Sculptra- P030050

1
Sculptra- P030050

• Herbert Lerner, MD
• Division of General, Restorative and Neurological
  Devices
• Plastic and Reconstructive Surgical Devices
  Branch
• FDA
• March 25, 2004

2
Sculptra- Indication for Use

• Sculptra is intended to correct shape and contour
  deficiencies resulting from facial fat loss
  (lipoatrophy) in people with human
  immunodeficiency virus.

3
Material

• Sculptra is a sterile solution consisting of
• PLLA
• Sodium Carboxy-methyl cellulose
• Mannitol
• Sterile Water

4
SCULPTRAP030050

• FDA Review Team
• Herb Lerner, MD- Clinical Lead
• Charles Durfor, PhD- Pre-clinical
• David Berkowitz, VMD- Toxicology
• Phyllis Silverman, MS- Statistics
• Kim Struble- PharmD- Clinical (CDER)
• Sybil Wellstood- Manufacturing
• Mary Wollerton- Patient Labeling

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Sculptra Toxicology

• Previous Medical uses of Sculptra Components

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P030050 Toxicology Testing
ISO/FDA Test Recommendation Results/Comments
Cytotoxicity No cytotoxicity. Test article placed directly on agar surface.
Sensitization No significant sensitization. Sixteen guinea pigs injected intradermally.
Systemic Toxicity No Toxicity. Intraperitoneal injections in mice at IP at 5.6 ml/kg.
Subchronic Toxicity No Toxicity. Intracutaneous 90-days. Normal foreign body reaction to implant material (only 5 sites examined).
Genotoxicity No significant mutagenesis. Bacterial reverse mutation assay. No increase in aberrations. Chromosomal aberration assay. No increase in micronuclei. Mouse micronucleus Assay.
Hemocompatibility Complement activation not affected. Measured CH50 and SC5b-9.Normal hemolysis testing not needed.
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Sculptra Physical Characteristics

• Molecular weight 40 50 thousand
• PLLA particles irregular shape
• 40-63 microns
• 2 hours required for optimal suspension
• Physically chemically and microbiologically
  stable for 72 hours after suspended.

8
Sculptra Resorption Kinetics

• No weight loss for 24 weeks in phosphate buffer
  at pH 7.4 at 37 degrees C.
• 19 weight loss at 50 degrees C.
• Foreign material seen histologically after
  intradermal implantation for 90 days in rats.

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Published In-Vivo Resorption Studies on PLLA

• Resorption rate is function of molecular weight,
  crystallinity, and particle size.
• Compact PLLA rods of 95,000 Daltons were
  implanted subcutaneously in rats.
• 1 month 19 degraded
• 3 months 40 degraded
• 6 months 56 degraded

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Sculptra

• New-Fill is the name of the device as it is
  commercially available outside the US. Sculptra
  is the intended name of the device as it will be
  marketed in the US. For this review, the use of
  these names is interchangeable. The components of
  the two are identical.

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SCULPTRASTUDY DESIGN

• Presented are 5 investigator-sponsored studies.
• 2 studies are from Europe
• 3 studies are from the US
• All were single center studies
• No study was a randomized, controlled, or blinded
  study as we are used to seeing for a PMA
• All were Open label
• TCT (Total Cutaneous Thickness)

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Vega Study-France

• Inclusion Criteria
• HIV
• Plasma HIV viral load lt5000 copies/ml
• Current HAART treatment 3 months
• HAART for at least 3 years
• Buccal adipose tissue lt2mm

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Vega Study-France

• Exclusion Criteria
• Cutaneous Kaposis Sarcoma of the face
• Infection or concurrent herpes labialis
• Previous facial fillers within 6 months
• Unwilling to meet study follow-up time tables.

