Summary of the pipeline

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

Postby Shayk » Mon Jun 26, 2006 4:42 pm

Dignan

This news is music to my ears. I'm so glad they've done some research in addition to the "auto-immune" anti-inflammatory properties of estrogen and that it sounds promising.
Treatment with either estradiol or the ERalpha ligand significantly reduced this gray matter pathology.

The fact that they used a ligand suggests to me that if something eventually comes of this, it should be suitable for men as well. 8)

I think I posted this before but it may be worth repeating. Development of 17 alpha 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.


Maybe they should add MS to the list of diseases with potential therapeutic benefit. :wink:

Thanks Dignan

Sharon
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Postby dignan » Thu Jul 06, 2006 6:36 am

Another one for phase I: TK54



LTKfarma announces its creation and names advisory board

July 6 2006 - LTKfarma, a biopharmaceutical company focused on developing and marketing cell therapy products derived from modified T-cells to treat leukemia and autoimmune diseases, announced today its creation and the appointment of its advisory board. The company, founded in March 2006, selected the new board members because of their considerable industry experience, which will enable them to provide skills, counsel and governance as LTKfarma accelerates its clinical development.

"The know-how and experience of our advisory board members, coupled with our sound intellectual property portfolio, mean that we can move forward with accelerating the clinical development of our lead product TK54, currently in Phase I/II, and with raising funds for Phase II/III trials," declared Laurent de Narbonne, MD, LTKfarma Chairman.

LTKfarma's IP portfolio is based on an exclusive license granted in March 2006 by the University of Pierre et Marie Curie (Paris VI). Under the terms of this agreement, LTKfarma has exclusive rights to use 31 patents (26 of which have already been granted) grouped into six families. The license grants LTKfarma worldwide rights, in Europe, the US and Japan. The company is currently working on the development and marketing of TK54, a cell therapy product based on modified T-cells. TK54 uses suicide gene technology and could reduce risks linked to graft versus host disease (GVHD), one of the main complications of bone marrow grafts and which results in the death of 20-60 percent of cases according to different estimates. The first applications of TK54 target bone marrow grafts for leukemia sufferers and severe forms of autoimmune diseases such as scleroderma, multiple sclerosis and rheumatoid arthritis.

The new board members, all of whom bring complementary skills and experience, are:

Alain Clergeot, MD, Executive MBA/HEC, President of Chugai Pharma France. Tamara Joseph, LLM, JD, Executive Vice-President, General Counsel and Corporate Secretary of Mayne Pharma Ltd, former General Counsel of Transkaryotic Therapeutics and former Vice-President of Biogen Idec. David Klatzmann, University Professor, MD, DSc, Director of the Biology and Therapeutics Laboratory for Immune Pathologies (CNRS/University of Pierre et Marie Curie), head of the Biotherapy Center at the Pitié-La Salpêtrière Hospital. Jean-François Labbé, HEC, former European President of Hoechst Marion Roussel and COO of ProStrakan. Laurent de Narbonne, MD, Executive MBA/HEC, General Manager of Octapharma France, Belgium and Luxemburg, former International Marketing Director at Biogen Idec, and formerly with Parke Davis France. Leo van Wersch, DPharma, and JD, former President of Procter & Gamble Pharmaceuticals France and Vice-President Procter & Gamble Pharmaceuticals Europe.

About LTKfarma LTKfarma is a biopharmaceutical company focused on the development and marketing of cell therapy products derived from modified T-cells in the treatment of leukemia and severe forms of autoimmune pathologies (scleroderma, multiple sclerosis, rheumatoid arthritis). Incorporated in March 2006, and led by Chairman Laurent de Narbonne, the company is based in the Evry Genopole(R) biotech cluster just south of Paris. LTKfarma has exclusive rights to use 31 patents (26 of which have already been granted) in six families following an exclusive license granted in March 2006 by the University of Pierre et Marie Curie (Paris VI). The license grants LTKfarma worldwide rights, in Europe, the US and Japan. During its creation, LTKfarma carried off the first special jury prize in the 7th National Business and Innovative Technologies Creation Contest organized by the National Minister of Research and France's innovation agency, OSEO ANVAR. The company recently received a laureate in the Senate Tremplins Enterprise Awards, a competition sponsored by France's upper legislative body.

