Rituxan results from ECTRIMS

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Rituxan results from ECTRIMS

Postby dignan » Sat Oct 13, 2007 8:14 am

Looks like rituxan is pretty good at reducing lesions, but then so is high-dose interferon, but it's effect on relapses isn't quite as impressive. I guess I'm more hopeful about rituxan as a treatment for PPMS anyway, so relapses won't matter in that trial.



Safety and efficacy of rituximab in adults with relapsing-remitting multiple sclerosis: results of a phase II placebo-controlled, multicentre trial through 48 weeks

E. Waubant, S. Hauser, D.L. Arnold, T. Vollmer, J.P. Antel, R. Fox, A. Bar-Or, M. Panzara, N. Sarkar, S. Agarwal, A. Langer-Gould, C. Smith (San Francisco, USA; Montreal, CAN; Phoenix, USA; Cleveland, USA; Cambridge, South San Francisco, USA)

Objective: To investigate the safety and efficacy of rituximab (RTX) in treating relapsing remitting MS (RRMS).

Background: Evidence exists for a pathogenic role of antibodies and B cells in MS, identifying B cells as a potential therapeutic target. RTX, an antibody selectively depleting CD20+ B cells, offers a unique opportunity to evaluate this hypothesis.

Design/Methods: In a double-blind, controlled trial, 104 patients (Pts) with RRMS were randomized to 1000 mg intravenous RTX (n=69) or Plc (n=35) on days 1 and 15 and followed for 48 weeks (Wks). The primary endpoint was the total number of gadolinium (Gd)-enhancing lesions at Wks 12, 16, 20, and 24. Secondary MRI and clinical endpoints were total number of new Gd lesions, change in T2 lesion volume, and proportion of Pts relapsing at various timepoints through 48 Wks.

Results: The primary endpoint was met with RTX, with a significant (p<0.0001) mean reduction in total Gd-enhancing lesion counts at Wks 12, 16, 20, and 24 vs. Plc (mean 0.5 RTX vs. 5.5 Plc, 91% relative reduction). Over the same period, RTX significantly (p<0.0001) reduced the number of new Gd-enhancing lesions vs. Plc (mean 0.16 RTX vs. 4.5 Plc). Mean reduction in T2 lesion volume from baseline to Wks 24 and 36 was significantly greater in RTX vs. Plc (p=0.0077 and p=0.0041, respectively). The proportion of Pts with relapses was significantly reduced in RTX vs. Plc at Wk 24 (34.3% vs. 14.5%, p=0.0238) and Wk 48 (40% vs. 20.3%, p=0.037), a relative reduction of 58% and 49%, respectively. Adjusted annualized relapse rate during 48 Wks was the same as at 24 Wks with RTX (0.37) although no longer statistically significant compared with Plc (0.72, p=0.086). Excepting infusion-associated adverse events (AEs), infection-associated AEs and serious AEs were comparable between groups through 48 Wks. While a greater proportion of RTX (78.3%) vs. Plc (40.0%) Pts experienced infusion-associated AEs within 24 hours of the first infusion, with the second infusion, AEs were comparable with RTX (20.9%) vs. Plc (40.0%).

Conclusions/Relevance: In Pts with RRMS, a single course of RTX was generally safe and well tolerated through 48 Wks and led to significantly fewer Gd-enhancing lesions, T2 lesion volume, and relapses through 24 Wks. The effects on Gd lesions and relapses appeared durable through 48 Wks. These results provide evidence of B cell involvement in the pathophysiology of MS. We continue to monitor long-term safety of RTX in this population.

ECTRIMS link
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An interesting piece

Postby Nemotoday » Sat Dec 08, 2007 1:56 pm

http://www.businessweek.com/magazine/co ... 924207.htm

It is still early days for Rituxan in autoimmune disease, but there have been some important milestones. On a Saturday in the summer of 2006, the MS research team gathered in a conference room to review early results of a key Rituxan trial.

As they studied MRI scans of patients' brains, they were amazed to discover that the signs of the nerve-ravaging disease had dropped by 91%. "I can forever remember sitting in this room and watching a story unfold that we really hadn't seen before," recalls Craig Smith, a medical director at Genentech.

