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    You are here : Home » MS Research News » Drugs » ATX-MS-1467

    ATX-MS-1467

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    MS patients in Bristol 'hopeful' as drug trial launched

    Apitope LogoA treatment to halt the progress of multiple sclerosis could become a reality for sufferers after the launch of a major trial in Bristol.

    The new drug developed in the city has been found to stop the immune system's attack on the covering of the nerve cells. Unlike other treatments the drug does not seem to prevent the immune system fighting viruses.

    It has been developed by Bristol University spin-off company, Apitope, who believe it could prevent relapses and stop further degeneration as a result of the condition.

    A study of how the treatment works in 40 people has now been launched and patients are being recruited for the trial.

    Multiple sclerosis (MS) affects the central nervous system, which controls movement and balance. In people with the neurological condition the protective covering of the nerve fibres – called the myelin sheath – becomes damaged and disrupts the way messages are sent to the rest of the body.

    It can leave people with a range of problems including numbness, pain, a tingling sensation, issues with vision and fatigue. There are different types of MS. People with the relapsing form of the condition may experience symptoms for a period of time before they subside. Relapses can last days, weeks or months. In secondary progressive MS, symptoms will gradually worsen, with or without relapses.

    A study of six people with this form of MS has already been carried out in Bristol. The latest research project is being led by the National Hospital for Neurology and Neurosurgery in London, which is recruiting people with the relapsing form of MS to study how the treatment, currently known as ATX-MS-1467, works.

    It is made of man-made peptides that mimic natural ones and is injected under the skin once a fortnight.

    As previously reported in the Evening Post, part of Apitope's operation is now based in Belgium, but the scientific base of the firm remains in Bristol.

    The company is also working on therapies for other auto immune diseases – where the body's immune system attacks itself – and hopes to move on to clinical trials for these potential treatments within 18 to 24 months.

    Apitope chief executive Keith Martin said: "It is a very interesting and exciting approach to the treatment of auto immune diseases generally but also MS.

    "The important thing is that what we are doing is targeting our approach to the part of the immune system that is going wrong and not touching any other part, which is a significant improvement.

    "The pre-clinical data we have got suggests we can significantly prevent relapses by 80 to 90 per cent. What we need to be able to do now is demonstrate in the clinic and in patients that that is the case.

    "We are very excited about the potential to treat the disease, not just to prevent relapses, but to treat the underlying cause."

    Another clinical trial will follow the current one, which is being carried out at sites across the country, including Oxford and Plymouth.

    Source: thisisbristol (c) Northcliffe Media 2011 (31/03/11)

    Apitope starts new ATX-MS-1467 clinical trial

    Apitope LogoApitope, the European biotech company developing therapeutic peptides to treat autoimmune and allergic diseases, today announced the start of its second Phase I clinical trial of ATX-MS-1467, in patients with Multiple Sclerosis (MS).

    MS is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, disabling neurological disease in young adults, with most sufferers developing the disease between the ages of 20 and 40. The World Health Organization estimates that up to 2.5 million people suffer from MS worldwide with women affected 1.8 times more frequently than men.

    ATX-MS-1467, an investigational peptide-based therapeutic derived from Apitope’s proprietary technology platform, has already completed successfully a Phase I clinical trial in six patients with secondary progressive MS (SPMS). This new Phase I study aims to build on the results from the initial study and investigates safety and proof-of-principle of ATX-MS-1467 in 40 patients with relapsing forms of MS (RMS).

    The clinical trial will be carried out at up to ten sites across the UK.

    Dr. Jeremy Chataway, Chief Investigator for trials, of the National Hospital for Neurology and Neurosurgery in London commented:

    “I am excited to work with Apitope on the clinical trials of ATX-MS-1467. This has the potential to serve as a treatment option for patients with multiple sclerosis.”

