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    You are here : Home » MS Research News » Drugs » RTL-1000

    RTL-1000

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    Myelin reactive MHC constructs trial

    HLA-DR2Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG-) 35-55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice.

    Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects.

    Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2(+) MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations.

    Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2-60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment.

    Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair.

    Yadav V et al. Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study. Autoimmune Dis. 2012;2012:954739. Epub 2012 Apr 5.

    Comment

    For T cells to be activated they must see the antigenic peptide (a fragment of a protein, such as a myelin protein) in the context of major histocompatibility complex in addition to co-stimulatory signals provided by molecules such as CD80 and CD86. However it the T cell does not get the costimulatory signals it either triggers the T cell to be silenced by a process called anergy, of the cells are stimulated to commit suicide. It only does this and would not be expect to have any side-effects, unlike current immunosuppressive drugs that removes alot of the immune repertoire and can lead to increased susceptibility to infection. It is clear from genetic studies that HLA-DR2 is a variant of the major histocompatibility complex that is a predisposing susceptibility factor for MS. This molecule is common in Northern Europeans and accounts for a reason why MS is more common in Northern Europeans.

    This HLA-DR2 molecule has been linked to a myelin peptide (a small stretch of amino acids) with the idea that this drug called RTL1000 will inhibit myelin-reactive T cells. They have shown that this works in mice and can inhibit MS-like disease from developing. However, I believe the efficacy claims are wildly exaggerated. In my opinion there is absolutely no reason why this molecule would promote repair and remyelination directly. However because it inhibited the damaging immune response it may of allowed the natural repair processses to do some repair, but this is very differnt from the the drug actually causing repair as implied.

    This new drug has passed through its first test in humans, the next one will be do this in MSers. Whilst this paper is perhaps and advertisement for investors, it has to be said the authors have declared conflicts of interest,as long as your arm, because the are recieving stuff for doing the study. However this all transparent and above-board. If MS is not autoimmune then the approach will fail.

    Source: MouseDoctor Blog (09/05/12)

    Positive results for RTL1000 phase 1 Multiple Sclerosis trial

    Artielle LogoArtielle ImmunoTherapeutics, a clinical stage biopharmaceutical company announced the presentation of "Results of a Phase 1 safety study of RTL1000, a recombinant T-Cell receptor ligand specific for an immunodominant MOG peptide, in multiple sclerosis." The results were presented yesterday by one of Artielle's founding scientists, Arthur Vandenbark, Ph.D., at the Congress of the European Federation of Neurological Societies in Florence, Italy.

    The presentation showed that this Phase 1 Study met its primary objective, which was to evaluate the safety profile and determine the maximum tolerated dose (MTD) of a single IV dose of RTL1000. Secondary objectives of the study were also met; these were to determine the pharmacokinetic profile of RTL1000 and assess immunologic parameters in a subset of Multiple Sclerosis (MS) patients. This was a first-in-human, double-blind, placebo controlled trial that enrolled 34 subjects with relapsing-remitting and secondary progressive MS at six centers in the United States. All subjects were followed for clinical and MRI changes, pharmacokinetics and cytokine levels in plasma and blood mononuclear cells.

    According to Dr. Arthur Vandenbark, "This trial demonstrated that RTL1000 was safe and did not exacerbate MS disease activity at any of the tested doses. Although this study was not designed to assess efficacy, immunological data in a subgroup of patients indicated RTL1000 was biologically active."

    "The successful completion of this Phase 1 study represents a major milestone in the potential treatment of this devastating disease and in the development of our proprietary platform technology," said Dr. Al Ferro, President and CEO of Artielle ImmunoTherapeutics, Inc. "We plan to move aggressively to bring these novel, first-in-class products to the market place."

    Worldwide, multiple sclerosis (MS) is thought to affect more than 2.5 million people. MS is a chronic autoimmune disease caused when T cells, part of the body's immune system, attack the central nervous system (CNS), which is made up of the brain, spinal cord and optic nerves. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. In MS, activation of these T cells triggers the release of inflammatory cytokines that lead to the destruction of the myelin, the fatty substance that surrounds and protects the nerve fibers in the central nervous system. When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing the variety of symptoms that can occur.

