Summary of the pipeline

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

Postby dignan » Thu Jan 19, 2006 9:13 am

A little update from Novartis on FTY720...



- FTY720 (fingolimod), seeking to become the oral once-daily treatment for relapsing forms of multiple sclerosis, has been approved in several European countries to start the first Phase III trial. Discussions are underway with the FDA on starting this trial in the U.S., which is a two-year, double-blind pivotal trial in relapsing-remitting MS patients comparing 1.25 mg and 0.50 mg doses with placebo. A second trial in relapsing-remitting MS patients is scheduled to start later in 2006 in which 1.25 mg and 0.50 mg doses will be compared to an interferon. Data for 12 months in a Phase II study presented in 2005 confirmed the substantial efficacy of FTY720 in significantly reducing the relapse rates of patients with this disease.

http://www.primezone.com/newsroom/news.html?d=92533
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Postby carolew » Thu Jan 19, 2006 11:32 am

Finally a name for this coumpound! Thanks for the info as usual.
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Postby flipflopper » Thu Jan 19, 2006 12:49 pm

I also wanted to thank you for the info Dignan. I spoke with the manager of the clinical research unit (at the ms clinic where I go) early last December. But, he was unable to answer some questions that I had at that point. He was the contact person for the study because it was too early to have someone assigned to the FTY720 clinical trial. There were two things I have been DYING to know concerning this clinical trial and your post answered both. I will see my ms neurologist again next week and he might have been able to answer my questions. I’m still grateful for your post. Thanks!!!
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Postby dignan » Sat Jan 21, 2006 10:49 am

Another one for "pre-clinical". I like the idea of this because they are taking the profound effects of pregnancy on disease processes and trying to develop a treatment...seems promising...Is it just me or is Israel on the leading edge of MS research?



Amelioration of autoimmune neuroinflammation by recombinant human alpha-fetoprotein.

Exp Neurol. 2006 Jan 16;
Irony-Tur-Sinai M, Grigoriadis N, Lourbopoulos A, Pinto-Maaravi F, Abramsky O, Brenner T.
Laboratory of Neuroimmunology, Department of Neurology, the Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem 91120, Israel.

Alpha-fetoprotein (AFP) is a 65-kDa oncofetal glycoprotein found in fetal and maternal fluids during pregnancy. Clinical remissions during pregnancy have been observed in several autoimmune diseases, such as multiple sclerosis (MS), and have been attributed to the presence of pregnancy-associated natural immune-reactive substances, including AFP which can exert immunomodulatory effects on immune cells. In this study, we tested the effect of recombinant human AFP (rhAFP) isolated from transgenic goats, which contain the genomic DNA for hAFP, on experimental autoimmune encephalomyelitis (EAE), the animal model used for the study of MS. RhAFP treatment markedly improved the clinical manifestations of EAE, preventing central nervous system (CNS) inflammation and axonal degeneration. RhAFP exerted a broad immunomodulating activity, influencing the various populations of immune cells. T cells from treated mice had significantly reduced activity towards the encephalitogenic peptide of myelin oligodendrocyte glycoprotein (MOG), exhibiting less proliferation and reduced Th1 cytokine secretion. Moreover, AFP affected the humoral response, causing an inhibition in MOG-specific antibody production. The expression of CD11b, MHC class II and the chemokine receptor CCR5 was also down-regulated. This is the first study demonstrating reduced inflammation and axonal damage exerted by recombinant AFP. In light of our findings, rhAFP may serve as a potential candidate for treatment of MS and other autoimmune diseases.

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Postby dignan » Sat Jan 21, 2006 4:06 pm

Turns out the rhAFP I just posted about is the same as Merrimack Pharmaceuticals' MM-093, and that's already on the list under "Phase I". It's already in Phase II for arthritis, so let's hope it's soon to start a phase II for MS.
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Postby Shayk » Sat Jan 21, 2006 6:08 pm

Dignan

You are so good. :) Thanks for all of your hard work.

Sharon
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Postby dignan » Thu Jan 26, 2006 10:02 pm

Another one for pre-clinical...



Preclinical and phase I clinical trial of blockade of IL-15 using Mik{beta}1 monoclonal antibody in T cell large granular lymphocyte leukemia.

Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):401-6. Epub 2005 Dec 30.
Morris JC, Janik JE, White JD, Fleisher TA, Brown M, Tsudo M, Goldman CK, Bryant B, Petrus M, Top L, Lee CC, Gao W, Waldmann TA.
Metabolism Branch, Center for Cancer Research, and Office of Cancer Complementary and Alternative Medicine, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Twelve patients with T cell large granular lymphocyte leukemia and associated hematocytopenia were treated in a phase I dose-escalation trial with the murine monoclonal antibody Mikbeta1. Mikbeta1 identifies CD122, the beta-subunit shared by the IL-2 and IL-15 receptors. At the doses administered in this study the antibody inhibited the actions of IL-15 on both natural killer and T cells and that of IL-2 when the intermediate-affinity IL-2 receptor was expressed. Mikbeta1 treatment was not associated with significant toxicity or with the development of an immune response to the infused monoclonal antibody. At these doses of Mikbeta1, >95% saturation of the IL-2/IL-15beta receptor (CD122) on the surfaces of the leukemic cells was achieved. Furthermore, in seven patients this led to the down-modulation of the receptor from the surfaces of the leukemic cells. Nevertheless, no patients manifested a reduction in peripheral leukemic cell count or an amelioration of their hematocytopenia. This latter observation may reflect the fact that the monoclonal T cell large granular lymphocyte leukemia leukemic cells of the patients did not produce IL-2 or IL-15 or require their actions for cell survival. In light of the lack of toxicity and lack of immunogenicity of the antibody observed in the present study and the role for IL-15 in the pathogenesis of autoimmune diseases, clinical trials should be performed using the humanized version of Mikbeta1 in groups of patients with human T cell lymphotropic virus I-associated myelopathy/tropical spastic paraparesis, rheumatoid arthritis, multiple sclerosis and refractory celiac disease.

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Postby dignan » Sat Jan 28, 2006 1:41 pm

According to ClinicalTrials.gov this phase II is complete, just waiting for results now...


Evaluation of an Altered Peptide Ligand (NBI-5788) in Patients With Relapsing Multiple Sclerosis (MS)

This study has been completed.
Sponsors and Collaborators: Neurocrine Biosciences
Immune Tolerance Network
Information provided by: Neurocrine Biosciences

http://www.clinicaltrials.gov/ct/show/N ... 5?order=89
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Postby dignan » Sat Jan 28, 2006 1:45 pm

Didn't realize they're actually doing a phase III study of cyclophosphamide now...



Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients With Secondary Progressive Multiple Sclerosis

This study is currently recruiting patients.
Verified by University Hospital, Bordeaux October 2005
Sponsors and Collaborators: University Hospital, Bordeaux
Programme Hospitalier de Recherche Clinique (PHRC), Ministère de la Santé, France
Information provided by: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT00241254

Purpose
Preliminary not-controlled clinical studies of the efficacy of monthly intravenous cyclophosphamide administration in secondary progressive multiple sclerosis reported encouraging results, but no randomized controlled trial has been conducted so far. The primary objective of this trial is to evaluate the efficacy of IV cyclophosphamide as compared to IV methylprednisolone administered every 4 weeks during 1 year and every 8 weeks during 1 year, on the delay to confirmed disability deterioration as assessed by the Expanded Disability Status Scale (EDSS) in patients with secondary progressive multiple sclerosis. The secondary objectives are to evaluate safety, tolerability and efficacy at 2 years on the Multiple Sclerosis Functional Composite (MSFC), the percentage of patients with disability deterioration (EDSS) and the number of relapses. An intention-to-treat statistical analysis will be carried out.

Phase III

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Active Control, Parallel Assignment, Efficacy Study

Official Title: A Double-Blind, Two-Arm, Multicenter, Randomized Trial to Evaluate Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients With Recent Secondary Progressive Multiple Sclerosis: P.R.OM.E.S.S Study

Further study details as provided by University Hospital, Bordeaux:

Primary Outcomes: Delay to disability deterioration as assessed by the Expanded Disability Status Scale (EDSS: 0.5 or 1 point increase, depending on baseline score) evaluated every 4 weeks for one year, then every 8 weeks for one year

Secondary Outcomes: - Proportion of patients with disability deterioration (EDSS: 0.5 or 1 point increase, depending on baseline score); - Multiple Sclerosis Functional Composite (MSFC) and the Z scores of MSFC three components; - Number of MS relapses; - Proportion of patients with adverse events and delay of occurrence of adverse events; - Quality of life questionnaires; - Disability autoquestionnaires; Main time of assessment : 2 years.

Expected Total Enrollment: 360

Background
Preliminary not-controlled clinical studies of the efficacy of monthly intravenous cyclophosphamide administration in secondary progressive multiple sclerosis reported encouraging results, but no randomized controlled trial has been conducted so far. A slight efficacy of Methylprednisolone has been reported in this indication.

Objectives
The primary objective is to evaluate the efficacy of IV cyclophosphamide on the prevention of disability deterioration in patients with secondary progressive multiple sclerosis.

