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European Academy of Dermatology and Venereology (EADV)

Management of psoriasis with biological agents in clinical practice

Lisbon 2011


Contents 3.

When and how should a patient begin biological therapy? Professor Carle Paul

Paul Sabatier University, Toulouse, France

7.

Long-term Management of Plaque Psoriasis with Biological Therapies Profesor Christopher Griffiths

Universidad de Manchester, Manchester, Reino Unido

11.

Exploring the Use of Anti-p40 Therapy Dr. Paulo Varela

Centro Hospitalar de Gaia/Espinho, Porto, Portugal


When and how should a patient begin with biological therapy? Professor Carle Paul Paul Sabatier University, Toulouse, France

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 treatments that provide them with immediate benefits. Indications that justify the transition from conventional systemic therapy into biological therapy are: 1) Loss of efficacy 2) Contraindications of its use due to cardiovascular, liver, kidney or hematologic pathologies in patients. 3) Secondary effects and lack of drug tolerability1. During this transition of therapies, multiple concerns 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

avoid severe psoriasis relapses? And, finally, do treatment efficacy and safety change if different alternatives or strategies are used during the transition of drugs? At present, few biological therapies 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 Assessment) 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 effectiveness 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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TRANSIT3,4 Study Design

Graphic 1 Arm 1

Patients ≤ 100kg Dose: 45 mg UST

R

Arm 2 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. Arm 1

Patients > 100 kg Dose:90 mg UST

Week

-4

R

Arm 2

0

4

8

12

16

Efficacy and Safety

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 randomized 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

Life Quality

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 inferior 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 assessing the efficacy and patients’ life quality. Eight pa-

Results of safety in week 123,4

Graphic 2

Arm 1 UST/MTX immediate discontinuation

Arm 2 UST/MTX gradual discontinuation

Patients with one or more

146 (59.8%)

Patients with serious AE

7 (2.9%)

Patients with discontinuity

Adverse Events (AE)

Total (n=489) Patients ≤ 100 kg n= 391

Patients > 100 kg n=98

154 (62.9%)

235 (60.1%)

65 (66.3%)

5 (2.0%)

7 (1.8%)

5 (5.1%)

2 (0.8%)

1 (0.4%)

3 (0.8%)

0

AE of special interest 1 (0.4%)

0

0

1 (1.0%)

Malignancies

0

0

0

0

Major cardiovascular events

0

0

0

0

Severe infections

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EďŹƒcacy at Week 123,4 Arm 1 UST/MTX immediate discontinuation Arm 2 UST/MTX gradual discontinuation

15

15.2 15.4

10

11.5

12 8.5 8 5

0

2.9

0

2

4

6

8

10

2.8 12

Weeks

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). Brazo 1

No difference was found between both arms of the study in terms of number of adverse events and the Brazo 2 type of reported adverse events. Serious adverse events frequency was of 2.9% in the group of immediate 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.

100 Patients with PGA of 0 to 1 (%)

PASI Score

20

Graphic 3

80

69.5

65.3 60 40 20 0

0.4 Baseline Week 12

0.4 Baseline Week 12

Conclusions: 1. Dermatologists have few available data based on evidence about the safety and efficacy supporting the transition from traditional systemic therapies into biological therapies. 2. Ustekinumab is a therapy that has proved to be effective and with proper tolerability in patients with poor response to methotrexate. 3. There are studies on ustekinumab that present 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 decrease.

As regards efficacy, no differences were found between 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 discontinuation 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 discontinuation of methotrexate and 2.8 in the arm of progressive drug discontinuation. Therefore, it is concluded that both strategies of treatment transition are similar in effectiveness (see Graphic 3).

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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 Management of Plaque Psoriasis with Biological Therapies Professor Christopher Griffiths

Manchester University, Manchester, United Kingdom

Long-term follow-up of patients treated with biological 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 efalizumab, which in Phase III trials presented with three-years follow-up1, did not report serious adverse 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-

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 stable 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

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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 Needed to Harm: the number of patients that need to be treated to observe an adverse event) of TNFinhibitor therapy. This study concluded that the beneficial effects of the treatment were greater than serious toxicity events. All studied TNF-inhibitors presented a similar safety profile, without significant statistical differences. The experience on ustekinumab (UTS) safety is supported in several studies4,5. An analysis of the safety 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

treatment with 45 mg and 24.1% in patients with 90 mg, for a calculated rate of treatment discontinuation 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 constant over time, without exceeding the expected cardiovascular events calculated for the general population. (See Graphic 4).

