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NEW DRUGS IN CLINICAL DEVELOPMENT

Advance Evaluated Information for Confidential use by NHS Managers and Budget Holders
with additional data on health service impact

APLIGRAF
Summary
Clinical Impact
• Apligraf is a human skin equivalent for use as wound healing agent. The proposed licence indications are the
treatment of partial and full thickness skin loss in ulcers of venous aetiology, and the treatment of partial and full
thickness neuropathic diabetic foot ulcers, both of greater then three to four weeks duration.
• Venous Leg Ulcers (VLU): There has been one randomised, open-label trial, examining the efficacy of Apligraf
compared to treatment with Unna’s boot in 275 patients with a VLU over a six month period. A significantly
greater number of patients in the Apligraf group showed complete healing at six months compared to comparative
treatment (63% vs. 49%), a NNT of 7. There was no difference in the rate of recurrence at one year between the
Apligraf and control groups (12% in Apligraf patients vs. 15.9% in control patients, p=0.48). Adverse events and
reasons for dropout were similar in both groups
• Diabetic Foot Ulcers (DFU): There has been one 12 week, randomised open-label trial examining the efficacy of
Apligraf compared to saline moistened gauze (a dressing not commonly used in the management of DFUs in the
UK), in 208 diabetic patients with a DFU of at least two weeks duration. A significantly greater number of patients
in the Apligraf group showed complete healing at the end of the twelve weeks compared to treatment with
moistened gauze (56% vs. 38%), an NNT of 5. At six month follow-up, rate of ulcer recurrence did not vary
significantly between groups and adverse events and reasons for dropout were similar in both groups

Financial issues and NHS Impact

• Apligraf is an adjunct to, and not a substitute for, good wound care, adequate debridement, treatment of infection,
and pressure off-loading, and so costs will be in addition to these interventions. Apligraf does not address the
underlying disease and so normal steps need to be taken to prevent recurrence.
• VLU has a prevalence of about 90,000 people in the UK, of which up to 40% may not heal satisfactorily with good
wound care alone. Therefore 36,000 patients could be treated (60/100,000 of the general population). For DFU, it
is estimated that 50,000 people in the UK have ulcers and up to 40% of these may not heal satisfactorily with good
wound care alone. Therefore, 20,000 patients could be treated (33/100,000 of the general population). Currently
the cost of Apligraf is not known and so it is difficult to predict financial impact. If the price is similar to that in the
US, an application may cost approximately £765 and a maximum course £3825, per patient. This may be offset in
part by theoretical savings from other areas e.g. dressing costs, staff time etc.
• Apligraf, once manufactured, has a shelf-life on five days and must be kept at a controlled temperature between
21° and 30°C. There may, therefore, be logistical difficulties in terms of receiving orders and organising clinics. It
is likely that Apligraf will only be made available to approximately 20-30 specialist centres in the UK.

Date Published: December 2001 Monograph Number: 3/01/07

Region of Origin to whom queries should be directed: North Thames

• Monographs for unlicensed drugs/indications must not • The information contained herein will be superseded in
be circulated to prescribers. due course.
• Not to be used for commercial purposes. • Copyright UKMIPG 2001.
 APLIGRAF
APPROVED NAME Not known.

BRAND NAME Apligraf.

SYNONYM Graftskin, Human Skin Equivalent (HSE).

PROPOSED INDICATION For the treatment of partial and full thickness skin loss in ulcers of venous
aetiology (Venous Leg Ulcers), which extend through the dermis but without
tendon, muscle, capsule or bone exposure and the treatment of full and partial
thickness neuropathic diabetic foot ulcers (DFU) which extend through the
dermis but without tendon, muscle, capsule or bone exposure, both of greater
than three to four weeks duration.

PRESENTATION Apligraf is a bi-layered living skin equivalent. It consists of a 65 to 75 mm

diameter disc of living human skin equivalent, separated by a permeable
membrane from a nutrient medium. It is packaged in a plastic container, sealed
within a plastic bag containing an atmosphere of 10% carbon dioxide. Once
manufactured Apligraf has a shelf life of five days.

LICENCE STATUS Submitted to the EMEA. If approved it may be licensed early 2002. Apligraf is
currently available in Switzerland and North America.

THERAPEUTIC CLASS Not yet known.

DOSE Determined by wound response. Current data suggests that given good
wound care, most wounds which heal do so with two applications spaced at
least four weeks apart. No more than five applications should be given.

