Developmental Clinical Studies - new use of a licensed drug in preventing autoimmunity after alemtuzumab treatment of MS
Lead Research Organisation:
University of Cambridge
Department Name: Clinical Neurosciences
Abstract
Multiple sclerosis (MS) is an autoimmune disease in which the patients? own immune system attacks their brain and spinal cord causing damage. It is the most common cause of disability in young adults in the western world.
Alemtuzumab is the most effective drug treatment of multiple sclerosis tested to date; not only does it prevent new attacks, it also improves disability. Alemtuzumab works by binding to and killing lymphocytes, cells which normally fight infections but which mistakenly attack nerves in multiple sclerosis. Although effective, alemtuzumab has side effects, in particular, 1 in 3 patients develop a new autoimmune disease after treatment. In other words, as their immune system grows back it begins to attack other parts of their body, most commonly the thyroid gland.
We believe that these autoimmune diseases occur because of the way the immune system grows back after alemtuzumab: by expanding up the small pool of lymphocytes not depleted by alemtuzumab. We propose to get round this by giving a drug which boosts the thymus gland to produce new lymphocytes. We will treat 42 MS patients with alemtuzumab; half will also receive a licensed drug that boosts the thymus and half will be given a placebo. Our final measure of the success of our approach will be the proportion of patients in each group who go to develop an autoimmune disease after alemtuzumab. But, one year into the trial, we will have a ?stop-go? point where we measure the activity of the thymus in our patients; if the trial drug does not seem to be boosting the thymus we will stop the trial early.
Our work is important - enabling patients to receive alemtuzumab without the risk of developing autoimmunity would represent a huge step forward in the management of multiple sclerosis. Furthermore this trial tests a general strategy for encouraging the recovery of the immune system in humans, and as such, has implications for people with HIV or those recovering from chemotherapy.
Alemtuzumab is the most effective drug treatment of multiple sclerosis tested to date; not only does it prevent new attacks, it also improves disability. Alemtuzumab works by binding to and killing lymphocytes, cells which normally fight infections but which mistakenly attack nerves in multiple sclerosis. Although effective, alemtuzumab has side effects, in particular, 1 in 3 patients develop a new autoimmune disease after treatment. In other words, as their immune system grows back it begins to attack other parts of their body, most commonly the thyroid gland.
We believe that these autoimmune diseases occur because of the way the immune system grows back after alemtuzumab: by expanding up the small pool of lymphocytes not depleted by alemtuzumab. We propose to get round this by giving a drug which boosts the thymus gland to produce new lymphocytes. We will treat 42 MS patients with alemtuzumab; half will also receive a licensed drug that boosts the thymus and half will be given a placebo. Our final measure of the success of our approach will be the proportion of patients in each group who go to develop an autoimmune disease after alemtuzumab. But, one year into the trial, we will have a ?stop-go? point where we measure the activity of the thymus in our patients; if the trial drug does not seem to be boosting the thymus we will stop the trial early.
Our work is important - enabling patients to receive alemtuzumab without the risk of developing autoimmunity would represent a huge step forward in the management of multiple sclerosis. Furthermore this trial tests a general strategy for encouraging the recovery of the immune system in humans, and as such, has implications for people with HIV or those recovering from chemotherapy.
Technical Summary
We propose to test the efficacy of a licensed drug to prevent autoimmunity caused by reconstitution following lymphocyte depletion. The specific context of this trial is autoimmunity after alemtuzumab (formerly ?Campath-1H?) treatment of multiple sclerosis, but positive results would have implications for many clinical contexts. Alemtuzumab is arguably the most effective treatment of multiple sclerosis to date; if autoimmunity, its most significant adverse effect, could be minimised then many more people would benefit from this efficacy.
Multiple sclerosis is the most common cause of disability in young adults in the Western world, effecting 100,000 people in the United Kingdom. Treatments to date have been only partially effective. Alemtuzumab is a lymphocyte-depleting humanised anti-CD52 monoclonal antibody, investigated by us as a treatment of multiple sclerosis since 1991; it is a rare example of academic-led translational medicine. Our phase 2 results of treatment of early relapsing-remitting multiple sclerosis demonstrate greater efficacy of alemtuzumab, compared to standard licensed therapy (interferon-beta1a), than any other treatment of multiple sclerosis. An unprecedented result was that that disability of patients five years after alemtuzumab was improved from baseline. Phase 3 trials of alemtuzumab will complete by Q42011 and submissions for licensing will be in Q32012.
T-cell reconstitution after alemtuzumab occurs by expansion of peripheral T-cells that have escaped depletion, rather than by the generation of new T-cells via the thymus. This results in a population of T-cells that are restricted in diversity and skewed towards auto-reactivity. It is likely that these cells cause the main adverse effect of alemtuzumab, namely autoimmunity months to years after treatment (30% of patients develop thyroid autoimmunity and 3% idiopathic thrombocytopenic purpura); this risk is increased in patients with high serum IL-21.
The hypothesis underlying this trial is that autoimmunity after alemtuzumab will be reduced if this peripheral T-cell expansion is suppressed by increasing thymic production of naive T-cells. Our investigational drug has these effects in a variety of animal models. It is licensed for use in humans (for a different indication) and is well tolerated. To date no-one has investigated its effect on thymic reconstitution in humans. So, we propose a double-blind randomised (1:1) placebo-controlled trial of our investigational agent in 42 patients treated with alemtuzumab for relapsing remitting multiple sclerosis who are at high-risk of developing. The primary outcome measure will be the development of secondary autoimmunity following treatment.
Multiple sclerosis is the most common cause of disability in young adults in the Western world, effecting 100,000 people in the United Kingdom. Treatments to date have been only partially effective. Alemtuzumab is a lymphocyte-depleting humanised anti-CD52 monoclonal antibody, investigated by us as a treatment of multiple sclerosis since 1991; it is a rare example of academic-led translational medicine. Our phase 2 results of treatment of early relapsing-remitting multiple sclerosis demonstrate greater efficacy of alemtuzumab, compared to standard licensed therapy (interferon-beta1a), than any other treatment of multiple sclerosis. An unprecedented result was that that disability of patients five years after alemtuzumab was improved from baseline. Phase 3 trials of alemtuzumab will complete by Q42011 and submissions for licensing will be in Q32012.
T-cell reconstitution after alemtuzumab occurs by expansion of peripheral T-cells that have escaped depletion, rather than by the generation of new T-cells via the thymus. This results in a population of T-cells that are restricted in diversity and skewed towards auto-reactivity. It is likely that these cells cause the main adverse effect of alemtuzumab, namely autoimmunity months to years after treatment (30% of patients develop thyroid autoimmunity and 3% idiopathic thrombocytopenic purpura); this risk is increased in patients with high serum IL-21.
The hypothesis underlying this trial is that autoimmunity after alemtuzumab will be reduced if this peripheral T-cell expansion is suppressed by increasing thymic production of naive T-cells. Our investigational drug has these effects in a variety of animal models. It is licensed for use in humans (for a different indication) and is well tolerated. To date no-one has investigated its effect on thymic reconstitution in humans. So, we propose a double-blind randomised (1:1) placebo-controlled trial of our investigational agent in 42 patients treated with alemtuzumab for relapsing remitting multiple sclerosis who are at high-risk of developing. The primary outcome measure will be the development of secondary autoimmunity following treatment.