    The primary end point of the trial is safety and tolerability but secondary end points are designed to provide proof of principle. ATX-MS-1467 will be administered either intra-dermally or sub-cutaneously once every two weeks for 16 weeks, with a further 24 weeks of follow up.

    Apitope is developing ATX-MS-1467 with Merck Serono, one of the leading pharmaceutical companies in the treatment of MS. Under the terms of the agreement between the two companies, Apitope is responsible for all Phase I development of ATX-MS-1467. Merck Serono will take over development of the compound at the beginning of Phase II clinical trials.

    Dr. Keith Martin, CEO of Apitope added:

    “ATX-MS-1467 is the first therapeutic developed from Apitope’s innovative technology platform and this trial builds on the positive results in our first study.”

    About ATX-MS-1467

    ATX-MS-1467 consists of four synthetic peptides that mimic naturally occurring peptides derived from human Myelin Basic Protein (MBP), a key autoantigen in multiple sclerosis. ATX-MS-1467 has been designed from naturally occurring MBP fragments and is intended to selectively inhibit the immune system's harmful attack on the protective myelin sheath surrounding the nervous cells while preserving the normal immune response to any harmful antigens, such as infections.

    Source: Apitope International N.V. (18/05/10)

    Apitope announces licensing agreement for ATX-MS-1467 for Multiple Sclerosis

    Apitope Logo

    Apitope, a Bristol University spinout company that is looking at a potential therapy for people with Multiple Sclerosis (MS), has announced a licensing agreement for up to €154 million in upfront, development and commercialisation milestone payments, in addition to royalties, to develop its peptide therapeutic for the treatment of MS.

    Apitope founded by Professor David Wraith in the University’s Department of Cellular and Molecular Medicine, has granted exclusive worldwide rights to Merck Serono to develop and commercialise Apitope’s peptide therapeutic product, ATX-MS-1467. Apitope is eligible to receive up to €154 million in upfront, development and commercialisation milestone payments, in addition to royalties on the net sales of products resulting from the collaboration.

    Dr Neil Bradshaw, Director of Enterprise at the University, said: “The agreement marks a significant step forward for Apitope and is a milestone for enterprise at the University, especially in terms of our involvement in helping to accelerate the technology’s development from the laboratory into the market place.

    “It is also further evidence of the significant economic impact of research conducted here at Bristol.”

    ATX-MS-1467 is a novel peptide-based therapeutic derived from Apitope’s proprietary technology platform. Under the terms of the agreement, Apitope will receive an upfront payment and will initially be responsible for the further development of ATX-MS-1467, for which Merck Serono will fund the costs. Merck Serono will be responsible for all development activities from the beginning of Phase II clinical trials. The company will also provide committed funding to Apitope for research on other novel therapeutic peptides for the treatment of MS.

    This peptide therapeutic has completed an initial clinical study in patients with MS. It is designed to induce immunological tolerance of the body’s T-cells to key autoantigens involved in the pathogenesis of MS.

    Dr Keith Martin, CEO of Apitope, said: “We are very pleased that ATX-MS-1467 has attracted a major pharmaceutical partner such as Merck Serono with extensive experience and leadership in the development of therapies for MS.

    “We view this collaboration as confirmation of Apitope's ability to develop early-stage first-in-class therapies for autoimmune diseases. In addition to continuing to build our in-house diagnostic platform in MS, we look forward to progressing ATX-MS-1467 with Merck Serono.”

    Professor Wraith said: “This collaboration with Merck Serono greatly upholds the approach that we have developed for treatment of devastating autoimmune conditions such as Multiple Sclerosis. We look forward to working with one of the leaders in the field of MS therapy.”

    ATX-MS-1467 consists of four short peptides that are derived from myelin basic protein, a key autoantigen in MS. It is specifically designed to target up to 70 per cent of MS patients who have a specific genetic profile.

