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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #481
    Just to make it clear what Seikagaku is testing. The idea is a simple one. The enzyme is being injected into the core of a bulging disc in order to digest its proteoglycans and thereby shrink the disc sufficiently to reduce pressure on the nerve roots. This procedure would eliminate or at least postpone the need for more invasive discectomy surgery.

  2. #482
    Quote Originally Posted by Wise Young View Post
    While success in the first trial may attract more subjects for future trials, I am not sure that we want to attract subjects for that reason alone. People volunteer for the trials because they want to help their community identify therapies that restore function.
    I'll be honest, I don't know what the SCI community in China is like and what motivates volunteers for the trials. That would be a very interesting thing to know.

    Achieving greater consensus amongst scientists for which treatment to take to trial. Who is this consensus for? Is it for the SCI community, companies, the regulatory agencies, clinicians, or the investors? If the consensus is intended for the investors, so that they will invest in the trials, the risk vs. profit analysis will probably proceed as follows. If investors can get regulatory approval on a product at a low cost, such as $12 million vs. industry standard of $2 billion, it would be a very attractive investment even if the risk of failure is relatively high. If the consensus is intended for companies who have potential products for trial, the knowledge that the trial will be done efficiently and rapidly for a limited investment would be more important than the promise of the therapy, which the company believes in anyway. If the consensus is for the SCI, scientific, clinical, and regulatory communities, it would be nice to have more support but the results of the trials will be the only things that matter and will speak louder than any pre-trial consensus. Should we be delaying trials for such consensus? Do you see any prospect of consensus amongst spinal cord injury scientists now?
    Personally, I have no faith in any of the commercial entities operating in the spinal cord injury arena for chronic Cure. This is purely my personal opinion and by no means would I want to preach about it. I believe in this climate we need to look at a new model for translating medical science for smaller markets - perhaps one in the arena of social enterprise projects.

    The reality is market forces could see Acorda, NeuralStem, Stem Cells Inc, Invivo Therapeutics et al find a lower hanging fruit to spinal cord injury and we could continue to see spin without substance from CEOs to raise stock prices as they operate on fumes. There is a lot of BS out there sadly. But back to topic......

    There are obviously different types of investors. Community-based investors want to see efficacy first and foremost. It's not about delaying trials by waiting for a consensus. You can't put the cart before the horse. As you say we'll never get a consensus from many many scientists due to various conflicts of interest. But if you put yourself in my shoes, I cannot hand money over to a scientist that appears a lone wolf either. So I will naturally look for opinions from multiple sources before parting with my cash.

    As you say, you want to choose the therapy which offers the greatest probability of efficacy before undertaking the mammoth task of running a clinical trial. And just as you say that SCINetChina offers an opportunity to commercial entities to cheaply test their products but could it also be that additional pre-clinical work can offer an opportunity to those responsible for managing the clinical trial network funds to ratify a therapy before a large financial outlay?

    Ultimately it comes down to where the money is coming from. If a commercial entity is willing to wholly fund the trial with less pre-clinical data - then that is their choice I suppose. However, if the money is coming from the Community, then you have to be a bit more careful before spending the money.

    Better risk management. What are the risks of clinical trials? Clinical trial risks fall into three categories: clinical trial execution, product safety, and treatment efficacy. Obviously, if the trials don't get executed well, the investment is wasted. A serious safety issue can kill a product (or worse, somebody). Even minor safety issues will make the product more difficult to approve and eventually to market. Treatment efficacy is of course important because an ineffective therapy will not receive regulatory approval. However, a robust mechanism of action is often considered more important than preclinical evidence of therapeutic efficacy in animal models because animal models don't always predict the human response and some therapies cannot be adequately tested in animals.
    What do you mean by "a robust mechanism of action"?

    With regard to chondroitinase, please consider the following. Acorda Therapeutics has licensed a use patent for chondroitinase for spinal cord injury from James Fawcett and his colleagues. To my knowledge, Acorda does not hold the composition of matter patent, which is held by a Japanese food company that discovered the bacterial gene. They do not hold the processing patent, which was filed by another Japanese company (Seikagaku) that developed methods to isolate and purify chondroitinase. Neither of these companies have licensed their patents to Acorda. Seikagaku apparently has licensed its processing patent to another Japanese company. Also, both of these patents are relatively old and will probably run out in a relatively short time. Finally, several competing products may soon make chondroitinase enzyme obsolete as a therapy.
    1. Jerry Silver has a small molecule drug, a polypeptide that can be given systemically to block the receptor that mediates the inhibitory effects of CSPG. I assume that it has been licensed to a company. There are reports that it is effective.
    2. Emory University has patented a form of chondroitinase that is less heat sensitive and apparently more potent that the standard bacterial chondroitinase.
    3. Several groups have successfully inserted chondroitinase into cells that then secrete the enzyme, so that these cells can be transplanted into the injury site and deliver chondroitinase locally at much less cost.
    4. A human enzyme that breaks down chondroitin-6-sulfate-proteoglycans has been discovered.