COST/COURSE In the US Apligraf is $1070 (approximately £765) per unit. Most applications
are of one unit.

ESTIMATED USAGE Apligraf is not expected to be a first line therapy. It will be used when good
wound care alone fails to heal the ulcer satisfactorily. Effective use requires
training and experience. The company plans to only make Apligraf available
to appropriately trained specialised wound care clinicians.

VLU has a prevalence of about 90,000 people in the UK, of which up to 40%
may not heal satisfactorily with good wound care alone. Therefore 36,000
patients could be treated (60/100,000 of the general population). For DFU, it is
estimated that 50,000 people in the UK have ulcers and up to 40% of these
may not heal satisfactorily with good wound care alone. Therefore, 20,000
patients could be treated (33/100,000 of the general population). [Personal
Communication: Novartis].

TREATMENT ALTERNATIVES Treatment Cost for treatment episode

Becaplermin 0.01% gel (Regranex) £275 per 15g tube
(for DFU)

Compression therapy (for VLU) and surgical debridement plus pressure off-
loading (for DFU) are the main treatments for these conditions but we are
unable to quantify costs for these as they are dependant on staff time, length
of hospital admission etc.

DRUG USAGE N/A

AREAS OF POTENTIAL USE Hospital [Y] Primary Care [unlikely].

