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Advances in Preventing Cytomegalovirus Disease in Stem Cell Transplant Recipients
The availability of effective antiviral drugs for CMV and, in particular, Maribavir is a benzimidazole riboside compound that has been
ganciclovir as pre-emptive therapy has changed the field substantially, shown in biochemical and genetic studies to inhibit the CMV protein
and has improved treatment options. However, the currently available kinase pUL97, the same kinase responsible for initiating the antiviral
drugs are limited by a number of drawbacks in addition to toxicity. activity of ganciclovir.
2,16
Distinct from the existing anti-CMV drugs,
Ganciclovir and foscarnet both require twice-daily intravenous maribavir has a novel mechanism of action mediated through the UL97
protein kinase that restricts viral DNA synthesis, assembly and even
virion maturation events beyond. Maribavir is a potent and selective
Pre-clinical pharmacokinetic and
competitive inhibitor of ATP binding in the kinase’s catalytic
toxicological studies have
region. The protein kinase pUL97 is highly conserved across clinical
strains of CMV, and has highly conserved homologues across other
demonstrated that maribavir has
herpesviruses, implying that the kinase is essential for survival of the
good oral bioavailability and a
virus and disease pathogenesis.
7,16–20
When pUL97 is inhibited,
whether via maribavir or a laboratory-generated deletion mutation,
favorable safety profile.
the efficiency of viral DNA replication is severely impaired, with
observed defects in encapsidation and nuclear egress, ultimately
administration. Ganciclovir can also be administered through reducing the viral yield.
16,18–20
intravitreal implant to patients with ocular disease (CMV retinitis).
However, the orally available prodrug valganciclovir is a valyl ester In vitro studies have shown that maribavir is more potent against
formulation of ganciclovir with bioavailability approximately 10 times CMV than ganciclovir, and is less toxic to bone marrow cells.
2,15
Pre-
that of oral ganciclovir, and undergoes rapid hydrolysis to ganciclovir clinical pharmacokinetic and toxicological studies demonstrated that
in the body. Although no controlled study has been performed in SCT maribavir has good oral bioavailability and a favourable safety
recipients, valganciclovir seems to be similar to ganciclovir in terms of profile. Furthermore, maribavir did not cause myelosuppression, and
efficacy, tolerability and adverse effects.
14
Furthermore, CMV clinical isolates resistant to both ganciclovir and
foscarnet have been reported due to mutations in the viral DNA
In November 2007, the European
polymerase gene UL54. Resistance mutations in the protein kinase
Medicines Agency (EMEA) designated
gene UL97 are also common in patients undergoing long-term
ganciclovir therapy.
7
maribavir as an orphan drug for
CMV patients with impaired
Ultimately, any new anti-CMV agents in development should be orally
cell-mediated immunity.
bioavailable for convenience, with superior efficacy and an improved
safety profile.
New Candidate for Cytomegalovirus Disease Prevention exhibited a lower toxicity than currently available anti-CMV drugs.
21
Ganciclovir and cidofovir are, respectively, nucleoside and nucleotide Phase I clinical studies testing maribavir as a prophylactic agent
analogues. Ganciclovir requires initial monophosphorylation by the against CMV showed effective antiviral activity in vivo, and it was
CMV UL97, while both require additional phosphorylation by cellular well tolerated across a range of doses, the most commonly reported
enzymes for activation before they can act as competitive inhibitors adverse event being taste disturbance.
22,23
Results from phase II
studies affirmed the drug’s strong antiviral activity, marking a
statistically significant reduction in the rate of CMV reactivation in SCT
Any new anti-cytomegalovirus agents in
recipients in all three dosage groups (100mg BID, 400mg QD,
400mg BID).
24
The promising early data with maribavir will be
development should be orally
confirmed in ongoing studies. Currently, international phase III studies
bioavailable for convenience, with
are under way to evaluate the efficacy, safety, tolerability and
prophylactic use of maribavir administered for the prevention of CMV
superior efficacy and an improved
disease in SCT and solid-organ transplant (SOT) patients.
24,25
Due to
safety profile.
the drug’s promising anti-CMV activity, the US Food and Drug
Administration (FDA) granted fast-track status to maribavir in February
2006 for preventing CMV infection in bone marrow transplant and
against their corresponding substrates at the CMV DNA polymerase SOT patients. In November 2007, the European Medicines Agency
binding site. If incorporated into CMV DNA, the drugs can block chain (EMEA) designated maribavir as an orphan drug for CMV patients with
elongation.
7
Foscarnet, a pyrophosphate analogue, occupies the impaired cell-mediated immunity.
pyrophosphate binding site on CMV polymerase and prevents
incoming dNTPs from being incorporated into viral DNA.
7
Because In vitro studies have shown that maribavir is active against all known
ganciclovir, cidofovir and foscarnet all target DNA synthesis in the viral CMV strains resistant to the commonly administered anti-CMV drugs
life cycle at the level of DNA polymerase, cross-resistance can occur at in the clinic.
24
CMV resistance to ganciclovir arises most commonly
the level of mutation in the CMV DNA polymerase. through mutations in the CMV UL97 gene;
7,20
cross-resistance to
EUROPEAN HAEMATOLOGY 2007 45
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