Hydroquinone Update/StrategiesJoel Schlessinger MD

Course Director, Cosmetic Surgery Forum

Disclosure of Relevant Relationships with IndustryJoel Schlessinger, MD

Advisory Board / Consultant

Abbott Pharma., Allergan, Amgen, Artes, Dermik, Galderma, Genentech, Glaxo, Health and Wellness Council of America, Kythera, MEDICIS, Mentor, Merz, MJD Communications, Novartis, Obagi, Ortho Pharma. (Johnson & Johnson), Stiefel, TheDerm.org

Researcher

3M Pharma., Abbot Pharma., Allergan, Amgen, Astellas, Barrier Therapeutics, Biogen, Centocor, Clay-Park Labs, Collagenix, Connetics, Dermik, Dow, ESC Medical, Fujisawa, Galderma, Genentech, Glaxo Pharma., GlenmarkPharma., HealthPoint, Immunex, Ipsen / Inamed, Kythera, MEDICIS, Mentor, Merz, Novartis, Novum, NUCRYST, Ortho Pharma. (Johnson & Johnson), PenedermPharma., Perrigo, Pfizer, QLT USA, Regeneratio PharmaAG, Sandoz, Schering Plough, StiefelLabs, UBC/Vitae

Stockholder

Allergan, Excel Cosmeceuticals, MEDICIS, J and J, Obagi

Proposed Rule

• Skin Bleaching Drug Products for OTC Use

• August 29, 2006

• No decision yet

• Could affect over 200 products in use

Current

• OTC 1.5% to 2% have GRASE (generally recognized as safe and effective)

• Majority of OTC and Rx HQs have 2% to 4%

• New rule would extend DESI, a 1962 rule, (Drug Efficacy Study Implementation) to those currently exempted from an NDA

Quote from Dr. Kligman

“If we give up on hydroquinone, we’re damn fools!”

New Rule

• FDA intends to consider all HQs, whether Rx or OTC, as new drugs!

• Could it extend even to TriLuma?

Evidence

• Some evidence of carcinogenicity in rats and mice in 1989 and 1992 following gavage (not dermal) administration

• HQ is highly absorbed (57%) in humans

• ? Ochronosis reports

Do the studies add up?

• 100 mg/kg/day HQ to mice via oral gavage

• 50 mg/kg/day HQ to rats via oral gavage

• No toxicity when administered via dermal route in animals

• 5% HQ for 13 weeks in rats only showed irritation

Absorption

• Absorption is highly species characteristic

• Metabolism is hepatic in humans and results in deactivation and detoxification in humans vs rats

• Rats tend to activate HQ

• Exposure route matters (oral vs dermal)

Ochronosis

• Unclear why it is so high in reports, but not evidenced in US

• Dermchat experience (no reports of ochronosis over 1400 members

• No reports of ochronosis in chemical factory workers or other issues

• Kligman: Concerns of ochronosis and cancer come from “bureaucrats who have no background.”

What else is there?

• Lumixyl: Oligopeptide that inhibits mushroom tyrosinase and human tyrosinase

• 43% reduction in melanin activity

• Non-toxic to melanocytes

• Can be used as an alternative to HQ

Obagi system and other HQ compounds

• Obagi with Botox study

• Obagi along with Botox had significant improvement in results than Botox with Cetaphil

• 100% of patients wished to continue on Obagi vs20% in the Cetaphil group

Figure 1. Hyperpigmentation.

0

1

2

3

4

0 30 60 90 120

Hydroquinone system + tretinoin

Standard skin care

None

Trace

Mild

Moderate

Severe

* P≤.05, ** P≤.01, *** P≤.001 compared with standard skin care

Mean

hyperpigmentation

score

Day

** *******

Figure 2. Fine lines and wrinkles.

0

1

2

3

4

0 30 60 90 120

Hydroquinone system + tretinoin

Standard skin care

None

Trace

Mild

Moderate

Severe

* P≤.05, ** P≤.01 compared with standard skin care

Mean

fine lines/

wrinkles

score

Day

** **

Figure 3. Patient satisfaction with overall improvement in facial appearance.

0

20

40

60

80

100

0 30 60 90 120 0 30 60 90 120

Satisfied

Extremely satisfied

Day

Standard skin care

Patients

(%)

20%

82%

89% 88% 89%

11% 12%

22%

55%

12%

[Significant between-group difference in overall ratings at days 30, 60, 90, and 120, P≤.001]

Hydroquinone system

+ tretinoin

0

20

40

60

80

100

30 60 90 120 30 60 90 120

Somewhat improved

Improved

Greatly improved

Figure 4. Effect of study treatment in further enhancing facial appearance

after botulinum toxin type A treatment (a comparison with the effect of past

treatment using botulinum toxin type A alone).

Patients

(%)

Day

71%79%

92%86%

12% 7%

Standard skin care

11% 8%

[Significant between-group difference in overall ratings at all timepoints, P≤.001]

Hydroquinone system

+ tretinoin

30%

10%

60%

Baseline

Day 120

Hydroquinone system

+ tretinoin

Standard skin care

64%

36%

69%

23%

65%

29%

7% Look younger/much younger

Look current age

Look older/much older

8%

Figure 5. Patient evaluation of facial appearance compared to age.

[Significant between-group difference in overall ratings at days 60, 90, and 120, P≤.05]

Figure 6. Burning.

0

1

2

3

4

0 30 60 90 120

Hydroquinone system + tretinoin

Standard skin care

None

Trace

Mild

Moderate

Severe

* P≤.05, *** P≤.001 compared with standard skin care

Mean

burning

score

Day

*

***

*

Figure 7. Dryness.

0

1

2

3

4

0 30 60 90 120

Hydroquinone system + tretinoin

Standard skin care

None

Trace

Mild

Moderate

Severe

** P≤.01, *** P≤.001 compared with standard skin care

Mean

dryness

score

Day

**

***

**

**

Figure 8. Peeling.

0

1

2

3

4

0 30 60 90 120

Hydroquinone system + tretinoin

Standard skin care

None

Trace

Mild

Moderate

Severe

*** P≤.001 compared with standard skin care

Mean

peeling

score****** *** ***

Day

Figure 9. Erythema.

0

1

2

3

4

0 30 60 90 120

Hydroquinone system + tretinoin

Standard skin care

None

Trace

Mild

Moderate

Severe

* P≤.05, *** P≤.001 compared with standard skin care

Mean

erythema

score

Day

**** ***

Before and After

Before and After

Before and After

Before and After