FDA Panel Backs Radiesse Approval, With Conditions

COSMECEUTICAL CRITIQUE: GINSENG, PAGE 18
Skin & Allergy News
www.skinandallergynews.com
V OL. 37, NO. 10 The Leading Independent Newspaper for Medical, Surgical, and Aesthetic Dermatology O CTOBER 2006
Dr. David Woodley is calling on dermatology leaders to support a
clinical study in children with dystrophic epidermolysis bullosa.
Funding Stalls DEB
Therapy Advance
BY ERIK L. GOLDMAN
Contributing Writer
S AN D IEGO — A gene therapy
for dystrophic epidermolysis
bullosa that could be delivered by
office-based dermatologists is feasible
and likely to be effective, but
advancement of this therapeutic
approach is hindered by lack of
funding, said Dr. David Woodley
at the American Academy of
Dermatology’s Academy 2006
meeting.
Dr. Woodley and his investigative
team at the University of
Southern California, Los Angeles,
have developed a method for
intravenous delivery of either
gene-corrected fibroblasts or the
type VII collagen that EB patients
lack, a therapy that would, in
essence, correct the fundamental
physiologic defect underlying this
disease.
In the fibroblasts of EB patients,
the gene coding for type
VII collagen is mutated. As a result,
patients are unable to produce
the anchoring fibrils that
moor the epidermis to the dermis.
Because the disorder is related
to a relatively discrete genetic
mutation, it is an ideal
candidate for gene therapy.
Dr. Woodley explained that he
and other investigators interested
in this disease have pursued several
different approaches to genebased
treatment.
The first was modeled after
advances in the treatment of severe
burns. It is now possible to
take biopsy samples from burn
victims, grow out large sheets of
keratinocytes, and graft these
sheets onto the burn sites. “We
wondered why this couldn’t
work in EB kids. Using a lentiviral
vector, we were able to genecorrect
the fibroblasts so they are
able to produce full-length type
VII collagen. So we could reverse
the EB phenotype.”
But the practicalities of the
grafting procedure dead-ended
this strategy. “This approach re-
See DEB Therapy page 28
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Mysteries
Of the Mouth
Patch test before removing
dental metals in suspected
lichenoid contact stomatitis.
PAGE 34
Chronic
Paronychia
Topicals, not systemics, get
to the root of this dermatitis.
PAGE 51
C A S E O F T H E M O N T H
An 82-year-old man presented at a weekly conference of clinicians
with nodules on his fingers of a few years’ duration. A
rheumatologist suggested seeing him again in 3 weeks for tests,
but a dermatologist found the cause of the nodules that same
day. What’s your diagnosis? See Case of the Month page 71.
COURTESY DR. BENJAMIN K. FISHER
FDA Panel Backs
Radiesse Approval,
With Conditions
Physician training program recommended.
BY ELIZABETH
MECHCATIE
Senior Writer
G AITHERSBURG, MD. — The
majority of a federal advisory
panel recommended approval of
an injectable calcium hydroxylapatite
implant for correcting
HIV-related facial lipoatrophy
and for correcting nasolabial
folds, with a list of conditions for
approval that included an adequate
physician training program
and postmarketing followup
studies.
At a meeting of the Food and
Drug Administration’s general
and plastic surgery devices panel
last month, the panel voted 5-2 in
favor of the conditional approval
Sunscreen Approval Paves
The Way for UVA Blockers
BY BETSY BATES
Los Angeles Bureau
C ORONADO, CALIF. — The
arrival of two new sunscreen
formulations in the U.S. market
will undoubtedly lead to better
UVA protection for patients, but
it remains to be seen whether either
will stack up to products
that are available in Canada and
Europe, Dr. Vincent DeLeo asserted
at the annual meeting of
the California Society of Dermatology
and Dermatologic
Surgery.
Earlier this year, the Food and
Drug Administration approved
of the product, Radiesse, for
these two indications. Radiesse, a
sterile, semisolid cohesive granular
implant that contains calcium
hydroxylapatite (CaHA)
granules in a gel, is manufactured
by BioForm Medical Inc.
and is approved in the United
States for treating vocal cord insufficiency
and oral maxillofacial
defects, and for tissue marking.
The same product is marketed in
Europe for facial aesthetics. (Another
version, Coaptite, which
contains larger CaHA particles, is
used for treating stress urinary incontinence
and other applications.)
