European Academy of Dermatology and Venereology (EADV)

Lisbon 2011

Management of psoriasis with biological agents in clinical practice

When and how should a patient begin biolo-gical therapy?Professor Carle PaulPaul Sabatier University, Toulouse, France

Contents

Long-term Management of Plaque Psoriasis with Biological TherapiesProfesor Christopher GriffithsUniversidad de Manchester, Manchester, Reino Unido

Exploring the Use of Anti-p40 TherapyDr. Paulo VarelaCentro Hospitalar de Gaia/Espinho, Porto, Portugal

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11.

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At present, there is little evidence on whether the transition from patients’ conventional systemic therapies into biological agents is safe. For instance, in most Phase II and III clinical trials conducted with biological therapy, patients should have a wash-out period without the drug prior to its use, but this period is not applicable in real life due to the fact that patients require interventions to keep their medical condition from worsening and treat-ments that provide them with immediate benefits.

Indications that justify the transition from con-ventional systemic therapy into biological therapy are:1) Loss of efficacy 2) Contraindications of its use due to cardiovascu-

lar, liver, kidney or hematologic pathologies in patients.

3) Secondary effects and lack of drug tolerability1.

During this transition of therapies, multiple con-cerns arise: Is it possible to make an abrupt change between both therapies without affecting the treatment safety? Is it necessary to carry out an overlapping period of both treatments in order to

Professor Carle PaulPaul Sabatier University, Toulouse, France

When and how should a patient begin with biological therapy?

avoid severe psoriasis relapses? And, finally, do treatment efficacy and safety change if different alternatives or strategies are used during the tran-sition of drugs? At present, few biological thera-pies offer enough evidence that responds to these types of questions.

The transition into adalimumab from etanercept, methotrexate or NB-UVB phototherapy has been tested in an open study2 in 152 patients with plaque psoriasis presenting a suboptimal response to these therapies. Patients discontinued the therapy as follows: two weeks before if they were taking etanercept, and a week for the rest of treatments. In week 16, a PGA (Physician’s Global Assess-ment) score 0/1 is reported in 52% of patients; post etanercept was of 48.8%, post methotrexate was of 61%, and post NB-UVB was of 48.3%.

The transition of methotrexate therapy into ustekinumab (UST) has been conducted in two studies3,4 assessing the tolerability and effective-ness of ustekinumab in patients diagnosed with moderate-to-severe psoriasis and poor response to methotrexate, at week 123 and 164. Both reports

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are based on the TRANSIT Study, which is an open, Phase IV study, conducted on 489 patients with moderate-to-severe plaque psoriasis and poor response to methotrexate. Patients were rand-omized 1:1 in both arms stratified by weight and height. Arm 1 started with UST immediately after discontinuation of methotrexate. Arm 2 started with UST overlapped with methotrexate, which was gradually decreased over four weeks. Patients were included based on an evaluation considering a PASI score of greater than or equal to 10 as poor

response to methotrexate, after eight consecutive weeks of treatment with weekly doses between 10 mg to 25 mg (see Graphic 1).

UST doses were adjusted according to patients’ weight: 45 mg for patients with a body weight in-ferior to 100 kg and 90 mg for patients with a body weight greater than 100 kg. The main objective was to verify adverse events presented at week 12. The secondary objective consisted in assess-ing the efficacy and patients’ life quality. Eight pa-

Graphic 1TRANSIT3,4 Study Design

-4 0 4 8 12 16

Patients ≤ 100kgDose: 45 mg UST

Arm 1: starts therapy with UST after discontinuing methotrexate immediately.Arm 2: starts therapy with UST overlapped with methotrexate and progressive methotrexate decrease in 4 weeks.

