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GS-008
A phase 2 dose-optimization study of lonafarnib with ritonavir for
the treatment of chronic delta hepatitis—end of treatment results
from the LOWR HDV-2 study
C. Yurdaydin1, R. Idilman1, O. Keskin1, C. Kalkan1, M.F. Karakaya1,
A. Caliskan1, E. Yurdcu1, S.C. Karatayli1,M. Bozdayi1, C. Koh2, T. Heller2,
J. Glenn3. 1Gastroenterology, Ankara University, Ankara, Turkey; 2Liver
Diseases Virology Section, Liver Diseases Branch, NIH/NIDDK, Bethesda;
3Gastroenterology and Hepatology, Stanford University, San Francisco,
United States
E-mail: [email protected]
Background and Aims: Lonafarnib (LNF) is an oral prenylation
inhibitor with demonstrated efficacy in patients infected with
hepatitis delta virus (HDV). This class of agents is known to be
associated with gastrointestinal side effects. Results of the LOnafarnib
With Ritonavir for HDV (LOWR HDV-1) study demonstrated that coadministering
LNF with ritonavir (RTV), an inhibitor of LNF
metabolism, increases the post-absorption levels of LNF, yielding
greater efficacy with lower LNF doses compared to LNF monotherapy.
The aim of LOWR HDV-2 is to identify optimal combination regimens
of LNF and RTV ± PEG-IFNα with efficacy and tolerability for longer
term dosing to induce clinically meaningful reductions in HDV-RNA
and ALT normalization, or enable HDV-RNA clearance.
Methods: 48 patients to date have been enrolled in 3 groups of LNF in
combination with RTV ± PEG-IFNα for 12 or 24 weeks, followed by 24
weeks of treatment-free follow-up (FU). Groups were divided into
high dose LNF (≥75 mg BID) + RTV 100 mg BID (n = 15,12weeks), low
dose LNF (25 or 50 mg BID) + RTV 100 mg BID (n = 20, 24 weeks) and
low dose LNF (25 or 50 mg BID) + RTV 100 mg BID + PEG-IFNα
180 mcg QW (n = 13, 24 weeks). Biochemical parameters and
quantitative serum HDV-RNA viral loads were measured.
Results: Low dose regimens had comparable antiviral efficacy with
less GI side effects than the high dose regimens. On 24-week
treatment, LNF 25 mg BID + RTV resulted in a mean log decline of
−1.74 ( ± 1.20 log10 IU/ml), comparable to the historical response to
PEG-IFNα observed in HIDIT-2. LNF 25 mg BID + RTV + PEG-IFNα,
however, resulted in a mean log decline of −5.57 ( ± 1.99 log10 U/ml),
with 3 of 5 (60%) subjects becoming HDV-RNA PCR-negative and 5 of
5 (100%) of subjects achieving HDV-RNA BLOQ. 2 of 11 (18%) subjects
who completed 12 weeks of LNF 50 mg BID + RTV to date became
HDV-RNA PCR-negative. 9 of 15 (60%) subjects with elevated baseline
ALT have normalized ALT at Week 24. LNF 25 or 50 mg BID based
regimens were associated with mostly grade 1 GI AEs. Results from
EOT and FU visits will be presented.
Conclusions: Low dose LNF (25 or 50 mg BID) with RTV ± PEG-IFNα
including all-oral LNF 50 mg BID + RTV, lead to HDV-RNA PCRnegativity.
LNF 25 mg BID + RTV + PEG-IFNα leads to the highest rate
of HDV-RNA PCR-negativity on 24-week treatment, and suggests that
LNF and PEG-IFNα have synergistic activity. These regimens are
generally well-tolerated, supporting longer duration studies of
greater than 24 weeks, which may lead to HDV cure.
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