A condition that physicians be
adequately educated and trained
See Radiesse page 20
Anthelios SX, which is an overthe-counter
product from La
Roche-Posay that contains a camphor
derivative (ecamsule/Mexoryl
SX) that is photostable and
specifically targets UVA radiation
(SKIN & ALLERGY NEWS, August
2006, p. 9).
The sunscreen also includes
two well-known but relatively
unstable UVA organic absorbers,
octocrylene and avobenzone
(Parsol 1789). It will have a sun
protection factor (SPF) of 15.
In other countries, Mexorylcontaining
Anthelios has been
available for several years at high-
See Sunscreen page 29

20 Dermatologic Surgery S KIN & ALLERGY N EWS • October 2006
Two Indications Green Lighted
Radiesse from page 1
in how to use the product received unanimous
endorsement from the panel. Bio-
Form is planning a training program and
will incorporate some of the panel’s recommendations,
Stephen L. Basta, president
and CEO of the company, said at the
meeting.
Another condition recommended for
the HIV-associated lipoatrophy indication
was completion of the 18-month followup
study being conducted by BioForm,
which panelists said should include data on
the texture of the implant, ease of injection,
events that require further evaluation,
and time needed to reinjection. The
label should also state that Radiesse was
studied specifically in patients with HIVrelated
lipoatrophy and that use for other
indications was unproved.
Nasolabial Fold Indication
For the nasolabial fold indication, the panel
agreed that Radiesse was effective for up
to 6 months, the length of the study submitted
for approval. But as a condition for
approval, the panel recommended that the
company conduct a postapproval study
specifically looking at the duration of the
cosmetic effects beyond 6 months, the effect
of repeated injections, and safety.
Other conditions were that the company
conduct a study of Radiesse in “people
of color”—who tend toward hypertrophic
scarring and keloid formation and were underrepresented
in the study submitted to
the FDA for approval of this use—and
that a statement be added to the product’s
label cautioning that safety and efficacy of
the product in black patients was not
known. In this study, there were 2 African
Americans, 11 Hispanic patients, and 2 patients
whose race was described as “other.”
(In the lipoatrophy study, about half the
patients were Fitzpatrick skin type IV-VI,
which was not associated with a greater
rate of adverse events; the company cited
these to address the issue of safety for
treating nasolabial folds. But the FDA executive
summary noted that the two patient
populations are not homogeneous
and that the HIV-positive patients in the
lipoatrophy study may have had a “diminished
capacity to mount a hypersensitivity
reaction.”)
According to the company, the proposed
label already includes a statement that the
product has not been studied for use in lip
augmentation and that adverse events have
been reported, so the panel did not include
this as a condition. The use of Radiesse for
lip augmentation has not been studied, and
based on reports the company has received,
lips are the most common site of
nodular formation associated with use of
Radiesse, Mr. Basta said.
Register now for this archived webcast at www.viralskindiseases.com
Introduction
Stephen K. Tyring, MD, PhD, MBA
Professor of Dermatology
Department of Dermatology
University of Texas Health Science Center
Houston, Tex.
Human Papillomaviruses:
Basic Virology to Clinical Management
Stephen K. Tyring, MD, PhD, MBA
Molluscum Contagiosum
and Treatment Options
Douglas W. Kress, MD
Chief of Pediatric Dermatology
Children’s Hospital of Pittsburgh
Pittsburgh, Penn.
Treatment of Cutaneous Warts:
An Updated Inventory
of Therapeutic Options
Robert B. Skinner, MD
Professor of Medicine
Department of Dermatology
University of Tennessee
Health Science Center
Memphis, Tenn.
PROGRAM DESCRIPTION
Viral skin diseases represent a major component in the busy practices of dermatologists. In this activity,
the focus is on the most common cutaneous viral diseases, genital/anal warts (condylomata acuminatum)
and common warts, caused by human papillomaviruses (HPV), and molluscum contagiosum, caused by
Poxviruses.
The manifestations of cutaneous viral infections range from simple erythematous, macular presentations to
papules, vesicles, pustules, ulcers, and crusting that may represent any of a long list of possible etiologies.
Clinicians must be able to accurately assess and differentiate among these manifestations and presentations,
particularly now because of the emerging possibility that the causative organisms may be the etiologic agents
responsible for smallpox infections or disseminated vaccinia. The poxviruses, especially, may mimic or be
mimicked by vaccinia, and clinicians should know the differences in the morphology of the lesions as well as
in the presentation, timing, and progression of these lesions.