Rituxan was approved to treat rheumatoid arthritis in February, 2006, and has captured 10% of the market. For patients such as Nancy Kowalski, the
sign-language interpreter, the drug has been a lifesaver. She got her first
infusion in March, 2007. While the needle was still in her arm she glanced at her hands and couldn't believe what she was seeing. "The swelling was going down." Kowalski has gone back to work.

Genentech will announce key Rituxan data in lupus and MS next year, and it's working on some completely new approaches to autoimmune disease.

The mandate, as always, is to consider ideas others might overlook. "There's this tremendous herd instinct out there," Levinson says. "That's a great opportunity, because often the crowd is wrong."
Keep smiling as who knows what good things might be around the corner and if the road snakes a bit keep going.
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Postby cheerleader » Wed Feb 13, 2008 2:31 pm

Not sure if this is old news....just published in NEJM today, results of Rituximab study for RRMS thru UCSF office.

http://pub.ucsf.edu/newsservices/releases/200802132/

best,
AC
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby thinkingoutloud86 » Wed Feb 13, 2008 5:17 pm

Saw the previous links/articles...i think the one I came across was about the same/similar study, but added the following information:

TOL

http://www.medpagetoday.com/Neurology/M ... is/tb/8345

"But despite the favorable results, rituximab's lead commercial sponsor, Genentech, is dropping the drug from further development for relapsing-remitting MS. Instead, the company is focusing on ocrelizumab, a second-generation agent with the same biological target, a spokesperson said."

Rituximab Effective Against MS in Phase II Trial
By John Gever, Staff Writer, MedPage Today
Published: February 13, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine. Earn CME/CE credit
for reading medical news
SAN FRANCISCO, Feb. 13 -- Two doses of rituximab (Rituxan) diminished relapsing-remitting multiple sclerosis lesions and clinical symptoms for nearly a year, researchers here said.
Action Points

* Explain to interested patients that the study found that rituximab reduced the number of relapses and the number and volume of lesions over 48 weeks in patients with relapsing-remitting MS.

* Explain that side effects rates were generally similar to placebo except for infusion-related reactions after the first rituximab dose.

* Point out that longer-term efficacy and rare side effects could not be determined in this study.

* Explain that rituximab is not approved for this indication and that the company making it does not plan to seek such approval.

The drug cut in half the number of patients developing relapses, relative to placebo, and reduced gadolinium-enhancing lesion counts to near zero after 48 weeks, reported Stephen L. Hauser, M.D., of the University of California San Francisco, and colleagues in the Feb. 14 issue of the New England Journal of Medicine.

"The results of this phase II trial provide MRI and clinical evidence that selective CD20-positive B-cell depletion is a potentially effective approach in the treatment of relapsing-remitting multiple sclerosis," they wrote.

But despite the favorable results, rituximab's lead commercial sponsor, Genentech, is dropping the drug from further development for relapsing-remitting MS. Instead, the company is focusing on ocrelizumab, a second-generation agent with the same biological target, a spokesperson said.

Dr. Hauser and colleagues reported final data from the double-blind, multicenter Helping to Evaluate Rituxan in Relapsing-Remitting Multiple Sclerosis (HERMES) trial.

It randomized 104 patients 2:1 to rituximab or placebo. The drug was given at 1,000 mg IV on days one and 15.

Patients 18 to 55 with at least one relapse during the preceding year and an entry score of no more than 5.0 on the Expanded Disability Status Scale were included.

Among the exclusion criteria were relapse within the previous 30 days or recent treatment with other biologics, immunosuppressant drugs, or systemic corticosteroids.

The study's primary endpoint was the effect on gadolinium-enhancing lesion counts as seen on MRI brain scans at weeks 12, 16, 20, and 24.

More than 80% of the rituximab group had no lesions at these evaluations, compared 51.4% of the placebo group (P<0.001).

Mean lesion counts across the evaluation points were 5.5 (SD 15.0) for placebo and 0.5 (SD 2.0) for rituximab.

The intergroup differences were similar for counts of new lesions.

The researchers also reported that lesion counts at week 48 were virtually unchanged from values at week 24 for both patient groups.

From baseline to week 36, the mean change in lesion volume was an increase of 417.8 cubic mm (SD 1,358.4) for placebo, compared with a decrease of 175.4 cubic mm (SD 1,187.6) for rituximab (P=0.008).

