Summary of the pipeline

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

Hopeful on FTY720

Postby Brownsfan » Wed Oct 26, 2005 3:06 pm

If the Japanese can build a car that gets 60+ mpg then I'm hopeful they are on the right track with FTY720. Plus, knowing that Elan or Biogen aren't involved makes me even happier :D
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Postby dignan » Thu Oct 27, 2005 8:21 am

I agree: Japan-good; Elan/Biogen-bad. It also makes me wonder whether we'll start to see treatments originating from China one day soon. I know MS is supposed to be much more common among people of northern European descent, but there must be a few MS sufferers in China given their population and the latitute of the northern part of the country.
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Postby dignan » Fri Oct 28, 2005 8:26 am

Damn, based on this info from the NMSS, I think I have to remove Avandia from Phase II.



No Benefit – Dr. D. H. Miller (University College London, Queen Square, UK) and colleagues administered either Avandia® (rosiglitazone maleate, GlaxoSmithKline, Inc., a drug used to treat diabetes which affects hormones involved in the immune response) or placebo to 51 people with relapsing-remitting MS. No significant differences were found in tissue damage as detected on MRI, or in clinical or immunological responses to treatment. Treatment was well tolerated. The group found no evidence to support further studies of Avandia in MS.

http://www.nationalmssociety.org/Research-2005Oct28.asp
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Postby dignan » Wed Nov 02, 2005 2:23 pm

Not exactly exciting, but I'll add MLN0415 as a pre-clinical substance.



Inflammation Clinical Update

The Company anticipates entering the oral, selective IKK inhibitor, MLN0415, into the clinic next year. This small molecule would inhibit IKK beta similar to VELCADE, by inhibiting NFkB. Preclinical data suggest that this molecule has activity across a variety of diseases including rheumatoid arthritis, multiple sclerosis, and chronic obstructive pulmonary disease. The Company's initial phase I study is expected to begin in the second half of 2006. This molecule is part of the sanofi-aventis development and commercialization collaboration.

http://www.medadnews.com/News/Index.cfm ... eid=286927
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Postby dignan » Thu Nov 03, 2005 8:34 am

Another preclinical,



TMC-2003 (to be re-designated CHR-1103) is a humanized monoclonal antibody directed to VLA-2, an integrin involved in maintenance of inflammation. In preclinical studies, TMC has demonstrated that anti-VLA2 therapy reduces inflammation in animal models of multiple sclerosis (MS), inflammatory bowel disease and rheumatoid arthritis. Following the completion of the transaction, Chromos intends to initially focus on development of TMC-2003 for treatment of acute episodes of relapse in relapse-remitting MS patients. Chromos expects to complete preclinical safety and toxicology studies by 2H-2006 and anticipates filing an Investigational New Drug application in Q4-2006, "We believe this product has great potential to fill a significant unmet medical need," said Mr. Duncan. "MS patients are underserved at present, as there is no effective therapy available to reduce the damage done during acute relapse."

http://www.biotech-intelligence.com/htm ... ebad7.html
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I am truly impressed

Postby IHaveMS-com » Thu Nov 03, 2005 9:52 am

Hi Dignan,

I have just gone through your summary of the pipeline, and I am truly impressed. This is a super resource for anyone looking to the future, and I hope we all are.

Best regards, Tim
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Postby dignan » Thu Nov 03, 2005 7:44 pm

Thanks Tim, I'm glad you liked it.

Here's another one. Maybe I'm getting ahead of myself, but they are saying they plan to start Phase II trials in 2006, so that's where I'm putting it.


New treatment for multiple sclerosis tested

November 2005 - NewScientist.com - A new pathway for treating multiple sclerosis may have been found, if “exciting” results in mice can be replicated in humans.

MS is an incurable degenerative disease caused by the body’s immune system attacking the protective myelin sheath encasing the nerves that make up the central nervous system. The nerve fibres become increasingly damaged by scar tissue known as sclerosis, which leads to paralysis and loss of speech and vision.

But researchers trying a novel therapy on a mouse version of MS report that the mice showed “almost no inflammation of the myelin sheath and no nerve damage”. Furthermore, MS is characterised by periods of remission and relapse, but the mice recovered with fewer and far less severe relapses.

The therapy targets immune system cells called T-cells. These malfunction in MS patients, producing inflammatory molecules that destroy the myelin sheath. The new treatment, which uses a class of molecules called kynurenines, works by inhibiting the T-cells’ production of inflammatory molecules and prompting them to produce agents that “mop up” the molecules.