Patients > 100 kgDose:90 mg UST

WeekEfficacy and

SafetyLife

Quality

R

R

Arm 2

Arm 1

Arm 2

Arm 1

Graphic 2Results of safety in week 123,4

Brazo 1 UST/MTX Suspensión

Brazo 2 UST/MTX Suspensión

Total (n=489)

pacientes con menos de 100 kg

n=391

pacientes con más de 100 kg n=98

146 (59.8%)

7 (2.9%)

2 (0.8%)

1 (0.4%)

0

0

154 (62.9%)

5 (2.0%)

1 (0.4%)

0

0

0

235 (60.1%)

7 (1.8%)

3 (0.8%)

0

0

0

65 (66.3%)

5 (5.1%)

0

1 (1.0%)

0

0

Arm 1 UST/MTXimmediate

discontinuation

Arm 2 UST/MTXgradual

discontinuation

Total (n=489)Patients ≤ 100 kg

n= 391Patients > 100 kg

n=98Adverse Events (AE)

Patients with one or more

Patients with serious AE

Patients with discontinuity

AE of special interest

Severe infections

Malignancies

Major cardiovascular events

5

tients dropped out of the study, four per each arm, one case was associated to a serious adverse event (Hepatitis B), one patient discontinued treatment due to pregnancy, and others upon researcher’s decision (see Graphic 2).

No difference was found between both arms of the study in terms of number of adverse events and the type of reported adverse events. Serious adverse events frequency was of 2.9% in the group of imme-diate discontinuation of methotrexate against 2% in the group of progressive decrease. No deaths, malignant diseases, major cardiovascular adverse events or tuberculosis were reported. The reported safety profile is consistent with the results of UST Phase III studies.

As regards efficacy, no differences were found be-tween both arms of treatment. At week 12, most patients in both arms achieved a clean or almost clean PGA: 65.3% in the group of immediate dis-continuation of methotrexate against 69.5% in the gradual drug discontinuation group. PASI median decreased approximately from 15, in both groups baseline, to 2.9 in the arm of immediate discon-tinuation of methotrexate and 2.8 in the arm of pro-gressive drug discontinuation. Therefore, it is con-cluded that both strategies of treatment transition are similar in effectiveness (see Graphic 3).

Graphic 3Efficacy at Week 123,4

20

15

10

5

00 2 4 6 8 10 12

40

20

65.3 69.5

0.40.4

WeeksBaseline Week 12 Baseline Week 12

Pati

ents

with

PG

A of

0 to

1 (%

)

PASI

Sco

re

0

60

80

100

15.215.4

11.512

8.5

8

2.9

2.8

Brazo 1

Brazo 2

Arm 1 UST/MTX immediate discontinuationArm 2 UST/MTX gradual discontinuation

Conclusions: 1. Dermatologists have few available data

based on evidence about the safety and efficacy supporting the transition from tra-ditional systemic therapies into biological therapies.

2. Ustekinumab is a therapy that has proved to be effective and with proper tolerability in pa-tients with poor response to methotrexate.

3. There are studies on ustekinumab that pre-sent different mechanisms of transition of treatment with methotrexate, reporting safety and efficacy profiles similar in both groups, that of immediate discontinuation of methotrexate and progressive drug de-crease.

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Bibliography:

1. Pathirana D, et al. J Eur Acad Dermatol Venerol. 2009; 23 suppl 2: 1-70.2. Strober B, et al. Presented at the 68Th Annual meeting of the AAD. 5-9 mar 2010, Miami, USA. P3306.3. C Paul, L puig et al. Presented at EADV, Oct 20-24 2011, Lisboa, Portugal Po1121.4. K Reich, L puig et al. Presented at EADV, Oct 20-24 2011, Lisboa, Portugal Po1123.

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Long-term follow-up of patients treated with bio-logical therapy is of utmost importance in order to recognize adverse events related to new, highly effective drugs, but whose long-term safety has not been determined yet.

At this point, we should recall the case of efali-zumab, which in Phase III trials presented with three-years follow-up1, did not report serious ad-verse effects impeding its use. But then, as from 2008, progressive multifocal encephalopathy was recognized as an adverse effect associated with the chronic use of this drug, reason why it was withdrawn from the market.