    I don't know how much these factors are influencing Acorda's decisions but they have said that they are doing safety and other studies to produce chondroitinase for trial. These studies are not trivial and require substantial work, investment, and time. I am sure that if a foundation said that they would be willing to fund a chondroitinase trial, it could be done.

    Wise.
    With regards to Ch'ase - well, the fact that one enzyme and its usage has licenses and patents spanning across 3 or 4 commercial entities and that we could still be many years away from a clinical trial for SCI is quite frankly bullshit (pardon my language)!

    As for the safety and "other" studies that Acorda are allegedly undertaking - that's what we call a "party line" in my profession.

    Im sad that with such long-standing careers in the spinal cord injury arena that James Fawcett, Wise Young and Jerry Silver cannot come together and grab the Ch'ase story by the scruff of the neck and drag it through the pipeline by hook or crook. Im sure the Community would get behind such a project. I certainly would.
    Last edited by Fly_Pelican_Fly; 02-11-2013 at 09:35 PM.

  3. #483
    This (to my eyes) disaster in the years long hold-up of chondroitinase getting into trials is why I asked in another thread, regarding Dr. Silvers new peptide:
    Quote Originally Posted by ay2012 View Post
    Would it be possible, though, to structure an agreement to license the technology so it doesn't get stuck in purgatory with respect to SCI clinical trials, like chondroitinase? What would keep the new peptide from falling into a similar fate once big pharma gets involved?
    I'll admit I'm naive as to the licensing agreements and how this stuff actually plays out. Perhaps someone could shed some light.

  4. #484
    At present we know that our peptide is highly effective at acute stages following contusive injury, far more effective than chondroitinase either delivered via injection or via lenti-viral delivery. However, we do not yet know if the peptide works at chronic stages. We have just begun an experiment testing the peptide in 3 month post contusive injury animals. We do know that in our C2 hemisection, respiration model that ch'ase works quite nicely 1.5 years after injury. We have not tried the peptide yet in this model. It may likely turn out that for chronic injury we will need both the enzyme and the peptide. The enzyme can be used to effect immediate changes in allowing for synaptic plasticity and the peptide for stimulating long term plastic changes. In addition, and I am most excited, that we will be adding a form of intraspinal microstimulation (a technique similar to but even more effective than epidural stimulation) to further help to wake up the circuitry below the chronic lesion.
    Last edited by jsilver; 02-11-2013 at 10:35 PM.

  5. #485
    Quote Originally Posted by Wise Young View Post
    cripwalk, the phase I trial needs to be done outside of China. Wise.
    Dr. Young, no offence, but I wasn't looking for you to tell me what won't help. I would hope that among those with some skin in the game, someone knows where it CAN be started.

    I assume you are basically stating there are issues which prevent SCIChinaNet from conducting the trials. Which is fine (although obviously discouraging). Who CAN conduct the trials? Hopefully the SCI research community is organized enough to know who has the capability. From there, we simply need to create the infrastructure necessary to test.

    I've no doubt that the road is quite long and complex. But I see no way in which some organization wouldnt help.

    1. What do we need?
    2. How can we get it?

    Once those fundamental questions are answered, we can start moving in the right direction. Nothing can change without answering those two questions. Let's start.

  6. #486
    Quote Originally Posted by jsilver View Post
    At present we know that our peptide is highly effective at acute stages following contusive injury, far more effective than chondroitinase either delivered via injection or via lenti-viral delivery. However, we do not yet know if the peptide works at chronic stages. We have just begun an experiment testing the peptide in 3 month post contusive injury animals. We do know that in our C2 hemisection, respiration model that ch'ase works quite nicely 1.5 years after injury. We have not tried the peptide yet in this model. It may likely turn out that for chronic injury we will need both the enzyme and the peptide. The enzyme can be used to effect immediate changes in allowing for synaptic plasticity and the peptide for stimulating long term plastic changes. In addition, and I am most excited, that we will be adding a form of intraspinal microstimulation (a technique similar to but even more effective than epidural stimulation) to further help to wake up the circuitry below the chronic lesion.
    Wow - keep at it Jerry

  7. #487
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    Dr J Silver

    Don't take as disrespect but when do you hope to take your trials to humans trials. Can you you give an expected time frame? When it may or may not happen like 2015 - 2018 approx

    Your rat experiments seem to be positive in most cases but like others were getting tired of the rat taking the spot light sorry to sound impatient but im running out of time at 47 and twenty twos in this chair and i would like to see myself retire walking, and fucking and anything else my wife i had enjoyed before the accident.

