Summary of the pipeline

A board to discuss future MS therapies in early stage (Phase I or II) trials.

Postby JFH » Tue Sep 20, 2005 10:02 am

dignan wrote:... I decided that I would try to keep the list purely disease-modifying therapies and not drugs targeted at aleviating symptoms.


I'm probably being immensely dense :oops: but I cant quite see the distinction between the two! Since there aint a cure arent DMTs there only to aleviate symptoms?? :?

Anyway great work Dig much appreciated :)
John
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Postby dignan » Tue Sep 20, 2005 1:41 pm

I'm no expert, but the way I'm looking at it is that a disease-modifying therapy is one that actually seeks to slow down the disease process. In the case of the CRABs, they aren't bad at cutting back on new lesions, they're better than nothing in cutting back a bit on relapses and they're not much better than nothing on slowing the progression of disability.

I guess it's a bit of an imaginary line, but part of the reason I put this list together is my frustration with other lists, like the US NMSS list that Melody (thanks Melody) posted a link to which include all the studies that are going on with MS patients right now. It's great, but I always end up wading through the list looking for the new disease-modifying treatments. I always feel like half of that NMSS list is new studies on the CRABs or Novantrone.

That's it.
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Postby bromley » Wed Sep 21, 2005 2:10 am

Dignan,

I have to agree completely on the NMSS list - it says 150-160 drugs in trial but, as you say, many of the trials are for exisiting drugs (head to head trials) or existing drugs with an add on e.g Copaxone + chewing gum etc.

My area of 'expertise' is defence (mainly equipment programmes). What I like about the US is the 'black programmes' which are going along without anyone really knowing about them (no publicity). Then all of a sudden the US Air Force is given some super stealth fighter which no one knew about. I hope there are some black programmes relating to MS drugs i.e. one comes to market unexpectedly. Unfortunately, too often, some annoucnement is made of a possible therapy and then it takes a decade to get it to market (and then it ends up killing people!). If only they (governments) could trnasfer a fraction of the spend on defence programmes to MS research - then we would be looking at much quicker timescales!


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Postby Katman » Wed Sep 21, 2005 5:47 am

Hear, hear, Bromley! True statement. I frequently do not comprehend how people can not find anything to do but kill people. One percent of the weapons budget would go a long, long way toward improving quality of life . But you know all this so I will be quiet.

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Postby dignan » Wed Sep 21, 2005 11:02 am

Added another statin (pravastatin) to the list. It is being tested in France and http://www.clinicaltrials.gov/ claims it is in Phase III, but there are only 40 participants in the trial -- that seems wrong one way or another. Either there are more than 40, or it is a phase II not a phase III, so I put it in Phase II.
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Postby dignan » Tue Sep 27, 2005 1:07 pm

Added a couple of new ones under Phase I and pre-clinical. It's always a bit of a guessing game in the early stage ones because the drug makers announce the diseases for which they think the substance might be effective, but phase I trials aren't really MS-specific, so they could test for just about anything if the Phase I trial is successful.
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Postby dignan » Tue Oct 04, 2005 4:19 pm

Lots of great new info out there Bromley, thanks. I added GEMSEP1 to Phase II and I might be jumping the gun a little, but based on your post I'm moving Campath to phase III.
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Thank you!

Postby kitkat2 » Tue Oct 04, 2005 6:22 pm

Your dedication to keeping us all up-to-date is greatly appreciated!

Now I have a list to bring with me to the neuro's.

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Postby dignan » Thu Oct 06, 2005 12:26 pm

Another one to add to phase I from the ACTRIMS/ECTRIMS conference.



Blockade of CD154: immune monitoring studies from a phase I clinical trial in relapsing multiple sclerosis

L. Kasper, J. Channon-Smith, K. Ryan, C. Fadul, I. Kasper, R. Noelle (Lebanon, USA)

Objective: To assess immunological parameters in subjects with relapsing MS following inhibition of CD154.

Background: MS is associated with a Th1 biased immune response that requires costimulation via CD40/154 ligation. A dose escalation (1,5,10,15 mg/kg) Phase I clinical trial (Kasper LH et. al ECTRIMS 2003) was performed to assess safety and tolerability as assessed by clinical, laboratory and MRI outcome in response to CD154 blockade.

Design/Methods: Subjects in the high dose cohort (15mg/kg) were selected for the immunologic studies and treated with fully humanized anti-CD154 q other week x 4. PBMC were isolated at baseline, week 2, 4, 6, 8 and analyzed for phenotypic shift by FACS and proliferative response in vitro. Supernatant was assayed for cytokine/chemokine production by multiplex.

