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Produced by an NHS collaboration of

the United Kingdom Medicines


Information Pharmacists’ Group
and The National Prescribing Centre

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].

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APLIGRAF
INTRODUCTION mechanism is by the production of growth factors,
which stimulate healing by secondary intention from
Chronic wounds such as diabetic ulcers, venous ulcers the wound edges [6]. Evidence for this is provided by
and pressure sores are a major cause of morbidity and instances of rapid wound healing even with incomplete
a major expense to the health service, particularly in graft ‘take’ [7]. In the third mechanism, Apligraf serves
primary care. Prevalence of venous leg ulcers (VLU) as a semi-permanent occlusive cover under which
is estimated to be 150-300 per 100,000 of the population growth factors are delivered [6].
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- EFFICACY
400 million (based on 1991 prices) a major component
of which is nursing time [1]. About 60-80% of chronic Venous leg ulcers
leg ulcers are associated with venous insufficiency [2].
Currently VLU are managed by GPs, community nurses Evidence for the efficacy of Apligraf in the treatment
and in the hospital setting, usually by compression of venous ulcers is provided by a single randomised
therapy [1]. At some point in their lives, 15% of patients open label trial [8]. This multicentre study (based in 15
with diabetes will develop a foot ulcer [3,4]. Of these centres) randomised 309 patients and evaluated 275
patients, approximately 5-15% will require a lower patients. Efficacy was assessed at six months with
extremity amputation. Foot ulcers are one of the most safety additionally assessed at twelve months. Prior to
costly aspects of treating diabetes, with most patients enrolment, about 50% of patients had ulcers that had
being managed in the community by district nurses [3]. 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
THE TECHNOLOGY and received compression therapy with a zinc oxide
impregnated paste bandage (Unna’s boot) and a self-
Apligraf (graftskin) is a human skin equivalent adherent elastic wrap. Compression therapy was re-
containing living allogeneic cells. It is manufactured applied weekly for the first eight weeks of the study.
from cultured human fibroblasts and keratinocytes In the Apligraf group (n=146), Apligraf was applied
derived from donated neonatal foreskin with each sheet directly to the ulcer followed by the same secondary
derived from a single donor. It comprises a layer dressings, without the Unna’s boot. Apligraf could be
containing fibroblasts in a lattice of bovine, type 1 applied a maximum of five times during the initial three
collagen equivalent to the dermis and an epidermis weeks of the study. After eight weeks, or on complete
equivalent containing differentiating keratinocytes. healing, both treatment groups used graded elastic
Towards the end of manufacture, the epidermal layer stockings as a means of compression for the remainder
is exposed at a liquid/air interface so that a stratum of the study.
corneum develops. This provides good barrier
properties against infection, mechanical pressure and The primary efficacy endpoints were incidence of
desiccation, and mechanical strength allowing easier complete healing by six months and the time required
handling. Apligraf does not contain other components for complete healing. The percentage of patients with
of normal skin such as dendritic and capillary complete wound closure by six months was 63% in
endothelial cells. Apligraf differs from technologies the Apligraf group and 48.8% in the control group
where autologous cells are cultured to provide an (p = 0.02) giving a number needed to treat (NNT) of
epidermal layer. It is available without the delay 7. The median number of days to complete wound
involved in culturing autologous cells and avoids the closure was 61 in the Apligraf group (range 9 to 233
need for skin grafting and consequent creation of donor days) and 181 in the control group (range 10 to 232
wound sites [5]. 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
MECHANISM OF ACTION 92 days vs. 190 days for the control group (p = 0.001).
In ulcers of less than six months duration, before the
There are three possible mechanisms of action by which trial commenced, the difference was not statistically
apligraf may stimulate wound healing [6]. The apligraf significant (46 vs. 89 days to closure p = 0.5). Duration
may ‘take’ in the same way as a skin graft with of ulcer was not, however, stratified across the two
persistence of graft cells in the wound site. The second groups. There was no difference in the rate of

