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Based on the recent intrathecal methotrexate thread, I added it to phase II of the pipeline.

Hey,

I'm not sure if someone has already mentioned this, because I didn't read all 10 pages of the thread, but CHR-1103 is the new designation for TMC-2003 (i.e. it's the same monoclonal antibody).

NZ

You dont need to read every page just the first! Dignan kindly monitors posts here and updates the list.

CHR1103 is #9 on the preclinical list BTW.

Thanks for the info-I'll delete TMC-2003 from the list then.

Another one for pre-clinical, but at least they are talking about starting a phase I trial in 2006.



Incyte Announces First Quarter Financial Results and Provides Update on Drug Discovery and Development Programs

BUSINESS WIRE - May 4, 2006 - Incyte Corporation today announced its financial results for the first quarter 2006 and reported on the company's most advanced drug discovery and development programs.

Recent developments include:

-- Continued advancement of a lead follow on oral CCR2 antagonist, INCB8696, which we expect to advance into clinical development later this year. We intend to develop INCB8696 as a treatment for multiple sclerosis, and possibly for the second undisclosed indication we retained under our recent collaboration with Pfizer.

Update on Drug Discovery and Development

Inflammation Portfolio
CCR2 Antagonist Program
Under our collaborative research and license agreement with Pfizer, we have retained exclusive worldwide rights to certain CCR2 antagonist compounds for two indications, MS and a second indication which, for competitive reasons, we have not disclosed. We have no obligations to Pfizer on preclinical development candidates we may pursue in these indications.

We expect to complete IND-enabling studies and to begin a Phase I trial in healthy volunteers for our lead compound, INCB8696, in the second half of 2006.

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Added a couple of pre-clinical candidates from Can Fite BioPharma. (CF101 and CF402). CF101 is going into phase IIb trials for RA, so they might be able to start trials for MS at phase II -- we'll see.

Added Epratuzumab to pre-clinical. They are in phase III lupus trials, so hopefully when they start on MS, they can not pass go and go directly to phase II.

Early in the pre-clinical stage still, but it's something...



A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF.

Mol Immunol. 2006 May 10;
Krinner EM, Raum T, Petsch S, Bruckmaier S, Schuster I, Petersen L, Cierpka R, Abebe D, Molhoj M, Wolf A, Sorensen P, Locher M, Baeuerle PA, Hepp J.
Micromet AG, Staffelseestr. 2, D 81477 Munich, Germany.

The pro-inflammatory cytokine GM-CSF is aberrantly produced in many autoimmune and chronic inflammatory human diseases. GM-CSF neutralization by antibodies has been shown to have a profound therapeutic effect in animal models of rheumatoid arthritis, inflammatory lung diseases, psoriasis and multiple sclerosis. Moreover, the absence of GM-CSF in null mutant mice ameliorates or prevents certain of these diseases. Here we describe the biophysical and biological properties of a human anti-GM-CSF IgG1 antibody designated MT203, which was derived by phage display guided selection. MT203 bound with picomolar affinity to an epitope on human and macaque GM-CSF involved in high-affinity receptor interaction. As a consequence, the antibody potently prevented both GM-CSF-induced proliferation of TF-1 cells with a sub-nanomolar IC50 value and the production of the chemokine IL-8 by U937 cells. MT203 neutralized equally well recombinant (r) human (h) GM-CSF from Escherichia coli and yeast, and also normally glycosylated GM-CSF secreted by human lung epithelial cells in response to IL-1beta stimulation. Furthermore, MT203 significantly reduced both survival and activation of peripheral human eosinophils as may be required for effective treatment of inflammatory lung diseases. The antibody did not show a detectable loss of neutralizing activity after 5 days in human serum at 37 degrees C. Based on its favorable properties, MT203 has been selected for development as a novel anti-inflammatory human monoclonal antibody with therapeutic potential in a multitude of human autoimmune and inflammatory diseases.

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Another one for pre-clinical - LLDT-8. The thing I'm happy to see here is that this research comes from China. I'd love to see the MS research world harness some more of the immense brain-power in China and India.



(5R)-5-Hydroxytriptolide (LLDT-8 ), a novel triptolide derivative, prevents experimental autoimmune encephalomyelitis via inhibiting T cell activation.

J Neuroimmunol. 2006 May 17; [Epub ahead of print]
Fu YF, Zhu YN, Ni J, Zhong XG, Tang W, Zhou R, Zhou Y, Dong JR, He PL, Wan H, Li YC, Yang YF, Zuo JP.
Laboratories of Immunopharmacology and Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.

A novel triptolide derivative (5R)-5-hydroxytriptolide (LLDT-8 ) has been shown to have potent immunosuppressive activities. Here LLDT-8 was evaluated in experimental autoimmune encephalomyelitis (EAE), the model of multiple sclerosis (MS).

LLDT-8 reduced the incidence and severity of EAE, which was associated with the inhibition of the MOG 35-55 lymphocyte recall response, anti-MOG 35-55 T cell responses, interleukin (IL)-2 and interferon (IFN)-gamma production. In vitro, LLDT-8 inhibited primary T cells proliferation, division, IL-2 and IFN-gamma production stimulated with anti-CD3/28.

These findings highlight the fact that LLDT-8 prevents EAE by suppressing T cell proliferation and activation, with a potential for treatment of MS.

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Another pre-clinical one, sort of...peptidomimetics of apoE protein, COG133...



Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis.

J Pharmacol Exp Ther. 2006 Jun 1;
Li FQ, Sempowski GD, McKenna SE, Laskowitz DT, Colton CA, Vitek MP.
Division of Neurology, Department of Medicine, Duke University Medical Center.