    As demonstrated in animal studies, RTL1000 inhibits the activation of myelin-reactive T cells, preventing the release of inflammatory cytokines and causing the release of anti-inflammatory cytokines. Artielle has also shown in models of MS that animals treated with RTL1000 demonstrate repair of the myelin sheath.

    Source: Artielle ImmunoTherapeutics (15/09/09)

    Hope for MS
    400,000 people in this country suffer from multiple sclerosis, or MS, and there’s still no cure. Now, a new drug is showing promise.

    Rich Elliott is having fun with his daughter. But it’s hard work just staying on his feet.

    "It’s difficult to walk and stay upright without falling," Elliott said.

    At 36, Elliott is fighting a daily battle with MS. He is now part of a small group of people in the United States testing a new drug. At this point, he’d settle for anything that keeps the debilitating symptoms from getting worse.

    "I’d know that this is as bad as it’s gonna get, and I could handle that," Elliott continued.

    Researchers say current MS therapies affect more than just the bad cells. They can also harm good cells that protect the body’s nervous system.

    "It’s like having a sledge hammer to kill a fly," said Arthur Vandenbark, Ph.D., Neurologist at O.H.S.U./V.A. Medical Center in Portland, Ore.

    Dr. Vandenbark and his team designed RTL-1000 to zero-in on the bad cells that cause MS. It works by binding to those cells’ receptors and inactivating them. Pictures from an animal study show MS before RTL and after. The MS cells simply disappear.

    "I think we can potentially reduce the symptoms a lot, maybe completely, in early stage patients," Dr. Vandenbark said.

    Researchers hope RTL will reverse damage already caused by MS, even for patients whose disease has progressed. For Elliott, it’s hard to imagine.

    "If I could walk on my own again without assistance, have a normal day, be able to use your fingers, to get it back would be incredible," Elliott said.

    He’s hopeful the new medication could hold the key.

    If RTL-1000 is proven effective in the fight against MS, scientists hope this kind of therapy may also be used to treat other auto-immune diseases, such as diabetes and rheumatoid arthritis. MS is about three-times more likely to occur in women than in men.

    Source: News 14 Carolina Copyright ©2007 TWEAN Newschannel of Raleigh, L.L.C (26/11/07)

    Drug's trials are just a start
    New multiple sclerosis therapy comes out of ‘translational research’.

    Scientists at Oregon Health & Science University have begun the first stage of clinical trials for a new drug they say has the potential to be a breakthrough treatment for people suffering from multiple sclerosis.

    In late May, physicians at OHSU injected the first Pacific Northwest patient with an experimental drug called RTL1000.

    The patient, Anne Foster of Montesano, Wash., so far has reported no adverse reaction to the drug – a positive development because early trials are intended to look for possible side effects.

    RTL1000 was developed by scientists working at OHSU and the Portland Veterans Affairs Medical Center. In experiments involving laboratory mice, “it was the best thing I’d seen in 35 years,” said Arthur Vandenbark, OHSU neurology professor, Veterans Affairs Medical Center scientist and head of the research team that discovered and developed RTL1000.

    MS affects more than 2.5 million people worldwide, 400,000 in the United States, and is projected to be a $76 billion market. Because it’s such a potentially lucrative field, institutions such as OHSU have begun to emphasise more than traditional basic research. In the medical field, it’s called “translational research” – breakthroughs that translate into patents and moneymaking therapies.

    RTL1000 is a product of such translational research. And Vandenbark’s opinion of its potential is especially noteworthy, since he is credited with inventing another drug, NeuroVax, that also is viewed as a possible MS breakthrough therapy.

    While Vandenbark stands to collect royalties from NeuroVax should it ever come to market, he said the lessons he has learned from his experience developing the drug and selling its patent have influenced the way he has gone about handling RTL1000.

    MS, which usually first strikes adults between the ages of 20 and 40, is caused by white blood cells, called T cells, that attack myelin, the sheath that insulates nerve fibres. The nerve fibres lose the ability to conduct impulses.

    In multiple sclerosis-infected mice, Vandenbark said, RTL1000 not only halted the damage done to myelin and nerve fibers, but it appeared to reverse the damage, essentially reversing the effect of MS. It works by binding to the T cells and rendering them inactive.

    For all its promise, RTL1000 is years away from coming to market as a therapy for MS. Eleven years in development, it is just now entering the first of three phases of clinical trials on humans that eventually could lead to approval by the federal Food and Drug Administration.

