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Biologics: The (Uphill?) Trek
toward Approval and Incorporation into Practice
Diane Cooper, PhD, Director, Clinical Research, Human Genome Sciences,
Inc., Rockville, Maryland, USA
In the 1960s moist wound healing was viewed as a 'revolution' in the treatment
of wounds and, by some, as a mistake. Industry bore the brunt of educating
clinicians in the theory underlying moisture as a good vs. a deleterious
intervention. Despite these efforts, the rationale soon became lost on
many clinicians and seldom was taught in Schools of Medicine or Nursing.
Some of the products used for moist wound healing (i.e., occlusive dressings),
however, led bench scientists to speculate about the constituents of the
fluid contained within them. Eventually studies led to significant efforts
by researchers over the past three decades to decipher the microenvironment
of the healing wound. As a result, the potential now exists to determine:
an acute from a chronic wound, the level of specific endogenous cytokines
within the wounded tissue, the level of exogenous growth factors applied
as well their activity over time, and the effect of bacteria, hypoxia
and inflammation on tissue repair. Despite these advances and the capability
of manufacturing proteins necessary for wound healing, the adoption and
use of these advancements in everyday clinical practice is slow and represents
an enormous challenge.
One stumbling block appears to be a lack of understanding related to the
requirements established for approval of various novel therapies. In the
United States, regulatory agencies require a distinct level of scrutiny
for biologics applied to wounds which is more stringent than that required
for devices; a fact that is poorly understood/valued by most clinicians.
Reimbursement, an issue of increasing significance, is challenged by the
societal view that wound care is simple and therefore, not costly. The
cost of supplies and medications, time required to treat open chronic
wounds, lost work time, and quality-of-life issues are seldom taken into
consideration as expenses. Instead, treatments for which minimal (if any)
scientific support exists are utilized, often without challenge. The length
of time to wound closure is not tracked, time to recurrence and incorporation
of therapies to prevent re-wounding are seldom chronicled.
The cost of conducting large multicenter, randomized, placebo-controlled,
double-blinded clinical trials is increasing. Study sample sizes to adequately
address the research question, the requirements for the numbers of subjects
to include in safety trials for topical agents, and comparisons between
a 'standardized care group' (placebo) which is seldom representative of
routine practice all weigh heavily on the efforts to demonstrate a meaningful
difference between a novel therapy and the comparator. The time for preclinical
work coupled with the protracted time necessary to enroll large trials
eat all away at the time to patent expiration. Yet, without the commitment
by industry to years of necessary work, few of the emerging findings about
wounds and quality wound care would be known or find their way into clinical
practice.
Questions that need to be addressed, such as: 1) given this set of conditions
and hurdles, what is the future of advanced wound healing? 2) And, acknowledging
the current wealth of information about wounds vis-a-vis their potential
for healing, can we turn a blind eye and return to past approaches to
care, simply because they appear less costly and are familiar (i.e., comfortable)
to the health care system and providers?
Topical Biologics: Their Contribution
to Science and Tissue Repair
Diane Cooper, PhD, Director, Clinical Research, Human Genome Sciences,
Inc., Rockville, Maryland, USA
Tissue repair is an extremely complex set of processes, which have only
recently been elucidated. No longer can wounds be considered as repeat
manifestations of the same events. The etiology, duration of the wound,
its micro-environment and the predominant means by which closure is affected
are increasingly forming the basis for both clinical trial design and
treatment decisions by wound care experts. Many of the recent advances
in tissue regeneration and repair have emerged as a result of dedicated
research in conducting multicenter, randomized, placebo-controlled, blinded
clinical trials to evaluate topical bio-logics. Reports in the literature
on basic fibroblast growth factor (bFGF), transforming growth factor beta
(TGFb), keratinocyte growth factor-2 (KGF-2), and platelet derived growth
factor BB (PDGF-BB) have shed light on healing, particularly altered healing.
Much of this information now serves as a foundation for moving forward
in studying the effect of exogenous proteins on tissue repair, as well
as determining how specific wound types should be 'readied' and treated.
When reviewing this literature, it is important to focus not only on the
degree of statistical support for the results of these clinical trials,
but to also concentrate and learn from the unique characteristics identified
for the specific wound type under investigation. Access to large numbers
of patients with similar wounds, who are studied in a controlled manner,
provides a wealth of previously undocumented information. Increased scrutiny
of these study results needs to occur if future clinical trials are to
be well designed and if the information is to be translated into implications
for clinical practice, reimbursing bodies and regulatory agencies.
The ultimate goal of research is to develop theory and a sequence of steps
exists that, if followed, is more likely to ensure a meaningful outcome.
This sequence (descriptive and categorical studies followed by correlational
work, leading ultimately to predictive or experimental research), however,
is seldom followed by investigators studying a phenomenon. As a result,
diversions occur, the original question becomes clouded and the research
'story', in many areas of science, becomes disjointed and protracted.
One example of non-adherence to the steps toward theory-building has been
the study of tissue repair, in particular the repair of chronic wounds.
A number of biologics have recently advanced into clinical trials in humans
using the experimental design as the approach to testing the hypotheses.
At this juncture, only one has received approval by the United States
Food and Drug Administration (US FDA) for use in chronic wounds, recombinant
PDGF-BB (i.e., Regranex®).