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APLIGRAF
recurrence at one year between the Apligraf (95%CI 1.23 – 3.74). The average number of
and control groups (12% in Apligraf patients vs. Apligraf applications was 3.9 (maximum
15.9% in control patients p=0.48). Adverse allowable under the protocol was 5).
events and reasons for dropout were similar in
both groups. At six months the incidence of ulcer recurrence
was 5.9% in the Apligraf group and 12.9% in
The compression provided by the elastic bandage the control group (this result was not significant).
used was lower than current guidelines, which The number and types of adverse effects were
suggest 40mmHg at the ankle to reverse venous similar, except for the development of
hypertension. Unna’s boot provides low resting osteomyelitis at the studied ulcer site (2.7% in
pressure but high pressure during activity and is Apligraf group, 10.4% in control group) and
the preferred method of treating leg ulcers in amputations at the studied limb (6.3% in Apligraf
the US [1]. Apligraf has not been studied with group, 15.6% in control group).
the 4-layer compression bandage systems which
are commonly used in the UK. In addition, Moistened gauze treatment is not standard
Apligraf is not expected to be a first line therapy. treatment for DFUs in the UK and so it is not
It will be used when good wound care alone known how Apligraf would compare with other
fails to heal the ulcer satisfactorily and it is not primary dressings e.g. foams. Again, Apligraf is
known if this is the patient group that this not expected to be a first line therapy and will
trial examined. 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
Diabetic foot ulcers whether these results will be directly applicable
to that patient group.
Evidence for the efficacy of Apligraf in the
treatment of DFUs is provided by a single
randomised, open-label trial [9]. This multicentre Other Uses
study (based in 24 centres) involved 208 diabetic
patients with full thickness neuropathic ulcers Apligraf has been studied in other conditions
of at least two weeks duration. All patients where skin integrity is compromised such as
completed a one week screening period during epidermolysis bullosa [10], burns [11] and split
which healing response to saline moistened skin graft donor sites [12]. The company has
gauze after aggressive debridement was not applied for a licence for these uses at present.
assessed. Those with a 30% or more decrease
in ulcer size with gauze treatment were excluded
from continuing in the trial. Patients were then PHARMACOECONOMIC AND
randomised to treatment with Apligraf (n=112) QUALITY OF LIFE DATA
or saline moistened gauze (n=96). Apligraf
patients had Apligraf applied on day 0 and One company sponsored pharmacoeconomic
repeated once weekly for a maximum of four evaluation of Apligraf in hard-to-heal VLUs has
further applications. All patients received the been published [13]. The analysis is based on
same adjunctive treatment including extensive the efficacy data in Falanga et al [8] and
surgical debridement and weight off-loading. concludes that Apligraf is more cost effective
than compression therapy with Unna’s boot in a
The primary efficacy parameter was complete US perspective of a commercial health plan.
wound healing at twelve weeks. This was With the exception of healing rates (derived from
achieved in 56% of Apligraf treated patients and the clinical trial) and costs of Apligraf (provided
38% of controls. The difference was statistically by the manufacturer) all components are
significant (p = 0.0042) and produced a NNT of modelled. This model withstands a range of
5. The Kaplan-Meier median time to complete sensitivity analyses where assumptions on
wound closure was 65 days for Apligraf probabilities of healing, recurrence, and the costs
compared to 90 days for control. The odds ratio of Apligraf and of hospitalisation are varied, but
for complete healing for an Apligraf treated ulcer is not based on actual health care costs. The
compared with a control treated ulcer was 2.14 model is based on a US health care setting, which