Effects on relapses were a secondary outcome. The researchers found that 40% of placebo patients had experienced relapses by week 48 compared with only 20.3% of patients on rituximab (P=0.04).

Except for infusion-related events after the first dosing, adverse effects were generally similar for both treatments. Certain infections were more common with rituximab, including urinary tract infections (14.5% versus 8.6%) and sinusitis (13% versus 8.6%). On the other hand, infection-associated serious adverse events were seen in 5.7% of patients receiving placebo, compared with 2.9% of the rituximab group.

Substantially more patients in the placebo group discontinued treatment prematurely (40% versus 15.9%), the researchers said.

About a quarter of patients developed antibodies against rituximab, a chimeric molecule that retains some murine elements.

Genentech spokeswoman Nikki Levy said that although these anti-drug antibodies had no apparent clinical effects, the finding helped motivate the company's decision to pursue ocrelizumab in place of rituximab for relapsing-remitting multiple sclerosis.

Ocrelizumab is a humanized anti-CD20 antibody. Levy said Genentech believes it "may offer safety advantages," and the company is now discussing a phase II trial design with the FDA for the drug.

Further complicating the situation is a legal dispute between Genentech and Biogen Idec involving both agents. The partners disagree about certain aspects of the clinical development program and have taken the dispute to arbitration.

Levy said a ruling could include an injunction blocking clinical trials of rituximab and/or ocrelizumab, but would not comment on when a ruling may come down.

Genentech is now conducting a phase II/III trial of rituximab in primary progressive MS.

In an accompanying editorial, Henry McFarland, M.D., of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., observed that the HERMES data were wanting in some important respects.

"A phase II trial leaves many questions unanswered; these include the duration of the treatment effect, the effect of progression of disability, and -- most important -- the types of adverse events that may occur at low frequency," he wrote.

Nevertheless, the short-term efficacy as measured by lesion accounts was "remarkable," he said.

He also agreed with the researchers that the findings confirm the importance of B cells in MS pathology and their value as a drug target.

How rituximab works in multiple sclerosis remains unclear. The researchers said it does not seem to involve direct reduction of B-cell-produced autoantibodies.

They suggested that another function of B cells, antigen presentation, is more likely to account for rituximab's efficacy.

They also suggested that another mechanism may involve inhibition of cytokines released from B cells that promote T-cell activity.

Multiple sclerosis affects about 400,000 people in the U.S. Some 85% of cases begin with the relapsing-remitting form, but about one-third of these eventually become fully progressive, according to a 2001 Institute of Medicine report.

Currently, rituximab is approved for treating several forms of non-Hodgkin's lymphoma and as second-line biologic therapy in rheumatoid arthritis.
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Postby dignan » Wed Feb 13, 2008 7:17 pm

Hey, AC and TOL, thanks for the info. I'll take rituxan for RRMS out of the pipeline in phase 2.
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Postby bromley » Thu Feb 14, 2008 7:27 am

Perhaps Biogen will still take forward a Phase III trial of Rituximab for RR.

The US MS Society is also funding a Phase II trial of Rituximab for RRMS which is due to report this year. The trial dates back to 2002 so the results should cover 6 years.

Anne H. Cross, MD
Washington University
Saint Louis, MO
Region: Gateway Area Chapter
Term: 4/1/02-9/30/08
Funding Required: $627,832

“A phase II trial of Rituxan in multiple sclerosis” A clinical trial of an immune-based therapy for treatment of relapsing-remitting MS.


B cells are immune cells that make antibodies and may play a key role in the development of MS. Anne Cross, MD, is conducting an early phase trial to determine the potential value of removing B cells as a treatment for MS. In this trial, she is testing the safety of Rituxan® (rituximab, a drug that depletes B cells from the human circulation) in people with relapsing-remitting MS. This drug is approved by the FDA to treat certain types of cancer, and has been shown to remove all circulating B cells for as long as nine months after four doses.