    Apitope operates from the SETsquared Business Acceleration Centre at the University of Bristol where they have benefited from the extensive support activities of Nick Sturge and his team.  Nick Sturge, Centre Director, said: “This is an exciting boost for Bristol as it demonstrates the world-leading biotech research and development that is being carried out here. Combined with Apitope’s recent €10 million investment, this deal confirms the positive impact that we can have in helping businesses to grow.”

    Source: University Of Bristol © 2002-2009 University of Bristol (17/03/09)

    Makers of potential Multiple Sclerosis vaccine, forced to quit UK

    Apitope Logo

    Apitope Technology Ltd is a biopharmaceutical company that specialises in developing treatments for allergy and autoimmune diseases.

    Formed as a spin-out company in 2002, Apitope announced in 2007 it had developed a vaccine designed to halt multiple sclerosis in its tracks. Cherry Lewis talked to Professor David Wraith, founder and Chief Scientific Officer, about the vaccine and his struggle to get funding for clinical trials.

    David: About ten years ago, Geoff Watts from the BBC came to talk to me about autoimmunity for his Medicine Now programme that went out on Radio 4. One of the things we discussed was a new discovery we'd made that was a way of developing vaccines for treating autoimmune diseases and allergies, so-called therapeutic vaccines. They are based on the concept that has been well known for almost a century, namely allergic desensitisation, where people are given injections of the allergen that causes the reaction.

    Cherry: Is that the same principle as a vaccine for smallpox?
    David: Not really. With the smallpox vaccine, you're giving an attenuated form of the infectious agent which boosts the immune system without actually causing the disease. What we're talking about here are disorders of the immune system which respond to innocuous things such as house dust and pollen that cause an allergy, or proteins in your body that cause autoimmune diseases. In multiple sclerosis, for example, which is an autoimmune disease, the immune system attacks the myelin sheath around nerve cells - the insulating layer that allows the cells to conduct electrical signals. This causes the nerves to function poorly or die and the symptoms of MS to appear. In these 'hypersensitivity' diseases, the immune system is over-responding. We have developed vaccines that can control the immune response, based on the antigens to which the immune system is responding.

    Cherry: So how do you activate this desensitisation? 
    David: There is a set of cells in the body called T-lymphocytes (T cells). Now we know that T cells respond to very small fragments (peptides) of whatever is causing the allergy or the autoimmune disease. We have developed a method of identifying and administering certain peptides so that instead of causing damage, they actually suppress the immune reaction.

    Cherry: How very exciting. What happened next?
    David: Well, I was talking to Geoff Watts about things and explaining how the biggest challenge we now faced was taking this to the next step, but that it was proving difficult to find funding. Although we have some very large and highly successful venture capital companies in the UK, none of them are funding medical development at an early stage.

    Cherry: What's the reason for that? Is it too high risk?
    David: And it's too long term. But what happened to us was very fortunate.

    An 'angel' investor heard about the programme and offered to help us.

    He gave us the money to develop our approach to the point where we could take it into clinical trials.

    Cherry: That's a powerful argument in favour of talking to the media.
    David: Yes, we had a really great discussion and Geoff got very excited about what we had discovered. I'm sure his enthusiasm helped convey the significance of this work. So the business angel provided enough funds for us to develop the vaccine and do what is called 'tox testing' to prove it's safe. You have to prove that the vaccine is not toxic in animals by giving them doses 500 times higher than you would give humans. When this proved successful we were ready to take it to clinical trials, but then we faced another funding hurdle.

    For more than two years we discussed funding with the DTI but that eventually fell through for various reasons. I found the whole business incredibly frustrating. Eventually we were awarded a University Translation Award by the Wellcome Trust and that provided close on £1 million for the first clinical trial in humans. This was set up in 2007 under Professor Neil Scolding in the Department of Neurology at Frenchay Hospital here in Bristol. It was what we call a Phase I safety study.

