RE: Promising new drug for Crohn's disease

[Guest guest]

Dave, how old is this drug. What are the potentially dangerous side effects?

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

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1507 E. Sunset Drive

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Promising new drug for Crohn's disease

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/18512248Kobayashi 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/18653729Another 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.

htmBlocking 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)

[Guest guest]

Dave, how old is this drug. What are the potentially dangerous side effects?

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

Cell:

1507 E. Sunset Drive

Waukesha, WI 53189

LoriUSA@...

www.Lori.FirstWeber.com

Promising new drug for Crohn's disease

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/18512248Kobayashi 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/18653729Another 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.

htmBlocking 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)

[Guest guest]

>

> Dave, how old is this drug.  What are the potentially dangerous

side effects?

Hi Lori;

It's relatively new ... just approved by FDA in February 2008 for

treatment of psoriasis. It's made by a company called Centocor.

Please see this article for details:

http://www.medicalnewstoday.com/printerfriendlynews.php?newsid=96802

I understand that it has had few reported adverse effects:

http://www.medscape.com/viewarticle/563787

" Ustekinumab is a very high performance drug, utterly much more

effective for psoriasis than any currently available agent, " lead

investigator Craig Leonardi, MD, an associate clinical professor of

dermatology from St. Louis University Medical School in Missouri,

told Medscape Dermatology. " Patients had a terrific response, it's

infrequently administered, and the best part is that its safety

profile is very clean. "

" So far, the data that have been presented show great efficacy and

good safety, " Dr. Feldman said. " Even a single dose can give some

patients considerable and persistent improvement. "

" This agent is more effective than currently available treatments, "

Dr. Okamoto said. " However, the judgment of the safety of this agent

[compared with] currently available treatments requires additional

studies. "

" Overall, adverse events (AE) in PHOENIX 2 were similar between

groups. Through week 12, at least 1 AE occurred in 49% of the placebo

group, in 53% of the ustekinumab 45-mg group, and in 48% of the 90-mg

group. Study discontinuation because of an AE occurred in 0.2% of the

ustekinumab 45-mg group, 1% of the ustekinumab 90-mg group, and 2% of

the placebo group. At least 1 serious AE occurred in 2%, 1%, and 2%

of patients in the respective groups. "

" The most common AE was nasopharyngitis, which occurred with similar

frequency in all groups. All other AEs occurred at a frequency of

less than 2%, including headache, upper respiratory infection,

arthralgia, fatigue, and diarrhea. There was 1 death, from

cardiomyopathy, in the high-dose group, which was judged not to be

treatment related. No changes in laboratory parameters were noted. "

Best regards,

Dave R.

[Guest guest]

Dave, thank you for always keeping us updated on new drugs/advances and for explaining the usefulness of these new findings.

Ricky

PSC 2003> To: > Date: Wed, 20 Aug 2008 05:44:49 +0000> Subject: Promising new drug for Crohn's disease> > Dear All;> > You've probably all heard of the drug called infliximab, used for > treatment of Crohn's disease, and more recently ulcerative colitis. > > > 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:> ______________________________> >> 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)> > > > > > > > ------------------------------------> >