About the technology LTKfarma develops products based on research by Pr David Klatzmann, Director of the Biology and Therapeutics Laboratory for Immune Pathologies (CNRS/University of Pierre et Marie Curie) and head of the Biotherapy Center at the Pitié-La Salpêtrière Hospital, and his collaborators, and by Pr François Lemoine (Faculty of medicine Pierre et Marie Curie) and Dr José Cohen (Inserm). TK54 is a cell therapy product made up of modified T-cells, which express "suicide" genes. These genes code for a viral enzyme, the herpes virus thymidine kinase (TK). TK is able to transform chemically an inactive drug (ganciclovir, usually used for the treatment of herpes infections) into a derivative that is toxic to dividing cells, which then die by "cellular suicide". Thus the target cells into which the TK gene has been introduced die if an only if they are in the presence of ganciclovir and in division. This is the case with the T-cells present in the graft, which are frequently the cause of graft versus host disease. This complication, which often resists other types of treatment, is a frequent cause of death. The treatment consists of the injection of modified T-cells expressing TK followed by treatment with ganciclovir if graft versus host disease occurs.

http://www.pharmalive.com/News/index.cf ... id=33%2C34
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Postby LisaBee » Wed Jul 12, 2006 4:57 pm

Dignan,

I scanned over the updated pipeline list and didn't see Vitamin D on it anymore. I thought there was ongoing work on Vit D out of Toronto? Am I missing it, or did something happen to remove it from the list?

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Postby dignan » Thu Jul 13, 2006 6:41 am

I looked at the original source of that information, which was from the Canadian MS Society, from May 2004. I then scoured the net looking for any signs of life and came up empty. Since it was only supposed to be an early stage trial, I can't imagine that it could take this long to post/publish results, so unless somebody can show that it's ongoing, I assumed it died a quiet death -- that's what I assume happens to every pre-clinical and phase I study that fails -- a quiet death.

But I would LOVE for somebody to show me that I was wrong and that they are still going, or published something I missed!
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Postby LisaBee » Thu Jul 13, 2006 4:09 pm

Thanks, Dignan. Well, bah. I better quit saying there is a study going on out there. My understanding was the initial study was a range-finding on dose of Vitamin D only. I know that recruiting subjects that meet the criteria is an impediment, and well, testing a vitamin is a funding problem as well, no blockbuster profits in that. I'd like to dig out the researchers on the early pilot study and see what happened. If they ran the study and the results were negative, I would assume they would publish that, since there is all this speculation on the role of vitamin D in MS causation. I suspect that it just fell through, or it took longer to get enough subjects recruited and it is still ongoing.
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Postby dignan » Thu Jul 27, 2006 6:09 am

INCB8696 is one already on the pre-clinical list. Looks like it will be going to human trials starting early next year based on this bit from Incyte's quarterly results announcement.



CCR2 Antagonist Program

Under our collaborative research and license agreement with Pfizer, we have retained exclusive worldwide rights to certain CCR2 antagonist compounds for multiple sclerosis (MS) and a second indication which, for competitive reasons, we have not disclosed.

We expect to complete IND-enabling studies in the second half of 2006 and begin a Phase I trial in healthy volunteers for our lead compound, INCB8696, early next year followed by a Phase II trial in MS patients.

<shortened url>
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Postby LisaBee » Thu Jul 27, 2006 3:23 pm

Dignan,

I am very happy to report that the Vitamin D trial out of Toronto is indeed alive. Here is a 2006 abstract, presented in the June 2006 IOF World Congress on Osteoporosis in Toronto. I had to copy text off an adobe file and some letters dropped, but here it is. This was the Phase 1, but I understand that Phase II work has begun with more MS subjects. Please add Vitamin D back to your Phase II list. - Lisa


A PHASE I SAFETY, DOSE-ESCALATION STUDY OF VITAMIN D3
WITH CALCIUM IN PATIENTS WITH MULTIPLE SCLEROSIS
Kimball S1, Vieth R1, UrsellM2, O’Connor PG2, Gray B2; 1Mount
Sinai Hospital, 2St. Michael’s Hospital, Toronto, ON, Canada
Background: Although vitamin D3 is often used in the treatment
of osteoporosis, a Phase I, dose-.nding study has never been
undertaken to our knowledge. Vitamin D3 may play a role in the
development and/or progression of multiple sclerosis (MS).
Objective: To perform a dose-.nding study, characterizing the
therapeutic safety of vitamin D3 with calcium supplements in
patients with MS.
DESIGN: In a Phase I, escalating-dose design, vitamin D3 (100
to 1,000 mcg/day) was given orally over 28 weeks to 12 patients
with clinically de.nite MS. Calcium was also given orally at the
current recommended daily intake (1000 mg/day). Every 6 weeks,
serum and urine calcium, serum liver enzymes, creatinine, protein
and electrolytes were monitored, and the vitamin D3 dose increased
incrementally, ending after 4 weeks of supplementation at
1,000 mcg/day. Disease activity was monitored based on annualized
relapse rates and magnetic resonance imaging (MRI) scans of
the brain.
Results: Mean serum 25-hydroxyvitamin D (25(OH)D) concentrations
increased from 79.4 nmol/L at baseline to 452.6 nmol/L
(p<0.001). At the end of the protocol the highest individual
25(OH)D value was 810 nmol/L. Serum calcium levels and urine
calcium:creatinine remained within normal ranges (2.2–2.6
mmol/L and <1.0 respectively) for all participants, and did not
change signi.cantly (paired t-test). Liver enzymes, serum creatinine,
electrolytes and serum protein all remained unchanged and
within reference ranges. In terms of MS, there was no signi.cant
change in annualized relapse rates or the number of lesions on
MRI scans (indicators of active disease).
Conclusions: Despite attaining serum 25(OH)D concentrations
much higher than physiologic levels (>230 nmol/L), no participant
developed hypercalcemia, hypercalciuria or adverse clinical e.ects.
These data support the safety of higher vitamin D3 intakes, and
will help to de.ne serum 25(OH)D concentrations that could be
evaluated for the treatment of disease such as MS or osteoporosis.[/quote]
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Postby dignan » Thu Jul 27, 2006 7:15 pm