For this reason, studies of new biological drugs should not only provide data of their efficacy but also their safety. It is worth to mention that many of long-term safety studies are directed to patients with rheumatic pathologies and not to patients with dermatologic pathologies, such as psoriasis. This significantly influences the results presented, since patients with psoriasis have specific distinc-

Long-term Management of Plaque Psoriasis with Biological Therapies

tive characteristics due to their disease and prior treatments, all of which make them impossible to be compared to rheumatologic patients. For instance, patients with psoriasis have a higher risk of presenting skin cancer due to their higher risk of exposure to ultraviolet radiation (UVR), and they also present a higher risk of hepatotoxicity due to their chronic use of methotrexate.

As regards etanercept, there are studies that show that there is no evidence of cumulative toxicity over four years of treatment.

The REVEAL study2, which conducts a follow-up of patients under treatment with adalimumab over three years, shows how adverse event ratio is sta-ble over time, without any report of new emergent adverse events.

In 2010, Langley et al., published a study3 whose objective was to determine the risk-benefit balance of using TNF inhibitors (adalimumab, etanercept

Professor Christopher GriffithsManchester University, Manchester, United Kingdom

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and infliximab in psoriasis), calculating the NNT (Number Needed to Treat: the number of patients that need to be treated in order to observe the benefit of a therapy) and the NNH (Number Need-ed to Harm: the number of patients that need to be treated to observe an adverse event) of TNF-inhibitor therapy. This study concluded that the beneficial effects of the treatment were greater than serious toxicity events. All studied TNF-in-hibitors presented a similar safety profile, with-out significant statistical differences.

The experience on ustekinumab (UTS) safety is sup-ported in several studies4,5. An analysis of the safe-ty with four-year follow-up6 was conducted based on the experience gained so far6 (see Graphic 1).

50% of studied patients were obese, had a PASI score between 19 and 20, and had received prior treatments with phototherapy (65%), conventional systemic treatments (60%), and other biological treatments (50%).

Reports on treatment discontinuation over the four years were presented in 26.4% of patients under

Graphic 1Long-term Safety of Ustekinumab4,5,7,8,9,10

Overall evaluated patients

Patients’ follow-up per year

CO379T04(Phase II; n=320, controlled placebo for 20 weeks)1

PHOENIX I(Phase III; n=766, controlled placebo for 12 weeks)2

PHOENIX II(Phase III; n=1230, controlled placebo for 12 weeks)3

ACCEPT(Phase III; n=903, controlled placebo for 12 weeks)4

n=3117

4782

36 weeks

152 weeks

100 weeks

64 weeks

n=3117

6791

36 weeks

152 weeks

208 weeks

64 weeks

Safety follow-up

UST Development Program in Psoriasis Treatment2009 analysis

(3-year follow-up) 2010 analysis

(4-year follow-up)

treatment with 45 mg and 24.1% in patients with 90 mg, for a calculated rate of treatment discontinua-tion of 6% per year (see Graphic 2).

Adverse events rate did not vary over the four-year follow-up, and no new emergent adverse events were reported (see Graphic 3). The safety profile of ustekinumab is really high since, for instance, no cases of tuberculosis associated to the treatment3

were presented.

When comparing the data of onset frequency of other types of cancer, including and excluding non-melanoma skin cancer found in the four-year follow-up, and the data of the SEER (Surveillance Epidemiology and End Results) database in the United States, no significant statistical differences are observed.

Major cardiovascular event rate, such as severe myocardium infarct and strokes, was also con-stant over time, without exceeding the expected cardiovascular events calculated for the general population. (See Graphic 4).

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Graphic 2Discontinuation of Treatment over Four Years

n=3117

6791

36 semanas

152 semanas

208 semanas

64 semanas

Análisis 2010 (4 años de seguimiento)

606

160 (26.4%)

44 (7.3%)

0 (0.0%)

13 (2.1%)

31 (5.1%)

19 (3.1%)

4 (0.7%)

49 (8.1%)

Data from Phoenix t2 Study

Randomized subjects at week 0 and treated with UST

Subjects who discontinued treatment

RReasons for discontinuation

Adverse events

Worsening of psoriasis

Non-satisfactory therapeutic effect

Lack of response to protocol

Loss of follow-up

Death

Others

606

146 (24.1%)

48 (7.9%)

1 (0.2%)

15 (2.5%)

17 (2.8%)

24 (4.0%)

6 (1.0%)