    The trials process itself could last up to 10 years and cost up to $125 million, according to Vandenbark.

    Scientists temper excitement
    Vandenbark, who has been studying T cell receptors since the mid-1980s, is a perfect example of the new expectations facing researchers at medical centers and universities. For the first decade of his career he was looking at T cell receptors, he said, but without any real sense of what tangible applications might result.

    “It took me 10 years of my career to learn how to get there,” Vandenbark said. “I’m a basic scientist at heart, but I realise if you’re going to make an impact you have to be a translational scientist. You have to get up from the bench and animals and start treating people.”

    Dennis Bourdette, chairman of neurology in the OHSU School of Medicine and director of the Multiple Sclerosis Center of Oregon, is both excited about RTL1000’s potential and sobered by the obstacles the therapy must overcome.

    “It does have the potential to be a breakthrough drug for the treatment of MS,” Bourdette said. But, he added, the current optimism is based on the success RTL1000 has had in treating MS in animal models. That, Bourdette said, doesn’t always translate into the same effects in human trials.

    “Human patients are much more complex than the very controlled animal models that (scientists) are working with,” Bourdette said. “You take these mice that are genetically identical, you get to control everything. Because you’re dealing with this homogenous model you can get excited if you give four mice something and they get better. As a clinician, you have the breadth of experience to know you don’t get excited about one person or two or three people responding.”

    But it is that excitement that helps bring in investors and allows a new therapy such as RTL1000 to get off the ground, Vandenbark has learned.

    Investors bring on the cash
    Just as Vandenbark and his team of scientists have worked to devise a molecule to counter the renegade MS T cells, OHSU’s technology transfer office has had to devise a model to secure patents and find funding to carry the drug into clinical trials.

    It has done that by licensing RTL1000 to a Tigard-based biotechnology company called Artielle ImmunoTherapeutics Inc., set up to oversee the drug’s future.

    Artielle has found venture capitalists willing to put up an initial $11 million to get RTL1000 through Phase One clinical trials, which is when the drug is first tested on humans and which are designed to discover possible side effects.

    Vandenbark, for one, is not surprised that funding has been found for his new invention. “There’s so much money out there for investment,” he said of the biotechnology field. “If you’ve got something out there that works, there’s plenty of money. The investment houses are fat right now.”

    While RTL1000 begins Phase One clinical trials, NeuroVax is a step ahead, in Phase Two trials, designed to measure a new drug’s effectiveness.

    And the two drugs – both of which Vandenbark had a large hand in developing – will be competing against each other. NeuroVax’s approach is to boost the activity of T cells that regulate MS rather than rendering renegade T cells inactive.

    Joseph O’Neill, president and chief executive officer of the Carlsbad, Calif.-based Orchestra Therapeutics, which owns the rights to NeuroVax, said that competition could benefit both companies and MS sufferers.

    “I like our product because it’s elegant, and we’re in Phase Two so we’re further along,” O’Neill said. “Ultimately competition is going to be sorted out by which one works best with the fewest side effects. I guess you could say there’s a competition. But competition brings out the best in people.”

    Source: Portland Tribune Copyright 2007 Pamplin Media Group (20/07/07)

    OHSU tests MS drug in clinical trial
    A 55-year-old Montesano, Wash., woman will be the first person in the Northwest to be treated with a promising new multiple sclerosis drug developed entirely at Oregon Health & Science University and the Portland Veterans Affairs Medical Center.

    Anne Foster, who has secondary-progressive MS, will be the third person in the country to receive an infusion of the OHSU/VAMC-invented drug, RTL1000, as part of a Phase I trial when she arrives Monday for treatment at OHSU's Center for Health & Healing. She will be awake as the drug is administered intravenously and will stay in the hospital for 24 hours for evaluation.

    During the Phase I trial on RTL1000, initiated by Tigard-based Artielle ImmunoTherapeutics Inc., researchers will test the drug in a total of 30 participants at six study sites, including OHSU, Yale University, Indiana University, University of Kansas Medical Center, University of Maryland, and the MS Center at Evergreen, in Kirkland, Wash. They will evaluate its safety, determine a safe dosage range and identify side effects.

