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Old 04-21-2007, 09:56 PM #1
wannabe wannabe is offline
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Small study, open label, some risks, but still looks promising.

J Neurol. 2007 Apr 20; [Epub ahead of print]

Treatment of active secondary progressive multiple sclerosis with treosulfan.

Wiendl H, Kieseier BC, Weissert R, Mylius HA, Pichlmeier U, Hartung HP, Melms A, Kuker W, Weller M.
Dept. of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080, Wuerzburg, Germany, heinz.wiendl@klinik.uni-wuerzburg.de.

OBJECTIVE: To study the safety and efficacy of treosulfan, a cytotoxic alkylating agent, in patients with active secondary progressive multiple sclerosis.

BACKGROUND: Treosulfan (L-threitol-1,4-bis(methanesulfonate)) is a bifunctional alkylating agent with a favorable profile of side effects, approved for the treatment of ovarian cancer. Treosulfan has previously been shown to reduce the severity of experimental allergic encephalomyelitis under pre-therapeutic and therapeutic conditions. In human peripheral blood mononuclear cells, treosulfan reduces proliferative capacity and increases apoptosis.

STUDY DESIGN: This is a nonrandomized, open label study conducted in two centers. Eleven patients with active secondary progressive MS that failed to or did not qualify for approved disease modifying drugs were treated with treosulfan for 1 year. Patients received intravenous infusions of 7 g/m(2) every 4 weeks for 3 months (cycles 1-4, induction phase) with a predefined one-step dose escalation, thereafter every 3 months for the following 9 months (cyles 5-7, maintainance phase). Cranial MRI was performed every 3 months, EDSS and MSFC as well as physical examination were assessed at each clinical visit.

RESULTS: Treatment with treosulfan was safe and well tolerated. Nine of 11 patients remained on study drug over the complete treatment period and showed clinical stabilisation or improvement as determined by EDSS and MSFC. Two patients discontinued study drug because of leukocytopenia and withdrawal of consent, respectively. No clinical relapses were observed during the treatment period. Thus, the median number of relapses per year was reduced significantly by 1.5 (range -3 to 0), p < 0.016, compared to pre-study. Therapy with treosulfan lead to a clear reduction of MRI activity as revealed by a reduced number of Gd + enhancing lesions on T1 weighted images. The mean number and volume of T2 lesions remained unchanged over 1 year. Four out of 9 patients under treosulfan showed no detectable disease activity (no Gd enhancing lesions, no new or newly enlarging T2 lesions).

CONCLUSIONS: Application of treosulfan in MS was safe and well tolerated. Further studies are warranted to evaluate the efficacy of this treatment in secondary progressive MS.

PMID: 17446994 [PubMed - as supplied by publisher]
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Old 04-23-2007, 03:50 AM #2
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Thanks wannabe for this post along with your previous one. It is encouraging that more testing is being done for spms!! It seems like we were the "outcasts" for a long time.

Just fyi -- I always read everything here, but some days I'm just too sick to reply. Please -- keep them coming!!
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Old 04-23-2007, 08:00 AM #3
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Wannabe,

Thanks for that info...we don't see too much these days for SPMS patients.

Gee...another cancer drug being thrown at MS patients...there doesn't seem to be an end to these heavy duty immune system altering drugs being tested on MS sufferers! Sometimes a small number of patients can also play with the statistics in these trials...2 patients or 18% had to drop out due to side effects!

I sure wish they would find something else other than these powerful anti-cancer drugs to try on SPMS patients.

Harry
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Old 04-23-2007, 08:27 AM #4
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There's a few things at least these days. But considering how many people go on to become SPMS (like most of us), you'd think that there would be even more research. Since the RRMS drugs aren't that good at stabilizing MS, you'd think they would have tried their luck at trying to stabilize it when it got to the SPMS phase. Isn't one of those newer ones in clinical trials also targeting SPMS? I can't find any info on it right now though.

Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis

Journal Journal of Neurology
Publisher Steinkopff
ISSN 0340-5354 (Print) 1432-1459 (Online)
Issue Volume 250, Number 7 / July, 2003
Category ORIGINAL COMMUNICATION
DOI 10.1007/s00415-003-1089-x
Pages 834-838
Subject Collection Medicine
SpringerLink Date Thursday, February 19, 2004


Authors
Paola Perini, Paolo Gallo

Abstract
The safety and efficacy of pulse cyclophosphamide (CTX) therapy was investigated in patients with very active secondary progressive multiple sclerosis, characterized by frequent relapses and rapid disability progression. For this purpose the clinical and MRI effects were assessed.

Sixteen patients, 11 female and 5 male, were experiencing rapidly deteriorating disease, characterized by frequent and severe relapses as well as rapid progression (defined by an increase of more than 1 EDSS point in a period of 1 year). Mean relapse rate in the two years preceding CTX therapy was 3.0 ±1.4. Mean EDSS was 4.0±1.4 one year before therapy and 5.6±1.0 at study entry.

Treatment consisted in administration of high dose intravenous CTX every four weeks for one year and then every eight weeks for an additional twelve months. CTX dose was tailored to the patient’s white blood cell response, and ranged from 800 to 1,200 mg/m 2 body surface. MRI was performed before therapy and then at 12 (Y1) and 24 (Y2) months. Eight patients with similar clinical features constituted a control group. CTX therapy was safe and well tolerated, and no severe side effects were observed.

The EDSS decreased to 4.3±1.6 at Y1 (Y0 vs.Y1: p< 0.001) and to 4.1±1.6 at Y2 (Y0 vs.Y2: p< 0.001). Only four patients experienced relapses during the first year of therapy, while no relapses were observed during the second year of therapy. The mean relapse rate during therapy was 0.25 ±0.45 (p< 0.0001).No increase in T2 lesion load was observed over the two years. A significant clinical and MRI deterioration was observed in the control group.

Therapy with pulse CTX was able to stop disease activity and progression in patients with rapidly evolving secondaryprogressive MS.


http://www.springerlink.com/content/wdea7ebbpu399hy1/


General Information

Novantrone has been approved for use in reducing neurologic disability and/or the frequency of relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Novantrone is not indicated for the treatment of patients with primary progressive multiple sclerosis.

White blood cells can produce the symptoms of multiple sclerosis by attacking myelin, a fatty substance that surrounds nerve cells. Novantrone suppresses the activity of T and B cells, and in this manner slows the progression of the disease and reduces the frequency of relapses.

Multiple sclerosis is diagnosed in over 350,000 people in the United States. There is no one group of people who "get" multiple sclerosis; however, trends show that it often strikes between the ages of 30 and 50, and affects mostly women. Multiple sclerosis is most commonly found in Canada, the United States, South America, and Europe. (from the Multiple Sclerosis Foundation)

Clinical Results

The safety and effectiveness of Novantrone in multiple sclerosis were assessed in two randomized, controlled multicenter trials. One trial was conducted in subjects with secondary progressive or progressive relapsing multiple sclerosis. Neurological disability was evaluated based on the Kutzke Expanded Disability Status Scale (EDSS). This scale ranges from 0.0 to 10.0, with increasing scores indicating worsening condition. Subjects receive a placebo, 5 mg/m2 Novantrone, or 12 mg/m2 Novantrone administered intravenously every three months for two years. At 24 months, the mean EDSS change (month 24 value minus baseline) was 0.23 for the placebo group, -0.23 for 5 mg/m2, and -0.13 for 12 mg/m2.