36 (5.9%)

1212

306 (25.2%)

92 (7.6%)

1 (0.1%)

28 (2.3%)

48 (4.0%)

43 (3.5%)

10 (0.8%)

85 (7.0%)

Combined

Ustekinumab

90 mg 45 mg

Graphic 3Cumulative Rate of Serious Infections

n=3117

6791

36 semanas

152 semanas

208 semanas

64 semanas

Análisis 2010 (4 años de seguimiento)

0.0

1.0

2.0

3.0

4.0

≤48 weeks >48 a <96 weeks >96 a <144 weeks >144 weeks

Year 1 Year 2 Year 3 Year 4

Even

t rat

e pe

r pat

ient

eac

h ye

ar

(PY)

(IC

95%

)

Ustekinumab 45 mg Ustekinumab 90 mg Combined Ustekinumab

13191132

11

1798141724

31172548

35

1009763

7

124588510

21451646

17

718601

0

101387810

16721478

10

520369

5

8847618

13841130

13

1.15(0.61, 1.97)

1.05(0.45, 2.07)

1.14(0.55, 2.09)

1.68(0.32, 1.24)

0.00(0.00, 0.50)

1.03(0.60, 1.65)

1.13(0.54, 2.08)

0.92(0.37, 1.89)

1.37(0.96, 1.91)

1.69(1.09, 2.52)

1.97(0.49, 1.74)

1.35(0.44, 3.16)

NNYEvents

10

Placebo

Graphic 4Major Cardiovascular Event Rate

Ustekinumab 45 mg Ustekinumab 90 mg Combined Ustekinumab

0.0

1.0

2.0

3.0Placebo

732177

0

790203

2

792203

3

1582406

5

732182

1

11101113

6

11561138

4

22662251

10

732182

1

13192184

13

19062598

8

31174762

21

732182

1

13192857

16

19923934

18

31176791

34

Análisis año 2010

PY: no �ene traducciónEvents: eventos

Even

tos

por 1

00 P

Y

Periodo controlado Análisis año 2007 Análisis año 2009 Análisis año 2010

0.00(0.00, 1.00)

0.58(0.12, 0.00)

1.47(0.00, 4.31)

0.54(0.20, 1.17)

0.35(0.10, 0.00)

0.44(0.21, 0.02)

0.55(0.01, 0.02)

0.55(0.01, 3.00)

0.36(0.32, 0.01) 0.45

(0.27, 0.32)

0.50(0.00, 0.70)

0.31(0.13, 0.01)

0.60(0.32, 1.02) 0.44

(0.21, 0.02)0.551(0.01, 3.00)

nPYEventos

0.0

1.0

2.0

3.0

732177

0

790203

2

792203

3

1582406

5

732182

1

11101113

6

11561138

4

22662251

10

732182

1

13192184

13

19062598

8

31174782

21

732182

1

13192857

16

19923934

18

31176791

34

Even

ts p

er P

Y

Controlled Period Analysis in 2007 Analysis in 2009 Analysis in 2010

0.00(0.00, 1.69)

0.98(0.12, 3.56)

1.47(0.30, 4.31) 1.23

(0.40, 2.87) 0.54(0.20, 1.17)

0.35(0.10, 0.90)

0.44(0.21, 0.82) 0.55

(0.01, 3.06)0.55

(0.01, 3.06)

0.56(0.32, 0.91)

0.46(0.27, 0.72)

0.50(0.35, 0.70)

0.31(0.13, 0.61)

0.60(0.32, 1.02) 0.44

(0.21, 0.82)0.55(0.01, 3.06)

NPYEvents

Conclusions: • At present, biological therapies used for the treatment of psoriasis (TNF-

inhibitor and anti-IL-12/IL-23) offer patients an acceptable risk to benefit ratio.

• Long-termfollow-upofustekinumabinclinicalstudiesshowsthatitisasafe drug.

• Atpresent,multipleinternationalrecordshavebeencreatedtoconductlong-term follow-up of biological treatments in order to help understand their long-term safety profile.