This presentation will focus on a review of what the reported literature
has to tell us about the various clinical trials studying topical biologics
in tissue repair. Regardless of the approval status of the study agent,
an attempt will be made to separate out those findings that have merit
for consideration in practice as well as for future trial design. The
goal of the presentation is to begin to sort descriptive findings from
those where correlations have begun to emerge to predictive findings based
on experiments. Much has been studied. More time needs to be devoted to
the findings relevant for accelerating the emergence of wound healing
as a theory-based science.
Keratinocyte growth factors:
important players in epithelial repair processes
Sabine Werner, Susanne Braun, Ulrich auf dem Keller, Monika Krampert,
and Hans-Dietmar Beer, Institute of Cell Biology, ETH Zürich, Hönggerberg,
CH-8093 Zürich, Switzerland
Keratinocyte growth factor (KGF) and its homologue fibroblast growth factor-10
(FGF-10; KGF-2) are potent mitogens for various types of epithelial cells.
Previous studies from our laboratory demonstrated an important role of
these factors and their common receptor in re-epithelialization of skin
wounds. Furthermore, topical application of these growth factors was shown
to stimulate the wound healing process in animal models and also in patients
suffering from chronic ulcers. To gain insight into the mechanisms of
KGF/FGF-10 action we searched for genes, which are regulated by these
growth factors in keratinocytes of the skin. The genes that we identified
encode a putative novel transcription factor, a cell cycle regulator,
several enzymes involved in nucleotide biosynthesis, as well as the matrix
metalloproteinase stromelysin-2. These genes provide insight into the
mechanisms, which underlie the effects of KGF on epithelial cell migration,
proliferation and differentiation. A particularly important function of
KGF is its strong protective effect for various types of epithelial cells.
Recent results from our laboratory suggest a possible role of the transcription
factor Nrf-2 in this effect. Nrf-2 is a potent inducer of various detoxifying
enzymes and stress-inducible proteins. Thus the identification of the
Nrf-2 gene as a target of KGF action suggests that KGF can protect epithelial
cells from oxidative stress and other insults by inducing Nrf-2 expression,
which in turn enhances the production of protective molecules. Finally,
the observed up-regulation of peroxiredoxin VI, a peroxide-detoxifying
enzyme, in response to KGF might further explain the protective effect
of KGF for epithelial cells. Taken together, the functional characterization
of these novel KGF-regulated genes provides an explanation for the beneficial
effect of KGF/FGF-10 on the wound healing process.
References
Yvonne Tretter, Moritz Hertel, Barbara Munz, Gerrit ten Bruggencate, Sabine
Werner and Christian Alzheimer (2000). Induction of activin A is essential
for the neuroprotective action of bFGF in vivo. Nat. Med. 6, 812-815.
Barbara Munz, Hans Smola, Felix Engelhardt, Kerstin Bleuel, Maria Brauchle,
Iris Lein, Lee Ewans, Danny Huylebroeck, Rudi Balling and Sabine Werner
(1999). Overexpression of activin in the epidermis of transgenic mice
reveals new activities of activin in keratinocyte differentiation, cutaneous
fibrosis and wound repair. EMBO J., 18, 5205-5215.
Sabine Werner (1998). Keratinocyte growth factor: A unique player in epithelial
repair processes. Cytokine & Growth Factor Reviews 9, 153-165.
Sabine Werner and Hans Smola (2001). Paracrine regulation of keratinocyte
proliferation and differentiation. Trends Cell Biol. 11, 143-146.
Biological Monitoring of Wounds
Treated by Negative Pressure
R. Vanwijck, D. Manicourt, G. Feruzi-Lukina, Wound Healing Unit, Cliniques
Universitaires Saint Luc, 1200 Brussels, Belgium
Introduction
There are a large number of proteinases which are active in normal wound
healing responses; among them, the matrix metalloproteinases (MMPs) which
are part of a superfamily (of > 40 enzymes) which catabolizes the extracellular
matrix; their activity is partly regulated by the Tissue Inhibitors of
Metalloproteinases (TIMPs).There is general agreement that MMPs are elevated
in chronic compared with acute fluids. It is accepted that the balance
of MMPs and TIMPs following wounding appears crucial in directing successful
wound repair. The relationship between bacterial load to wound healing
is also well established. We studied the effect of negative pressure therapy
on this balance and on the bacterial burden of the wound.
Material and methods
The fluids of 32 wounds (6 subacute/26 chronic) treated by negative pressure
were collected in the tubing immediately after changing wound foam dressing;
the wounds were cleaned with NaCl solution. Samples were sent for qualitative
and quantitative bacteriology and for dosage of MMP-13, MMP-6, TIMP-1
by Enzyme Linked Immunoassay (ELISA).
Results
Negative pressure reduces the bacterial load of the wound but does not
modify the bacterial populations. There is a definite correlation between
a favourable evolution of the wound and a reproducible shift of the MMPs-TIMPs
balance towards the TIMPs. Wounds which poorly respond to negative pressure
therapy keep high levels of MMPs.
Conclusion
A comprehensive study of the biochemical composition of healing and non
healing wound fluids in a hospital environment highlighted the possibility
that biochemical markers could be used to evaluate wound healing. In the
future the development of selective MMP inhibitors may offer some hope
as therapeutic modality.
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