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Vega Study-France

• Study Design
• Fifty (50) patients enrolled to study effects if
  the device over time
• 47 patients completed the trial, 2 withdrew at 72
  weeks (schedules) and 1 withdrew due to an
  unrelated event.
• Open label, non-randomized, uncontrolled

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Vega Study-France

• Study Design
• Patients were given bi-weekly injections
• Safety endpoints designed to look for changes in
  biological parameters and AEs
• Efficacy endpoints change in TCT

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Vega Study-France

• Demographics
• Age- (mean) 44.9 6.8
• Gender- 98 male
• Race- 84 Caucasian
• 6 Hispanic
• 4 North African
• 2 Black African
• 4 Carribean

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Vega Study-France

• Demographics
• AIDS defining event- 50
• CD4 count- 397.1 168
• HIV viral load-(median)- 200 copies/ml (50-96k)
• (viral load lt5000 copies/ml- 86 of pts.)
• TCT cheeks- mean 3.0mm
• Adipose tissue lt2mm

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Vega Study-France

• Endpoints
• Safety- adverse events
• Treatment-related events
• Local and systemic
• Change from baseline CD4 cells
• Viral load
• Blood Lactic Acid levels

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Vega Study-France

• Results
• Bruising- 3
• Hematoma- 30
• Nodule- 52

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Vega Study-France

• Efficacy- Change from baseline in TCT (mm)
• Study demonstrated statistically significant
  increases from baseline to week 96-
• At 8 weeks mean change 5.2 mm (SD 1.7)
• At 24 weeks change was 6.4 mm (SD 1.6)
• At 48 weeks, change was 7.2mm (SD 1.3)
• At 72 weeks, change was 7.2 mm (SD 1.3)
• At 96 weeks, change was 7.0mm (SD 1.4)
• Photographic Assessment
• Visual Analogue Scale 0-10 scale (with 10 the
  most satisfying physical/emotional state)

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Vega Study-France
 
 

• Figure 1 Profile of Dermal Thickness by
  Ultrasound by Weeks From First Injection
•   

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Chelsea Westminster- England

• Inclusion Criteria
• HIV
• Moderate to severe lipoatrophy
• Not pregnant or lactating

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Chelsea Westminster- England

• Exclusion Criteria
• Active opportunistic disease or wasting
• Current growth hormone therapy
• Current chemotherapy for malignancy
• Known hypersensitivity to PLLA

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Chelsea Westminster- England

• Study Design
• 30 patients
• Half of group delayed 12 weeks as a comparator
• 30 pts. Treated
• 29 pts. Reported (1 declined data disclosure)

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Chelsea Westminster- England

• Study design
• Two groups of 15, the second group had
  injections delayed for 12 weeks
• Clinical exam, serum CD4 and viral loads obtained
• Facial Ultrasound
• VAS and HAD (Anxiety/ Depression scores)

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Chelsea Westminster- England

• Demographics
• Age- 41 years (mean)
• Gender- 28 males/ 2 females
• Race- 72 Caucasian
• 3 Black
• 24 Hispanic

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Chelsea Westminster- England

• Demographics
• Mead duration of HAART- 5.1 years
• Mean baseline CD4 count- 473.6
• Viral load (median) - 72.0 copies/ml

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Chelsea Westminster- England

• Endpoints
• Safety-
• Change in viral load
• Change in CD4 count
• Change in blood chemistry
• Adverse Events
• Efficacy-
• Buccal skin thickness measurements
• Change in facial appearance- MD and Pt.
  assessments

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Chelsea Westminster

• Adverse events-combined groups
• Injection site bruising- 38
• Injection site discomfort- 10
• Injection site erythema- 10
• Injection site inflammation- 10
• Injection site nodule- 31
• VAS scores improved
• Clinical lab parameters unchanged

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Chelsea Westminster

• BASELINE TO WEEK 12

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• Common Finding In Both Studies-
• Nodule at injection site
• 52 VEGA
• 31 CW
• Discussion-
• Onset average up to 218 days (9 to 748)
• Most reported as mild and not visible
• No histological data available

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US Studies

• APEX-001
• Investigator Sponsored Compassionate Use Study
• Open label, uncontrolled, non-randomized study
• 100 patients
• 1-6 treatment sessions (average-3)
• 1-8 cc of New-Fill per treatment session
• Demographics similar to previous studies
• HIV 14 years
• Mean age 44.5
• 82/96 patients Caucasian

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US Studies

• Inclusion Criteria
• HIV
• Demonstrable photographic lipoatrophy
• Exclusion Criteria
• Active Infection, Kaposis sarcoma or Herpes on
  the face
• Facial injections within last 3 months
• Treatment with interferon or steroids

34
US Studies

• Safety results-
• Adverse events considered mild
• 6 nodules reported in 85 patients at 3 weeks
• 39 nodules in 70 patients seen at 12 months
• Efficacy results-
• High patient satisfaction- 8.8/10
• High investigator rating from 3.2 to 1.36
  (lower score is better)

