Biomedical Engineering Reference
In-Depth Information
For example, a drop in efficacy compared to existing gold
standards may be tolerated where a product is associated with
fewer side effect concerns in a low severity disease, but a once-
weekly cancer treatment is unlikely to be viewed favorably if
survival rates are slightly lower.
Comparative efficacy must be taken into account when
developing novel or next-generation products designed to be
more convenient to administer, cheaper, or simply a me-too
in the market. All other aspects being equal, a less-
frequently dosed version of an existing therapeutic protein
would not require any improvement in efficacy to capture
market share. However, factors such as cost and safety are
also considered by regulators, physicians, patients, and
payers. HGS' albumin fusion, Zalbin/Joulferon (albinter-
feron-
a
2b), was discontinued in October 2010 after the FDA
declined to approve the product on the basis of its efficacy
and safety being slightly worse than for Pegasys
1
, despite
the primary endpoint of noninferiority being met with
statistical significance. Combining a partner with an active
protein in an FP or conjugate may not always exhibit
the desired level of efficacy in clinical trials. Most notably,
large partners such as an Fc domain or albumin used for
half-life extension can dampen activity of the fusion via
steric hindrance [4].
Where a disorder is poorly addressed by existing treat-
ments, the efficacy challenge will be low compared to those
that are already covered by several adequate options. For
developers exploiting a novel disease pathway to achieve a
step change in treatment, sales can be higher and compara-
tively safe from competing alternatives. Examples of this
include the emergence of the anti-TNF class or Genzyme's
non-FP enzyme replacement therapy, Cerezyme.
1
FPs can
provide new mechanisms for treating diseases, giving a firm
advantage in the market. Compared to larger mAbs, several
Ab fragment fusions are designed to offer improved tissue
penetration, potentially raising efficacy for the treatment of
cancer and other diseases. These benefits will be most
applicable where the efficacy of existing approaches is
hampered by target accessibility. Similarly, in the CNS
therapy area, fusion or conjugation to transferrin has been
shown to facilitate the transport of a partner protein across
the blood-brain barrier [39,40].
As stated earlier, almost all of the FPs identified are
injectable. Furthermore, biologic products are typically
priced at a premium to small molecule treatments (see
Chapter 2). As such, without providing a sufficient
improvement in efficacy or being more commercially
attractive in some other aspect, FPs may struggle to capture
market share in a number of indications. Established
marketed products will have a well-defined efficacy profile
and where side effect concerns are not problematic, phy-
sicians may feel more comfortable prescribing products
that have a longer history of use. It should be noted that
new treatments can also be positioned to be used in
addition to, rather than instead of existing treatments,
potentially reducing competitive pressures. Complemen-
tary or synergistic combinations can raise the changes of
commercial success. In terms of efficacy, the competitive
standing of a development stage product will only be clear
after pivotal trials have been undertaken. We consider this
as further highlighting the importance of having a strong
ranking against several factors for commercial success.
One strategy for improving the prospects of a new product
against tough competition is to target-specific patient
segments, such as those that do not adequately respond
to existing options, or a subset in which the new product is
more efficacious. Companion diagnostics can aid the
identification of such groups. An example outside of the
FP space is Roche's Zelboraf (vemurafenib), which is in
development for the treatment of melanoma in patients
whose cancer is shown as having the mutant BRAF protein.
While such stratification reduces the number of applicable
patients, using a diagnostic potentially improves the like-
lihood that stronger efficacy data will be generated. It
couldbeviewedasalowerriskstrategytofirstensure
approval and launch through a small patient subset, since
label expansion can subsequently be sought, with devel-
opment costs offset by initial sales.
3.2.3 Safety Profile
Medicine regulatory agencies in major markets have a
primary objective of ensuring patient safety. Prescribing
physicians take a similar view and the safety profile of
a product plays a critical role in determining its approval
prospects and the level of sales it will achieve. The
risk-reward ratio offered by a product will depend on
the indication it addresses and side effects will be consid-
ered more tolerable where sufficient efficacy benefits are
offered, particularly in severe diseases. As highlighted
earlier with HGS' Zalbin, falling just slightly short of
regulators' safety requirements can prevent even a product
with administration benefits and clear efficacy from reach-
ing the market.
Immunogenicity has historically been a key area of
concern with biologic products or attached moieties,
both in terms of side effects and inactivation due to
neutralizing antibodies. Measures such as humanization,
use of human-derived proteins, sequence changes, and
alternative post-translational modifications have served
to reduce the immunogenicity of developed biologics.
As such, FP platforms must offer low immunogenicity if
they are to compete. FPs specifically designed as thera-
peutic vaccines to stimulate the immune system are though
a clear exception (see Section 3.1.6.3).
As detailed in the half-life extension discussion earlier, a
number of FPs aim to improve on the safety of PEGylation.
PEG is nonbiodegradable and concerns have been raised
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