Interim results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection

Introduction: Currently there are no specific treatment regimens for Hepatitis D Virus (HDV) infected patients. Myrcludex B (MyrB) is a first‐in‐class entry inhibitor exerting its antiviral function by blocking the jointly used HBV/HDV receptor sodium taurocholate co‐transporter NTCP. In a preceding Phase 2a trial we showed that monotherapy with 2mg MyrB induced HDV RNA decline of 1log in 6/7 patients at w24 and demonstrated synergism with peg IFNα. Here we present interim results of a Phase 2b clinical trial on 120 chronically HBV/HDV co‐infected individuals receiving 2, 5, and 10mg MyrB daily in combination with TDF or TDF alone. Methods: 120 HBeAg‐negative patients with chronic Hepatitis D were randomized in four treatment arms. Treatment with TDF 245mg/day started not less than 12w prior to MyrB. MyrB was administered s.c. once daily at 2 (A), 5 (B) or 10mg (C) for 24w followed by a 24w period continuing TDF. Patients in arm D received TDF alone. The primary endpoint was HDV RNA negativation or decrease by ≥2log10; secondary endpoints include ALT normalization, AEs, blood bile acids levels and MyrB‐antibodies. Results: Safety: MyrB was generally well tolerated with 118 drug related AEs (mild n=90, moderate n=25, severe n=3), mainly temporary injection site reactions and lab abnormalities. From six reported SAEs 5 were unrelated to the study drug and 1 was ALT elevation during follow up. Two SAEs led to study medication withdrawal. Efficacy: At w12, HDV RNA levels declined in all groups treated with MyrB at any dose with mean reductions from BL by 1.24log10 IU/ml in A (n=16), 1.40log10 IU/ml in B (n=18) and of 1.74log10 IU/ml in C (n=17). TDF treated patients (D) showed no serum HDV RNA reduction (0.09log10 IU/ml, n=17). While all patients with elevated ALT levels in the MyrB arms showed a pronounced decline of ALT‐levels (with complete normalization in 7/21 (A), 5/21 (B), and 9/22 (C)) no such tendency was observed for the TDF arm. At w24 HDV serum RNA levels further declined in B (1.63log10 IU/ml; n=7) and C (2.42log10 IU/ml; n=10) regardless of previously normalized ALT. No further decline of HDV RNA was observed in D (0.015log10 IU/ml (n=9)). HBsAg showed no significant changes in all arms. MyrB induced elevations of conjugated bile salts. Conclusion: Administration of MyrB was safe and well tolerated even at doses saturating NTCP (5mg and 10mg). The dose‐dependent HDV RNA decline was accompanied by a pronounced tendency of ALT normalization after 12weeks. As expected for an entry inhibitor HDV RNA declined by an elimination kinetic in most patients. Accordingly, HDV negativation may be expected upon prolonged treatment durations.