    The aim is to prove that the vaccine can be given safely to humans and there are no adverse effects. Six MS patients at quite an advanced stage of the disease were given our vaccine, memorably called ATX-MS-1467. At the end of the trial, no safety issues had been identified and one patient even showed remarkable improve-ment in her eyesight. I think it's fair to say that the trial was highly successful.

    Cherry: So where are things now?
    David: We are now ready to develop the vaccine further and take it to full clinical trials, but we've had to raise a lot more money. Dr Keith Martin, who's the CEO of Apitope, and I have spent the last two years going through endless rounds of talking to funding agencies, venture capital companies, etc, trying to raise the funds, but sadly we haven't been able to raise any funds in the UK. We had various European investors - from Sweden, Germany, Switzerland, France - all willing to join a syndicate to fund our next development. But in order for us to stay in this country, they needed an investor in the UK to take the lead.

    Cherry: And you couldn't find one?
    David: We couldn't find one. There isn't a biomedical venture capital company in the UK who doesn't know about us, who hasn't looked at our business plan. Finally we were introduced to a group of Belgium- and Luxembourg-based investors who were very interested and we have just signed a deal with them worth  ?10 million (£7.7 million). Apitope will now move to Belgium, locating its head office in Diepenbeek, and be called Apitope International NV. The current UK-based Apitope will stay in the UK and become a wholly owned subsidiary of the Belgian company. Among the funders is the University of Hasselt, which will provide support in exchange for an equity stake and will join forces with Apitope by providing its own research on diagnostics.

    Cherry: How do you feel about that?
    David: Our decision to move out of the UK highlights the difficulties UK biotech companies have in raising support, even before the recent financial crisis, especially when it comes to bridging the gap between academic-funded research and advanced clinical studies, where the outcomes are a safer bet. Nevertheless, we have now got the funding so the trials will go ahead and ultimately this will lead to safer and more effective treatments for people with MS.

    Helen Yates, Chief Executive of the Multiple Sclerosis Resource Centre (MSRC) said, "Whilst this work is very encouraging in terms of its potential to help people affected by MS, it is a damning indictment on the funding streams in the UK that it is such a struggle for people like Professor Wraith to gain funding to translate academic knowledge into advanced clinical trials.  Nevertheless the vaccine looks to hold great hope for everyone in the MS community."

    Source: University Of Bristol and MSRC (11/03/09)

    Novel peptide therapeutic, ATX-MS-1467 Multiple Sclerosis treatment, licensing agreement announced

    Apitope logo

    Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today the signature of a research, development and commercialization agreement with Apitope Technology (Bristol) Ltd., a wholly owned subsidiary of Apitope International NV. Under this agreement, Apitope has granted exclusive worldwide rights to Merck Serono to develop and commercialize Apitope's product ATX-MS-1467. This peptide therapeutic has completed an initial clinical study in patients with multiple sclerosis (MS). It is designed to induce immunological tolerance of the body's T-cells to key autoantigens involved in the pathogenesis of MS.

    ATX-MS-1467 is a novel peptide-based therapeutic derived from Apitope's proprietary technology platform. Under the terms of the agreement, Apitope will receive an upfront payment and will initially be responsible for the further development of ATX-MS-1467, for which Merck Serono will fund the costs. Merck Serono will be responsible for all development activities from the beginning of Phase II clinical trials. Merck Serono will also provide committed funding to Apitope for research on other novel therapeutic peptides for the treatment of MS.

    Under the terms of the agreement, Apitope is eligible to receive up to EUR 154 million in upfront, development and commercialization milestone payments, in addition to royalties on the net sales of products resulting from the collaboration.

    "This partnership with Apitope strengthens our position as a leader in the field of innovative research and development in multiple sclerosis," said Bernhard Kirschbaum, Executive Vice President Research and Development at Merck Serono. "ATX-MS-1467 represents a novel, targeted approach and may have the potential to complement existing MS drugs by offering a novel mode of action. By applying our existing stratified medicine approaches, we will also identify those MS patients who should benefit most from this potential treatment."