  8. #488
    Quote Originally Posted by Fly_Pelican_Fly View Post
    I'll be honest, I don't know what the SCI community in China is like and what motivates volunteers for the trials. That would be a very interesting thing to know.
    I estimate that about 800,000 people in China live with chronic spinal cord injury. Some kind people translate almost all posts in the Cure Forum on this web site (CareCure) into Chinese and many people in China read the posts here avidly. China recently committed 0.5% of their GDP to translational medicine projects. So, China is going to become a very good place to do spinal cord injury clinical trials in the coming years.

    Quote Originally Posted by Fly_Pelican_Fly View Post
    Personally, I have no faith in any of the commercial entities operating in the spinal cord injury arena for chronic Cure. This is purely my personal opinion and by no means would I want to preach about it. I believe in this climate we need to look at a new model for translating medical science for smaller markets - perhaps one in the arena of social enterprise projects.

    The reality is market forces could see Acorda, NeuralStem, Stem Cells Inc, Invivo Therapeutics et al find a lower hanging fruit to spinal cord injury and we could continue to see spin without substance from CEOs to raise stock prices as they operate on fumes. There is a lot of BS out there sadly. But back to topic......
    I am surprised that you are taking such a pessimistic view. Several of the companies that you mention are committing millions of dollars to test their products in spinal cord injury. By the way, these companies exist to make profit and we should not expect them to behave any differently from any other commercial company. Several other disease conditions have similar numbers of affected people as spinal cord injury and have benefited from clinical trials funded by companies. A good example is multiple sclerosis. If you do a search on clinicaltrials.gov, there are 995 studies listed for multiple sclerosis, many of them funded by companies. Shouldn't our goal be to recruit these companies to invest in chronic spinal cord injury research by showing them that they can make a profit in spinal cord injury as well?

    Quote Originally Posted by Fly_Pelican_Fly View Post
    There are obviously different types of investors. Community-based investors want to see efficacy first and foremost. It's not about delaying trials by waiting for a consensus. You can't put the cart before the horse. As you say we'll never get a consensus from many many scientists due to various conflicts of interest. But if you put yourself in my shoes, I cannot hand money over to a scientist that appears a lone wolf either. So I will naturally look for opinions from multiple sources before parting with my cash.
    Do you think that there are many "community-based investors"? I know only a few serious community investors. Regarding consensus, probably the one therapy that does have some consensus amongst scientists is chondroitinase. But despite this consensus, no consortium of community-based investors has stepped up to fund this therapy. Why not?

    Quote Originally Posted by Fly_Pelican_Fly View Post
    As you say, you want to choose the therapy which offers the greatest probability of efficacy before undertaking the mammoth task of running a clinical trial. And just as you say that SCINetChina offers an opportunity to commercial entities to cheaply test their products but could it also be that additional pre-clinical work can offer an opportunity to those responsible for managing the clinical trial network funds to ratify a therapy before a large financial outlay?
    Choosing therapies to test in clinical trials is not easy and is often an exercise in choosing the best of available therapies with incomplete data. Invariably, there are more experiments and tantalizingly better therapies just around the corner. The reason why I keep asking you to choose a therapy is to get you to engage in the task of choosing to illustrate the factors that influence the choice. I hope that the exercise convinced you that therapies that are safe, available, and robustly effective in chronic spinal cord injury are not that abundant. The data is always incomplete and never good enough. The question is whether or not it is worthwhile delaying the clinical trials until you do more studies, wait until anticipated improvements in the therapy becomes available, and use the therapy for acute or subacute spinal cord injury. The other option is to decide that the therapy is safe, that it is the best available therapy, that it has a reasonable chance of succes, and that further animal studies would not improve the clinical trial design significantly. Our decision at ChinaSCINet is to go with the best safe and available therapy for chronic spinal cord injury and test the therapy rigously.