Done! Lisa, you're my new hero. It was Bromley for a while, but I'm SO over that now.

Thank you so much for digging up that info. Am I remembering correctly that there are 40 IUs in a microgram? Because that would mean they were testing doses up to 40,000 IU per day, with no ill effects! Great stuff.
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Acorda Therapeutics

Postby Grumpster » Fri Aug 04, 2006 8:23 am

Hello all,

I have been watching this little known company for a while. Check out www.acorda.com

They are researching drugs to help repair damaged nerves by blocking the channels that are leaking as a result of myelin damage. Very exciting stuff for those of us who have loss of function from nerve damage. They are focused on MS and spinal cord injury.

I'll keep my fingers crossed for this one.
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Postby dignan » Fri Aug 18, 2006 7:30 am

For the first one of these two pre-clinicals, I'm glad to see research coming out of China.



A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation.

J Pharmacol Exp Ther. 2006 Aug 16;
Fu YF, Zhu YN, Ni J, Zhong XG, Tang W, Re YD, Shi LP, Wan J, Yang YF, Yuan C, Nan FJ, Lawson BR, Zuo JP.
Shanghai Institute of Materia Medica.

The reversible S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002) suppresses antigen-induced specific immune responses, particularly Th1-type responses. Experimental autoimmune encephalomyelitis (EAE) is thought to be a type 1 helper T cell (Th1) cell mediated inflammatory demyelinating autoimmune disease model of human multiple sclerosis (MS). In this study, we examined the effects of DZ2002 on active EAE induced by myelin oligodendrocyte glycoprotein (MOG) 35-55 in female C57BL/6 mice. Administration of DZ2002 (50 mg/kg/day, i.p.) significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG 35-55 specific T cell proliferation and Th1-type cytokine production. In vitro studies also demonstrated that DZ2002 inhibited anti-CD3/28 induced naive T cell activation concomitant with the down-regulation of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D3, and the up-regulation or protection of the CDK inhibitor p27.

These findings highlight the fact that DZ2002 likely prevents EAE by suppressing T cell activation, and suggest its utility in the treatment of MS and other Th1-mediated inflammatory diseases.

<shortened url>



A BAFF antagonist suppresses experimental autoimmune encephalomyelitis by targeting cell-mediated and humoral immune responses.

Int Immunol. 2006 Aug 16;
Huntington ND, Tomioka R, Clavarino C, Chow AM, Linares D, Mana P, Rossjohn J, Cachero TG, Qian F, Kalled SL, Bernard CC, Reid HH.
Neuroimmunology Laboratory, Department of Biochemistry, La Trobe University, Bundoora, Victoria 3086, Australia.

BAFF [B cell-activating factor of the tumour necrosis factor (TNF) family] and APRIL (a proliferation-inducing ligand) are two TNF family members with shared receptors. While, physiological roles for APRIL are not fully understood, BAFF is critical for B cell homeostasis and also acts as a co-stimulator of T cells. Using a B and T cell-mediated mouse model of multiple sclerosis (MS), myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), we observed that a BAFF/APRIL antagonist (soluble BCMA-Fc) inhibited central nervous system inflammation and demyelination such that it suppressed the onset and progression of clinical symptoms of EAE. In addition to dramatically reducing the titre of MOG-specific auto-antibodies, this treatment also induced a switch in the subtype of the Th cell population characterized by marked alterations in cytokine production following re-stimulation with MOG in vitro. Indeed, hBCMA-Fc therapy led to significant increases in the level of transforming growth factor beta, while the levels of Th1 cytokines were markedly diminished. These results not only identify BAFF as a critical factor in maintaining humoral immunity in EAE but also support its role in T lymphocyte responses.