4
APLIGRAF
may not be applicable to the UK. The cost CONTRAINDICATIONS/
estimates were most sensitive to a change in PRECAUTIONS
the cost of hospitalisation, which is likely to vary
in different areas. No account is taken of any In the US, Apligraf is contraindicated in clinically
alterations in service delivery that would be infected wounds and in patients with known
necessary to facilitate use of Apligraf. allergies to bovine collagen or hypersensitivity
to the components of its shipping medium. In
A small pilot study (n=14) assessed health- clinical trials patients with significant medical
related quality of life in VLU patients treated conditions which impair wound healing or those
with Apligraf during the previous twelve weeks treated with immunosuppressive agents or
[14]. This pilot study showed statistically steroids were excluded, as were pregnant or
significant improvements in pain and other breast-feeding women. Patients with wounds
physical health dimensions but is compromised experiencing significantly impaired arterial
by small sample size, the inclusion of only circulation were excluded from the two main
successfully treated patients and the potential studies. Those with wounds which were
for recall bias and so the results should be infected, or in an area where cellulitis or vasculitis
interpreted with caution. was present were also excluded. In a case series
reporting the use of Apligraf in DFUs and
pressure sores Apligraf was ineffective where
ADVERSE EFFECTS the wound was adjacent to an area of
osteomyelitis [16].
Adverse effects seen in clinical trials include
wound infection, cellulitis, osteomyelitis of the Allergic reactions to components of the Apligraf
underlying bone and amputation on the study limb. agarose shipping medium and bovine collagen
In the VLU trial [8] there were no significant have been reported. The product should be
differences in the frequency of wound infection, discontinued if the patient shows any evidence
cellulitis or pain, the three main adverse effects. of an immunologic reaction [15].
No significant differences were found between
the two groups in drop-out rates or reasons for
discontinuation. Similar results were seen in the SERVICE IMPLICATIONS
DFU trial. Occurrence rates were not
significantly different to controls, except for Apligraf is not expected to be a first line therapy.
osteomyelitis and amputation, which occurred It will be used when good wound care alone
at a lower rate with Apligraf [9]. fails to heal the ulcer satisfactorily. Effective use
requires training and experience and the
There was no evidence for the development of company plans to only make Apligraf available
antibody responses to the collagen or the human to appropriately trained specialised wound care
cells in Apligraf and no clinical evidence of physicians. Establishment of wound care clinics
rejection or of an immunological response. may require considerable reorganisation of
Apligraf does not contain immunogenic cells such services in some areas if Apligraf were to be used
as dendritic cells, endothelial cells and optimally; this may not fit with local priorities.
leukocytes. The trials were, however, small and
may not have been of sufficient size to detect A 1985 survey found that for 83% of leg ulcers,
some adverse effects. care was carried out entirely in the community
[17]. Apligraf, once manufactured has a shelf
As Apligraf contains living human tissue there life of five days and must be kept at a
is the possibility of the transmission of infective controlled temperature between 21° and
agents. The company tests the cell banks from 30°C. This may present logistical difficulties in
which Apligraf is derived for known human and terms of receiving orders and organising clinics.
animal viruses, retroviruses, bacteria, fungi, yeast
and mycoplasma. All bovine material is obtained In clinical trials, Apligraf was used as an adjunct
from countries free from bovine spongiform to current best therapy. It is not a substitute for
encephalopathy (BSE) [15]. good wound care in venous and diabetic ulcers