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

Graphic 1 Safety follow-up 2009 analysis (3-year follow-up)

2010 analysis (4-year follow-up)

Overall evaluated patients

n=3117

n=3117

Patients’ follow-up per year

4782

6791

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

36 weeks

36 weeks

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

152 weeks

152 weeks

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

100 weeks

208 weeks

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

64 weeks

64 weeks

UST Development Program in Psoriasis Treatment

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Discontinuation of Treatment over Four Years

Graphic 2

Ustekinumab Data from Phoenix t2 Study

45 mg

90 mg

Combined

606

606

1212

160 (26.4%)

146 (24.1%)

306 (25.2%)

Adverse events

44 (7.3%)

48 (7.9%)

92 (7.6%)

Worsening of psoriasis

0 (0.0%)

1 (0.2%)

1 (0.1%)

Non-satisfactory therapeutic effect

13 (2.1%)

15 (2.5%)

28 (2.3%)

Lack of response to protocol

31 (5.1%)

17 (2.8%)

48 (4.0%)

Loss of follow-up

19 (3.1%)

24 (4.0%)

43 (3.5%)

Death

4 (0.7%)

6 (1.0%)

10 (0.8%)

Others

49 (8.1%)

36 (5.9%)

85 (7.0%)

Randomized subjects at week 0 and treated with UST Subjects who discontinued treatment RReasons for discontinuation

Cumulative Rate of Serious Infections

Event rate per patient each year (PY) (IC 95%)

Ustekinumab 45 mg 4.0

Year 1

Graphic 3

Ustekinumab 90 mg

Combined Ustekinumab

Year 2

Year 3

1.13 (0.54, 2.08)

1.14 (0.55, 2.09)

Year 4

3.0 1.69 (1.09, 2.52)

2.0 1.0

1.97 (0.49, 1.74)

1.37 (0.96, 1.91)

1.03 (0.60, 1.65)

0.92 (0.37, 1.89)

1.35 (0.44, 3.16)

1.15 (0.61, 1.97) 1.05 (0.45, 2.07)

1.68 (0.32, 1.24) 0.00 (0.00, 0.50)

0.0

N NY Events

≤48 weeks 1319 1132 11

1798 3117 1417 2548 24 35

>48 a <96 weeks 1009 763 7

1245 885 10

2145 1646 17

>96 a <144 weeks 718 601 0

1013 878 10

1672 1478 10

>144 weeks 520 369 5

884 761 8

1384 1130 13

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Major Cardiovascular Event Rate Placebo

Ustekinumab 45 mg

Graphic 4

Ustekinumab 90 mg

Combined Ustekinumab

Events per PY

3.0

2.0

1.47 (0.30, 4.31) 1.23 (0.40, 2.87) 0.98 (0.12, 3.56)

1.0

0.54 0.56 0.44 0.60 0.50 (0.20, 1.17) 0.44 (0.32, 0.91) (0.21, 0.82) (0.35, 0.70) 0.55 0.55 (0.32, 1.02) (0.21, 0.82) 0.55 0.46 0.35 (0.01, 3.06) (0.01, 3.06) 0.31 (0.01, 3.06) (0.27, 0.72) (0.10, 0.90) (0.13, 0.61)

0.00 (0.00, 1.69) 0.0

Controlled Period N PY Events

Analysis in 2007

Analysis in 2009

Analysis in 2010

732 790 792 1582 732 1110 1156 2266 732 1319 1906 3117 732 1319 1992 3117 177 203 203 406 182 1113 1138 2251 182 2184 2598 4782 182 2857 3934 6791 0 2 3 5 1 6 4 10 1 13 8 21 1 16 18 34

Conclusions: • At present, biological therapies used for the treatment of psoriasis (TNFinhibitor and anti-IL-12/IL-23) offer patients an acceptable risk to benefit ratio. • Long-term follow-up of ustekinumab in clinical studies shows that it is a safe drug. • At present, multiple international records have been created to conduct long-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 Therapy Dr. Paulo Varela

Centro Hospitalar de Gaia/Espinho, Porto, Portugal

IL-12 and IL-23 cytokines share a subunit called p401 (see Graphic 1). These interleukins (IL) activate the production of Th1 and Th7 lymphocytes, which contribute to the formation and intensification of the inflammatory response with the production 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 function, such as plaque psoriasis, rheumatoid arthritis (RA), psoriatic arthritis, Crohnâ&#x20AC;&#x2122;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

p40 Subunit in IL 12 and IL 231

Graphic 1

p19

p35

p40 IL-12

p40 IL-23

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

DC

Graphic 2

DC

IL-23

IL-1ß

IL-12 CD4+

CD4+

Tc17 Tc1

Th1 IFN-γ, TNF-α

responses, giving the drug a promising future in dermatology. In pyoderma gangrenosum, the expression of IL23 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.

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Th17 IL-17, IL-22, TNF-α

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


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.

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PRESS

Buenos Aires Argentina

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 physicianâ&#x20AC;&#x2122;s training and educational purposes only. Summary prepared by the Staff of Circle Press based on their attendance to the Symposium. Image: Shutterstock


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STE0512MI-CP3-Ce

Management of psoriasis with biological agents in clinical practice  

Congress of European Academy of Dermatology and Venereology (EADV), Lisboa 2011.