Advances in the understanding of the natural history and treatment of common viral skin diseases highlight
the need for a continuing educational process that guides the clinician in patient management, including the
latest treatment options, such as topical immune response modifier therapy.
This activity will provide dermatologists with current information regarding the nature of viral skin diseases
caused by HPV and poxviruses and will help clinicians remain up-to-date on patient applied and physician
applied therapies in the treatment of genital warts, common warts, and molluscum contagiosum.
INTENDED AUDIENCE
This activity has been developed for dermatologists, primary care physicians, and other clinicians who are
involved in the diagnosis and treatment of viral skin diseases.
EDUCATIONAL OBJECTIVES
After reading this supplement and taking the test, participants should be able to:
• Summarize the current understanding of the pathogenesis of human papillomavirus (HPV) infections of
the skin—as manifested by genital/anal and common warts—and the role of local immune responses in
the clearing of infection.
• Discuss the HPV types that are associated with external genital/anal warts and with cervical
malignancies, and explain the role of diagnostic testing in the management of patients with external
genital/anal warts.
• Recognize the most common presentations of human papillomavirus (HPV) and poxvirus infections, as
well as the atypical morphologic characteristics that must be considered in diagnosing various types of
warts and molluscum contagiosum.
• Describe the methods that may be used to confirm a clinical diagnosis of molluscum contagiosum, and
explain when such methods should be used.
• List and explain the destructive/ablative methodologies and the pharmacologic treatments that are
currently available for treating genital/anal and common warts and molluscum contagiosum.
• Name and describe the factors that should be considered in choosing a specific therapeutic regimen
for individual patients.
ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance with the Essential Areas and Policies of
the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of
the Elsevier Office of Continuing Medical Education (EOCME) and Skin & Allergy News. The EOCME
is accredited by the ACCME to provide continuing medical education (CME) for physicians.
CME CREDIT STATEMENT
The EOCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit .
Physicians should only claim credit commensurate with the extent of their participation in the activity.
Financial Support: This CME activity is supported by an educational grant from
Panel Members’ Concerns
Like others on the panel, Dr. Michael
Miller, professor and deputy chairman in
the department of plastic surgery at the
University of Texas M.D. Anderson Cancer
Center, Houston, agreed that there
was reasonable assurance that Radiesse
was safe and effective for the lipoatrophy
indication. The benefits for this population
were “enormous,” and although the cosmetic
effect of Radiesse was not permanent,
its effect was “good, if not better
than anything else” used for HIV-associated
lipoatrophy. He cautioned, however,
that Radiesse works by creating a volume-filling
scar, which is acceptable only
if it achieves the desired effect.
Several panelists agreed with Dr. Miller,
who said that the study convincingly
showed efficacy and that its long history
of use for various indications helped mitigate
the unknowns.
Dr. Michael Olding, chief of the division
of plastic surgery, George Washington
University, Washington, said that while
he had concerns about the lack of information
in histology and the length of
durability, he pointed out that no significant
complications were observed in the
study and the quality of improvements
seen in the patient photographs, in his
view, “surpassed” the results of other
treatments, at least photographically.
The dermatologist on the panel, Dr.
Amy E. Newburger of Scarsdale, N.Y.,
who voted against approval for both indications,
expressed concern about the extensive
off-label cosmetic use of Radiesse
that has already occurred and is expected
post approval, and about the lack of human
histologic data for the product. She
said the study in HIV-associated lipoatrophy
was not large or rigorous enough to
make her feel comfortable about effectiveness
and safety, referring to reports of
serious adverse reactions associated with
Radiesse reported to the FDA’s adverse
event reporting database, including reports
resulting from unapproved use in lips.
And while the study on the nasolabial
folds indication was a better study than the
lipoatrophy study, she said there were
“too many unknowns remaining” to vote
for approval for this indication. Radiesse
Continued on following page

October 2006 • www.skinandallergynews.com Dermatologic Surgery 21
Continued from previous page
lasts longer than hyaluronic acid fillers, so
a more rigorous study is needed to achieve
“any level of comfort regarding safety,” she
said.
Stephen Li, Ph.D., president of Medical
Device Testing and Innovations, Sarasota,
Fla., who also voted against approval for
both indications, echoed the concern about
the lack of human histologic data, pointing
out that Radiesse’s migration and dissipation
patterns and its reaction with other
fillers in patients were unknown.
The FDA usually follows the recommendations
of its advisory panels, which
are not binding.
