A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B

Abstract

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-inclass
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 (p<0.001). No significant changes
in HBsAg levels occurred. In hepatitis delta, 6/7 and 7/7 of
patients with data available experienced >1log10 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.

Full text

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 (p<0.001). No significant changes in HBsAg levels
occurred. In hepatitis delta, 6/7 and 7/7 of patients with data available experienced >1log10 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.