5
APLIGRAF
or pressure off-loading in diabetic foot ulcers. It has per 100,000 who may have the potential to use Apligraf.
been suggested that a learning curve exists for optimum If all these patients received Apligraf at the estimated
use of Apligraf [9,18]. It is likely that it will only be price above, this would cost in the region of £92,000-
available to specialist centres, perhaps only 20-30 in £230,000 per 100,000 population.
the UK and that clinicians will have undergone a training
programme conducted by peers who have significant For DFU, it is estimated 50,000 people have ulcers
experience with the use of Apligraf [18]. and up to 40% of these may not heal satisfactorily with
good wound care alone. Therefore potentially 20,000
Assuming Apligraf is priced similarly to its US price, in patients, or 33 per 100,000 could be applicable to use
the UK, an application would cost approximately £765 Apligraf. If all these patients received Apligraf, this
(exchange rate of 1.4 dollars to the pound). A treatment would cost approximately £50,000-£125,000 per
course would therefore cost between £1530-£3825 per 100,000 population.
patient.
Potential savings could be made if a reduction in hospital
Based on figures from the company VLU has a admissions, dressing changes, staff time, amputations
prevalence of about 90,000 people in the UK, of which and rehabilitation costs are seen in patients receiving
up to 40% may not heal satisfactorily with good wound Apligraf. However, the financial implications of having
care alone. There are, therefore, 36,000 patients, or 60 to reconfigure services has not been assessed here.

References foot ulcers: a prospective randomized multicenter clinical trial.


1. NHS Centre for Reviews and Dissemination. Compression therapy Diabetes Care 2001; 24(2): 290-5
for venous leg ulcers. University of York. Effective Health Care 10. Falabella AF, et al. Tissue engineered skin (Apligraf) in the healing
1997; 3(4): 1-12 of patients with epidermolysis bullosa wounds. Arch Dermatol
2. Scottish Intercollegiate Guidelines Network. The care of 2000; 1361225-30
patients with chronic leg ulcer. 1998; 26: 1-19 11. Waymack P, et al. The effect of a tissue engineered bilayered
3. NHS Centre for Reviews and Dissemination. Complications of living skin analog, over meshed split-thickness autografts on the
diabetes: Screening for retinopathy. Management of foot ulcers. healing of excised burn wounds. The Apligraf Burn Study Group.
University of York. Effective Health Care 1999; 5(4): 1-12 Burns 2000;26(7):609-19.
4. American Diabetes Association. Consensus development 12. Muhart M, et al. Behavior of tissue-engineered skin: a comparison
conference on diabetic foot wound care. 7-8 April 1999 Boston of a living skin equivalent, autograft, and occlusive dressing in
Massachusetts. Diabetes Care 1999; 22(8): 1354-60 human donor sites. Arch Dermatol 1999; 135(8): 913-8.
5. Novartis aplifgraf website. Available at: www.apligraf.com/content/ 13. Schonfeld WH, et al. An economic assessment of Apligraf
proddescrp.htm (Graftskin) for the treatment of hard-to-heal venous leg ulcers.
6. Alvarez OM, et al. A novel treatment for venous leg ulcers. J Wound Repair Regeneration 2000; 8(4): 251-7.
Foot Ankle Surg 1998; 37(4): 319-24 14. Mathias SD, et al. Health-related quality of life in venous leg
7. Choucair M, Faria D, and Fivenson D. Use of human skin ulcer patients successfully treated with Apligraf: a pilot study.
equivalent in the successful treatment of chronic venous leg ulcers. Advances in Skin & Wound Care 2000; 13(2): 76-8.
Wounds 1998; 10(3): 97-104 15. Organogenesis Inc. Apligraf (graftskin) label. US. 2000
8. Falanga V, et al. Rapid healing of venous ulcers and lack of clinical 16. Brem H, Balledux J, Bloom T, Kerstein MD, Hollier L. Healing of
rejection with an allogeneic cultured human skin equivalent. diabetic foot ulcers and pressure ulcers with human skin equivalent:
Human Skin Equivalent Investigators Group. Arch Dermatol 1998; a new paradigm in wound healing. Arch Surg 2000; 135(6): 627-34
134(3): 293-300 17. Callam M, et al. Chronic ulceration of the leg: extent of the
9. Veves A, Falanga V, Armstrong DG, Sabolinski ML, The Apligraf problem and provision of care. BMJ 1985; 290:1855-6
Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is 18. Diabetic foot study group meeting. Tissue engineering for wound
effective in the management of noninfected neuropathic diabetic care. The diabetic foot; 4(3): 147-150