Summary of the pipeline

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

Postby dignan » Tue Dec 13, 2005 8:37 am

Brownsfan,
I think you're right about FTY720. I think the first trials it went through were for kidney transplant patients.
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Postby dignan » Thu Dec 15, 2005 9:52 am

LJP 1207 is mentioned here for a number of diseases, including MS, so I'm adding to pre-clinical.



La Jolla hails SSAO inhibitor potential

15/12/2005 - Latest data by La Jolla Pharmaceuticals indicate the potential of novel, orally active small molecule inhibitors of a central enzyme may provide clinical benefit for the treatment of stroke, ulcerative colitis, and other autoimmune diseases and inflammatory disorders.

The pharmaceuticals firm is championing the potential of semicarbazide-sensitive amine oxidase (SSAO) inhibitors, also known as vascular adhesion protein-1 or VAP-1, a dual-function molecule with enzymatic and adhesion activities.

SSAO contributes to the adhesion of white blood cells to endothelial cells and is greatly amplified in blood vessels at sites of inflammation. The enzyme activity also produces molecules that can exacerbate inflammation.

Increases in the levels of plasma or membrane-associated SSAO have been reported for many inflammation-associated diseases including rheumatoid arthritis, inflammatory bowel disease, diabetes, atherosclerosis, and chronic heart failure.

Semicarbazide-sensitive amine oxidase (SSAO) belongs to a ubiquitous family of copper-containing amine oxidases (CuAOs). SSAO is also known as vascular adhesion protein-1 (VAP-1) and has been identified as one of the adhesion molecules involved in the leukocyte-extravasation process.

In preclinical studies conducted by Company scientists, SSAO inhibitors blocked both the enzymatic and adhesion functions of SSAO and were shown in animal models to be potent inhibitors of disease activity.

The first paper, published in the Journal of Pharmacology and Experimental Therapeutics on December 8, 2005 by Xu et al, indicated that a selective SSAO inhibitor, LJP 1207, could provide clinical benefit in the treatment of stroke.

Data published in this paper demonstrated that treatment in an animal model with LJP 1207 resulted in marked reduction in the adhesion and infiltration of white blood cells into the blood vessels of the brain after the occurrence of stroke and significantly less neurological damage.

"Our findings with La Jolla's inhibitor of SSAO/VAP-1 in stroke are particularly exciting," said Dale Pelligrino, Professor and Director, Neuroanesthesia Research Laboratory, University of Illinois at Chicago.

"Treatment with LJP 1207 as late as six hours after the onset of stroke in an animal model still had a positive protective effect of reducing inflammation and neurological damage."

The second paper, by Salter-Cid et al, was published in the Journal of Pharmacology and Experimental Therapeutics, volume 315, pages 553-562, 2005, providing further evidence of the potential of LJP 1207 to both acute and chronic inflammation.

In a mouse model of chronic inflammation resulting in ulcerative colitis, treatment with LJP 1207 significantly reduced mortality and loss of body weight, as well as colon injury and ulceration.

In a model of acute inflammation, treatment with LJP 1207 given either before or after inflammation was induced, resulted in the marked inhibition of both swelling and inflammation.

"These two papers highlight the impact of treatment with SSAO inhibitors on disease models of stroke, ulcerative colitis and general inflammation. The efficacy of our lead compounds has also been demonstrated in animal models of multiple sclerosis and rheumatoid arthritis," said Linnik.

"Although stroke is a leading cause of death and disability, there has been a lack of success in developing drug candidates to treat stroke. We are excited about the potential to provide a novel oral anti-inflammatory therapy for the treatment of a spectrum of diseases that are caused or worsened by inflammation."

http://www.drugresearcher.com/news/ng.a ... rs-protein
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Postby dignan » Tue Dec 20, 2005 11:03 am

As usual, I'm going to jump the gun a bit based on backpacker2006's post and move RPI-78M to phase II trials since they have already done phase I for other indications and are planning to submit and IND for a Phase II MS study soon.
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Pre Pipeline "Hormone" Therapies

Postby Shayk » Tue Dec 20, 2005 3:12 pm

Dignan--Thanks for continuing to do an outstanding job.

Here are couple of " hormone therapies" in the works that really don't qualify for MS therapies yet, but some day they might. :wink: I do think they have potential for neuroprotection in MS.