The secondary objectives are to evaluate safety, tolerability and efficacy of IV cyclophosphamide on the Multiple Sclerosis Functional Composite (MSFC) and the number of relapses.

Study design
Randomized double-blind two-arm controlled trial.

Intervention
Experimental group : IV cyclophosphamide infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.

Control group : IV methylprednisolone infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.

http://www.clinicaltrials.gov/ct/show/N ... 54?order=6
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Postby bromley » Sat Jan 28, 2006 2:25 pm

Dignan,

You must be due a day off. But thanks for all your hard work.

I'm not sure how many treatments are on the list but we must be nearing 120. Over the next few months a number of the Phase II trials should start reporting results.

I wonder if the CRAB manufacturers keep a track of the drugs in the pipeline?

Ian
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Postby gopi » Tue Jan 31, 2006 5:40 pm

Hi,

I didn't find this drug which is in research phase. I dont know whether it belongs here or not. Any way if it related you could add it to the Summary of drugs in pipeline.

***********************************************

New Drug (LGD5552) Prevents EAE in Animals

Scientists from the Neurological Sciences Institute at Oregon Health & Science University have shown that an investigative drug for multiple sclerosis and related diseases prevented disease development when tested on animal models.

The drug, LGD5552, prevented rats from developing a well-established animal model of MS. San Diego-based Ligand Pharmaceuticals Inc. collaborated in, and funded, the study. The results are being presented today at Endo 2004, the national meeting of The Endocrine Society in New Orleans, La.

"While there is much more research to be done on this compound, these initial results are very exciting," explained Bruce Bebo Jr. Ph.D., a scientist at NSI and assistant professor of neurology in the OHSU School of Medicine. "LGD5552 is a member of a class of drugs called non-steroidal selective glucocorticoid receptor modulators with very effective, anti-inflammatory properties and a profile of tissue selectivity resulting in limited side-effects when compared to other drugs currently used to treat MS and related diseases."

Bebo and his collaborators studied rats suffering from experimental autoimmune encephalitis, a commonly studied animal model for human MS that has been used for about 50 years. The researchers provided some of the animals with LGD5552 at the time of disease induction. A second group of animals received a related anti-inflammatory called prednisolone. The third group of animals went untreated.

While the untreated animals developed paralysis , prednisolone-treated animals suffered reduced effects and LGD5552-treated animals remained free of weakness. In addition, the LGD5552-treated animals maintained their body weights, while other animals in the study lost weight. Animals that received the test drug also didn't develop inflammatory lesions in the spinal cord as did other animals. These lesions also are common in humans suffering from MS.

"One encouraging prospect of LGD5552 is that our data shows the compound will have reduced side effects," Bebo said. "Current medications available for MS and related disorders can cause high blood pressure, fat metabolism problems and osteoporosis. While additional research needs to be conducted on the orally administered test drug, we believe these commonly witnessed side effects will be reduced. "

"Glucocorticoids have been used to treat MS for decades. Unfortunately, they have lots of side-effects which limit how long you can use them," Said Dennis Bourdette, M.D., chairman of the OHSU Department of Neurology and Director of the MS Center of Oregon. "LGD5552 and related drugs open the possibility of treating MS patients long-term with a glucocorticoid-type drug without all the side-effects. This is a very exciting prospect."

"We are very excited about the data indicating that LGD5552, a non steroidal-glucocorticoid with tissue selective properties, prevents disease development in a model of multiple sclerosis," said Andres-Negro Vilar, M.D., Ph.D., Ligand's executive vice president research and development and chief scientific officer. "In the initial study, designed to assess the potential of the compound for the treatment of multiple sclerosis, LGD5552 showed efficacy equivalent to the current standard of therapy, the steroidal glucocorticoid prednisolone. In addition, our compound showed a more robust response to treatment, as no animals in study developed the disease. In contrast, 25 percent of animals in the prednisolone-treated group presented a blunted disease process in spite of treatment. Since LGD5552 exhibits an improved side effect profile as compared with steroidal glucocorticoids, this new family of compounds may provide novel avenues for more prolonged use of non-steroidal glucocorticoids for the treatment of multiple sclerosis."

Ligand discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, pain, skin diseases, men's and women's hormone-related diseases, osteoporosis, metabolic disorders, and cardiovascular and inflammatory diseases. Ligand's proprietary drug discovery and development programs are based on its leadership position in gene transcription technology, primarily related to Intracellular Receptors (IRs) and Signal Transducers and Activators of Transcription (STATs). For more information, go to www.ligand.com.

