LEO Pharma Announces That Picato® (ingenol mebutate) gel has Been Approved by US FDA for Once-Daily, 2 or 3 day Treatment of Actinic Keratoses

COPENHAGEN, Denmark, January 26, 2012 /PRNewswire/ –

LEO Pharma today announced that Picato(R) (ingenol mebutate) gel (0.015%, 0.05%) has
been approved by the US Food and Drug Administration (FDA) as a treatment for actinic
keratoses (AK) on the face, scalp, trunk and extremities. Picato(R) gel is a once-daily,
field-directed topical treatment for AK, a potential precursor to non-melanoma skin cancer
caused by cumulative sun exposure. Treatment with Picato(R) gel is completed over two
consecutive days for AK on the trunk and extremities and over three consecutive days on
the face and scalp.

Actinic keratoses often appear as red, scaly skin lesions mainly seen on sun-exposed
areas such as the face, the scalp and extremities, where they can occur as a singlelesion
or multiple lesionsacross an entire field.[1] The lesions are typically caused by
cumulative UV exposure and the condition affects an increasing number of people,
especially in Europe, the US and Australia.[2] According to the Skin Cancer Foundation,
they affect about 58 million Americans and are the most common form of pre-cancer.[3]

Actinic keratoses are precursors to skin cancer and can progress to squamous cell
carcinoma (SCC), a type of non-melanoma skin cancer which is the second most common type
of skin cancer.[4] The risk of progression to SCC increases with the number of lesions
present[5] and it is impossible to predict which lesions will develop into skin cancer. A
study has shown that around 65 percent of cases of squamous cell carcinoma may begin as
actinic keratoses.[6]

Picato(R) (ingenol mebutate) gel is a field-directed topical therapy which enables
treatment of an area affected by actinic keratoses. It is available in two different
concentrations: for treatment of the face and scalp, the gel is applied at a concentration
of 0.015% once daily, completing treatment in three consecutive days, whereas for
treatment of the body, the gel is applied once daily for two consecutive days at a
concentration of 0.05%.The FDA approval is based on data from four phase III studies in
over 1000 patients treated with ingenol mebutate (n=503) or placebo (n=502) showing that
ingenol mebutate applied once-daily for two or three consecutive days is significantly
more effective than placebo at clearing actinic keratoses. [7-10]The most common Local
Skin Reactions (LSRs) included erythema, flaking/scaling, crusting and swelling. Other AEs
occurring in greater than or equal to 2 percent of subjects treated with Picato(R) in the
phase III clinical trials included pain, pruritus and infection at the site of
application, as well as periorbital edema and headache when applied on face or scalp.

Commenting on today’s announcement, Mark Lebwohl, M.D, Professor and Chair, Department
of Dermatology, Mount Sinai Medical Center in New York, said,”Since there is no way to
predict which actinic keratoses will advance to skin cancer, early detection and treatment
of lesions are critical. What makes this new therapy particularly exciting is the two or
three day course of treatment.”

Gitte P. Aabo, Chief Executive Officer of LEO Pharma, said, “Actinic keratoses affect
millions of people, but many are not aware that they have the condition or that in some
cases it can lead to skin cancer.Picato(R) gel requires just two or three consecutive days
of treatment, compared to several weeks or months for existing topical therapies. We
believe this shorter duration of treatment will be well received by both patients and
clinicians. The approval of Picato(R) gel is another important step in LEO Pharma’s goal
of becoming one of the world’s leading dermatology companies.”

LEO Pharma expects Picato(R) to be available to US physicians in March 2012.

About Picato(R) gel

Picato(R) is a topical gel containing ingenol mebutate, derived from the Euphorbia
peplus plant. The dried plant passes through an extraction, purification and
crystallization process over approximately five months to become an active pharmaceutical
ingredient (API). For the production of Picato(R) gel, a carefully selected cultivar of
Euphorbia peplusplant is grown by farmers for LEO Pharma in Queensland, Australia, to
ensure consistency in performance.

