Biomedical Engineering Reference
In-Depth Information
regarding potential kidney issues, particularly in patients
with impaired renal function [11]. As well as reduced dosing
frequency, a longer half-life can produce more consistent
plasma levels, avoiding the dose spikes and greater side
effects that can be associated with regular dosing of a short
half-life product. Similarly, several targeted FPs or compa-
rable conjugates aim to offer improved safety by acting in a
more specific and selective manner—such as FPs that use an
Ab-binding domain to deliver IL-2 to cancer cells (see
Section 3.1.6.2). Tailoring drug delivery to target only
certain cell types or certain areas of the body reduces the
concentrations experienced elsewhere, potentially reducing
side effects or allowing higher doses without safety issues.
However, care must be taken to ensure that the target is not
also present in other locations, or that the binding domain
does not also have affinity for unintended targets. This is
highlighted by the case of non-FP immunotoxin Mylotarg,
which was withdrawn from sale after further studies showed
it to be associated with a higher rate of toxicity and death due
to unintended delivery to CD33
for superior rewards but can be associated with greater
uncertainty. The greatest threat to drug developers is that
expensive Phase III trials will fail to show the desired results
or have to be repeated. Costs and risk will vary on a case-by-
case basis; however, FP developers seeking partnership
deals should consider at an early stage how the risk-reward
balance of a project may be perceived. A product candidate
will not only compete for investment funds with others'
candidates in the same disease space but also with projects in
other business areas.
Aside from clinical trials, a further major cost of drug
development can relate to manufacturing facilities. Novel
product structures can require newmanufacturing facilities
to be built and these upfront costs have a disproportionate
impact on the financial risk-reward balance. Furthermore,
production staff will have less experience of running and
optimizing a new process. For these reasons, approaches
that are in keeping with existing production capabilities
will be viewed more favorably—to a mAb developer, a
conjugated Ab may be more likely to be selected over a
targeted toxin FP. Further cost factors must also be taken
into account.
cells in the liver [22].
Possible variation in the genetic makeup or expressed pro-
teome of patients must also be taken into account—a
treatment may be safe in the majority of patients but have
severe consequences in a subgroup.
As with patient stratification for efficacy purposes, clini-
cal trials and approved indications can also be tailored for
only patients who respond to treatment, or trials can be
avoided in those who experience side effects. Such
approaches can allow FPs or comparable conjugated pro-
teins/mAbs to command a strong commercial advantage
over alternatives. It should though be noted that while
certain products may be safer in theory, it can take many
years before this is clinically demonstrated. Similarly, novel
or adjusted approaches can also bring about new safety
concerns. The gold standard treatments for osteoporosis,
bisphosphonates, are effective but are not broken down in
the body and are either excreted via the kidneys or deposited
in bone, where they can remain for decades. Long-term
exposure and inhibition of bone resorption is thought to
cause a number of serious side effects, albeit rare. Amgen's
non-FP mAb Prolia
1
(denosumab) employs a differentiated
mechanism of action, but is considerably more expensive
and will take many years before it can be shown to offer a
superior long-term side effect profile. The Prolia FREEDOM
extension study is due to run for 10 years.
þ
3.2.4.1 Manufacturing and Cost of Goods Sold We
have defined FPs as the genetic fusion of two proteins.
Theoretically, most, if not all, FPs could also be produced
using chemical attachment. The decision of whether to use
an FP or chemical approach relates primarily to manufactur-
ing costs and consistency.
As described in this chapter, there will be a range of FP
and non-FP product structures that can potentially be used to
target a disease pathway. Only certain manufacturing meth-
ods will be practically applicable in each case, affecting the
costs of production and therefore the profitability of product.
Large human proteins can be complex, with multiple func-
tional domains that undergo extensive post-translational
modification or have to be folded in a specific manner.
As a result, only certain cell culture media may be capable
of appropriate expression of a certain product or structure.
Traditionally, mAbs, for example, have been produced only
in mammalian cells, in particular Chinese hamster ovary
(CHO) cells, which are favored for their ability to assemble
complex multisubunit proteins and perform modification
such as glycosylation [41].
Out of the 43 FPs identified in Phase II development of
above, 29 are produced in mammalian expression systems;
19 of which use CHO cells, while four FPs are produced in
HEK-293 cells, which are originally derived from human
embryonic kidney cells and can therefore produce modifi-
cations more closely aligned with those of natural human
proteins. Lower antigenicity is particularly beneficial for
products such as recombinant blood factor Fc fusions
(rFVIII-Fc and rFIX-Fc) that are intended to be administered
over many years [42].
3.2.4 Cost Factors
The costs associated with the development and sale of an FP
can have a significant bearing on its chances of achieving
commercial success. The size and length of clinical trials
required for a product will vary depending on the indication
sought and the degree to which its efficacy and safety profile
must be demonstrated. Novel approaches may offer scope
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