Results: Data analysis was performed on the subjects in the 15mg/kg group only. There was neither a dose nor frequency related effect in response to PHA, OKT3, PMA/ionomycin or tetanus toxoid. There was no observed shift in total white blood cell, monocyte or lymphocyte counts. Phenotypic analysis failed to show any shift in CD3, CD4, CD8, CD56, CD45 or CD19 expression. There was no evidence of CD154+ expression on CD3+ T cells or CD40 expression of the CD3- population. vAn increase in both absolute and relative % CD25+/CD3+CD4+ from baseline (range 8-10%) to post therapy (range 45-52%) was observed in all treated subjects. A similar increase in CD45R0+/CD25+ population from baseline (range 11-18%) to post therapy (range 26-43%) was observed. There was no change in skin DTH response to tetanus or mumps antigens post therapy.. Multiplex analysis of supernatant identified a potential shift in the production of several cytokines/chemokines including IL-4, IL-5, IL-6, MCP-1 suggestive of a Th2 polarization compared to age matched normal subjects. There was no demonstrable Ig isotype switching.

Conclusion: These mechanistic studies suggest that in this small cohort of relapsing MS subjects treated with anti-CD154 a subtle but potentially important shift in immunologic parameters can be observed. This includes a phenotypic skewing toward a CD4+/CD25+ phenotype consistent with an amplification of the T reg population as well as a Th2 cytokine polarization. Further immunologic analysis of the archived cells including FoxP3 expression, T reg suppression assay, proliferation to MBP peptides and ELISPOT is now underway. Supported by NIH AI61938
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Postby dignan » Thu Oct 13, 2005 7:18 am

Here's one I'll add to Phase II. It says Phase I/II and it started in 1998.



T-Cell Vaccination In MS

This study is currently recruiting patients.
Verified by Sheba Medical Center September 2005
Sponsored by: Sheba Medical Center
Information provided by: Sheba Medical Center
ClinicalTrials.gov Identifier: NCT00220428

Purpose
To evaluate the safety of T cell vaccination in MS patients

Study Type: Interventional
Study Design: Educational/Counseling/Training, Randomized, Open Label, Historical Control, Single Group Assignment, Efficacy Study

Official Title: The Effect Of T-Cell Vaccination In Multiple Sclerosis -Phase I/II Safety And Efficacy Trail
Further Study Details:
Primary Outcomes: safety assesment of T-cell vaccination in nonresponding MS patients
Expected Total Enrollment: 20

Study start: July 1998; Expected completion: December 2007
Last follow-up: July 2005; Data entry closure: July 2007
Immunization of MS patients with irradiated autologous encephalitogenic myelin peptides(EMP) specific T-cell lines or clones Clinical immunologic and neuroradiologic evaluation.

http://www.clinicaltrials.gov/ct/show/N ... 8?order=64
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Postby dignan » Wed Oct 19, 2005 10:17 am

Just added this one to Phase II.



Efficacy of Anti-Tubercular Vaccination in Multiple Sclerosis

This study is currently recruiting patients.
Verified by S. Andrea Hospital July 2005

Purpose
The frequency of auto-immune diseases (including multiple sclerosis) is increasing in industrialised countries.

According to an hypothesis which is receiving a wide international credit, this may be due to the fact that the populations of these countries are increasingly less exposed to microbes further to the improvement of hygienic conditions and to the use of antibiotics.

If exposure to microbes is lacking, also their regulatory function is missed with a consequent possible onset of auto-immune symptoms.

For this reason, it is deemed that by exposing the immune system of a patient to an ancient microbe, being complex and important in man evolution, like the Tuberculosis Mycobacterium, it is possible to rebalance the immune system.

Condition: Multiple Sclerosis

Intervention Drug: Bacille of Calmette-Guerin

Phase: Phase II/Phase III

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind, Placebo Control, Parallel Assignment, Efficacy Study

Official Title: Phase 2-3 Use of Bacille Calmette-Guèrin (BCG) Vaccine in Patients with a First Clinical Demyelinating Episode. A Multicenter, Randomized, Single Blind Study.

Further Study Details:
Primary Outcomes: number of gad-enhancing lesions in T1 at 1,2,3,4,5,6 months; number of lesions in T1 and new lesions in T2 at 1,2,3,4,5,6 months

Secondary Outcomes: volume of T2 lesions at 0 and 6 months; volume of T1 lesions (black holes) at 0 and 6 months
Expected Total Enrollment: 100

Study start: November 2001
Last follow-up: September 2006

Vaccination with the Tuberculosis Mycobacterium has proved to be effective in the animal model of multiple sclerosis, experimental allergic encephalitis.

In a study of phase I-II our group has demonstrated the safety of this therapy together with preliminary evidence.

The study includes patients with an initial disease (diagnosis supported by paraclinical criteria): single clinical poly or mono-sympotmatic attack in the 6 months preceding the study, MR picture compatible with MS.