The work began with Larry Steinman at Stanford School of Medicine in California, US, and Michael Platten at the University of Tubingen in Germany, and colleagues, selecting a break-down product – a kynurenine – of a naturally occurring amino acid called tryptophan. Tryptophan is a constituent of most proteins and is known to play an important role in immunity.

The group then induced an MS-type illness called experimental autoimmune encephalomyelitis in 24 mice. On the occasion of their first relapse half were given a daily dose of a synthetic version of the kynurenine for 49 days.

“All the mice went into remission, but the mice on the tablets stayed healthy for much longer," says Platten. "The relapses were far less severe and they did not have a return of the paralysis. The drug actually suppressed the disease and slowed its progression.”

The mice on the tablets also had “re-programmed” T-cell function, he adds: “Instead of being pro-inflammatory, the T-cells became anti-inflammatory, helping to heal the myelin sheath and suppressing paralysis.”

Examination of the mice at the end of the experiment showed that the treated mice had undamaged nerve cells and no spread of the condition to the brain, whereas this had occurred in the untreated control group. There were no apparent any side effects from the treatment.

“And, when we gave a blood transfusion from mice who had received the treatment to other sick mice, the transferred T-cells retained their ability to suppress the disease,” adds Steinman, suggesting that the therapy may only need to be administered for a short period.

Peter Brophy, an MS expert at the University of Edinburgh in the UK, says the research is very exciting, providing an “interesting new pathway after a dearth of new ideas for MS treatments".

"It’s completely different to any of the treatments around at the moment, and the study shows a really striking effect on T-cell behaviour,” he says. “The fact that it can be given orally rather than by injection [like all current treatments] also makes it attractive.”
Safety tested

But Brophy cautions that the mouse model of MS, while the best animal model available, does show differences to the human disease and drugs that have worked on mice in the past, have not had the same success in humans.

Another advantage kynurenine has over other candidate treatments is that it is has already proved its safety. Not only is it a derivative of an amino acid that occurs naturally in the body, but it has passed phase I clinical trials in Japan as a potential treatment for allergy sufferers.

“I expect we will be able to proceed directly to phase II clinical trials in patients in the 2006 and start helping people with MS,” Steinman says.

Journal reference: Science (vol 310, p850)

http://www.newscientist.com/channel/health/dn8263.html
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Postby Brownsfan » Thu Nov 03, 2005 9:05 pm

"Tryptophan is a constituent of most proteins and is known to play an important role in immunity"

In other words, Happy Thanksgiving! :D
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Tryptophan

Postby Melody » Fri Nov 04, 2005 4:40 am

Turkey does have the makings of a natural sedative in it, an amino acid called tryptophan. Tryptophan is an essential amino acid, meaning that the body cannot manufacture it. The body has to get tryptophan and other essential amino acids from food. Tryptophan helps the body produce the B-vitamin niacin, which, in turn, helps the body produce serotonin, a remarkable chemical that acts as a calming agent in the brain and plays a role in sleep. So you might think that if you eat a lot of turkey, your body would produce more serotonin and you would feel calm and want a nap.

That was the conclusion that led many people to begin taking a dietary supplement of tryptophan in the 1980s as a way to treat insomnia, but the U.S. Food and Drug Administration banned tryptophan supplements in 1990 because of an outbreak of eosinophilia-myalgia, a syndrome that causes muscle pain and even death. The FDA said contaminated
tryptophan supplements caused the outbreak.

http://home.howstuffworks.com/question519.htm
But nutritionists and other experts say that the tryptophan in turkey probably won't trigger the body to produce more serotonin because tryptophan works best on an empty stomach. The tryptophan in a Thanksgiving turkey has to vie with all the other amino acids that the body is trying to use. So only part of the tryptophan makes it to the brain to help produce serotonin.

It is the whole traditional Thanksgiving meal that can produce that after-dinner lethargy. The meal is quite often heavy and high in carbohydrates -- from mashed potatoes, bread, stuffing and pie -- and your body is working hard to digest that food. Also, if you drink alcohol with your dinner, you will likely feel its sedative effect, too.

