The advent of a novel category of oral ESAs have been assessed as a new therapeutic agent for anemia management in non-DX CKD ptns.
ORAL ESAs
o ESA: erythropoiesis-stimulating agent.
o
Hct: haematocrit
o
HDX: haemodialysis
I. Investigational agents in non-DX ptns: Roxadustat
for therapy of anemia in non-DX CKD ptns (April
2021).
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs): The advent of a novel category of oral ESAs have been assessed
as a new therapeutic agent for anemia management in non-DX CKD ptns. Unlike
other ESAs agents that are replacing to certain degree the endogenous EPO, HIF PHIs may trigger the
renal and hepatic transcription of the EPO gene that results in a higher level of endogenous EPO. Efficacy of HIF PHIs was evaluated
in a phase 3 trial of >
2700 non-DX CKD ptns & anemia (mean HB 9 g/dL) and were randomly receiving the HIF
PHI, Roxadustat, or placebo 3 times weekly,
to target an HB of at least 11 g/dL. Compared to
placebo, ptns on roxadustat were more prone achieving the target HB (77 vs 9 %) and achieving an HB level between 10-12
g/dL for a higher % of time (82 vs 28 %).
Furthermore, compared with placebo, roxadustat has induced 74 % total decline in the requirements
for other therapies of anemia (e.g., iron, ESA, or BTx) and 63 % decline in the BTx requirements
alone. However, all-cause MR (21 vs 18 %), CVS events (23 vs 21 %), and total serious adverse events (57 vs 54 %) were increasing
among ptns receiving roxadustat as compared to ptns on placebo. Serious untoward
effects that were more commonly reported with roxadustat may include HT, UTI, & pneumonia. Similar observations have been seen in
smaller phase 3 studies from the European Union, China, and
Japan. Other HIF PHIs agents under
clinical trials include vadadustat, daprodustat, & molidustat. As HIF pathway
is regulating or interacting with several biologic processes, there is wide
interest in the non-EPO adverse
effects that may include - to certain degree – a higher risk of malignancy, thrombotic events, CVS disorders, Dc retinopathy & CKD deterioration, among others still requiring long-term evaluation
of the treated ptns. None of the above members have
been approved yet in the US.
II. Investigational agents
in DX ptns: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) are a novel category of oral ESAs conistituting a potential future therapeutic option for anemia control in
DX ptns. Unlike
other ESAs agents replacing
the endogenous EPO, HIF PHIs trigger the
transcription of the EPO gene in the
kidneys and liver, resulting in a higher levels of the endogenous EPO. The effectivness of HIF PHIs have been tested in a Chinese trial (305 DX ptns) treated with EPOa for at least 6 wks before the engagment to the trial. Ptns have been randomly assigned
to receive the HIF PHI roxadustat or EPO alfa 3 times/weekly/26
wks. By the end of the clnical period, roxadustat was NOT inferior
to EPOa in the improvement
HB levels (mean
changes from the baseline 0.7 vs 0.5 mg/dL, resp). Moreover, roxadustat have triggered a higher
decline in hepcidin level as
compared to EPOa (-30.2 vs -2.3 ng/mL). Ptns involved in the roxadustat g have shwon:
1)
More prevalent hyper-k+ &
2)
Upper respiratory tract infection.
On the other hand, ptns in the EPO alfa > showed more
prevalent HT. As HIF pathways have been incriminated on several biologic interactions, there’s
increasing concern about the non-EPO untoward impacts, e.g.:
1)
Higher risk of cancer, thrombotic
events, and CVS disease,
2)
Rapidly progressed Dc retinopathy, & CKD,
- that requiring a long-term
follow-up period of the managed ptns. No one agent has been practically approved
in the US.
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