    OHSU and VAMC researchers who developed RTL1000 are enthusiastic about the drug's potential. Named for the "recombinant T-cell receptor ligand" that is the center of its activity, RTL1000 is a highly selective protein that binds to disease-causing white blood cells, or T-cells, and inactivates them.

    MS is caused by a subgroup of pathogenic T-cells that attack myelin, the fatty sheath insulating nerve fibers in the brain and spinal cord, and cause the fibers to lose their ability to conduct impulses. RTL1000 was bioengineered to bind specifically to the T-cells believed to cause MS, and then inactivate or "stun" these cells.

    Arthur Vandenbark, a professor of neurology and molecular microbiology and immunology at the OHSU School of Medicine, and senior research career scientist at the VAMC, led the RTL1000 research team that included Halina Offner, a professor of neurology and anesthesiology and peri-operative medicine at OHSU and the VAMC, and Gregory Burrows, OHSU research associate professor of neurology.

    Vandenbark called the clinical trial with RTL1000 "the holy grail" of his research.

    In early studies that Vandenbark, Offner and Burrows conducted on mouse models for MS, RTL1000 appeared to reverse demyelination and nerve fiber damage. That meant the drug was both neuroregenerative and neuroprotective.

    RTL1000's appearance in a clinical trial is the culmination of more than 20 years of work by MS scientists and clinicians at OHSU and the VAMC to develop a treatment that enhances the body's natural ability to control disease-causing T-cells. They recently helped launched an international trial for another MS drug invented by Vandenbark and Offner, called NeuroVax, that boosts the activity of protective T-cells that regulate MS. This treatment approach, referred to as T-cell receptor peptide vaccination, may also prove useful for treating a variety of autoimmune diseases, such as diabetes mellitus and rheumatoid arthritis.

    Source: Portland Business Journal © 2007 American City Business Journals, Inc. and its licensors. All rights reserved. (22/05/07)

    Artielle ImmunoTherapeutics Initiates Clinical Trials For Multiple Sclerosis
    Artielle ImmunoTherapeutics, Inc. today announced that the company has initiated a Phase I clinical trial to evaluate its novel drug candidate, RTL1000, for the treatment of multiple sclerosis (MS). RTL1000 is a novel protein drug with a highly-selective mechanism of action that targets pathogenic T-cells responsible for triggering and sustaining MS.

    The trial is currently open for enrollment and is a multi-center, double-blind, placebo controlled, single dose Phase I study to be conducted with 30 MS patients in the United States. The clinical trial is designed to assess the safety and pharmacokinetic properties of RTL1000. The study will be conducted at research centers located in New Haven, Connecticut; Indianapolis, Indiana; Kansas City, Kansas; Baltimore, Maryland; Portland, Oregon and Seattle, Washington.

    "The initiation of Phase I clinical trials is an important milestone for Artielle," said Al Ferro, Ph.D., president and CEO of Artielle. "In addition to demonstrating that RTL1000 is safe for human use, this initial trial is designed to provide pharmacokinetic and mechanistic data that will enable us to plan for later-stage clinical trials."

    "RTL1000 has demonstrated impressive pre-clinical data in several different disease models and has the potential to add significantly to the clinical options for patients with this disease," said Dennis Bourdette, M.D., chair and Swank professor, department of Neurology, Oregon Health & Science University (OHSU). "There remains a critical unmet need for new therapies for this disease, and I am delighted to be involved with this program."

    "The highly selective mechanism of action of this drug suggests it could have a very interesting profile as a new therapy. It targets only those cells involved in the disease process," said Arthur Vandenbark, Ph.D., senior research career scientist at the Portland Veteran Affairs Medical Center and professor in the department of Neurology and department of Molecular Microbiology & Immunology at OHSU. "We look forward to seeing this therapy advance into human testing."

    About RTL1000

    MS is caused when T cells, part of the body's immune system, target nerves in the spinal cord and brain creating lesions in the myelin sheath.

    In MS, activation of these T cells triggers the release of inflammatory cytokines that lead to the destruction of the myelin. RTL1000 disrupts the activation of the T cells, preventing the release of the inflammatory cytokines and causing the release of anti-inflammatory cytokines. RTL1000 has been found to be both safe and efficacious in animal models of MS.

    SOURCE: Artielle ImmunoTherapeutics, Inc. (15/03/07)

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