Biomedical Engineering Reference
In-Depth Information
fungi or plants). By camparison, identified fusions are all
produced in mammalian cells apart from one, Amgen's
AMG-386 which is a peptide-Fc fusion (peptibody) and
can utilize bacterial fermentation.
The two albumin fusions in late-stage development (both
Phase III) are being developed by Human Genome Sciences
(HGS) (albiglutide partnered with GlaxoSmithKline) and
Teva (albugranin) and Teva. Although the technology has
passed through several stages of ownership, HGS gained
rights when it acquired Principia in 2000, and Teva after
acquiring CoGenesys in 2008. HGS' Zalbin/Joulferon
1
(albinterferon-
a
-2b) was previously the most advanced albu-
min fusion but was discontinued in October 2010. Existing
treatment options for hepatitis C virus infection include
unmodified interferon (IFN)-
a
given three times weekly or
pegylated IFNs given once-weekly. Pharmacodynamic model-
ing supported treatment with Zalbin at 2- or 4-week intervals
[7]. Although Zalbin met the Phase III primary endpoint of not
being statistically inferior to Pegasys (PEG-IFN-
a
2a), safety
and efficacy results were slightly worse [8,9]. This came
despite the rationale that the increased half-life of Zalbin
would maximize drug exposure and therefore viral suppres-
sion, as well as initial studies that suggested lower immuno-
genicity with Zalbin. Trials of higher dose Zalbin been halted
earlier due to the occurrence of serious respiratory adverse
events. The FDA took the view that limited clinical benefit did
not warrant the increased risk and issued a Complete
Response Letter. HGS and partner Novartis subsequently
discontinued development. These experiences highlight the
low tolerance of regulators to approve more convenient dosing
formulations without a suitable risk-benefit ratio.
Other FP extended half-life approaches are available, but
currently in earlier stages of development. In 2007, Pfizer
acquired BioRexis and its transferrin fusion-based half-life
extension technology. Similarly, GlaxoSmithKline acquired
Domantis in 2006 to gain access to its domain antibody
(dAb) technology. Albumin-binding antibodies (AlbudAbs)
are dAbs that are designed to bind to human serum albumin
(SA), raising the half-life of a dAb from less than an hour, to
several days. By fusing a protein of interest to an AlbudAb,
half-life extension can be conveyed without the need for
albumin itself to be included in the FP [10]. These smaller
FPs potentially allow administration via inhaled, topical, and
even oral formulations, depending on the partner protein.
The principles behind AlbudAb fusions can also be applied
to other antibody fragment forms or binding components.
Ablynx is using albumin targeting to extend the half-life of
constructs including bispecific nanobodies, while
Affibody's Albumod
TM
technology relates to fusions involv-
ing a 5 kDa albumin-binding domain (ABD). Roche (then
Genentech), Isogenica, and Philochem have developed fur-
ther half-life extension structures based on albumin-binding
elements. In each case, the active protein can be attached
either as part of an FP, or by conjugation.
3.1.3.3 Nonfusion Alternatives A number of nonfusion
half-life extension technologies exist. As with Fc and albu-
min fusion, these largely relate to increasing the size of the
protein in order to reduce degradation and clearance. Attach-
ment of one or more polyethylene glycol (PEG) chains
(PEGylation) is the most widely adopted approach and
has been validated by several successful marketed products.
The large PEG chains can form a shield that protects a
protein from proteolytic degradation, while not overly
blocking its activity. Renal excretion is also slowed and
immunogenicity can be improved. PEG is comparatively
low cost to produce and well understood, but it is non-
biodegradable and concerns have been raised regarding
potential kidney issues, particularly in patients with
impaired renal function [11]. Improvements upon standard
PEGylation have been sought, including more consistent
manufacture (Polytherics' site-specific conjugation) and
altered pharmacokinetics (Enzon's releasable PEGylation).
Alternatives to PEG in development include polysialic
acid (Xenetic Biosciences, PolyXen
1
), hyaluronic acid, and
sugars (Fresenius' HESylation
1
). Approaches that involve
peptide chains can potentially also be produced using
genetic fusion, such as XL-protein's PASylation
1
and
Amunix's XTEN. Strategies to reduce degradation and
extend the half-life of therapeutic proteins do not only
include direct attachment of other molecules. Particles or
microspheres can be used, potentially protecting proteins to
the extent that permits oral dosing [12]. Similarly, Flamel
Technologies' Medusa (R) nanogel is a looser entrapment
approach (pGluVE or PGA A1).
In an interesting scenario, Eli Lilly was developing
two human GLP-1 products—dulaglutide (GLP-1-Fc,
LY2189265) and GLP-1-PEG (LY2428757), positioned as
alternatives to the GLP-1 analog peptide exenatide, which is
available in a twice-daily injectable (Byetta
1
) and more
recently, a once-weekly form (Bydureon
TM
; approved in
the EU, but in registration in the United States with a decision
date of January 28, 2012). At this time, dulaglutide (GLP-1-
Fc) appears to have been preferentially progressed into
studies. Several other next-generation GLP-1 candidates
are also in development, including HGS/GlaxoSmithKline's
albumin fusion, albiglutide. We have forecast dulaglutide and
albiglutide to be in the top 6 FP drugs by sales in 2016 (see
Chapter 2). Following its acquisition of CovX in 2007, Pfizer
is undertaking Phase I studies of PF-04856883/CVX-096,
which is based on CovX-Body technology wherein a linker is
added to the GLP-1 peptide. This linker is subsequently bound
by a specific injected antibody, which serves to increase the
half-life of the peptide. ConjuChem was developing an albu-
min-GLP-1 conjugate CJC-1134-PC, however, development
may have ceased following liquidation of the company. The
range of approaches highlights the level of competition that
can be faced by longer half-life products. Advantages or
disadvantages of each can depend on the specific application
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