    "We are very pleased that ATX-MS-1467 has attracted a major pharmaceutical partner such as Merck Serono with extensive experience and leadership in the development of therapies for multiple sclerosis," said Keith Martin, CEO of Apitope. "We view this collaboration as confirmation of Apitope's ability to develop early-stage first-in-class therapies for autoimmune diseases. In addition to continuing to build our in-house diagnostic platform in MS, we look forward to progressing ATX-MS-1467 with Merck Serono."

    ATX-MS-1467 consists of four short peptides that are derived from myelin basic protein, a key autoantigen in MS. It is specifically designed to target up to 70% of MS patients who have a specific genetic profile.

    Source: Merck Serono (13/01/09)

    Proof of principle clinical trial of ATX-MS-1467 for Multiple Sclerosis

    Apitope logo

    Apitope International NV, the autoimmune peptide therapy company, and Fast Forward, LLC, the National Multiple Sclerosis Society’s subsidiary devoted to bridging the gap between research and drug development, today announced a partnership to support Apitope’s proof of principle clinical trial of ATX-MS-1467. This peptide therapeutic vaccine is designed to target and prevent the abnormal pathological immune response in multiple sclerosis (MS).

    The agreement with Apitope is the first in a series of partnerships between Fast Forward and early stage biotechnology companies. “We are pleased to partner with Apitope to accelerate the development of innovative therapies for MS,” said Dr. Timothy Coetzee, Fast Forward’s Executive Director. “ATX-MS-1467 has the potential to redirect the immune system in MS which is essential to minimizing the damage to the nervous system in this highly debilitating disease.” Adds Dr. Coetzee “We are concerned about the small number of therapies in development for MS relative to other diseases and the impact that the current economic climate will have on development of new treatments for people with MS. Fast Forward is committed to reversing this trend by deploying its resources to spur development of innovative MS therapies and bring them to market as quickly as possible.”

    “Ironically, it was a fellowship from the US National MS Society that was the catalyst to devoting my life to MS research,” said Professor David Wraith, chief scientific officer and founder of Aptitope. “It is with great pride that I, together with Apitope, come back to a partnership with the Society for a potentially life altering therapy in people with multiple sclerosis.”

    The National Multiple Sclerosis Society funds research in a range of scientific areas including immune mechanisms, genetics, nerve regeneration, and symptom managements. The agreement with Apitope is a part of the Society’s Fast Forward initiative through which Fast Forward will partner with early stage biotechnology and pharmaceutical companies to develop treatments, diagnostics, medical devices, and related technologies to treat, reverse, and ultimately cure MS. Under terms of the agreement, Fast Forward will provide Apitope with up to $1 million toward the Proof of Principle clinical trial of ATX-MS-1467. In addition, Fast Forward will receive warrants for purchase of shares in the company.

    “The National MS Society’s support provides a strong independent validation of our approach to the treatment of MS,” said Dr. Keith Martin, CEO of Apitope. “We are very grateful for this funding from a world leader in MS research.”

    Following more than 15 years of research by Prof Wraith and his team, ATX-MS-1467, which consists of four short peptides derived from myelin basic protein, a key autoantigen in MS, was taken into clinical trials in 2006. The therapy is a highly selective treatment for MS targeting the major histocompatability complex (MHC) class II molecule to regulate T cell activity. The company recently announced results from the initial clinical trial in secondary progressive MS patients, which indicated that the drug was safe and well tolerated with promising early evidence of efficacy.

    Source: Pharmalive ©2008 Canon Communications Pharmaceutical Media Group (24/12/08)

    ATX-MS-1467 - Positive Immunological Data In Multiple Sclerosis
    Final Phase I/IIa data shows safety and tolerability, plus efficacy.

    Apitope Technology (Bristol) Ltd., the developer of peptide-based therapies for autoimmune diseases and allergy, announces today final results of a Phase I/IIa clinical trial of ATX-MS-1467 to treat Multiple Sclerosis (MS). Immunological analyses showed a significant down regulation of the T-cell response to the autoantigen (myelin basic protein) whilst the important normal immune responses were left unchanged.