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US Studies

• APEX002
• Investigator sponsored IDE
• HIV
• 100 patients
• Average of 3.5 treatments/patient
• Similar demographics
• Average time HIV 11.9 yrs
• Average years HAART therapy- 13

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US Studies

• Adverse Events- mild
• Soreness and nodules
• 6 nodules in 99 patients
• 19 pts. With injection site soreness
• 2 pts. With transient fever
• High patient satisfaction-
• Scores went from 3.71 to under 1 (lower score is
  better)

37
US Studies

• US Study- Hermosa Beach
• Open label, uncontrolled, non-randomized
• Similar demographics and treatment schedule
• 1-6 treatments/patient
• Up to 6 cc per treatment
• Average time HIV 13 years
• Average time HAART- 9 years

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US Studies

• Inclusion/Exclusion criteria
• Similar to Apex studies
• HIV
• Lipoatrophy
• Infections of face, Kaposi's sarcoma
• Treatment with interferon or steroids
• Uncontrolled DM, lactic acidosis

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US Studies

• Endpoints
• To evaluate the quantifiable improvement in
  facial wasting after serial intradermal
  injections of New-Fill
• Safety-
• In repeated treatments
• Efficacy
• Durability of New-Fill
• Psychological impact on patients

40
US Studies

• Results
• Adverse events-mild
• 8 nodules in 87 patients
• High patient satisfaction
• Average increase TCT- 6mm _at_ 6 mos.
• Average mm initial 7.44
• Average mm-end of tx. 13.92
• Average mm- 6 mos. 13.22
• Average mm- increase 5.78

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Conclusion- Overall Safety

• In general, the majority of treatment related
  events are mild pain, bruising and swelling at
  the injection site.
• Device events are generally palpable subcutaneous
  nodules (up to 50)
• No major AEs reported

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Conclusion- Overall Efficacy

• TCT analysis in VEGA study demonstrates increased
  TCT.
• Dermal thickness changes in the CW study also
  demonstrate significant enhancement of dermal
  thickness
• Photographic evidence of sustained efficacy is
  shown

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Conclusion- Overall Efficacy

• Quality of Life assessments show improvement from
  the baseline

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Statistical Summary

• No masking or use of validated severity scale
• Total Skin Thickness (TCT) was used as surrogate
  endpoint for improved appearance
• Statistically significant (plt0.001) increases in
  TCT observed in Vega and CW Studies
• Treatment effect was independent of time on
  HAART, baseline CD4 counts, or baseline skin
  thickness
• Increase in skin thickness correlated pictorially
  with improved appearance

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• Thank you

46
Panel Question-1

• 21 CFR 860.7(d)(1) states that there is a
  reasonable assurance that the device is safe when
  it can be determined that the probable benefits
  to health from use of the device for its intended
  uses, when accompanied by adequate instructions
  for use and warnings against unsafe use, outweigh
  any probable risks. Considering the data in the
  PMA, please comment on whether there is a
  reasonable assurance that the device is safe.

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Panel Question- 2

• 21 CFR 860.7(e)(1) states that there is a
  reasonable assurance that a device is effective
  when it can be determined, based on valid
  scientific evidence, that in a significant
  portion of the target population, the use of the
  device for its intended uses and conditions of
  use, when accompanied by adequate directions for
  use and warnings against unsafe use, will produce
  clinically significant results. Considering the
  data in the PMA, is there reasonable assurance
  that the device is effective?

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Panel Question- 3

• Patients in the European studies (79) were
  followed-up for periods ranging from 24 weeks to
  2 years, and those in the U.S. studies (286) were
  followed up to 2 years. If you agree that there
  is enough evidence in the PMA to support the
  safety and effectiveness of the device, do you
  feel that a post-approval study to assess the
  long term use of this device should be initiated,
  and if so, please advise FDA as to the type of
  data you feel should be collected, and the
  appropriate duration of follow-up.

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Panel Question- 4

• A large volume of this device (up to 11cc. per
  treatment) is required to achieve an optimal
  cosmetic effect, and precise placement of the
  material in the correct dermal plane (deep dermis
  or subcuticular layer) is important. Please
  advise FDA whether a physician training program
  is indicated for those wishing to use this
  device, and if so, what type of training would be
  appropriate.