Promising new drug for Crohn's disease

[Guest guest]

Dear All;

You've probably all heard of the drug called infliximab, used for

treatment of Crohn's disease, and more recently ulcerative colitis.

Infliximab is a monoclonal antibody (mab) against tumor necrosis

factor alpha (TNFa), and inhibits inflammation, although it has many

potential adverse effects.

The promising new " mab " currently being tested is an antibody against

a common subunit of interleukin-12 and interleukin-23 ...

Ustekinumab (a horrible name to pronounce, for sure!). This drug had

already shown promise in treatment of psoriasis (an inflammatory skin

disease), and has now been shown to be effective in Crohn's disease:

______________________________

Gastroenterology. 2008 Jul 17. [Epub ahead of print]

A Randomized Trial of Ustekinumab, a Human Interleukin-12/23

Monoclonal Antibody, in Patients With Moderate to Severe Crohn's

Disease.

Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S,

Johanns J, Blank M, Rutgeerts P; for the Ustekinumab Crohn's Disease

Study Group.

Mayo Clinic, Rochester, Minnesota.

BACKGROUND & AIMS: Interleukin-12 and interleukin-23 are inflammatory

cytokines implicated in Crohn's disease pathophysiology. Ustekinumab

is a monoclonal antibody against the p40 subunit of interleukin-

12/23. METHODS: We performed a double-blind, cross-over trial of the

clinical effects of ustekinumab in 104 patients with moderate-to-

severe Crohn's disease (population 1). Patients were given

subcutaneous placebo at weeks 0-3, then ustekinumab at weeks 8-11;

subcutaneous ustekinumab at weeks 0-3, then placebo at weeks 8-11;

intravenous placebo at week 0, then ustekinumab at week 8; or

intravenous ustekinumab at week 0, then placebo at week 8.

Furthermore, an open-label trial evaluated the effects of 4 weekly

subcutaneous injections or 1 intravenous infusion of ustekinumab in

27 patients who were primary or secondary nonresponders to infliximab

(population 2). RESULTS: In population 1, clinical response rates for

the combined groups given ustekinumab were 53% and 30% (P = .02) at

weeks 4 and 6, respectively, and 49% and 40% (P = .34) at week 8. In

a subgroup of 49 patients who were previously given infliximab

(neither primary nor secondary nonresponders), the clinical response

to ustekinumab was significantly greater than the group given the

placebo (P < .05) through week 8. In population 2 (n = 27), the

clinical responses at week 8 to subcutaneous and intravenous

ustekinumab were 43% and 54%, respectively. There was no increase in

the number of adverse or serious adverse events in patients given

ustekinumab through week 8 compared with placebo. CONCLUSIONS:

Ustekinumab induced a clinical response in patients with moderate-to-

severe Crohn's disease, especially in patients previously given

infliximab. PMID: 18706417.

______________________________

It's likely that this new drug, Ustekinumab, is inhibiting both the

Th1 and Th17 driven inflammation in the gut, but my guess would be

that it's the inhibition of the Th17 cells that is the most important.

Interleukin-23 (IL-23) is produced by dendritic cells in the gut, and

stimulates Th17 cells to produce interleukin-17 (IL-17) which then

causes inflammation. The IL-23/IL-17 pathway seems to be very

important in driving inflammation in both Crohn's disease and

ulcerative colitis:

Holtta V, Klemetti P, Sipponen T, Westerholm-Ormio M, Kociubinski G,

Salo H, Rasanen L, Kolho KL, Farkkila M, Savilahti E, Vaarala O 2008

IL-23/IL-17 immunity as a hallmark of Crohn's disease. Inflamm. Bowel

Dis. 14: 1175-1184.

http://www.ncbi.nlm.nih.gov/pubmed/18512248

Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R,

Kitazume MT, Nakazawa A, Sugita A, Koganei K, Isobe KI, Hibi T 2008

IL-23 differentially regulates the Th1/Th17 balance in ulcerative

colitis and Crohn's disease. Gut Jul 24 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/18653729

Another reason for suspecting the Th17 pathway as the primary target

of Ustekinumab is that the gene IL-23R (the receptor for IL-23

expressed on Th17 cells) has been convincingly shown to be a

susceptibility gene for psoriasis, IBD and other inflammatory

diseases:

http://www.psc-literature.org/IL-23R.htm

Blocking IL-23 with Ustekinumab would prevent the interaction of IL-

23 with its receptor, IL-23R.

It is not yet known whether these Th17 cells are involved in the

pathogenesis of PSC, and whether or not Ustekinumab would be

effective in PSC. But any promising new drug for IBD is noteworthy,

and it at least offers some hope that new treatments for PSC may be

on the horizon.

Best regards,

Dave

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