Gene therapy to bet on: protecting neurons from stress hormones
during conditions of excitotoxic injury to neurons, glucocorticoids can exacerbate cell death. A recent study has developed a 'trifecta' of ingenious viral vector-based approaches to modify the neuronal stress response and to diminish this exacerbation both in vitro and in vivo. Stress hormone gene therapy in the brain is now off and running.


The second is a Phase I Clinical Trial of 17alpha-Estradiol as a Neuroprotective Therapeutic Agent

Despite its meager hormonal activity, 17alpha-E2 is as potent as 17beta-E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others....

Thus, by serving as a mitoprotectant, 17alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues.


17 alpha-estradiol is a form of estrogen, but given the list of diseases they're targeting, it seems to me they probably think it would be safe for men as well. :) MS is not listed, but that may be a reflection of the "auto-immune" and/or "neurodegenerative" debate about MS. I definitely think there's a neurodegenerative component to MS and I'm as optimistic as ever about the potential of hormones for men and women with MS.

I'm not asking that either of them be added to the "Drug Pipeline" list, but thought they are noteworthy developments in neuroprotection that may eventually be applicable to MS.

--sharon
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Postby dignan » Tue Dec 20, 2005 3:57 pm

Thanks for that information. I always like to hear about stuff like this. And I'm with you that hormones are a promising avenue to explore for MS. The second they mention plans to test on people with MS or mice with EAE, I'll gladly throw it into the pipeline.
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Postby Brownsfan » Tue Dec 20, 2005 5:08 pm

If I'm not mistaken, Montel Williams takes hormone replacement therapy. Not sure how this has worked for him, but he seems fine on his show.
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Another drug Cathepsin S

Postby Dunmann » Thu Dec 22, 2005 8:34 am

Here's another drug by Medivir that appears to be in pre-clin. I dont believe you have this one on your list (which by the way is excellent!). Below is a link to the company's website related drug.

http://www.medivir.com/v3/en/RnD/projec ... sin_s.aspx


Dunmann.
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Postby dignan » Thu Dec 22, 2005 4:43 pm

Added Cathepsin S to pre-clinical, thanks for the information.
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Postby gkalman » Fri Dec 23, 2005 1:02 pm

dignan, is the updated list available anywhere, or will you post it every once in a while?

Anyway, there is another to add to pre-clinical:
STA-5326 from Synta

Oral IL-12 inhibitor. Not yet in trials for MS. Is in trials for Crohn's and psoriasis.

see:
http://www.syntapharma.com/PrdOralIL12Inhibitor.aspx
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Postby Baumer » Fri Dec 23, 2005 1:55 pm

The updated list is available as the first post on the first page of this thread. Dignan updates that post regularly.

Hope everyone has a Merry Christmas :)
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Postby dignan » Fri Dec 23, 2005 5:49 pm

Thanks for the update, and yes, the first post in this thread is the list that gets updated whenever there's something new.

That's a tough one to know where to put in the pipeline since it's already going into phase II for other indications, but not MS...I guess you're right though, call it pre-clinical until they start MS-specific research.
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Postby dignan » Mon Dec 26, 2005 8:16 pm

DW908e -- new one to add to Phase I from a presentation on the Tanabe website. Can't find any other references to it, but what the heck. Merry Christmas.


www.tanabe.co.jp/english/ir/reports/20050310e-T0047.pdf
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Postby dignan » Sat Jan 07, 2006 5:30 pm

Enough for me to add Arvanil to the pre-clinical list.



Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis.

J Neuroimmunol. 2006 Feb;171(1-2):110-9. Epub 2005 Oct 18.
Malfitano AM, Matarese G, Pisanti S, Grimaldi C, Laezza C, Bisogno T, Di Marzo V, Lechler RI, Bifulco M.
Dipartimento di Scienze Farmaceutiche, Universita' di Salerno, Via Ponte don Melillo 84084 Fisciano (Salerno), Italy; Department of Immunology, Hammersmith Campus, Imperial College London, UK.

This study examined the immunomodulatory effect of arvanil, a synthetic capsaicin-anandamide hybrid.

Arvanil inhibits lymphocyte proliferation and IFN-gamma production. The phenotype of activated CD4+T cells treated with arvanil shows a down-regulation of T cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and anandamide do not induce apoptosis on CD4+T cells. Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB.

In vivo, arvanil ameliorates experimental autoimmune encephalomyelitis in the SJL/J mouse. Our findings have relevance for the use of arvanil and related compounds as a novel immunotherapeutic approach in the treatment of multiple sclerosis.