    Every therapy has advantages and disadvantages. Consider umbilical cord blood and lithium. The great advantage of umbilical cord blood and lithium is that these two therapies have been used to treat humans for many years and have a long history of safe use. Cord blood is the richest and youngest post-natal source of stem cells and has even more stem cells than bone marrow. Finally, it can be HLA-matched and obtained from a cord blood bank. We had no trouble getting regulatory approval to take cord blood and lithium to clinical trial. Unfortunately, there is no source of rat umbilical cord blood. Rats do not have enough umbilical cord blood to use as therapy and of course no rat cord blood bank exists. So, investigators usually used human cord blood to treat rats. If we use human cord blood to treat rats, we must use cyclosporin to prevent rejection. Cyclosporin unfortunately suppresses axonal growth as well as the effects of lithium. So, we could not test the combination of umbilical cord blood and lithium in preclinical studies. In 2007, after we completed the observation study, showing that ChinaSCINet can do trials, we decided to go ahead with phase I and II trials of HLA-matched umbilical cord blood and lithium. Our phase II trials are showing promising effects of the treatment, including fiber growth across the injury site and a majority of subjects walking with a rolling cart at 6-12 months. Should we abandon the therapy at this stage, do more animal studies, or go ahead to phase III?

    Now, consider chondroitinase. Dozens of studies suggest that chondroitinase improves recovery of animals when infused intrathecally or injected into partially injured spinal cords. Chondroitinase causes surviving axons to sprout to make more connections and some axons do grow across the injury site. Unfortunately, the enzyme is sensitive to body heat, oxidizes, and loses activity over time at body temperatures, so fresh enzyme must injected every few days. Chondroitinase also comes from proteus vulgaris, one of the most common bacteria that infect the bladder. So, many people have antibodies against the enzyme. Finally, drug is less effective in chronic contusion models and is more effective when applied shortly after injury and in combination with other therapies, including peripheral nerve grafts and lithium. So, ideally, a systematic preclinical program should be carried out to assess combinations of therapies that have reported efficacy of chondroitinase in chronic spinal cord contusion model.

    Several recent studies suggested that some other enzymes break down CSPG better than chondroitinase. For example, one study reported ways to increase and preserve the potency of chondroitinase. Mountney, et la. (2012) reported that sialidase (an enzyme from V. cholera) breaks down CSPG, increases axonal growth and recovery in spinal cord contusion, and is completely stable during a 2-week infusion period. Tauchi, et al. (2012) reported that a human enzyme called ADAMTS-4 not only degrades proteoglycans but breaks down the core proteins of CSPG’s. Local administration of AADAMTS-4 to injured spinal cord injury sites promotes axonal sprouting and regeneration, as well as locomotor recovery. Jakeman, et al. (2011) reported that mice recover much better when a single intraparenchymal injection of chondroitinase to the lumbar enlargement after a mid-thoracic spinal cord contusion. This raises the question whether administration of chondroitinase to the injury site is the best approach and that perhaps chondroitinase should be delivered to the lumbar cord instead. So, should we stop and do experiments to confirm these results in chronic spinal cord contusion models so that we can inject a better form of the chondroitinase, sialidase, or ADAMTS-4 into the lumbar enlargement? Should we wait for Jerry’s CSPG receptor blocker? Should we use Cethrin or ibuprofen?

    Quote Originally Posted by Fly_Pelican_Fly View Post
    Ultimately it comes down to where the money is coming from. If a commercial entity is willing to wholly fund the trial with less pre-clinical data - then that is their choice I suppose. However, if the money is coming from the Community, then you have to be a bit more careful before spending the money.
    All clinical trial networks are funded by a combination of funding sources. For example, ChinaSCINet is funded by a combination of private, industry, government, and other sources. Private donors in Hong Kong have contributed about US$4 million to date. Stemcyte has contributed about $5 million in umbilical cord blood, clinical trial insurance, direct trial cost support, meetings, preclinical treatment development, and other support. One substantially unappreciated source of funding comes from the clinical trial investigators themselves. For example, all our investigators volunteered many thousands of hours of their time and staff for our trials. Many hold grants that support the trials, adding up to millions of dollars. I estimate that I have myself contributed about $50,000 directly and at least $250,000 in travel airfare alone. I have made more than 170 round trips between Newark and Hong Kong since 2001 for ChinaSCINet. Our donors, scientists, principal investigators, and outside scientific advisors participate in major decisions concerning the network.

    Quote Originally Posted by Fly_Pelican_Fly View Post
    What do you mean by "a robust mechanism of action"?
    The mechanism of action is unknown or unproven in most therapies. For example, while there is much data concerning the anti-inflammatory effects and growth factor production by umbilical cord blood mononuclear cells, the mechanisms of action by which these cells improve recovery in spinal cord injury are still not well-understood. In contrast, the mechanism of action by which chondroitinase acts is well-established and “robust”. If you heat up chondroitinase so that it loses its enzyme activity, its effect goes away. Although the mechanisms of action of lithium are more complex, they are also quite well established. Lithium acts by blocking glycogen synthetase kinase III-beta, a ubiquitous enzyme that phosphorylate and inhibit several critical nuclear factors (NFAT, WNT/beta-catenin, etc.). We (Zhu, et al. 2012; Qu, et al., 2012) recently found that lithium stimulates neurogenesis through increasing WNT/beta-catenin and NFAT but suppresses astrogliogenesis by blocking the intracellular messenger STAT3. In my opinion, Ibuprofen and Indomethacin also have “robust” mechanisms of action; they both strongly inhibit cyclooxygenase and RhoA.