There is a way to take advantage of the tryptophan in turkey. If you have trouble getting to sleep one night while there is still leftover turkey in the refrigerator, you could have a late snack of turkey and that, nutritionists say, might be the right amount of tryptophan on an empty stomach to help produce some serotonin.
John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
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Re: Tryptophan

Postby NHE » Sat Nov 05, 2005 7:22 am

Melody wrote:So you might think that if you eat a lot of turkey, your body would produce more serotonin and you would feel calm and want a nap.

A few years ago I started eating turkey sandwiches as a somewhat more healthy option than my usual ham or roast beef sandwiches. However, I had to go back to ham since I noticed that I was typically more tired in the afternoon on days that I had eaten a turkey sandwich. Can I directly attribute my afternoon tiredness to tryptophan? Probably not. However switching to a different sandwich meat fixed my problem. This is just my personal experience and the experience of others is sure to vary.

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Alferon N Injection - offlabel usage right now

Postby DS » Fri Nov 11, 2005 2:52 am

dignan,

Thanks for all the hard work you put into that list.
A few remarks though.
I noticed Alferon N Injection is in a phase 2 trial, however I don't think that's correct. Where did you get that information if I may ask?
Did you call the company?
Right now as far as I know, it's given off label when Avonex or Rebif seem to have lost their effectiveness.
Based on successful off label results they decided to make plans for a clinical trial, but right now what the company says is "it's in clinical development." That of course could be anything.
I heard they would like to do a phase 3 trial but there're 2 roadblocks ahead of them, money being one of them and the FDA's permission to start a phase 3 trial being the other one.
They can use all the help they can get but mind you, this is for RR-MS, so it will require a big phase 3 trial due to the fact that there already are some alternatives available, like Avonex and Rebif.
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Postby dignan » Fri Nov 11, 2005 9:55 am

Thank you for the reply. I hope people will point out mistakes I've made. I'm no expert and all I've done is compile info I find freely available online, plus add drugs that other users of Thisisms find out about.

I looked into it and found this from hemispherx.net:

Clinical Status: FDA Approved for the treatment of refractory Human Papilloma Virus (HPV). Multi-center Phase IIb study of ALFERON N Injection in subjects with relapsing-remitting Multiple Sclerosis who have discontinued interferon therapy because of clinical progression or intolerance, or who have developed neutralizing antibodies to recombinant DNA derived interferon.

Next Steps:
Phase III trial expected in Multiple Sclerosis to initiate in 4th Quarter 2005

http://www.hemispherx.net/content/inves ... t%20FS.pdf



And then there was this 2004 press release about the Phase IIb study:

Hemispherx Biopharma Launches Multiple Sclerosis Salvage Program with Natural Interferons

BUSINESS WIRE - June 14, 2004 - Hemispherx Biopharma, Inc. announced today that it submitted to the FDA a new clinical Protocol entitled "A multi-center, open label, study of Alferon N Injection® in subjects with relapsing-remitting multiple sclerosis, who have discontinued interferon-beta therapy because of clinical progression or intolerance, or who have developed neutralizing antibodies to interferon-beta."

Clinical Study Design

A multi-center, open label, phase IIb clinical trial will determine the safety and efficacy of Alferon N Injection®, a highly purified mixture of natural alpha interferons, in the treatment of multiple sclerosis (MS) patients who have discontinued their treatment of Avonex® or Rebif® or Betaseron® because of clinical progression or intolerance or neutralizing antibody formation. Specifically, the primary endpoint of the study will be annualized clinical relapse rate comparing baseline vs. week 48. Initially, fifty patients selected will be dosed with 5 million IU Alferon N Injection® every other day for a period of 48 weeks.

http://www.bioexchange.com/news/news_page.cfm?id=20498


But then the company doesn't talk about an ongoing MS trial anywhere else on their website. Have you talked to the company? The evidence is mixed from what I can see. And hey, if anyone else knows what's going on with Alferon for MS trials, feel free to chime in...
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Alferon N

Postby DS » Sun Nov 13, 2005 12:47 pm

I know the company a little bit and I know that the CEO always wanted to do more than he or his company could handle. That appears to have changed since early 2005. That's when they hired a COO and since then things are gradually improving.
The COO did a conference call in October (wallst.net) wherein he says Alferon N has been used by several doctors on quite an extensive number of patients and with good results.
Which is why I think it was used off label, not as part of a clinical trial.
I could be wrong obviously but all plans announced before January 2005 should be ignored, in my humble opinion.
And the fact that they don't say on their website that the trial is ongoing tells me it's not yet in a clinical trial. They gave the site a big update early this year.
Maybe they will use the off label data to ask the FDA permission to do a phase 3 trial?
I've not spoken to the company in quite some time. It's been several years since I talked to them about the HHV6 connection in MS and what they could do to help. That's another issue obviously and back then CFS was their biggest priority. It still is today but back then they hadn't yet acquired Interferon Sciences which is the company who developed Alferon N Injection.
I haven't spoken to them about Alferon N and MS.
All I know is what the COO said in the conference call he did on Wallst.net
When you have the time, I can tell you there are more than happy to help you find the answers you're looking for.
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Re: Hopeful on FTY720