Picato(R) gel is a topical, field-directed therapy which is self-administered by the
patient on to the affected areas of the skin once a day for two or three consecutive
days.Picato(R) has two concentrations and two application regimens to follow dependent
upon the location of the AK: Picato(R) gel can be applied over two consecutive days for
treatment of AK on the trunk and extremities and over three consecutive days on the face
and scalp.

Clinical trial history

To date, 18 clinical trials have been completed for the use of Picato(R), from phase I
trials through to pivotal phase III trials. In phase III clinical trials, 60[8] to 68[9]
percent of patients with actinic keratosis on the face and scalp saw 75 percent or greater
reduction of existing AKs (versus 7 to 8 percent with placebo, p<0.001). Picato(R) also
demonstrated efficacy in treating the trunk and extremities with 44[11] to 55[8] percent
of patients experiencing 75 or more percent reduction (versus 7 percent reduction for
placebo, p<0.001). Patients treated with Picato(R) saw 37[8]-47[9] percent complete
clearance of lesions on the face and scalp, and 28[10]-42[7] percent on the trunk and
extremities.

The most common LSRs included erythema, flaking/scaling, crusting and swelling. LSRs
peaked within the first week and generally resolved within two weeks in the majority of
patients treated on the face and scalp, and within four weeks for patients treated on the
trunk and extremities.Other AEs occurring in greater than or equal to 2 percent of
subjects treated with Picato(R) in the phase III clinical trials included pain, pruritus
and infection at the site of application, as well as periorbital edema and headache when
applied on face or scalp.

Important safety information

For topical use only; not for oral, ophthalmic, or intravaginal use. Eye disorders,
including severe eye pain, eyelid edema, eyelid ptosis, periorbital edema can occur after
exposure. Patients should wash hands well after applying Picato(R)gel, and avoid transfer
of the drug to the periocular area during and after application.Severe skin reactions in
the treated area, including erythema, crusting, swelling, vesiculation/pustulation, and
erosion/ulceration, can occur after application. Administration of Picato(R)gel is not
recommended until the skin is healed from any previous drug or surgical treatment. The
most common adverse reactions observed in clinical trials (greater than or equal to2 %)
are local skin reactions, application site pain, application site pruritus, application
site irritation, application site infection,periorbital edema, nasopharyngitis and
headache. There are no adequate and well-controlled studies of Picato(R)gel in pregnant
women. Picato(R) gel should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. The safety and effectiveness of Picato(R)gel
for actinic keratosis in patients less than 18 years of age have not been established.

Please see full prescribing information available at http://www.leo-pharma.us.

About actinic keratoses

Actinic keratoses are skin lesions, the majority of which are caused by cumulative UV
exposure (usually from the sun) in fair-skinned people.Lesions are often red, scaly and
may initially be mistaken for a rash or other skin irritation, but do not improve over
time. The number of patients with actinic keratoses is both large and rapidly growing,
especially in Europe, the US and Australia, with the American Academy of Dermatology
estimating that 60% of predisposed persons older than 40 have at least one actinic
keratosis lesion. [11-12]People at high risk are often over the age of 40 and tend to have
fair skin and a history of sun exposure.[11]

The most important risk factor for the development of actinic keratoses is cumulative
UV-radiation, which is reflected in the geographical distribution of prevalence in the
susceptible population. Similarly, an increase in vacational and recreational sun exposure
during the past decade has led to the increased prevalence.[13] AKs are more common in
males, and individuals with a fair skin type are predisposed.Additional risk factors that
have been identified include advanced age and immunodeficiency. Immuncompromised patients
show a significant increase in AKs, with a 65 to 250 fold higher risk for AKs and invasive
SCC.[14]

Actinic keratoses are considered to be the earliest stage in the development of
non-melanoma skin cancer,with the potential to progress to squamous cell carcinoma, a
non-melanoma cancer which is the second most common type of skin cancer.[15] The average
person developing multiple actinic keratoses, also known as field cancerization, has an up
to 10% risk of one or more of these lesions developing into squamous cell cancer within
ten years.[16] The risk of progression to SCC increases with the number of lesions
present[5] and it is impossible to predict which lesions will develop into skin cancer. A
studyhas shown that around 65 percent of squamous cell carcinoma cases may begin as
actinic keratoses.[6] and patients with the condition are six times more likely to develop
any type of skin cancer than people without it.[17]

About LEO Pharma

Founded in 1908, LEO Pharma is an independent, research-based pharmaceutical company.
LEO Pharma develops, manufactures and markets pharmaceutical drugs to dermatologic and
thrombotic patients in more than 100 countries globally. The company has its own sales
forces in 61 countries and employs more than 4,600 employees worldwide. LEO Pharma is
headquartered in Denmark and is wholly owned by the LEO Foundation. For more information
about LEO Pharma, visit http://www.leo-pharma.com.