    Quote Originally Posted by Fly_Pelican_Fly View Post
    With regards to Ch'ase - well, the fact that one enzyme and its usage has licenses and patents spanning across 3 or 4 commercial entities and that we could still be many years away from a clinical trial for SCI is quite frankly bullshit (pardon my language)!

    As for the safety and "other" studies that Acorda are allegedly undertaking - that's what we call a "party line" in my profession.

    Im sad that with such long-standing careers in the spinal cord injury arena that James Fawcett, Wise Young and Jerry Silver cannot come together and grab the Ch'ase story by the scruff of the neck and drag it through the pipeline by hook or crook. Im sure the Community would get behind such a project. I certainly would.
    I understand your anger and sadness but it is important that people learn from this experience. The fact that the chondroitinase composition of matter and processing patents have been spread out over multiple companies is probably the main reason why few companies have been willing to invest in clinical trials of chondroitinase for spinal cord injury. A composition of matter patent (such as the original patent describing the source of a material or the gene) is sometimes called a “blocking” patent because a company that holds such a patent can block anybody from producing and marketing the material without their permission. A processing patent is less strong because anybody can tweak the process a bit and claim that they have invented a new and different process. A use patent is the weakest of all patents. While the original company may not be able to market chondroitinase to treat spinal cord injury, the company owning the composition-of-matter patent can block another company’s use, production, or marketing of the chondroitinase.

    One way that Acorda can get around a blocking composition of matter patent is to create new (i.e. mutant) forms of chondroitinase that may be less immunogenic and more effective, develop these, produce them, and take them to trial. I use to sit on the board of Acorda but stepped down last year and cannot discuss confidential board information. However, the following is public information. Acorda is a public for-profit commercial company with obligations to their shareholders. In 2010, Acorda held two chondrotinase related U.S. patents (http://www.wikinvest.com/stock/Acord...Chondroitinase), one issued Australian patent, and approximately 40 pending chondroitinase patent applications involving fusion proteins, deletion mutants, and chondroitinase ABCI mutate enzymes, methods of use, and novel chondroitinase compositions. Acorda is investing seriously into developing better forms of chondrointase for clinical trial. I have told Acorda that I would be very happy to take their best form of chondroitinase to clinical trial.

    What can the community do about this situation? If there were a group of deep-pocketed “spinal cord injury community investors”, a consortium can be formed to license the patents from the various commercial entities and then find or fund a company to take the original chondroitinase to clinical trial. This is not an inexpensive proposition and depends on the willingness of the parties to cooperate. There is also a veritable thicket of chondroitinase patents out there. Once the appropriate licenses have been obtained, a production team and facilities must be established and funds must be made available to manufacture and test clinical grade chondroitinase for preclinical and clinical studies. The production process and facilities must be approved by the FDA and detailed studies must be done to ensure that the treatment is safe. Because it is the first time that chondroitinase would have been taken to clinical trial in spinal cord injury, the FDA is likely to require a full set of safety and product studies. Injecting the enzyme into a spinal disc is not the same as injecting it into the spinal cord and the FDA will have much more stringent purity criteria for the spinal cord. If a very good team is formed to do this, I think that chondroitinase can be available for trial in 3 years for about $5 million.

    The other option is to wait, which is what I am doing for the following reasons. First, I believe that the new forms of chondroitinase will be better, more potent, and less immunogenic (hence safer). For example, you really don’t want to be filling fresh enzyme into a pump every week, find out that the drug causes arachnoiditis or meningitis (inflammation of the arachnoid and meninges), or cause autoimmune problems, etc. Second, more animal studies are being done by many laboratories, testing combinations of chondroitinase with other therapies and cell transplants. Each of these studies will help improve the design of a chondroitinase study. Third, within a year, we will know whether or not umbilical cord blood mononuclear cells and lithium improve walking recovery in people with chronic spinal cord injury. If it does, we have a perfect combination therapy to add chondroitinase to. Finally, people are looking at other therapies that may do the same thing or more than chondroitinase. If it turns out that the CSPG receptor blocker, Cethrin, or even Ibuprofen is better, that is great.

    Wise.
    Last edited by Wise Young; 02-12-2013 at 12:05 PM.

