBsAg for a reason period of time is not sufficient to re-constitute the immune response for most patients to clear the virus. However, if ARC520, since it can be given by injection, is given for a longer period of time, will that increase the chance of clearing the virus (in combination with antivirals or alone)?
I read a paper by Stephan Urban in which he stated from his research, the mechanism of intrahepatic replenishment of the cccDNA pool and the mechanism of re-infection are dependent on the existing cccDNA in the nucleus. Against the replenishing of the cccDNA pool, we have the loss of cccDNA due to liver cells turnover. I have no idea about the rates of these events. Hence my questions.
With ARC520, it is now clear from observation by REPLICor regarding its REP9AC that a deep reduction of serum HBsAg for a reason period of time is not sufficient to re-constitute the immune response for most patients to clear the virus. However, if ARC520, since it can be given by injection, is given for a longer period of time, will that increase the chance of clearing the virus (in combination with antivirals or alone)?
It is from a HDV/HBV co-infected patient, so cannot draw any firm conclusion. HDV/HBV co-infected patients have a much greater need for an effective treatment.
Any comments on the dosages, bile acid elevation, and hbvdna decline?
Many thanks in advance.
Many thanks in advance.
Myrcludex only prevents virus entry into liver cells. I don't see why HBsAg level should decline. The drop in hbvdna is, to me, unexpected. But this seems to demonstrate that Myrcludex is having some effect, also shown by the bile acid elevation.
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recommended to everybody to get paper and pen and graphically depict cohorts, groups and results.
dosage: It became apparent during the trial, that only the highest dose group had any chance. But as predicted, even 10mg is insufficient to block ntcp to such completion that the even the very low reinfection rate that hbv needs to stably infect ( less than one virion per week per virus producing cell) is blocked enough to afford shrinkage of the infected cell pool.
Dosages of 20 to 50mg are needed to achieve that degree of entry inhibition.
At these dosages, the accumulation of toxic bile acids would lead to intolerable side effects. 3 times 8 grams of bile acid need to be transported by the ntcp pump from the portal vein back into the liver, blocking this enourmously active high performance detoxification pump will lead to a severe bile acid toxicity syndrome.
Moderate shifts in the reinfection and disease dynamics were expected, hence the moderate alt/DNA lowering effect at higher doses.
the nonreporting of the quant hbsag with the exception of one HDV coinfected patient on interferon shows that likely no relevant reduction in cccDNA content was achievable.
IMO in one day two hopes of originally promising concepts of hbv treatments were severely dampened. The arrowhead iRNA only achieved a .3 log reduction of quant hbsag where 3 to 4 logs are required to start a phase of low hbsag levels as a base for enhancing immune treatment.