    As previously announced, the therapeutic peptide vaccine was found to be safe and well tolerated in Secondary Progressive Multiple Sclerosis (SPMS) patients with no treatment related serious adverse or adverse events reported.

    Although the trial was not designed to show efficacy, there is preliminary evidence of a positive clinical response to ATX-MS-1467 in two of the six patients. One patient with optic neuritis resulting from the neuroinflammatory process involved in MS continues to demonstrate a clinically significant improvement in visual acuity post treatment. Additionally, a second patient has shown improvement in the Gd-enhanced MRI scan indicating a reduction in neuroinflammatory processes in the brain.

    "We are extremely pleased with these results in secondary progressive MS patients. The peptides are very well tolerated in this patient group", said Dr Keith Martin, CEO of Apitope. "Also, we now have good indicators that these peptides may be a significant improvement on current therapies available to patients with MS, a disease with huge unmet medical need."

    The immunological analyses showed a reduction of up to 40% in myelin basic protein-induced T-cell proliferation one month after the course of treatment with ATX-MS-1467 while the T-cell response to PPD (a constituent of the BCG vaccine) was unchanged.

    "These preliminary clinical and immunological data are very encouraging and support the preclinical and scientific evidence on which this product is based", said Professor David Wraith, CSO of Apitope and Professor of Experimental Pathology at the University of Bristol.

    Apitope expects to begin a final Phase II trial of ATX-MS-1467 before the fourth quarter this year with full results expected within 24 months of the trial start. This trial will be designed as a double-blind placebo controlled study in MS patients with the more frequently encountered relapsing remitting form of MS.

    Along with development of ATX-MS-1467 Apitope is continuing development of a diagnostic blood test for MS and expects to complete the clinical validation in patients with all forms of MS in the next 12 months.

    ATX-MS-1467, is a vaccine containing four peptides derived from human myelin basic protein that targets the major histocompatibility complex (MHC) class II molecule and has been specifically designed and developed to treat MS patients. The recently completed ATX-MS-1467 Phase I/IIa open label trial was designed as a dose escalation study to assess the safety and tolerability with all six patients receiving five escalating doses given 7 to 14 days apart of 25, 50, 100, 400 and 800 followed by a repeat of the 800 microgram dose.

    ABOUT APITOPE TECHNOLOGY (BRISTOL) LTD

    Apitope is a biopharmaceutical company engaged in the research and development of treatments for allergy and autoimmune diseases. The Company is developing novel advantaged products representing major advances in therapy and addressing critical unmet needs that can revolutionise the treatment of chronic autoimmune and allergic disorders. Apitope was established at the University of Bristol in January 2002 by Professor David Wraith and initially funded by Mr Richard Daniels.

    The company has a patented platform technology for the design of peptide therapeutics (ApitopesTM) to treat autoimmune and allergic diseases. This novel Apitope technology is based on established scientific evidence showing that soluble, synthetic peptides can reinstate tolerance and attenuate pathological immune responses. The therapy is specifically designed from naturally occurring antigenic proteins to selectively inhibit the immune system's harmful attack on the body while preserving the normal immune response to harmful antigens, such as infections. The unique Apitope peptides function as tolerogens, exerting their therapeutic effect via an highly selective immune re-balancing process that, in pre-clinical studies, has been linked to the induction of IL-10 secreting regulatory T cells. Behaving as Antigen Processing Independent epiTOPES (ApitopesTM), the peptides induce tolerance to abnormal immune responses.

