A phase IV open label study in moderate to severe chronic plaque psoriasis subjects transitioning from previous systemic antipsoriasis therapies (methotrexate, cyclosporine, retinoids or PUVA, NBUVB) to Raptiva 1 mg/kg/ week therapy.

Psoriasis is an inflammatory skin disorder that affects between 1 and 2% of the
general population. It is characterised by an increased proliferation of the
epidermis, and presents as well-defined thickened erythematous patches
typically covered with a silver scale. Current therapies for psoriasis are
unsatisfactory as none are curative, and in addition the most effective agents
are associated with potentially serious side effects. In all cases, psoriasis
is a chronic condition requiring long-term medication.
Although the aetiologies and pathologies of psoriasis are not well understood,
the discovery that T-cells are centrally involved in the development of
psoriasis, and the continued elucidation of the inflammatory pathways in
psoriasis, are leading to the development of new biological therapeutic agents
to treat these conditions.
Physicians anticipate using cell-adhesion molecule (CAM) antagonists, which
affect T-cell function in the treatment of psoriasis and using tumour necrosis
factor (TNF) inhibitors, which affect TNF in the inflammatory cascade, in the
treatment of psoriasis.
For further information, please refer to the current Raptiva Investigator
Brochure (11).

Objectives:
To assess the safety of transitioning subjects to Raptiva therapy from standard
oral systemic or phototherapy by overlapping with Raptiva whilst tapering the
initial systemic therapy or phototherapy dose.
The secondary objective is to evaluate the efficacy of Raptiva in subjects with
moderate to severe chronic plaque psoriasis over a 12-week period
The study aims to provide management guidance to physicians who are
transitioning subjects with moderate to severe chronic plaque psoriasis from
phototherapy or systemic anti-psoriatic medication to Raptiva.

Trial Design:
The trial is an open-label, non-comparative, non-randomised study in subjects
with moderate to severe chronic plaque psoriasis who have failed to respond to,
or who have a contraindication to, or are intolerant to other systemic
therapies, including methotrexate, cyclosporine and PUVA, and are transitioned
to Raptiva.
Subjects meeting these criteria but currently on systemic treatments not listed
above, as e.g. retinoids or phototherapies e.g. NBUVB can also be included in
the trial.
The multi-centre trial will be conducted at approximately (but not limited to)
20 sites in Canada and EU countries.
Subjects will start Raptiva on Day 1 with a first dose 0.7mg/kg/SC, followed by
1 mg/kg/wk SC for the following 11 weeks, while gradually tapering off their
current systemic therapy over 6 weeks.
The tapering of systemic treatment will be as follows:
• Wk 0-1 (Day 1-14) at pre-trial dose systemic or UV;
• Wk 2-3 (Day 15-28) at approximately half dose systemic (or approximately
half of the cumulative dose of UV sessions);
• Wk 4-5 (Day 29-42) at approximately one quarter of the pre-trial dose of
systemic or approximately one quarter of the cumulative dose of UV;
• No systemic or UV from Wk 6-12 (Day 43-85)
The study will be of 12 weeks duration with a 14 day screening period. A 30-day
safety follow-up visit will be conducted for all subjects following study
completion or withdrawal.

Psoriasis is a life-long systemic disease that starts early in life and affects
the quality of life significantly. Current therapies are limited due to
cumulative toxicities that leave unmet medical needs. The main oral drugs used
to control psoriasis have known serious systemic side effects e.g. cyclosporine
may cause nephrotoxicity and arterial hypertension, while methotrexate is an
immunosuppressive agent with known hepatotoxicity especially if alcohol is
taken with the drug.

Raptiva has not been studied extensively in combination with systemic
antipsoriasis drugs such as cyclosporine, and their concomitant use may
increase the risk of malignancies and lymphoproliferative disorders.
The Investigator Brochure details the safety profile of Raptiva. Estimated
total exposure from clinical trials and post-marketing treatment is about
30,000 subject-years.
Very common adverse drug reactions (ADRs) seen during treatment with Raptiva in
large placebo-controlled clinical trials were mild to moderate dose-related
flu-like symptoms including headache, fever, chills, nausea or myalgia, as well
as reversible lymphocytosis and leucocytosis up to 3.5 times the upper limit of
normality (ULN).
Common ADRs include back pain, asthenia, human anti-human antibody (HAHA) (HAHA
to Raptiva was detected in 6% of subjects, with no differences in
pharmacokinetics, clinically noteworthy adverse events or clinical efficacy
between subjects with or without HAHA response), reversible alkaline
phosphatase increase (less than 3 times ULN), asymptomatic and transient ALT
increase (less than 2.5 times ULN), arthralgia and erythrodermic and pustular
forms of psoriasis.
Uncommon ADRs include injection site reactions, thrombocytopenia and psoriasis
arthritis as well as uticaria, rash and allergic reactions.
Additional ADRs have been identified during post-marketing surveillance, but an
exact quantification of frequency has not been established. These reactions
include aseptic meningitis, severe infections, inflammatory
polyradiculoneuropathy, and facial palsy.
The combination of safety, efficacy, and quality of life endpoints provides a
comprehensive benefit: risk assessment of psoriasis therapies.
Using this combination, a favourable absolute benefit: risk has been
established during development of Raptiva marked by improvement of skin and
health status with a favourable safety profile. Previous Raptiva studies have
shown that about 40% of the subjects achieved favourable benefit -risk control
of their disease.