2
 APLIGRAF
INTRODUCTION
Chronic wounds such as diabetic ulcers, venous ulcers
and pressure sores are a major cause of morbidity and
a major expense to the health service, particularly in
primary care. Prevalence of venous leg ulcers (VLU)
is estimated to be 150-300 per 100,000 of the population
and increases with age to about 2,000 per 100,000 in
those over 80 years. Annual costs to the NHS of leg
ulceration have been estimated to be as high as £230-
400 million (based on 1991 prices) a major component
of which is nursing time [1]. About 60-80% of chronic
leg ulcers are associated with venous insufficiency [2].
Currently VLU are managed by GPs, community nurses
and in the hospital setting, usually by compression
therapy [1]. At some point in their lives, 15% of patients
with diabetes will develop a foot ulcer [3,4]. Of these
patients, approximately 5-15% will require a lower
extremity amputation. Foot ulcers are one of the most
costly aspects of treating diabetes, with most patients
being managed in the community by district nurses [3].
THE TECHNOLOGY
Apligraf (graftskin) is a human skin equivalent
containing living allogeneic cells. It is manufactured
from cultured human fibroblasts and keratinocytes
derived from donated neonatal foreskin with each sheet
derived from a single donor. It comprises a layer
containing fibroblasts in a lattice of bovine, type 1
collagen equivalent to the dermis and an epidermis
equivalent containing differentiating keratinocytes.
Towards the end of manufacture, the epidermal layer
is exposed at a liquid/air interface so that a stratum
corneum develops. This provides good barrier
properties against infection, mechanical pressure and
desiccation, and mechanical strength allowing easier
handling. Apligraf does not contain other components
of normal skin such as dendritic and capillary
endothelial cells. Apligraf differs from technologies
where autologous cells are cultured to provide an
epidermal layer. It is available without the delay
involved in culturing autologous cells and avoids the
need for skin grafting and consequent creation of donor
wound sites [5].
MECHANISM OF ACTION
There are three possible mechanisms of action by which
apligraf may stimulate wound healing [6]. The apligraf
may ‘take’ in the same way as a skin graft with
persistence of graft cells in the wound site. The second
3
mechanism is by the production of growth factors,
which stimulate healing by secondary intention from
the wound edges [6]. Evidence for this is provided by
instances of rapid wound healing even with incomplete
graft ‘take’ [7]. In the third mechanism, Apligraf serves
as a semi-permanent occlusive cover under which
growth factors are delivered [6].
EFFICACY
Venous leg ulcers
Evidence for the efficacy of Apligraf in the treatment
of venous ulcers is provided by a single randomised
open label trial [8]. This multicentre study (based in 15
centres) randomised 309 patients and evaluated 275
patients. Efficacy was assessed at six months with
safety additionally assessed at twelve months. Prior to
enrolment, about 50% of patients had ulcers that had
persisted for more than one year. Control patients
(n=129) had their ulcer dressed with a non-adherent
primary dressing followed by a cotton gauze bolster
and received compression therapy with a zinc oxide
impregnated paste bandage (Unna’s boot) and a self-
adherent elastic wrap. Compression therapy was re-
applied weekly for the first eight weeks of the study.
In the Apligraf group (n=146), Apligraf was applied
directly to the ulcer followed by the same secondary
dressings, without the Unna’s boot. Apligraf could be
applied a maximum of five times during the initial three
weeks of the study. After eight weeks, or on complete
healing, both treatment groups used graded elastic
stockings as a means of compression for the remainder
of the study.
The primary efficacy endpoints were incidence of
complete healing by six months and the time required
for complete healing. The percentage of patients with
complete wound closure by six months was 63% in
the Apligraf group and 48.8% in the control group
(p = 0.02) giving a number needed to treat (NNT) of
7. The median number of days to complete wound
closure was 61 in the Apligraf group (range 9 to 233
days) and 181 in the control group (range 10 to 232
days) (p = 0.003). Subgroup analyses showed that in
patients with ulcers of greater than six months duration
the median number of days to complete healing was
92 days vs. 190 days for the control group (p = 0.001).
In ulcers of less than six months duration, before the
trial commenced, the difference was not statistically
significant (46 vs. 89 days to closure p = 0.5). Duration
of ulcer was not, however, stratified across the two
groups. There was no difference in the rate of
 APLIGRAF
recurrence at one year between the Apligraf
and control groups (12% in Apligraf patients vs.
15.9% in control patients p=0.48). Adverse
events and reasons for dropout were similar in
both groups.
The compression provided by the elastic bandage
used was lower than current guidelines, which
suggest 40mmHg at the ankle to reverse venous
hypertension. Unna’s boot provides low resting
pressure but high pressure during activity and is
the preferred method of treating leg ulcers in
the US [1]. Apligraf has not been studied with
the 4-layer compression bandage systems which
are commonly used in the UK. In addition,
Apligraf is not expected to be a first line therapy.
It will be used when good wound care alone
fails to heal the ulcer satisfactorily and it is not
known if this is the patient group that this
trial examined.
Diabetic foot ulcers
Evidence for the efficacy of Apligraf in the
treatment of DFUs is provided by a single
randomised, open-label trial [9]. This multicentre
study (based in 24 centres) involved 208 diabetic