Apolipoprotein E (apoE), well known to play a role in lipid transport and cholesterol metabolism, also exerts anti-inflammatory and neuroprotective effects in the CNS. Recent clinical and genetic studies display an association between APOE genotype and the progression and severity of multiple sclerosis, raising the possibility that modulation of apoE may be a novel treatment for multiple sclerosis.

Using a murine experimental autoimmune encephalomyelitis (EAE) model of human multiple sclerosis, we found that peptidomimetics of apoE protein, COG133, substantially reduce the clinical symptoms of EAE and promote remission from the disability when administered before or after onset of disease. Most notably, fusion of COG133 to a protein transduction domain creates COG112, a modified apoE-mimetic peptide with significantly enhanced anti-inflammatory bioactivities in vitro, and improved therapeutic effects on EAE in vivo, which renders a nearly full remission from the disability. Histopathological analysis showed that COG112 and COG133 attenuated demyelination and significantly diminished the number of peripheral cells infiltrating into the spinal cord. ApoE-mimetics also interfered with several mechanisms relevant to the pathogenesis of EAE and multiple sclerosis, including activation of macrophages, subsequent production of nitric oxide and inflammatory cytokines, and lymphocyte proliferation.

These data suggest that apoE-mimetics represent a multidimensional therapeutic for multiple sclerosis capable of inhibiting the inflammatory cascade, modulating immune cell function, and reducing clinical signs, which may have novel utility for the treatment of inflammatory autoimmune diseases.

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Dignan,

AZD5904 can be moved up to Phase I

Ian

http://c.moreover.com/click/here.pl?j551440828&w=464753

Done. Thanks for the update.

Based on the US MS Society's clinical trials update, there's only one thing I saw that isn't on the pipeline list:



Agent: Lymphocytapheresis (removal of immune cells), Imuran® (azathioprine) + prednisone

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

Possible mechanism: May down-regulate IL-2 production and CD4/8 ratio and upregulate CD11b+CD8+ cells and neutrocytes (lymphocytapheresis) / Releases 6-MP and inhibits nucleic acid biosynthesis, preventing proliferation of cells that amplify immune response (Imuran)/Closes damaged blood-brain barrier, reducing inflammation in CNS (prednisone)

Study description: Comparison with "best standard of care"

Dose/route: Year 1 - LCP tiw for 2-3 mos, every other week for 2-3 mos to achieve depletion + Imuran 2.5 mg/kg po + prednisone 15 mg qod po; year 2 - LCP every 4 wks + Imuran + prednisone, then wean

Outcome parameters: EDSS, MRI, quality of life, physician/patient global assessment, safety

Type of MS: SP
Number of Subjects: 42
Start date: Planned
Observation period: 3 years
Investigators: A. Reder and others
Sites: University of Chicago and others
Results/Publications: Not available
Funding: Private funding
ClinicalTrials.gov Link: Not available
Last update: 2005

...and the winner of the 2006 award for "Potential MS treatment with the longest name" is ... 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside!



5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates experimental autoimmune encephalomyelitis via modulation of endothelial-monocyte interaction.

J Neurosci Res. 2006 Jun 12;
Prasad R, Giri S, Nath N, Singh I, Singh AK.
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.

Experimental autoimmune encephalomyelitis (EAE) is a model for studying multiple sclerosis (MS), a chronic demyelinating disorder of the CNS. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of AMP-activated protein kinase (AMPK), has been reported to show antiinflammatory and immunomodulatory effects in various models of inflammation. Recently, we have reported AICAR-mediated attenuation of active and passive EAE in mouse model [Nath et al. (2005) J. Immunol. 175:566-574].

Here we used a rat model of acute EAE to show antiinflammatory effects of AICAR after daily treatment starting at onset of the disease. By maintaining the blood-brain barrier (BBB), AICAR-administered animals showed lower clinical scores compared with untreated EAE animals. AICAR inhibited the infiltration of inflammatory cells across the BBB, resulting in lowered expression of proinflammatory mediators in the CNS and protection from severe demyelination. By using in vitro model of endothelial-leukocyte interaction, we showed that AICAR inhibited adhesion of monocytes to tumor necrosis factor-alpha-activated endothelial cells. One of the mechanisms of this action is through down-regulation of expression of endothelial cell adhesion molecules via modulation of nuclear factor kappaB activation.

The data suggest that AICAR attenuates EAE progression by limiting infiltration of leukocytes across the BBB, thereby controlling the consequent inflammatory reaction in the CNS.

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More research on hormones that sounds promising...



Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.

J Neurosci. 2006 Jun 21;26(25):6823-33.
Morales LB, Loo KK, Liu HB, Peterson C, Tiwari-Woodruff S, Voskuhl RR.
Multiple Sclerosis Program, Department of Neurology, University of California, Los Angeles, Los Angeles, California 90095, USA.

Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms.

Here we investigated whether treatment with an estrogen receptor alpha (ERalpha) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms.

EAE was induced in wild-type, ERalpha-, or ERbeta-deficient mice, and each was treated with the highly selective ERalpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes.

ERalpha ligand treatment ameliorated clinical disease in both wild-type and ERbeta knock-out mice, but not in ERalpha knock-out mice, thereby demonstrating that the ERalpha ligand maintained ERalpha selectivity in vivo during disease. ERalpha ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNFalpha, interferon-gamma, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/beta3-tubulin+/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3+) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1-2 d after the onset of clinical signs. Treatment with either estradiol or the ERalpha ligand significantly reduced this gray matter pathology.

In conclusion, treatment with an ERalpha ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.

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