Re: Don - Psoriasis

[Guest guest]

Hi Don;

A new biological agent is proving to be much more effective for

psoriasis than tumor necrosis factor (TNF-a) inhibitors. The new

biological agent targets interleukin 23 (IL-23) which seems to be key

in provoking Th17 cells that produce interleukin-17 that causes

inflammation. The anti-IL-23 agent is also being tested in Crohn's

disease:

___________________

Nat. Rev. Drug Discov. 7: 880-881 (2008)

Trial watch: novel biologic for psoriasis shows superiority over

current best-seller.

No authors listed

A Phase III trial of and 's investigational drug

ustekinumab in patients with moderate to severe psoriasis has shown

that it is more effective - and requires far fewer injections - than

etanercept (Enbrel;Amgen/Wyeth). In the 12-week study, reported at the

17th meeting of the European Academy of Dermatology and Venereology

(abstract FP1336), ustekinumab (45 mg or 90 mg), given by injection

at the start of the study and again at 4 weeks, was compared with

etanercept, which was given twice a week every week. In the

ustekinumab groups, 68% and 74% of participants (45 mg or

90 mg dose, respectively) met the primary end point of a 75%

reduction in psoriasis severity at the end of the trial compared with

57% of patients on etanercept.

A key component in the pathogenesis of psoriasis - a chronic

inflammatory skin disorder characterized by red, scaly plaques - is

the migration of T cells into the epidermis and release of

inflammatory mediators such as tumour-necrosis factor-alpha

(TNF-a), leading to hyperproliferation. Traditional treatments for

psoriasis, such as topical steroids or methotrexate, have limitations

including inconvenience and toxicity, respectively. However, several

novel biologics that offer more effective treatment have been

approved in recent years, including the TNF-a antagonist etanercept.

Ustekinumab is a human monoclonal antibody that antagonizes

signalling by the heterodimeric cytokines interleukin 12 (IL12) and

IL23 by binding to their shared p40 subunit. Studies suggest that

IL23 might be particularly important in psoriatic plaques (J. Am.

Acad. Dermatol. 57, 1059-1068;2007). It is thought that IL23

stimulates a subset of T cells to produce IL17, which then synergizes

with interferon-gamma (INFg) - which facilitates T cell infiltration

into the epidermis - to increase the production of pro-inflammatory

cytokines by keratinocytes.

" A key need for new treatments is to move beyond disease control " ,

says Feldman, Professor of Dermatology, Pathology and Public

Health Science at Wake Forest University, USA. Indeed, in the recent

trial, more patients in the two ustekinumab groups achieved " cleared "

or " minimal " psoriasis severity scores (65% and 71%, respectively,

compared with 49% in the etanercept group). The trial also indicated

a further significant benefit of ustekinumab - the intermittent,

convenient dosing schedule. " Patients will value this highly, " says

Feldman. This was also demonstrated in two earlier placebo-controlled

trials (Lancet 371, 1665-1674; 2008; Lancet 371, 1675-1684; 2008), in

which the response to ustekinumab was maintained during the 12 weeks

between injection times.

Although the current trial was relatively short, the two earlier

placebo-controlled trials also showed that ustekinumab was well

tolerated for 52-76 weeks. However, this still represents a " small

safety database compared with currently available treatments such as

adalimumab, etanercept and infliximab [which all target TNF-a], " says

Alice Gottlieb, Chair and Dermatologist in Chief, Tufts Medical

Center, Boston, USA. Lack of long-term safety data - in particular

regarding the potential for malignancy - was also raised as a concern

during an FDA advisory committee meeting in June 2008.

The committee unanimously recommended approval of ustekinumab, but

extended the review period until December of this year. A marketing

application has also been submitted to the EMEA. As has been

demonstrated for TNF-a inhibitors, inhibiting IL12 or IL23 might also

be beneficial in other immune disorders, including psoriatic

arthritis - an important potential benefit, says Gottlieb, as ~30% of

patients with psoriasis also have psoriatic arthritis. Several other

agents targeting IL12 or IL23 for various immune disorders are

also in development (TABLE 1).

Table 1. Development status of IL12 and IL23 antagonists*

Drug (company), Indication , Development status

Ustekinumab ( & )

Psoriasis Preregistration

PA, Crohn's disease, MS, Phase II

ABT-874‡ (Abbott)

Psoriasis, Phase III

Crohn's disease, Phase II

Apilimod§ (Synta Pharmaceuticals)

RA, Crohn's disease, Phase II

Multiple sclerosis, Preclinical

*Information (on compounds targeting the shared p40 subunit of

interleukin 12 (IL12) and IL23) was obtained from the Investigational

Drugs Database from Reuters.

‡Discontinued for multiple sclerosis and inflammatory disease; no

development reported for autoimmune disease or rheumatoid

arthritis.

§Discontinued for psoriasis.

MS, multiple sclerosis; PA, psoriatic arthritis; RA, rheumatoid

arthritis

___________________

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

> On another topic, does anyone suffer from psoriasis? Some sources

say that cyclosporin helps. I'm not going there. My TX Doc says that

if you have one autoimmune disease, you'll get some more. Very

comforting.

 

> Don