patients with full thickness neuropathic ulcers
of at least two weeks duration. All patients
completed a one week screening period during
which healing response to saline moistened
gauze after aggressive debridement was
assessed. Those with a 30% or more decrease
in ulcer size with gauze treatment were excluded
from continuing in the trial. Patients were then
randomised to treatment with Apligraf (n=112)
or saline moistened gauze (n=96). Apligraf
patients had Apligraf applied on day 0 and
repeated once weekly for a maximum of four
further applications. All patients received the
same adjunctive treatment including extensive
surgical debridement and weight off-loading.
The primary efficacy parameter was complete
wound healing at twelve weeks. This was
achieved in 56% of Apligraf treated patients and
38% of controls. The difference was statistically
significant (p = 0.0042) and produced a NNT of
5. The Kaplan-Meier median time to complete
wound closure was 65 days for Apligraf
compared to 90 days for control. The odds ratio
for complete healing for an Apligraf treated ulcer
compared with a control treated ulcer was 2.14
4
(95%CI 1.23 – 3.74). The average number of
Apligraf applications was 3.9 (maximum
allowable under the protocol was 5).
At six months the incidence of ulcer recurrence
was 5.9% in the Apligraf group and 12.9% in
the control group (this result was not significant).
The number and types of adverse effects were
similar, except for the development of
osteomyelitis at the studied ulcer site (2.7% in
Apligraf group, 10.4% in control group) and
amputations at the studied limb (6.3% in Apligraf
group, 15.6% in control group).
Moistened gauze treatment is not standard
treatment for DFUs in the UK and so it is not
known how Apligraf would compare with other
primary dressings e.g. foams. Again, Apligraf is
not expected to be a first line therapy and will
be used when good wound care alone fails to
heal the ulcer satisfactorily. It is not clear if this
is the patient group that this trial examined and
whether these results will be directly applicable
to that patient group.
Other Uses
Apligraf has been studied in other conditions
where skin integrity is compromised such as
epidermolysis bullosa [10], burns [11] and split
skin graft donor sites [12]. The company has
not applied for a licence for these uses at present.
PHARMACOECONOMIC AND
QUALITY OF LIFE DATA
One company sponsored pharmacoeconomic
evaluation of Apligraf in hard-to-heal VLUs has
been published [13]. The analysis is based on
the efficacy data in Falanga et al [8] and
concludes that Apligraf is more cost effective
than compression therapy with Unna’s boot in a
US perspective of a commercial health plan.
With the exception of healing rates (derived from
the clinical trial) and costs of Apligraf (provided
by the manufacturer) all components are
modelled. This model withstands a range of
sensitivity analyses where assumptions on
probabilities of healing, recurrence, and the costs
of Apligraf and of hospitalisation are varied, but
is not based on actual health care costs. The
model is based on a US health care setting, which
 APLIGRAF
may not be applicable to the UK. The cost
estimates were most sensitive to a change in
the cost of hospitalisation, which is likely to vary
in different areas. No account is taken of any
alterations in service delivery that would be
necessary to facilitate use of Apligraf.
A small pilot study (n=14) assessed health-
related quality of life in VLU patients treated
with Apligraf during the previous twelve weeks
[14]. This pilot study showed statistically
significant improvements in pain and other
physical health dimensions but is compromised
by small sample size, the inclusion of only
successfully treated patients and the potential
for recall bias and so the results should be
interpreted with caution.
ADVERSE EFFECTS
Adverse effects seen in clinical trials include
wound infection, cellulitis, osteomyelitis of the
underlying bone and amputation on the study limb.
In the VLU trial [8] there were no significant
differences in the frequency of wound infection,
cellulitis or pain, the three main adverse effects.
No significant differences were found between
the two groups in drop-out rates or reasons for
discontinuation. Similar results were seen in the
DFU trial. Occurrence rates were not
significantly different to controls, except for
osteomyelitis and amputation, which occurred
at a lower rate with Apligraf [9].
There was no evidence for the development of
antibody responses to the collagen or the human
cells in Apligraf and no clinical evidence of
rejection or of an immunological response.
Apligraf does not contain immunogenic cells such
as dendritic cells, endothelial cells and
leukocytes. The trials were, however, small and
may not have been of sufficient size to detect
some adverse effects.
As Apligraf contains living human tissue there
is the possibility of the transmission of infective
agents. The company tests the cell banks from
which Apligraf is derived for known human and
animal viruses, retroviruses, bacteria, fungi, yeast
and mycoplasma. All bovine material is obtained
from countries free from bovine spongiform
encephalopathy (BSE) [15].
5
CONTRAINDICATIONS/
PRECAUTIONS
In the US, Apligraf is contraindicated in clinically
infected wounds and in patients with known
allergies to bovine collagen or hypersensitivity
to the components of its shipping medium. In
clinical trials patients with significant medical
conditions which impair wound healing or those
treated with immunosuppressive agents or
steroids were excluded, as were pregnant or
breast-feeding women. Patients with wounds
experiencing significantly impaired arterial
circulation were excluded from the two main
studies. Those with wounds which were
infected, or in an area where cellulitis or vasculitis