  9. #489
    Cripwalk,

    I hope that I did not offend you with my terse comment. I just wanted to remind you and others that ChinaSCINet cannot conduct first-in-human clinical trials on overseas therapies in China. We can do so in Hong Kong and Taiwan, by the way, but not in China. Please read the long missive that I wrote to Pelican. Much of that was intended for you as well.

    Wise.


    Quote Originally Posted by cripwalk View Post
    Dr. Young, no offence, but I wasn't looking for you to tell me what won't help. I would hope that among those with some skin in the game, someone knows where it CAN be started.

    I assume you are basically stating there are issues which prevent SCIChinaNet from conducting the trials. Which is fine (although obviously discouraging). Who CAN conduct the trials? Hopefully the SCI research community is organized enough to know who has the capability. From there, we simply need to create the infrastructure necessary to test.

    I've no doubt that the road is quite long and complex. But I see no way in which some organization wouldnt help.

    1. What do we need?
    2. How can we get it?

    Once those fundamental questions are answered, we can start moving in the right direction. Nothing can change without answering those two questions. Let's start.
    Last edited by Wise Young; 02-12-2013 at 11:44 AM.

  10. #490
    Quote Originally Posted by Wise Young View Post
    I estimate that about 800,000 people in China live with chronic spinal cord injury. Some kind people translate almost all posts in the Cure Forum on this web site (CareCure) into Chinese and many people in China read the posts here avidly. China recently committed 0.5% of their GDP to translational medicine projects. So, China is going to become a very good place to do spinal cord injury clinical trials in the coming years.
    I hope so. Speaking from experience, most participants in the West that take part in a clinical trial as intrusive as an intra-spinal cell transplant are motivated by the probability of functional or sensory return rather than their noble contribution to the scientific field. Maybe I'm meeting and talking to the wrong people.

    I am surprised that you are taking such a pessimistic view. Several of the companies that you mention are committing millions of dollars to test their products in spinal cord injury. By the way, these companies exist to make profit and we should not expect them to behave any differently from any other commercial company. Several other disease conditions have similar numbers of affected people as spinal cord injury and have benefited from clinical trials funded by companies. A good example is multiple sclerosis. If you do a search on clinicaltrials.gov, there are 995 studies listed for multiple sclerosis, many of them funded by companies. Shouldn't our goal be to recruit these companies to invest in chronic spinal cord injury research by showing them that they can make a profit in spinal cord injury as well?
    You have a lot more faith in the commercial model than I do. Probably because you have seen a number of therapies make it through the pipeline successfully (MP, 4-AP). So from your perspective, it's not impossible. Fair enough.

    However, in my personal opinion the market forces for drug development have changed. Money is not flowing as it once was. It's no surprise to see organisations like U2FP, ARM, PatientsLikeMe, FasterCures working at changing the status quo to liberate medical innovation from some of the daunting hurdles that exist right now. (Admittedly, you may not see them as daunting but many others do).

    A question for you - with or without the $20m that CIRM are handing over to Stem Cells Inc, do you think they'll have the funding to get through a Phase III/IV if a Phase II is successful? Where will that money come from? Or do they hope that a Big Pharmaceutical will come along and give them a hand? Or maybe another handout from CIRM? And if so, what are the guarantees that the Big Pharmaceutical or other body wants to continue on the path originally set out for spinal cord injury. Money always comes with strings. Hence my pessimism.


    Do you think that there are many "community-based investors"? I know only a few serious community investors. Regarding consensus, probably the one therapy that does have some consensus amongst scientists is chondroitinase. But despite this consensus, no consortium of community-based investors has stepped up to fund this therapy. Why not?
    This is always going to be a two-way relationship. These days large philanthropic investors want to see business plans, milestones and returns on investment (not financial) - just like any VC. These people do exist. However, it's up to researchers and the Community to pitch these projects to them in a compelling manner. Otherwise, we sit and wait for small and medium-sized biotechs struggle along looking to work the markets to raise funds to translate therapies to the bedside. Putting my faith in these small entities to facilitate a Cure for chronic spinal cord injury makes me very very nervous.

    If the murky patent/license issues could be solved, I think a consortium to fund Ch'ase would be very do-able. As you say, the situation is a lesson that we should all learn from. If you're breaking things down to basics, intellectual property always comes second to humanity. I'd hope you would agree with that.

    I am glad that SCINetChina is ready to take Ch'ase to trial. Let's see where ISRT take us next for this particular line.

    I hope that the exercise convinced you that therapies that are safe, available, and robustly effective in chronic spinal cord injury are not that abundant. The data is always incomplete and never good enough.
    I dont think this particular exercise has convinced me of that - but rather I had already realised that.