References

1. Stockfleth E, Kerl H. Guidelines for the management of actinic keratoses. Eur J
Dermatol 2006;16(6):599-606.

2. Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E, et al. The
burden of skin diseases: 2004 a joint project of the American Academy of Dermatology
Association and the Society for Investigative Dermatology. J Am Acad Dermatol
2006;55(3):490-500.

3. Skin Cancer Facts, Skin Cancer Foundation.

4. Lansbury L, Leonardi-Bee J, Perkins W, Goodacre T, Tweed JA, Bath-Hextall FJ.
Interventions for non-metastatic squamous cell carcinoma of the skin. Cochrane Database
Syst Rev 2010(4):CD007869.

5. Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk
Australian population. Int J Cancer 1990;46(3):356-61.

6. Feldman SR, Fleischer AB, Jr. Progression of actinic keratosis to squamous cell
carcinoma revisited: clinical and treatment implications. Cutis 2011;87(4):201-7.

7. Anderson L, Melgaard A, Xu Z. Multicenter, randomized, parallel-group,
double-blind, vehicle-controlled, phase 3 study to evaluate the efficacy and safety of
PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head
locations (Study PEP005-028). Poster presented at: 22nd World Congress of Dermatology 2011
May 24-29 Seoul, Korea. Poster P2180.

8. Berman B, Melgaard A, Larsson T. Multicenter, randomized, parallel-group,
double-blind, vehicle-controlled phase 3 study of the efficacy and safety of PEP005
(ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (face or
scalp) (Study PEP005-016). Poster presented at: 22nd World Congress of Dermatology 2011
May 24-29 Seoul, Korea. Poster P2179.

9. Lebwohl M, Melgaard A, Xu Z. Randomized, parallel-group, double-blind,
vehicle-controlled, multicenter phase 3 study of the efficacy and safety of PEP005
(ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (Study
PEP005-025). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul,
Korea. Poster P2181.

10. Swanson N, Melgaard A, Larsson T. Multicenter, randomized, parallel-group,
double-blind, vehicle-controlled phase 3 study to evaluate the efficacy and safety of
PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head
locations (Study PEP005-014). . Poster presented at: 22nd World Congress of Dermatology
2011 May 24-29 Seoul, Korea. Poster P2182.

11. Drake LA, Ceilley RI, Cornelison RL, Dobes WL, Dorner W, Goltz RW, et al.
Guidelines of care for actinic keratoses. Committee on Guidelines of Care. J Am Acad
Dermatol 1995;32(1):95-8.

12. Ko CJ. Actinic keratosis: facts and controversies. Clin Dermatol 2010;28(3
):249-53.

13. Ulrich M, Drecoll U, Stockfleth E. Emerging drugs for actinic keratosis. Expert
Opin Emerg Drugs 2010;15(4):545-55.

14. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl
J Med 2003;348(17):1681-91.

15. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing
actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol 1998;37(9):677-81.

16. Berman B, Amini S, Valins W, Block S. Pharmacotherapy of actinic keratosis. Expert
Opin Pharmacother 2009;10(18):3015-31.

17. Chen GJ, Feldman SR, Williford PM, Hester EJ, Kiang SH, Gill I, et al. Clinical
diagnosis of actinic keratosis identifies an elderly population at high risk of developing
skin cancer. Dermatol Surg 2005;31(1):43-7.

        Contact
        Helga Heyn
        Corporate External Relations Manager
        Tel.: +44(0)207-269-9364
        E-mail: helga.heyn@leo-pharma.com

SOURCE LEO Pharma