<shortened url>
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Postby dignan » Wed Jan 11, 2006 6:51 pm

LF 15-0195, now there's a catchy name...



LF 15-0195 Treatment Protects against Central Nervous System Autoimmunity by Favoring the Development of Foxp3-Expressing Regulatory CD4 T Cells.

J Immunol. 2006 Jan 15;176(2):839-47.
Duplan V, Beriou G, Heslan JM, Bruand C, Dutartre P, Mars LT, Liblau RS, Cuturi MC, Saoudi A.
Institut National de la Sante et de la Recherche Medicale Unite 563, Institut Federatif de recherche 30, and Universite Paul Sabatier, Hopital Purpan, Toulouse, France;

Experimental autoimmune encephalomyelitis (EAE) is an instructive model for the human demyelinating disease multiple sclerosis. Lewis (LEW) rats immunized with myelin-basic protein (MBP) develop EAE characterized by a single episode of paralysis, from which they recover spontaneously and become refractory to a second induction of disease.

LF 15-0195 is a novel molecule that has potent immunosuppressive effects in several immune-mediated pathological manifestations, including EAE. In the present study, we show that a 30-day course of LF 15-0195 treatment not only prevents MBP-immunized LEW rats from developing EAE but also preserves their refractory phase to reinduction of disease. This effect is Ag driven since it requires priming by the autoantigen during the drug administration.

In contrast to other immunosuppressive drugs, short-term treatment with this drug induces a persistent tolerance with no rebound of EAE up to 4 mo after treatment withdrawal. This beneficial effect of LF 15-0195 on EAE does not result from the deletion of MBP-specific Vbeta8.2 encephalitogenic T cells. In contrast, this drug favors the differentiation of MBP-specific CD4 T cells into Foxp3-expressing regulatory T cells that, upon adoptive transfer in syngeneic recipients, prevent the development of actively induced EAE.

Finally, we demonstrate that the tolerance induced by LF 15-0195 treatment is not dependent on the presence of TGF-beta. Together, these data demonstrate that short-term treatment with LF 15-0195 prevents MBP-immunized LEW rats from EAE by favoring the development of Foxp-3-expressing regulatory CD4 T cells.

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Postby dignan » Thu Jan 12, 2006 8:44 am

ATL1102 going back into phase II after a suspension...



Approval to restart Phase IIa trial in MS patients
Antisense Therapeutics (AUSTRALIA)
January 12, 2006

Antisense Therapeutics is pleased to report that the Ethics Committee of the University of Essen in Germany has approved the company's application to restart the Phase IIa trial of its antisense compound, ATL1102, for patients with relapsing remitting multiple sclerosis. The University of Essen is the primary trial site for the Phase IIa clinical trial. The Company now has the requisite approval and regulatory documentation in place to restart the Phase IIa trial at this centre.

Patient enrolment and dosing are expected to commence at the University of Essen in February/March 2006. The other 8 trial centres will, in turn, be initiated in the coming months. The treatment and patient monitoring stages of the 80-patient trial are expected to be completed by the end of 2006 assuming patient recruitment proceeds at the anticipated rate.

The Ethics Committee approval follows the recommendation of a specially convened Medical Advisory Board of independent medical experts to continue the drug's development.

Antisense CEO Mark Diamond said "We are pleased to have received this approval to progress the further development of our MS drug, which as stated by the Medical Advisory Board, appears to have significant potential as a therapeutic agent in relapsing-remitting MS."

He added that "The Company has been focussed on restarting the Phase IIa trial for ATL1102 in MS patients in an endeavour to restore the shareholder value that has been created over the last 4 years through successful preclinical animal studies and the completion of a Phase 1 clinical trial in humans." ATL1102 is a second-generation antisense inhibitor of an immune system protein called VLA-4 and is designed to block the synthesis of VLA-4 which is known to play a part in both the onset and progression of multiple sclerosis. ATL1102's mechanism of action in blocking VLA-4 is different to other drugs in development that target VLA-4 (including the monoclonal antibody Tysabri®) and represents a novel therapeutic approach to the treatment of MS.

Multiple sclerosis is a life long chronic disease of the central nervous system which is believed to affect as many as 2.5 million people worldwide. While existing drug sales for this disease were greater than US$4 billion in 2004 there remains a high demand for more effective and better tolerated treatments. The Phase IIa trial of ATL1102 will assess the activity and safety of the drug in MS patients.

http://www.biotech-intelligence.com/htm ... fcb63.html
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