This Is MS Multiple Sclerosis Community: Knowledge & Support

After careful consideration, this abstract gets my vote for most interesting news from ECTRIMS 2006. To cut to the chase, this small study showed a reduction in annual relapse rate sustained over 5 years of 87.5% (from an average of 1.0 per year to an average of 0.125 per year)! The other good news is they say they have the funding to do a phase II trial.



Immunomodulation - Part I

Thursday, September 28, 2006, 15:30 - 17:00

Short-term blockade of CD154 potentiates long term clinical and MRI remission of RRMS: A five-year follow up

L. Kasper, C. Fadul, K. Ryan, J. Smith, H. Wishart, I. Kasper, R. Noelle (Lebanon, New Hampshire, USA)

Objective: To assess clinical and MRI progression in subjects with relapsing MS following blockade of CD154, a critical co-stimulatory ligand required for CD4+ T cell effector activation.

Background: MS is associated with a Th1 skewed immune response that requires costimulation via CD40/154 ligation. Pre-clinical studies have suggested the importance of this co-stimulatory interaction in the pathogenesis of MS. A Phase I clinical trial (Kasper LH et. al ECTRIMS 2003) was performed to assess safety and tolerability in response to anti-CD154 blockade.

Design/Methods: For the Phase I trial, four cohorts (n=3 subjects/group) with relapsing MS each received doses of 1, 5, 10, or 15 mg/kg of fully humanized anti-CD154 every other week (n=4 doses/patient). Clinical, laboratory and MRI evaluations were performed at serial time points thru week 18 to assess safety and toxicity. All patients completed treatment without serious adverse events. Thereafter, all patients were followed clinically every 6 months and by MRI with Gd enhancement every year. Patients with acute flares were treated with steroids if indicated. Nine patients elected to be on approved immune modulating drug (3-high dose IFNbeta, 6- GA) during the first year post anti-CD154 treatment. No immediate effect of therapy on either EDSS or MRI was observed at 18 weeks post treatment.

Results: No statistically significant change in EDSS for the 4 groups of subjects was observed during the five year follow-up (Baseline EDSS 2.3±0.5 and 5 years 2.5±1.6 p=0.622). A correlation between dose and EDSS was significant (r=-.51 p<.05). Higher dose of anti-CD154 is associated with lower EDSS at 5 years. The average annual relapse rate during the five years was 0.125 (compared to 1.0 without immunotherapy). At 5 years post treatment, MRI lesion volume in subjects treated with anti-CD154 is 1.4 times that of baseline study. 3/12 patients have elected to remain off current approved therapies at 5 years.

Conclusion: The 5 year follow- up data for the Phase I trial using anti-CD154 demonstrates a profound reduction in clinical relapse rate that compares favourably to all currently approved drugs. These findings suggest that blockade of CD154 is a potentially important therapy for the treatment of RRMS. These promising long-term clinical outcomes warrant further studies in a closely monitored Phase II trial. Funding for this trial is in place and awaits availability of product.

Supported by NIH AI061938

Interesting background to this. It was an IDEC/Eisai trial drug (IDEC was bought by good old Biogen a few years back), and they aren't making it any more. So although there were some potential side effect issues, they were not that serious and now the trials can't start up again because Biogen isn't making the drug any more.



IDEC-131. IDEC/Eisai.

Dumont FJ.
Merck Research Laboratories, Department of Immunology, Rahway, NJ 07065, USA. francis_dumont@merck.com

IDEC, in collaboration with Eisai, is developing IDEC-131 (E6040), a humanized monoclonal antibody (mAb) against CD154, the ligand for CD40 also called CD40L or gp39, for the potential treatment of several autoimmune diseases. IDEC-131 is based on technology that IDEC licensed from Dartmouth Medical School where researchers demonstrated the biological effects of the anti-CD154 antibody in animal models of autoimmunity. In January 2001, phase II trials in psoriasis and idiopathic thrombocytopenic purpura (ITP) were initiated. By january 2002, a phase II trial in Crohn's disease was also ongoing. A pilot, multicenter, multiple-dose phase I trial in moderate-to-severe psoriasis was initiated in January 2001. This trial was ongoing in January 2002. IDEC, in collaboration with Dartmouth Medical School had also initiated a phase I trial in multiple sclerosis by March 1999. IDEC-131 was also previously being developed for systemic lupus ezythematosus (SLE), although no further development for this indication has been reported since the disclosure of disappointing phase II results in April 2000. Analysts at Morgan Stanley predicted in February 2002, that the product would be launched in 2005, with sales of US $25 million, rising to US $75 million in 2006.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_DocSum



From the NMSS

Agent: IDEC-131 (anti-CD40L or anti-CD154) SUSPENDED

Purpose of study: To control development of brain lesions and disease course

Possible mechanism: Targets CD40 ligand on T cells, reducing interaction with B cells and excessive antibody production

Study description: Double blinded

Dose/route: 15 mg/kg iv every other wk for 5 wks, then every mo for 3 mos

Outcome parameters: MRI, EDSS, MSFC, biologics, cognitive

Type of MS: RR

Number of Subjects: 46

Start date: January 2002

Observation period: 22 months

Investigators: L. Kasper and others

Sites: Dartmouth Medical School, Hanover, NH

Results/Publications: Potential safety risk of thromboembolism identified; FDA reviewed data and concluded that probably not related to treatment, but manufacturer is no longer making the drug (IDEC Pharmaceuticals press release, June 10, 2002; Science 2005 Mar 18;307(5716):1712-5)

Funding: NINDS, Immune Tolerance Network

Last update: 2005

http://www.nationalmssociety.org/pdf/re ... rial%22%22

OK Dignan, so I don't get it. Here are our pals at Biogen who seem pretty adept at following up on MS opportunities. They OWN this compound, everything looks sweet and then they stop. Only somebody there doesn't really stop 'cause 5 years later they look at results again. Can you tell me what this could mean? I have been a part of decision making in large corps but not pharma and this baffles me...

Lee

Nope, I can't explain it. I can make a wild guess, but that's about it. Since IDEC canceled the project, I assume before the Biogen buyout, maybe it got a bit lost in the shuffle while the merger was happening. Then, since the initial trial had some safety issues, perhaps that was the final nail in the coffin, even though the FDA concluded that the safety concerns probably weren't related to the treatment. While the merger was happening, Biogen already had avonex, and was eagerly anticipating tysabri being a new MS blockbuster of unprecedented, epic proportions.

I don't know, I'm guessing that based on this data, Dartmouth is likely having talks with Biogen about getting this going again. As you say, Biogen is pretty savvy, so I'd be surprised if the phase II doesn't happen soon...and in MS treatment time, "soon" means within 34 years...

You're right, I'm sure. It has to be an issue of timing and I wouldn't put out anymore than I had to for public consumption either. Who bought who when especially 5 years ago is sort of beyond my scope...

Lee