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An extract from: Review article: clinical pharmacology of current and
investigational hepatitis B virus therapies
Elise J. Smolders1,2,3 | David M. Burger3 | Jordan J. Feld4 | Jennifer J. Kiser1
2.3 | Secretion inhibitor
Secretion inhibitors reduce HBsAg and HBsAg subviral particle
(SVP) release from hepatocytes. The hypothesis is that these noninfectious
particles are partly responsible for the exhaustion of the
adaptive immune response in chronic HBV infection. Secretion inhibitors
reduce the number of SVP released, which may provide an
opportunity for the immunomodulating compounds to restore immune
function. In addition, HBsAg release is inhibited which is an
important endpoint for HBV treatment.
REP‐2139 is a secretion inhibitor under investigation; however
the exact mechanism of action is not totally understood.40,41
REP‐2139 is a nucleic acid polymer (NAP) which is a phosphorothioated
oligonucleotide (PS‐ON) and it is formulated as a chelated
complex (calcium or magnesium). REP‐2139 is administered
IV and studied in doses of 100‐500 mg/wk IV (calcium chelate) or
125‐250 mg/wk SC (magnesium chelate) (in NaCl 0.9%).42 Infusion
durations ranged from 1 to 2 hours. REP‐2139 was studied as
monotherapy (15‐30 weeks) and in combination with NA and/or
immune modulators (20‐48 weeks).41,43-46 With respect to pharmacology
and pharmacokinetics, no data in humans are available.
Several oligonucleotides have received regulatory approval
for conditions other than HBV including: mipomersen (homozygous
familial hypercholesterolemia),47 volanesorsen (familial
chylomicronemia syndrome),48 and inotersen (hereditary transthyretin‐
mediated amyloidosis).49 These drugs all have comparable pharmacokinetics,
so this could be an indication of the pharmacological
profile of REP‐2139: They are administered IV or SC, are highly
protein bound to plasma proteins and metabolised in tissue by endonucleases
into shorter oligonucleotides which are substrates
for exonucleases. The oligonucleotides are slowly renally excreted
(<4% in the first 24 hours) and the T1/2 varies from 2‐5 weeks to
1‐2 months. None of the drugs are substrates of CYP enzymes or
drug transporters.47-49
Efficacy of REP‐2139 was studied in patients from Bangladesh
and Moldova.41,43-46 Promising results in regard to HBsAg reduction
and HBsAg loss are presented with mono and combination
therapy of REP‐2139. However, study designs are complex, different,
and hard to interpret. In short, 3/1241 and 6/1243 patients
achieved HBsAg loss during REP‐2139 monotherapy and 12/24
achieved HBsAg loss in combination with NA and/or immune
modulators (20‐48 weeks). In the Bangladesh study (n = 12),41
the number of patients with HBsAg loss was increased when
REP‐2139 was combined with an immune modulator and/or NA
(9/12 vs 3/12). Rebound viremia was found between 12 and 123
(seven patients) weeks after EOT, which was still absent in two
patients after completion of follow‐up at week 135‐137.41 Shortterm
(<3 months) and long‐term (>12 months) HBV DNA loss was
achieved in 8/12 and 4/1241 and 4/5 and 4/5,43 respectively, of the
patients that did not have undetectable HBV DNA at the start of
therapy. Interim data from a larger trial (study 401), that included
a TDF lead‐in phase of 24 weeks followed by 48 weeks of treatment
with REP‐2139 combined with TDF and peg‐IFN‐α, found
that 24/40 patients had HBsAg seroconversion to anti‐HBs by the
end of treatment. This effect appeared sustained off drugs, 20/34
and 9/16 still had HBsAg loss and positive anti‐HBs at follow‐up
weeks 24 and 48, respectively .46
During treatment, reduction in platelet counts and ALT/AST
flares were frequently (33%‐68%) reported41,43-46 during monotherapy
but mostly after initiation of peg‐IFN‐α. These flares were
mostly self‐resolving. The researchers suggest that these ALT/AST
flares are a result of peg‐IFN‐α treatment restoring immunity against
infection.41,43-46 This fits the hypothesis of reducing HBsAg load,
providing an opportunity for controlling the infection with the help
of immune therapy (peg‐IFN‐α). However, thrombocytopenia and
hepatotoxicity warnings are included in drug labels of the other marketed
oligonucleotides.47-49
Another issue with PS‐ONs is that they increase the mineral urinary
excretion and therefore the patients must be supplemented
with calcium, magnesium, and vitamin D during infusion.
Most patients reported AEs during treatment, which were primarily
attributed to peg‐ IFN‐α therapy. The most frequently reported
infusion‐related AEs from the Bangladesh study were fever,
shivering, chills, body ache/cramping, and headache. The most
frequently reported AEs during monotherapy with REP‐2139 were
dyspepsia, reduced appetite, fever, weakness, loose stool/ increased
frequency of bowel movements, generalised body aches, pain, tingling
or lack of sensation in extremities, and back pain.41 For the
Moldova study, the most common toxicities were pyrexia, chills, conjunctival
hyperemia, headache, asthenia near the end of the infusion,
and white blood cell count reductions.45 By the end of the combination
exposure or during follow‐up, all patients had hair loss, dysphagia
and dysgeusia in the Bangladesh study, but this was attributed
to endemic heavy metal exposure at the study site.41 The AEs in the
study in Moldova were markedly different, which supports an environmental
effect for the AEs observed in the Bangladesh study.45
REP‐2139 in combination with peg‐IFN‐α and/or an NA shows
promising results concerning HBsAg loss. However, weekly IV administration
in combination with peg‐IFN‐α and/or an NA is a very
time‐consuming and some severe AEs are reported. The risk benefit
ratio will require evaluation. This will be determined based on
the long‐term follow‐up data of HBsAg and HBV DNA and whether
these two parameters are still undetectable after 1, 2, or 3 years of
follow‐up.
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发表于 2019-12-29 20:06