Our findings demonstrate that hBCMA-Fc acts on both effector arms of the immune response in EAE, a characteristic that may be of significant therapeutic value in the treatment of MS.

<shortened url>
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Postby CureOrBust » Wed Aug 23, 2006 12:32 am

chaperonin 10 (XToll) has finished its phase IIa trials http://www.cbio.com.au/investors_releases.html but i couldnt find the results on their web site?
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Postby dignan » Fri Aug 25, 2006 6:25 am

It's nice to see the phrase "gene therapy" with this one.



HSV-1-mediated IL-1 receptor antagonist gene therapy ameliorates MOG(35-55)-induced experimental autoimmune encephalomyelitis in C57BL/6 mice.

Gene Ther. 2006 Aug 24;
Furlan R, Bergami A, Brambilla E, Butti E, De Simoni MG, Campagnoli M, Marconi P, Comi G, Martino G.
[1] 1Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy [2] 2Department of Neurology, San Raffaele Scientific Institute, Milan, Italy.

Primary proinflammatory cytokines, such as IL-1beta, play a crucial pathogenic role in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), and may represent, therefore, a suitable therapeutic target. We have previously established the delivery of anti-inflammatory cytokine genes within the central nervous system (CNS), based on intracisternal (i.c.) injection of non-replicative HSV-1-derived vectors. Here we show the therapeutic efficacy of i.c. administration of an HSV-1-derived vector carrying the interleukin-1receptor antagonist (IL-1ra) gene, the physiological antagonist of the proinflammatory cytokine IL-1, in C57BL/6 mice affected by myelin oligodendrocyte glycoprotein-induced EAE.

IL-1ra gene therapy is effective preventively, delaying EAE onset by almost 1 week (22.4+/-1.4 days post-immunization vs 15.9+/-2.1 days in control mice; P=0.0229 log-rank test), and decreasing disease severity. Amelioration of EAE course was associated with a reduced number of macrophages infiltrating the CNS and in a decreased level of proinflammatory cytokine mRNA in the CNS, suggesting an inhibitory activity of IL-1ra on effector cell recruitment, as antigen-specific peripheral T-cell activation and T-cell recruitment to the CNS is unaffected. Thus, local IL-1ra gene therapy may represent a therapeutic alternative for the inhibition of immune-mediated demyelination of the CNS.

<shortened url>
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Postby dignan » Sun Aug 27, 2006 7:54 am

Another one for pre-clinical, but on the bright side, it's about preventing axonal degeneration.


Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE.

Brain. 2006 Aug 24;
Black JA, Liu S, Hains BC, Saab CY, Waxman SG.
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.

Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied.

We demonstrate here that oral administration of phenytoin provides long-term (up to 180 days) protection for spinal cord corticospinal tract (CST) and dorsal column (DC) axons in both monophasic (C57/BL6 mice) and chronic-relapsing (Biozzi mice) murine EAE. Untreated C57/BL6 mice exhibit a 40-50% loss of CST and DF axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein (MOG) injection. In contrast, only 4% of DF axons are lost at 90 days, and only 8% are lost at 180 days in phenytoin-treated C57/BL6 mice with EAE; only 21-29% of CST axons are lost at 90 and 180 days in phenytoin-treated C57/BL6 mice with EAE. Attenuation of dorsal column compound action potentials was ameliorated and clinical status was also significantly enhanced with phenytoin treatment at 90 and 180 days in this model. In addition, inflammatory cell infiltration into the dorsal columns was reduced in phenytoin-treated mice with EAE compared with untreated mice with EAE. Similar results were obtained in Biozzi mice with chronic-relapsing EAE followed for 120 days post-injection.

These observations demonstrate that phenytoin provides long-term protection of CNS axons and improves clinical status in both monophasic and chronic-relapsing models of neuroinflammation.

<shortened url>
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Postby bromley » Sun Aug 27, 2006 11:51 pm

Dignan,

More and more focus is being given to axonal protection (stopping axons degenerating). The research also mentions flecainade - I posted some research on this recently (see below). So there are two agents which look like they could stop axons degenerating.


<shortened url>

Given the importance of axonal degeneration - perhaps we should have a separate section (forum). This would capture all the research on 'neuro-protection', including these two agents and also cannaboids, stuff on sodium channels etc etc. Shayk is also very interested in neuro-protection like me. And testosterone in a small trial was shown to reduce tissue loss in men. I'll leave it to Aron to decide.

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Postby dignan » Tue Aug 29, 2006 6:45 am

Flecainide, excellent, I'll add it. It looks like it's in phase II for SPMS.
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