Located on OHSU's West Campus, the Neurological Sciences Institute at OHSU studies nervous and sensory systems using a wide range of techniques from the level of molecules to the level of behaving human beings.

OHSU includes the schools of dentistry, medicine, nursing and science and engineering; OHSU Hospital and Doernbecher Children's Hospital; numerous primary care and specialty clinics; multiple research institutes; and several outreach and community service units.

Contact: Jim Newman
newmanj@ohsu.edu
503-494-8231
Oregon Health & Science University



http://www.medicalnewstoday.com/medical ... ewsid=9657
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Postby dignan » Wed Feb 01, 2006 8:05 am

Thanks for the info.

Based on this: http://library.corporate-ir.net/library ... 6FINAL.pdf

I will add it to Phase I.
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Postby dignan » Wed Feb 01, 2006 2:56 pm

Already on the list in Phase II (GEM-SP), but at least it is moving on from IIa to IIb if they can raise some money.



GemacBio announces the successful conclusion of Phase IIa clinical trials for its new molecule designed to treat multiple sclerosis

February 1, 2006 - GemacBio, a biopharmaceutical company specialized in the development of innovative molecules for the treatment of chronic central nervous system and auto-immune diseases, announces today the successful conclusion of a Phase IIa clinical trial on patients suffering from multiple sclerosis. Understanding MS as a multifactorial disease lies at the heart of this advance. GemacBio scientists realized they needed to design a molecule that targeted all aspects of MS pathology. To achieve this, they grafted together several molecules occurring in the human body using a patented process. The resulting molecule applies this new approach in acting against a multifactorial pathology through a number of targets. The molecule is active in three areas: anti-inflammatory, immunomodulating, and neuroprotecting.

Compared to existing MS therapies, this molecule has the enormous additional advantage of oral (sub-lingual) administration. This patient-friendly, convenient route of administration allows improvement of the quality of life for patients who hitherto have had to receive frequent injections.

"We are delighted that a number of eminent clinical experts have expressed their support and a high level of interest in these positive Phase IIa results," said Thibault de la Rivière, CEO of GemacBio. "These encouraging results should reassure existing and future investors as we begin the quest for additional financial resources to enable us to carry out Phase IIb studies and move our molecules further in development and closer to the patient."

The Phase IIa trials took place in three sites in France for periods of between six and 18 months on 22 patients suffering from indications of secondary progressive multiple sclerosis. The trials showed 100 per cent tolerance and a very high safety profile for GemacBio's product.

"Our treatment has two major advantages," said Dr Michel Geffard, Chief Scientific Officer at GemacBio. "The first is the absence of side effects due to the product's low toxicity, an essential characteristic for the long term treatment of chronic diseases, and the second is the maximization of the therapeutic effect via the triple anti-inflammatory, immunomodulating and neuroprotecting action of our combinations of therapeutic molecules."

GemacBio, Bordeaux, is a biopharmaceutical company specialized in the development of innovative molecules for the treatment of chronic central nervous system and auto-immune disease. The company's initial focus is on multiple sclerosis and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). It has already validated its technological approach with a first Phase IIa clinical trial on multiple sclerosis. GemacBio's know-how is based on immunochemistry and the vectorization of small molecules to enhance their therapeutic effect. Gemacbio benefits from the presence of a strong multi-disciplinary scientific team combining biology, chemistry and immunology expertise. The company has raised EUR 4M in financing, principally from regional sources in south west France including IRDI (Institut Régional de Développement Industriel de Midi-Pyrenées), SOCRI (Sud-Ouest Capital Risque Innovation) and business angels.

http://www.pharmalive.com/News/index.cf ... egoryid=40
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French SPMS research

Postby gwa » Wed Feb 01, 2006 4:38 pm

This is exciting news for SPMS people as it is one of a few being tried on something other than mice or RRMS.

I wish more attention was paid to how the patients improved. It is all well and good for there to be no side effects, but their symptom improvement is where the usefullness would be.

gwa
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Postby bromley » Wed Feb 01, 2006 5:17 pm

anti-inflammatory, immunomodulating, and neuroprotecting


At last a company trying to treat the disease on all fronts. But I'm not sure why SP is the focus? If the drug delivers as intended then it would be beneficial to RR and PP (neuroprotective benefit).

But as GWA says the real test is whether it works and brings about improvements.

As for SP, there are a few drugs being trialled - Rituximab, Lamotringe (sp?) for example. The neuro-protective agents under investigation should be beneficial for all types. The real breakthrough will be therapies that regenerate lost axons, neurons and myelin. Maybe stem cells or maybe some other approach.


Ian
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