Study design 100 randomized patients (i.e. randomly assigned) to be included either in a group of 50 patients undergoing therapy or to a group of 50 patients receiving placebo.

Patients are followed up with monthly contrast MRI for 6 months. At the end of the six months the disease activity in the group of treated patients is benchmarked with the disease activity of the group of patients receiving placebo.

Safety is granted by the extremely wide diffusion of this kind of vaccination worldwide and by the previous study in patients affected by multiple sclerosis.

Eligibility
Ages Eligible for Study: 18 Years and above, Genders Eligible for Study: Both

Criteria
Inclusion Criteria:

* Patients with an initial disease (diagnosis supported by paraclinical criteria): single clinical poly or mono-sympotmatic attack in the 6 months preceding the study, MR picture compatible with MS

Exclusion Criteria:
* Therapy with corticosteroids in the last month
* Plasmaspheresis, administration of gamma globulins in the last three months
* Serious heart, renal, hepatic or haematological dysfunction defined by laboratory exams
* Evidence of infections
* Evidence of tubercolar disease

Italy, Roma - Department of Neurology - University of Rome La Sapienza, Rome, Roma, 00100, Italy; Recruiting

Giovanni Ristori, MD, Principal Investigator
Stefania Cannoni, MD, Sub-Investigator
Silvia Romano, MD, Sub-Investigator

http://www.clinicaltrials.gov/ct/show/N ... 0?order=51
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Postby dignan » Wed Oct 19, 2005 10:44 am

I'm adding this to Phase II as well, although it seems strange that this got to phase II without being noticed. If anybody knows anything about this one, I'm curious...



A Study to Assess the Effects of MK-0812 on Disease Activity in Patients with Relapsing-Remitting Multiple Sclerosis as Measured by MRI.

This study is currently recruiting patients.
Verified by Merck October 2005
Sponsored by: Merck
Information provided by: Merck

Purpose
The purpose of this study is to test MK-0812 on disease activity in patients with relapsing-remitting MS. Disease modifying activity will be assessed by measurement of brain lesions via MRI brain scans and an open label extension is offered.

http://www.clinicaltrials.gov/ct/show/N ... 5?order=92
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Postby Arron » Wed Oct 19, 2005 12:14 pm

Nice finds, as always. I find the tuberculosis trial to be quite interesting in approach.
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
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Postby Melody » Wed Oct 19, 2005 1:12 pm

My Mom had TB when she was younger so all of my siblings and myself test positive. At the time Mom had TB(prior to childbirth) she was living in Quebec which had very high averages. My one cousin that has been raised since he was 11 months old as my brother had both Mom and Dad with TB prior to their death. They did not die of TB but rather heart problems I believe. Not sure if this is true but we were told since we carried some of the TB germ through immunities from Mom we would never get TB. Both my children also show TB positive. My husbands family has no TB in it but again hard to say if that is relevant. I know our up bringings were different. I was raised on a dairy farm with all the milk and beef you could eat and then some. Hubby had two working parents out of the home and ate in my opinion mainly fast foods. I was raised in Quebec and he in Ontario. They also had one of the first microwaves and cooked everything in it. YUK as you can tell a microwave to me is my $800 dollar popcorn popper as well as range hood combo for the stove. Basically for looks at my house. Hubby when I met him was germ obsessed once again I'm a farm kid we thrived on germs.Does this all factor in I don't know but I like to chart all angles and the TB one is just one more to follow at this point. :lol:

:?: :?: :?: Does anyone here with MS know if they test positive for TB :?: :?: :?:
John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
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Postby dignan » Fri Oct 21, 2005 7:25 am

I'm almost reluctant to include this one since it is something being investigated to enhance interferons and allow them to be inhaled rather than injected...



Syntonix Autoimmune Disease Programs
Syntonix uses its Transceptor Fc construct technology to create new analogs of existing drugs to treat autoimmune disorders. Syntonix Pharmaceuticals has entered into an agreement with Serono (virt-x: SEO and NYSE: SRA) under which Serono has licensed worldwide exclusive rights to Syntonix’ Transceptor™ and SynFusion™ technologies for the development and commercialization of interferon-beta:Fc products. Syntonix’ technologies may enable the development of an interferon-beta therapy for multiple sclerosis (MS) that can be administered by inhalation. It has been demonstrated that certain Fc constructs can facilitate transport of therapeutic proteins across the lung epithelium through neonatal Fc receptor-mediated uptake. In in vivo experiments conducted by Syntonix and Serono, a proprietary interferon-beta:Fc molecule produced by Syntonix exhibited pharmacokinetic and pharmacodynamic properties that justify further development.

http://www.syntnx.com/autodis.php
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