A second trial evaluated Novantrone in combination with methylprednisolone (MP) and was conducted in subjects with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. A total of 42 subjects received monthly treatments of 1g of intravenous MP alone or approximately 12 mg/m2 of intravenous Novantrone plus 1 g of intravenous MP for six months. Subjects were evaluated monthly, and study outcome was determined after six months. The primary measure of effectiveness was a comparison of the proportion of subjects in each treatment group who developed no new Gd-enhancing MRI lesions at six months. Thirty-one percent of subjects receiving MP alone were without new Gd-enhancing lesions on MRIs, while 90% of subjects receiving Novantrone plus MP were without lesions. (from Novantrone Package Insert)

Side Effects

Possible adverse events associated with Novantrone include (but are not limited to) the following:



Nausea
Hair loss
Hypotension (low blood pressure)
Rashes
Urinary tract infection
Menstrual disorder

Mechanism of Action
Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.

Novantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2.

http://www.centerwatch.com/patient/drugs/dru651.html
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Old 04-23-2007, 10:41 PM #5
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Quote:
Originally Posted by wannabe View Post
There's a few things at least these days. But considering how many people go on to become SPMS (like most of us), you'd think that there would be even more research. Since the RRMS drugs aren't that good at stabilizing MS, you'd think they would have tried their luck at trying to stabilize it when it got to the SPMS phase. Isn't one of those newer ones in clinical trials also targeting SPMS? I can't find any info on it right now though.

I believe the trials you are thinking about are those being conducted by BioMs, and drug company in Edmonton, Canada. They have been working on a drug exclusively for SPMS for the past 6 or 7 years and have just begun the Phase III trials at numerous centers around the world. Early indications have shown it has some beneficial effect but until the Phase III trials are completed and the data analyzed, we won't know if this drug will really help SPMS patients.

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Old 04-23-2007, 11:53 PM #6
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Thanks Harry, that might be it. What's it called?

It's not exclusively for SPMS though is it? I thought it was also in trials for RRMS.

The name escapes me though. Thx. Your wife has SPMS doesn't she? How is she doing these days? Does she take a treatment?
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Old 04-24-2007, 08:19 AM #7
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Wannabe,

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Originally Posted by wannabe View Post
Thanks Harry, that might be it. What's it called?
The name at the moment is MBP8298. Here is a link for a brief description.

http://www.biomsmedical.com/clinicaltrial.asp

Quote:
It's not exclusively for SPMS though is it? I thought it was also in trials for RRMS.
I believe it is for SPMS patients only at this time.

Quote:
The name escapes me though. Thx. Your wife has SPMS doesn't she? How is she doing these days? Does she take a treatment?
Yes, Marg has had SPMS since 1996. She has been using Prokarin since June 2000 and it helps her symptoms quite a bit. But after she broke her leg in 2001 and been confined to a wheel-chair since then, all the "problems" associated with being in a chair full time has caused her general health to decline a fair amount.

Harry
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Old 04-24-2007, 11:36 AM #8
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So sorry to hear that Harry. It must be significant adjustments for both of you. Has she tried any of these possible treatments?
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Old 04-25-2007, 08:42 AM #9
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Hi Wannabe,

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Originally Posted by wannabe View Post
So sorry to hear that Harry. It must be significant adjustments for both of you. Has she tried any of these possible treatments?
I replied to this message last night but noticed this morning that it didn't make it !

For the past 6 years since breaking her leg, there have been large adjustments that Marg and I have had to make. Some days it is VERY difficult.

Marg has never tried any of the "approved" MS drugs. Being in medicine for 25 years, she never did like these medications. About 7 years ago her neuro at the time told her that in general, MS docs were quite disappointed in the CRAB drugs because they weren't doing what they thought they would do. Told her to take 2 good holidays a year and she would likely be better off.

The Prokarin has kept several of her MS symptoms in check but sitting in that wheel-chair certainly hasn't helped her overall general health. We seem to fix one problem and then two others show up. It's never ending.

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Old 04-25-2007, 09:17 AM #10
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That really sucks, Harry. Is there any possibility that she could get out of that chair with some PT? Even if it's just for awhile each day?

I'm in a scooter most of the time but can still stand and walk with a walker. I try to stand up as much as possible although the scooter does make me a bit lazy. I keep having to tell myself.."use it or lose it", to get me going.

I wish you Both Well.
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