Postby kareng7 » Sat Nov 19, 2005 7:13 pm

Brownsfan wrote:If the Japanese can build a car that gets 60+ mpg then I'm hopeful they are on the right track with FTY720. Plus, knowing that Elan or Biogen aren't involved makes me even happier :D


I was recently in Cambridge MA for a few weeks working for a client, and the route I took on foot to the train every day meant I passed by one of Biogen's offices. It was all I could do to stop myself from storming their lobby and shouting "We're mad as hell and we're not going to take it anymore!!"

Instead, I just scowled.
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Postby dignan » Tue Nov 22, 2005 8:56 am

I'm moving this from pre-clinical to phase I...



ChemoCentryx to Initiate Clinical Studies of CCR2 Antagonist CCX915; Investigational New Drug Application on File -- Studies to Commence by Year End

BUSINESS WIRE - Nov. 22, 2005 - ChemoCentryx, Inc., a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing orally-administered therapeutics that target the chemokine system, announced that the company has filed an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration to begin clinical studies of a proprietary small molecule inhibitor of the CCR2 chemokine receptor with which it expects to complete Phase I studies in 2006.

"Our orally-available compound, CCX915, is a highly selective inhibitor of the CCR2 chemokine receptor which is implicated in the damaging inflammation underlying multiple sclerosis and other autoimmune and inflammatory diseases," said Thomas Schall, Ph.D., President and Chief Executive Officer of ChemoCentryx. "Highly potent and selective antagonists of specific chemokine receptors represent new modes of action by which such diseases may be treated. I am very pleased with the progress we've made in advancing this novel compound rapidly from discovery to the clinic, and look forward to initiating clinical studies of this compound next month."

Preclinical studies of CCX915 have shown it to have a favorable safety and pharmacokinetic profile when given orally at dose levels sufficient to cause inhibition of CCR2 function. ChemoCentryx will now conduct initial clinical trials to examine the safety, tolerability and pharmacokinetics of CCX915 in humans. Dose-escalating studies in healthy volunteers will be performed to measure the blood levels of CCX915 and to assess its tolerability. Based on those results, ChemoCentryx plans to initiate proof-of-concept clinical trials of CCX915 in patients with multiple sclerosis (MS).

CCX915 was discovered by ChemoCentryx using the company's proprietary high throughput screening RAM Assay(TM), part of the company's EnabaLink(TM) drug discovery platform. CCX915 belongs to a new class of synthetic compounds that are chemically distinct from all known inhibitors of CCR2. CCX915 is one of several clinical-quality molecules inhibiting this receptor that have been identified by ChemoCentryx. Mechanism of action studies indicate that CCX915 and related compounds selectively inhibit CCR2-mediated migration of inflammatory white blood cells, but do not inhibit migration mediated by other chemokine receptors, even when administered at high concentrations. Based on the high degree of target specificity observed, CCX915 has the potential to avoid the undesirable side effects of traditional immunosuppressive therapies used in MS and other autoimmune disease indications.

About Multiple Sclerosis and the Role of the CCR2 Receptor
Multiple sclerosis (MS) is the leading cause of primary, non-traumatic neurological disability among young adults in the United States, Western Europe and Japan. The National Multiple Sclerosis Society of the United States estimates that approximately 2.5 million people are affected worldwide. MS is an autoimmune disease in which white blood cells infiltrate the central nervous system by crossing the blood-brain barrier, leading to inflammatory damage of the neural structures, including myelin and axons. The migration of inflammatory cells into the central nervous system is regulated by chemokines. A number of chemokine receptors have been implicated as playing a central role in the inflammatory pathways underlying MS. In particular, the CCR2 chemokine receptor is believed to be important in the formation of MS lesions as it appears to facilitate the movement of inflammatory cells across the blood-brain barrier.

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