    The company, initially, is testing the safety and efficacy of ApitopesTM in multiple sclerosis (MS) patients. Its lead product is ATX-MS-1467, a peptide vaccine, which up regulates T cells through the major histocompatibility complex (MHC) class II receptor. The vaccine is potentially a disease-modifying therapy specifically designed from a naturally occurring antigenic protein to selectively inhibit the immune system's harmful attack on the nervous system. The normal immune response to infection is preserved. The ATX-MS-1467 vaccine is an equal parts mixture of four soluble, synthetic peptides (ApitopesTM). The company plans to develop ApitopesTM for other chronic diseases including Type I diabetes, rheumatoid arthritis and the common allergies.

    * Apitope's Phase I/IIa protocol for MS was approved by the MHRA in February 2007

    * The Company is also developing an MS diagnostic, which is based on its proprietary technology, with a predicted launch date of Q4, 2009

    * A peptide vaccine to prevent Factor VIII intolerance is expected to enter clinical trials in late 2008.

    Source: Apitope Technology (Bristol) Ltd (31/01/08)

    Apitope vaccine may stop Multiple Sclerosis in its tracks
    UK biopharmaceutical firm Apitope has developed a vaccine that could halt multiple sclerosis in its relentless march to destroy nerve cells.

    The drug, called ATX-MS-1467, has now been tested in humans for the first time - in six Secondary Progressive Multiple Sclerosis (SPMS) patients in a Phase I/IIa trial - and the results so far are encouraging. No safety issues have been unearthed and one patient also showed good clinical improvement in their symptoms.

    The immune system attacks proteins it sees as dangerous and helps protect us from a myriad of pathogens. Occassionally these attacks can be devastating if it mistakenly sees proteins in our own body as dangerous and sets about destroying them. This autoimmune reaction leads to numerous diseases, such as Type I diabetes and Multiple Sclerosis.

    In the case of MS, the immune system wipes out the myelin sheath around nerve cells - an insulating layer that allows the cells to effectively conduct electrical signals. This causes the nerves to die and the symptoms of MS to appear, including visual problems, weakness, difficulties with balance and speech, severe fatigue, pain, impaired mobility and often disability.

    According to the MS International Federation, around 2.5 million people suffer from the incurable, progressive disease.

    Current therapies aim to reduce the inflammation around the nerve cells to offset further damage or, alternatively, to suppress the immune system. However, these broad approaches also suffer from significant side-effects such as an increased susceptibility to infections and a greater risk of cancer.

    Apitope has taken a different approach with their peptide based vaccine that seeks to retune the immune system so it no longer overreacts to proteins in the myelin sheath. One of these proteins in called myelin basic protein (MBP). This protein is chopped up inside a cell into different peptide strips. Some of these strips or epitopes then bind to a protein called major histocompatability complex (MHC) class II and are carried to the surface of the cell where they are presented to the immune system.

    Dr Keith Martin, CEO of Apitope, explained to DrugResearcher.com that if certain danger signals are present, then the MBP peptide epitopes can 'switch on' T cells and cause an inflammatory response that damages the myelin.

    However, and this is where the Apitope vaccine comes in, if the epitope is presented to the immune system in the absence of these danger signals, a different subset of T cells are switched on (called regulatory T cells) and instead of causing damage, these can suppress the immune system reaction to the epitope in question and thus make it more 'tolerant' to myelin. They do this through producing interleukin-10 (IL-10), an anti-inflammatory cytokine.

    One key part of this is to ensure the vaccine is only injected at sites where there are no danger signals. So, the clinicians doing the trial inject the drug in the periphery of the body and the regulatory T cells produced can then travel to the central nervous system (CNS) and begin to retune the immune system there.

    One problem remained however. Not all fragments of MBP are capable of causing the immune system to become tolerant to the protein. For example, the MBP peptide made up of amino acids 89 to 101 can induce an immune response both in terms of priming for T cell reactivity and inducing autoimmune encephalomyelitis (EAE) - the commonly used animal model for MS.

