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Anaemia Management
Novel Erythropoietin-like Drugs – A New Era in Anaemia Management
a report by
Iain C Macdougall
Consultant Nephrologist, Department of Renal Medicine, King’s College Hospital, London
Many nephrologists are relieved that we have moved on from the days difference between these products lies in their glycosylation pattern. Thus,
when a large number of dialysis patients were transfusion-dependent, with it was recognised that human EPO exists as a mixture of isoforms that differ
a haemoglobin level oscillating between 5 and 6g/dl up to around in both glycosylation and biological activity.
3
Other epoetins that have
9–10g/dl. Thus, the effects of a blood transfusion were short-lived. The recently become available or are still being developed include epoetin
advent of recombinant human erythropoietin (EPO) in the late 1980s omega
4
and epoetin delta,
5
as well as copy products of epoetin alfa and
transformed this desperate situation, allowing patients to use their own other biosimilar epoetins.
6
Again, all of these products share the same
bone marrow for red cell (RC) production and dramatically reducing the 165-amino acid sequence for epoetin alfa and epoetin beta, as well as the
number of blood transfusions used in dialysis units. Epoetin therapy was endogenous hormone. However, the cell culture conditions vary. Epoetin
found to be highly effective in the vast majority of patients with CKD omega is produced in baby hamster kidney (BHK) cells, whereas epoetin
anaemia, and adverse effects were uncommon or easily managed. delta is synthesised in human fibrosarcoma cell cultures (line HT-1080). The
However, due to the fairly short circulating half-life of plasma EPO latter product is produced by gene activation technology by transforming
(approximately six to eight hours),
1
patients required two or three injections the cell with the cytomegalovirus promoter.
7
Epoetin omega has been used
a week. Thus, there was a clinical need for longer-acting erythropoiesis- clinically in some eastern European, central American and Asian countries,
stimulating agents (ESAs), and several of these have been developed or are but does not have a US or European licence, while epoetin delta was
under development. To date, all licensed ESAs are protein-based, bearing approved by the European Medicines Agency (EMEA) in 2002. The first of
some structural resemblance to EPO itself. Thus, for agents such as the biosimilar epoetin products has already received a European product
darbepoetin alfa or Continuous Erythropoietin Receptor Activator (CERA), licence, and is being marketed in a number of European countries.
modifications have been made to the EPO molecule to allow it to have a
longer duration of action in vivo. Protein-based therapies have a number of Darbepoetin Alfa
disadvantages, notably immunogenicity (pure red cell aplasia [PRCA] This second-generation EPO analogue was created out of a realisation
caused by anti-EPO antibodies), storage and stability (must be stored at that adding extra N-linked carbohydrate chains to the EPO molecule
temperatures of around 4ºC) and administration (all currently licensed would render it more stable in vivo and give it a longer circulating
products are administered intravenously [IV] or subcutaneously). Various half-life. This was confirmed first in animals and later in humans.
8
This
strategies have been devised to circumvent the limitations of the currently translates clinically into less frequent dosing, with most patients receiving
available products (see Table 1), and these are discussed in this article. injections once weekly or once every other week. Further extension out
to once-monthly dosing with darbepoetin alfa may be possible in some
Protein-based Erythropoiesis-stimulating Agent Therapy patients, but it is not clear what dose penalty this incurs.
The original recombinant human EPOs (epoetin alfa and epoetin beta) have
now been in clinical use for nearly 20 years. Both products are Continuous Erythropoietin Receptor Activator
manufactured in cultures of transformed Chinese hamster ovary (CHO) cells The strategy used to synthesise this third-generation EPO analogue was to
that carry complementary DNA (cDNA) encoding human EPO.
2
Therefore, integrate a large pegylation chain into the EPO molecule via amide bonds
the amino acid sequence of both epoetins is identical, and the major between the N-terminal amino group of alanine and a number of amino
groups of lysine.
9
The molecular weight of CERA is approximately double
that of EPO, at around 60kDa. As with other pegylated therapeutic
Iain C Macdougall is a Consultant Nephrologist and Honorary
Senior Lecturer at King’s College Hospital, London. He has
proteins, the half-life of circulating CERA is considerably prolonged
been involved in numerous advisory boards in renal anaemia
compared with that of epoetin, at approximately 130 hours.
9
Thus, less
management worldwide, including the working parties
frequent dosing regimens of every two weeks and once monthly have been
responsible for both the 1999 and the 2004 versions of the
European Best Practice Guidelines, along with the work group tested in phase II and phase III clinical trials, and the product has recently
that produced the latest US KDOQI Guidelines on Renal
received a licence in both the US and Europe. As with the previous
Anaemia Management (2006; update 2007). He was a
previous Board member of the KDIGO initiative, and a Council
erythropoietic agents, CERA is still administered IV or subcutaneously, and
Member of the European Renal Association from 2004 until 2007. He is currently a Subject Editor adverse events seem to be similar to those associated with the epoetins or
for Nephrology Dialysis Transplantation. He developed his research interest in renal anaemia while
darbepoetin alfa. There is some evidence to suggest that the metabolic fate
a Clinical Research Fellow in Cardiff (1988–1991) and extended this interest during his
appointment at St Bartholomew’s Hospital (1991–1996), where he studied the potential role of
of CERA may be different from that of the existing products, with less
proinflammatory cytokines in mediating resistance to epoetin. Dr Macdougall is a combined
cellular internalisation following interaction with the EPO receptor, and
medical and science graduate of Glasgow University, Scotland, from which he was awarded a
first class honours BSc in pharmacology in 1980, and his medical degree in 1983.
certainly the binding affinity of CERA for the EPO receptor is much lower
than for endogenous or recombinant EPO. However, the benefits of the
E: Iain.Macdougall@kch.nhs.uk
greater stability in vivo far outweigh this minor biological disadvantage.
28 © TOUCH BRIEFINGS 2007