Dr. Cross is enrolling 30 people who already have tried interferon beta or glatiramer acetate, but continue to have active MS, as shown in clinical and MRI (magnetic resonance imaging) findings. Participants will continue to take these medications, to which are added four doses of Rituxan. Individuals will have three MRI scans before receiving the study drug, and three more after receiving the drug. These scans will be compared to assess the impact of Rituxan on the number and size of brain lesions (areas of inflammation or tissue damage). Throughout, participants will be monitored for safety.

If this drug proves to be safe and shows possible signs of benefit based on MRI, a larger trial to determine its effectiveness for treating this disease would be warranted.
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Rituximab for PPMS

Postby Smilingface » Fri Feb 15, 2008 5:48 pm

My neurologist today gave me hope that Biogen will take Rituximab forward
for PPMS inspite of Genentech's recent announcement. He said with what I thought was a fair amount of certainty that the trial results from the PPMS phase 3 trial will be released the end of March or beginning of April. I sure hope he knows something the rest of us don't. :)
Primary Progressive, Onset 10 years ago at age 42, diagnosis 6 years ago, Vit D, Chinese Herbs, Exercise, yoga. So far tried antibiotics, fumaric acid and 4AP. Currently participant in the FTY720/PPMS Trial.<br />
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Postby dignan » Sun Feb 17, 2008 4:49 pm

The timing of the release of the phase 3 trial results sounds reasonable to me. Lately, I've been wondering whether one trial would be sufficient to file for regulatory approval of rituxan for PPMS. It seems that there aren't hard and fast rules, but the norm for approval of MS drugs has become 2 phase 3 trials. Hopefully since there aren't any approved therapies for PPMS, a second trial won't be required. A statement from Craig Smith, neurology lead clinical scientist in the immunology department at Genentech, gives me hope that if the results are decent, they will file for approval of rituxan for PPMS around the middle of this year.

Results from that study are expected before the end of June. If the trial succeeds, Genentech may apply for U.S. approval to market Rituxan for MS patients, Smith said.


http://www.bloomberg.com/apps/news?pid= ... refer=news
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Postby Lyon » Sun Feb 17, 2008 5:37 pm

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Last edited by Lyon on Tue Nov 29, 2011 6:17 pm, edited 1 time in total.
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Second trial neccessary?

Postby Smilingface » Sun Feb 17, 2008 7:06 pm

Dignan, funny I've been wondering about the necessity of a second PPMS trial also. Because of , as you pointed out lack of treatment for PPMS, I'm wishfully thinking if the results are great, the second trial will be open-label.

I have seen the drug industry do that for other drugs... Ok just call me an optimist....
Primary Progressive, Onset 10 years ago at age 42, diagnosis 6 years ago, Vit D, Chinese Herbs, Exercise, yoga. So far tried antibiotics, fumaric acid and 4AP. Currently participant in the FTY720/PPMS Trial.<br />
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Postby Jean » Mon Feb 18, 2008 2:32 pm

And if it works for PPMS, we may hope it works for SPMS too. Let's cross fingers, as we say in France.
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Postby gibbledygook » Tue Feb 19, 2008 8:36 am

Epstein barr replicates in B lymphocytes as per this article: http://www.blackwell-synergy.com/doi/pd ... 2_4_1432.x
I wonder if a b lymphocyte is the same as a b cell...
Methinks it's time for some anti-viral licorice!
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby Lyon » Tue Feb 19, 2008 1:06 pm

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Last edited by Lyon on Tue Nov 29, 2011 6:10 pm, edited 1 time in total.
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Rituxan

Postby Brainteaser » Sat Mar 01, 2008 6:28 pm

Trials are great and I also will be looking forward to the results of the Rituxan study for PPMS, mid-year................but I was wondering if there is any anecdotal feedback at this point re Rituxan? - just as it has been good to hear of the personal experiences of others on this site with Campath, Revimmune etc.

Also, given that Rituxan is already out there for other conditions, can you do a 'self-trial' of the treatment anywhere? ie would anyone know if you can go anywhere in the world and have Rituxan administered for MS, privately?

Thanks,
Phil
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Postby Brainteaser » Sat Mar 01, 2008 11:32 pm

Just following up my post of earlier today, I have googled a smattering of instances of Rituxan being used off-label for the treatment of MS, generally in the US and at a cost of approx. $40k pa - but it would still be helpful to learn of particular experiences of people being treated with Rituxan, either via a trial or off-label.
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