    Unfortunately, there is no source of rat umbilical cord blood. Rats do not have enough umbilical cord blood to use as therapy and of course no rat cord blood bank exists. So, investigators usually used human cord blood to treat rats. If we use human cord blood to treat rats, we must use cyclosporin to prevent rejection. Cyclosporin unfortunately suppresses axonal growth as well as the effects of lithium. So, we could not test the combination of umbilical cord blood and lithium in preclinical studies.
    This is good information and a good example of why some pre-clinical animal studies are not always possible. Thankyou.

    I suppose some researchers will say, why not try in a larger animal model whereby umbilical cord blood can be sourced? Therefore conflict will no doubt come with the territory.

    We've seen similar conflict between researchers on the need to perform non-human primate studies before human trials.


    In 2007, after we completed the observation study, showing that ChinaSCINet can do trials, we decided to go ahead with phase I and II trials of HLA-matched umbilical cord blood and lithium. Our phase II trials are showing promising effects of the treatment, including fiber growth across the injury site and a majority of subjects walking with a rolling cart at 6-12 months. Should we abandon the therapy at this stage, do more animal studies, or go ahead to phase III?
    Does the Chinese FDA stipulate a minimum duration between completion of Phase II and start of a Phase III?

    I find it hard to get my head around moving to a Phase III without any evidence of motor or sensory recovery in Phase II. (Although I agree, we have to wait until we see the 12 month data before making the assumption that there will be no motor or sensory).

    FYI If you decide to move forward to a Phase III solely based on increased CPG-activated walking - then I personally wouldn't agree with that as I do not consider this as an appropriate outcome. I regard stepping and functional walking as two very different things. I dont say this flippantly but rather from my first hand experience. It's not an outcome I feel is synergistic with CST regeneration. But that's just my opinion and I have the same opinion of epidural stim btw. I dont like the term "locomotor recovery" as it has elements of grey.

    Hopefully we will see motor and sensory scores change in the Phase II data and this point will be moot

    Now, consider chondroitinase. Dozens of studies suggest that chondroitinase improves recovery of animals when infused intrathecally or injected into partially injured spinal cords. Chondroitinase causes surviving axons to sprout to make more connections and some axons do grow across the injury site. Unfortunately, the enzyme is sensitive to body heat, oxidizes, and loses activity over time at body temperatures, so fresh enzyme must injected every few days. Chondroitinase also comes from proteus vulgaris, one of the most common bacteria that infect the bladder. So, many people have antibodies against the enzyme. Finally, drug is less effective in chronic contusion models and is more effective when applied shortly after injury and in combination with other therapies, including peripheral nerve grafts and lithium. So, ideally, a systematic preclinical program should be carried out to assess combinations of therapies that have reported efficacy of chondroitinase in chronic spinal cord contusion model.

    Several recent studies suggested that some other enzymes break down CSPG better than chondroitinase. For example, one study reported ways to increase and preserve the potency of chondroitinase. Mountney, et la. (2012) reported that sialidase (an enzyme from V. cholera) breaks down CSPG, increases axonal growth and recovery in spinal cord contusion, and is completely stable during a 2-week infusion period. Tauchi, et al. (2012) reported that a human enzyme called ADAMTS-4 not only degrades proteoglycans but breaks down the core proteins of CSPG’s. Local administration of AADAMTS-4 to injured spinal cord injury sites promotes axonal sprouting and regeneration, as well as locomotor recovery. Jakeman, et al. (2011) reported that mice recover much better when a single intraparenchymal injection of chondroitinase to the lumbar enlargement after a mid-thoracic spinal cord contusion. This raises the question whether administration of chondroitinase to the injury site is the best approach and that perhaps chondroitinase should be delivered to the lumbar cord instead. So, should we stop and do experiments to confirm these results in chronic spinal cord contusion models so that we can inject a better form of the chondroitinase, sialidase, or ADAMTS-4 into the lumbar enlargement? Should we wait for Jerry’s CSPG receptor blocker? Should we use Cethrin or ibuprofen?
    These are excellent questions Wise. Is Acorda actually considering these things or are we expecting someone else to do it? If Ch'ase or any other line of science is indeed stuck in "purgatory" it's logical to look for alternatives. Now, the question from us is who all is discussing these alternatives in terms of translation and pre-clinical strategies? Or are we just shooting the breeze and waiting for some commercial entity to come along and lead this?