The safety profile of both products was
comparable, with the typical injection-related
side effects seen with other dermal
fillers, including ecchymoses and a significant
amount of erythema. Only 2 African
American patients were enrolled, which
was one of the main concerns raised in the
FDA review, although the company reported
no scarring, hyperpigmentation, or
keloid formation among the 15 patients of
color in the study, including the 2 African
Americans.
The FDA review also raised concerns
that Radiesse implants could mimic a tumor
in the soft tissue or interfere with x-
ray evaluations, because CaHA is visible radiographically,
and that nodules were not
better identified. (Although the company
did not report any evidence of nodules,
there were adverse event reports that could
have been interpreted to be nodules.)
To determine whether Radiesse implants
could mimic or obscure tumors, the company
performed a study of x-rays and CT
scans of 58 patients who had received
Radiesse injections for correction of nasolabial
folds or HIV lipoatrophy, including
patients who had received the first injections
at least 12 months earlier. In that
study, there was no evidence on CT scans
that Radiesse migrates from the point of injection.
Neither was there a significant risk
that Radiesse would mask or mistakenly be
interpreted as a benign or malignant tumor,
or that the implants would prompt biopsies
or further work-ups—even by radiologists
who don’t know the patient has had
them—because of the benign appearance
and bilateral placement, according to the
company. The implants are not always seen
on x-rays, as with CT scans.
The panel had some concerns about this
issue and that the presence of Radiesse
could be potentially confusing on an x-ray
or CT scan and would require more follow-up.
The panel also agreed that the
question of migration had not been completely
answered.
■
Radiesse
lasts longer than
hyaluronic acid
fillers, so a more
rigorous study is
needed to
achieve ‘any
level of comfort
regarding
safety.’
Lipoatrophy Indication
For approval of the lipoatrophy indication,
the company presented the results of an
open-label, nonrandomized, noncomparative
multicenter study using Radiesse in
100 HIV-positive patients, whose mean
age was 48 years and who had been receiving
highly active antiretroviral therapy
for at least 3 years.
Three months after the final treatment,
98% of the patients were very much improved
or much
improved from
baseline on the
Global Aesthetic
Improvement
Scale (GAIS),
the primary
end point of
the study (the
remaining 2%
were improved).
GAIS
ratings remained
improved
at 6 and
12 months,
with increased skin thickness that was
maintained until about 12 months. The
majority of patients said they were satisfied
and would recommend the treatment
at all three time points.
There were no unanticipated adverse
events, with injection-related adverse
events typical of dermal fillers, such as ecchymoses,
pain, erythema, and pruritus,
the most commonly observed. They were
mostly mild and occurred at the time of
injection or shortly afterward, and they did
not last long, according to Dr. Stacey Silvers
of the New York Eye and Ear Infirmary,
who presented these results on behalf
of BioForm. Contour irregularities
occurred but were transient and quickly
resolved, said Dr. Silvers, who reported no
financial ties to BioForm.
The nasolabial fold, split-face study
compared Radiesse to Cosmoplast in the
correction of nasolabial folds in 117 patients
aged 31-72 years, with nasolabial
folds rated 3 (a moderately deep wrinkle)
or 4 (a deep wrinkle with well-defined
edges) on the Lemperle Rating Scale
(LRS), with 12-month safety data on 47 patients.
At 3 months, nearly 85% of
Radiesse-treated folds were rated as superior,
based on the LRS, to the Cosmoplasttreated
folds, the primary effectiveness
end point. At 6 months, nearly 79% of
Radiesse-treated folds were considered superior
to the Cosmoplast-treated folds,
16% were equivalent, and 5% were inferior,
a secondary effectiveness end point.
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FINACEA is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.
Although some reduction of erythema which was present in patients with papules and pustules of rosacea
occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules
has not been evaluated.
FINACEA is for dermatologic use only, and not for ophthalmic, oral, or intravaginal use. FINACEA is contraindicated
in individuals with a history of hypersensitivity to propylene glycol or any other component of the formulation.
In clinical trials, sensations of burning/stinging/tingling occurred in 29% of patients, and itching in 11%,
regardless of the relationship to therapy. Post-marketing safety—Skin: facial burning and irritation; Eyes:
iridocyclitis on accidental exposure to the eye. There have been isolated reports of hypopigmentation
after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark
complexion, these patients should be monitored for early signs of hypopigmentation.
Please see brief summary of Prescribing Information on following page.
Results shown are the results for one patient.
Not all patients may have the same results.
*FINACEA was only studied in clinical trials for 12 weeks.
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Baseline
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Seeing is Believing