Bibliography: 1. Papp KA et al. J Am, Acad dermatol. Epub 16 sep 2010.2. Gordon K et al. J Am Acad dermatol. Epub 11 jul 2011.3. Langley RG et al. Br J Dermatol. 2010; 162 (6): 1349-58.4. Papp K et al, Lancet 2008; 371:1675-84.5. Leonardi C, et al. Lancet. 2008; 371:1665-74.6. Reich k et al. 20th EADV congress, 2011, Lisboa Portugal Po1153.7. Krueger GG, et al. N Engl J med. 2007; 356:580-92.8. Griffiths CEM, et al. N engk J Med. 2010; 362 (2):118-28.9. Gordon KB, et al. J Am Acad Dermatol. Epub 4 oct 2011.10. Reich K et al. 20th EADV congress, 2011, Lisboa, Portugal. Po1153.

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Exploring the Use of Anti-p40 TherapyDr. Paulo VarelaCentro Hospitalar de Gaia/Espinho, Porto, Portugal

IL-12 and IL-23 cytokines share a subunit called p401 (see Graphic 1). These interleukins (IL) acti-vate the production of Th1 and Th7 lymphocytes, which contribute to the formation and intensifica-tion of the inflammatory response with the pro-duction of IFNG (interferon-gamma), TNF-alpha (tumor necrosis factor-alpha), IL-17 and IL-222 (see Graphic 2).

At present, multiple diseases associated to the deregulation of Th1 and Th7 lymphocytes func-tion, such as plaque psoriasis, rheumatoid ar-thritis (RA), psoriatic arthritis, Crohn’s disease, and multiple sclerosis, among many others3,4,5,6, can be recognized. For these diseases, there are multiple clinical trials under course. At present, ustekinumab, which is a p40 subunit inhibitor, is acceptable and approved for the treatment of moderate-to-severe plaque psoriasis. However, off-label case reports have been conducted, such as the treatment of subacute cutaneous lupus7 and hidradenitis suppurativa8, with acceptable

Graphic 1p40 Subunit in IL 12 and IL 231

p35 p19

p40 p40

IL-12 IL-23

12

responses, giving the drug a promising future in dermatology.

In pyoderma gangrenosum, the expression of IL-23 has been identified in really high levels with an absence of IL-12 in active lesions of the disease; for this reason, ustekinumab treatments have been administered with a dose of 45 mg twice a week in week 0 and 4, presenting ulcer resolution and no relapses six months after ustekinumab discontinuation9.

In conclusion, ustekinumab, due to its selec-tive action mechanism, not only is a treatment that has proved its efficacy and safety in the treatment of moderate-to-severe plaque pso-riasis, but also has efficacy reports on other dermatological pathologies, in which, even though no specific studies have been conduct-ed, it promises to be a new alternative within the dermatological therapeutic options for pa-thologies difficult to manage.

Graphic 2IL 12 and IL 23 in the process of Th1 and Th17 cell differentiation2

Tc17

Th17Th1Tc1

IL-17, IL-22, TNF-α

DC DC

CD4+ CD4+

IL-1ß IL-23IL-12

IFN-γ, TNF-α

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Bibliography: 1. Nchieri G. nat rev immunol 2003; 3:133-46.2. Kryckek et al. J Inmunol. 2008; 181(7): 4733-41.3. Yeiding N,, Szapary P et al. Ann N Y acad Sci. 2011; 1222:30-9.4. Murphy Ca et al. J Exp Med. 2003; 198 (12): 1951-7.5. Berrebi D et al. Am J Pathol. 1998; 152(3): 667-72.6. Cua DJ et al. Nature. 2003; 421(6924): 744-8.7. Aieska de Souza, Trisha Ali-shaw, et al. Arch Dermatol. 2011; 147(8).8. Gulliver W et al. Poster presented at 69th AAD Congress, 4-8 feb 2011, New Orleans. P1153.9. Emmanuella Guenova et al. Arch Dematol. Pub on line june 16 2011.

The data and results presented herein were obtained from a conference on Medicine and the information summarized might be preliminary and subject to changes. This information is exclusively included for physician’s training and educational purposes only.

Summary prepared by the Staff of Circle Press based on their attendance to the Symposium.

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