    The mechanism of action is unknown or unproven in most therapies. For example, while there is much data concerning the anti-inflammatory effects and growth factor production by umbilical cord blood mononuclear cells, the mechanisms of action by which these cells improve recovery in spinal cord injury are still not well-understood. In contrast, the mechanism of action by which chondroitinase acts is well-established and “robust”. If you heat up chondroitinase so that it loses its enzyme activity, its effect goes away. Although the mechanisms of action of lithium are more complex, they are also quite well established. Lithium acts by blocking glycogen synthetase kinase III-beta, a ubiquitous enzyme that phosphorylate and inhibit several critical nuclear factors (NFAT, WNT/beta-catenin, etc.). We (Zhu, et al. 2012; Qu, et al., 2012) recently found that lithium stimulates neurogenesis through increasing WNT/beta-catenin and NFAT but suppresses astrogliogenesis by blocking the intracellular messenger STAT3. In my opinion, Ibuprofen and Indomethacin also have “robust” mechanisms of action; they both strongly inhibit cyclooxygenase and RhoA.
    Thanks for the explanation. Very interesting. I assume that the mechanism of action is always a moving target as the basic science surges forward.

    I understand your anger and sadness but it is important that people learn from this experience. The fact that the chondroitinase composition of matter and processing patents have been spread out over multiple companies is probably the main reason why few companies have been willing to invest in clinical trials of chondroitinase for spinal cord injury. A composition of matter patent (such as the original patent describing the source of a material or the gene) is sometimes called a “blocking” patent because a company that holds such a patent can block anybody from producing and marketing the material without their permission. A processing patent is less strong because anybody can tweak the process a bit and claim that they have invented a new and different process. A use patent is the weakest of all patents. While the original company may not be able to market chondroitinase to treat spinal cord injury, the company owning the composition-of-matter patent can block another company’s use, production, or marketing of the chondroitinase.

    One way that Acorda can get around a blocking composition of matter patent is to create new (i.e. mutant) forms of chondroitinase that may be less immunogenic and more effective, develop these, produce them, and take them to trial. I use to sit on the board of Acorda but stepped down last year and cannot discuss confidential board information. However, the following is public information. Acorda is a public for-profit commercial company with obligations to their shareholders. In 2010, Acorda held two chondrotinase related U.S. patents (http://www.wikinvest.com/stock/Acord...Chondroitinase), one issued Australian patent, and approximately 40 pending chondroitinase patent applications involving fusion proteins, deletion mutants, and chondroitinase ABCI mutate enzymes, methods of use, and novel chondroitinase compositions. Acorda is investing seriously into developing better forms of chondrointase for clinical trial. I have told Acorda that I would be very happy to take their best form of chondroitinase to clinical trial.

    What can the community do about this situation? If there were a group of deep-pocketed “spinal cord injury community investors”, a consortium can be formed to license the patents from the various commercial entities and then find or fund a company to take the original chondroitinase to clinical trial. This is not an inexpensive proposition and depends on the willingness of the parties to cooperate. There is also a veritable thicket of chondroitinase patents out there. Once the appropriate licenses have been obtained, a production team and facilities must be established and funds must be made available to manufacture and test clinical grade chondroitinase for preclinical and clinical studies. The production process and facilities must be approved by the FDA and detailed studies must be done to ensure that the treatment is safe. Because it is the first time that chondroitinase would have been taken to clinical trial in spinal cord injury, the FDA is likely to require a full set of safety and product studies. Injecting the enzyme into a spinal disc is not the same as injecting it into the spinal cord and the FDA will have much more stringent purity criteria for the spinal cord. If a very good team is formed to do this, I think that chondroitinase can be available for trial in 3 years for about $5 million.

    The other option is to wait, which is what I am doing for the following reasons. First, I believe that the new forms of chondroitinase will be better, more potent, and less immunogenic (hence safer). For example, you really don’t want to be filling fresh enzyme into a pump every week, find out that the drug causes arachnoiditis or meningitis (inflammation of the arachnoid and meninges), or cause autoimmune problems, etc. Second, more animal studies are being done by many laboratories, testing combinations of chondroitinase with other therapies and cell transplants. Each of these studies will help improve the design of a chondroitinase study. Third, within a year, we will know whether or not umbilical cord blood mononuclear cells and lithium improve walking recovery in people with chronic spinal cord injury. If it does, we have a perfect combination therapy to add chondroitinase to. Finally, people are looking at other therapies that may do the same thing or more than chondroitinase. If it turns out that the CSPG receptor blocker, Cethrin, or even Ibuprofen is better, that is great.

    Wise.
    Wise, do you know for a fact that the Seigakaku enzyme will not meet FDA purity criteria for the cord?

    Thanks for explaining Ch'ase patent situation. I agree there are lessons to be learned for commercial entities, community members and researchers in this case. I hope we do not see more cases like this in the future.

    Cheers
    Fly Pelican Fly

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