    However, the same peptide does not induce tolerance. So which peptides do and which don't? After much research, David Wraith, a Professor of Experimental Pathology at the University of Bristol, found the answer. He discovered that only peptide fragments that are the right size and shape to be presented to the immune system without further processing can go on to induce tolerance. The discovery led to the spin out of the company and also gave it its name and the name of this class of potential drug - Antigen Processing Independent epiTOPES or Apitopes. Prof. Wraith became the chief scientific officer at Apitope.

    First, the team use bioinformatics to design peptides that will bind to MHC strongly and, crucially, ones that can also adopt the right shape to bind.

    "If the peptide isn't the right shape, then it won't trigger a response," said Martin. "If they are in the right conformation, they won't require processing [and therefore will induce immune system tolerance]."

    He added that in the case of MS, Apitope identified five different peptide epitopes that looked like they would work and then proceeded to test them in a number of in vitro assays. After that process, four remained and these are what make up ATX-MS-1467. The advantage to having four is that there are different subtypes of MHC class II molecules and these four can bind to different ones, such that the "vast majority" of MS patients will be theoretically responsive to the drug.

    The initial signs are that the vaccine is effective. Given that the myelin sheath also contains other proteins that are thought to induce the immune system to attack, such as myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP), this is perhaps surprising at first. So how does a vaccine based only on MBP peptides also prevent these other proteins from sending the immune system into overdrive? The answer is 'bystander suppression'. The epitopes for a given protein antigen (in this case MBP) can also induce tolerance to other epitopes from the same antigen, and even epitopes from other antigens, such as MOG and PLP.

    "Essentially, the activity of the mixture is greater than the sum of its parts," explained Martin.

    Indeed, one patient on the trial has shown "remarkable improvement in her eyesight", explained Prof. Wraith.

    "Since the optic nerve is acutely sensitive to inflammation and optic neuritis is often one of the first symptoms of MS, this early indication of efficacy is very encouraging. It suggests that treatment with ATX-MS-1467 can suppress the inflammation associated with MS," he continued.

    The next step is to continue to monitor the six patients who have completed dosing in the Phase I/IIa trial so that a three month safety follow-up can be conducted. If the drug gets the all clear, Apitope will then continue with a Phase IIb proof-of-concept trial. If that proves successful, the firm will then look to partner the programme with a larger pharma company, although Martin said the company would be willing to partner earlier if the opportunity arose.

    Way before this drug makes it anywhere near the market though, Apitope hope to begin generating revenues thanks to a MS diagnostic test they have developed.

    Martin said that early diagnosis in MS is crucial as treatments that seek to slow down or halt the progression of the disease are obviously best given before the disease has had the chance to do too much damage. Even with existing treatments, there is evidence to suggest patients would have much better outcomes if they were diagnosed earlier he said.

    Unfortunately, the current process of diagnosing the disease can take a while, leaving patients untreated while the disease damages their nerves. Apitope have developed a blood test that can diagnose the disease much more quickly. The test is still undergoing regulatory tests but Martin said that Apitope hopes it will be available to doctors by the end of 2009. The same test also has the potential to be extended as a tool for other autoimmune diseases such as rheumatoid arthritis and lupus.

    Apitope's approach is also applicable to other immune hypersensitivity reactions and the firm has a programme to identify apitopes to prevent Factor VIII inhibitor formation, which can cause haemophilia. Martin said that he is confident the company will gain orphan drug status for this programme from the US Food and Drug Administration (FDA), although they haven't applied for it yet. This is important as the faster regulatory process for orphan drugs means that, if necessary, Apitope could bring that drug to market without a partner.

    Scientists at Apitope are also conducting preclinical tests on Type I diabetes and allergy peptides.

    The MS project remains the most advanced however, and it is this research that will make or break Apitope's approach to peptide induced tolerance. A great number of people with autoimmune diseases will be waiting with baited breath.

    Source: Outsourcing Pharam.com © 2007 – Decision News Media SAS – All Rights Reserved.(09/11/07)

    © Multiple Sclerosis Resource Centre

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