was present were also excluded. In a case series
reporting the use of Apligraf in DFUs and
pressure sores Apligraf was ineffective where
the wound was adjacent to an area of
osteomyelitis [16].
Allergic reactions to components of the Apligraf
agarose shipping medium and bovine collagen
have been reported. The product should be
discontinued if the patient shows any evidence
of an immunologic reaction [15].
SERVICE IMPLICATIONS
Apligraf is not expected to be a first line therapy.
It will be used when good wound care alone
fails to heal the ulcer satisfactorily. Effective use
requires training and experience and the
company plans to only make Apligraf available
to appropriately trained specialised wound care
physicians. Establishment of wound care clinics
may require considerable reorganisation of
services in some areas if Apligraf were to be used
optimally; this may not fit with local priorities.
A 1985 survey found that for 83% of leg ulcers,
care was carried out entirely in the community
[17]. Apligraf, once manufactured has a shelf
life of five days and must be kept at a
controlled temperature between 21° and
30°C. This may present logistical difficulties in
terms of receiving orders and organising clinics.
In clinical trials, Apligraf was used as an adjunct
to current best therapy. It is not a substitute for
good wound care in venous and diabetic ulcers
 APLIGRAF
or pressure off-loading in diabetic foot ulcers. It has
been suggested that a learning curve exists for optimum
use of Apligraf [9,18]. It is likely that it will only be
available to specialist centres, perhaps only 20-30 in
the UK and that clinicians will have undergone a training
programme conducted by peers who have significant
experience with the use of Apligraf [18].
Assuming Apligraf is priced similarly to its US price, in
the UK, an application would cost approximately £765
(exchange rate of 1.4 dollars to the pound). A treatment
course would therefore cost between £1530-£3825 per
patient.
Based on figures from the company VLU has a
prevalence of about 90,000 people in the UK, of which
up to 40% may not heal satisfactorily with good wound
care alone. There are, therefore, 36,000 patients, or 60
References
1. NHS Centre for Reviews and Dissemination. Compression therapy
for venous leg ulcers. University of York. Effective Health Care
1997; 3(4): 1-12
2. Scottish Intercollegiate Guidelines Network. The care of
patients with chronic leg ulcer. 1998; 26: 1-19
3. NHS Centre for Reviews and Dissemination. Complications of
diabetes: Screening for retinopathy. Management of foot ulcers.
University of York. Effective Health Care 1999; 5(4): 1-12
4. American Diabetes Association. Consensus development
conference on diabetic foot wound care. 7-8 April 1999 Boston
Massachusetts. Diabetes Care 1999; 22(8): 1354-60
5. Novartis aplifgraf website. Available at: www.apligraf.com/content/
proddescrp.htm
6. Alvarez OM, et al. A novel treatment for venous leg ulcers. J
Foot Ankle Surg 1998; 37(4): 319-24
7. Choucair M, Faria D, and Fivenson D. Use of human skin
equivalent in the successful treatment of chronic venous leg ulcers.
Wounds 1998; 10(3): 97-104
8. Falanga V, et al. Rapid healing of venous ulcers and lack of clinical
rejection with an allogeneic cultured human skin equivalent.
Human Skin Equivalent Investigators Group. Arch Dermatol 1998;
134(3): 293-300
9. Veves A, Falanga V, Armstrong DG, Sabolinski ML, The Apligraf
Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is
effective in the management of noninfected neuropathic diabetic
per 100,000 who may have the potential to use Apligraf.
If all these patients received Apligraf at the estimated
price above, this would cost in the region of £92,000-
£230,000 per 100,000 population.
For DFU, it is estimated 50,000 people have ulcers
and up to 40% of these may not heal satisfactorily with
good wound care alone. Therefore potentially 20,000
patients, or 33 per 100,000 could be applicable to use
Apligraf. If all these patients received Apligraf, this
would cost approximately £50,000-£125,000 per
100,000 population.
Potential savings could be made if a reduction in hospital
admissions, dressing changes, staff time, amputations
and rehabilitation costs are seen in patients receiving
Apligraf. However, the financial implications of having
to reconfigure services has not been assessed here.
foot ulcers: a prospective randomized multicenter clinical trial.
Diabetes Care 2001; 24(2): 290-5
10. Falabella AF, et al. Tissue engineered skin (Apligraf) in the healing
of patients with epidermolysis bullosa wounds. Arch Dermatol
2000; 1361225-30
11. Waymack P, et al. The effect of a tissue engineered bilayered
living skin analog, over meshed split-thickness autografts on the
healing of excised burn wounds. The Apligraf Burn Study Group.
Burns 2000;26(7):609-19.
12. Muhart M, et al. Behavior of tissue-engineered skin: a comparison
of a living skin equivalent, autograft, and occlusive dressing in
human donor sites. Arch Dermatol 1999; 135(8): 913-8.
13. Schonfeld WH, et al. An economic assessment of Apligraf
(Graftskin) for the treatment of hard-to-heal venous leg ulcers.
Wound Repair Regeneration 2000; 8(4): 251-7.
14. Mathias SD, et al. Health-related quality of life in venous leg
ulcer patients successfully treated with Apligraf: a pilot study.
Advances in Skin & Wound Care 2000; 13(2): 76-8.
15. Organogenesis Inc. Apligraf (graftskin) label. US. 2000
16. Brem H, Balledux J, Bloom T, Kerstein MD, Hollier L. Healing of
diabetic foot ulcers and pressure ulcers with human skin equivalent:
a new paradigm in wound healing. Arch Surg 2000; 135(6): 627-34
17. Callam M, et al. Chronic ulceration of the leg: extent of the
problem and provision of care. BMJ 1985; 290:1855-6
18. Diabetic foot study group meeting. Tissue engineering for wound
care. The diabetic foot; 4(3): 147-150