The drug, as given, was well tolerated without any immediate or long-term side-effects, such as thyroiditis or ITP, as reported in other trials (the CAMMS233 Trial, 2008). Although the sample was small, it was powered to capture changes in muscle strength even in a 6-month period owing to the availability of natural history data in the same patients. Even if the improvement was arguably modest, no other agent has shown any similar effect in the decline of the disease course. Some benefits noted with IVIg or with anti-thymocyte globulin were marginal and short-lived (Dalakas et al., 1997; Lindberg et al., 2003). Because IBM is predictably disabling and notoriously resistant to therapies, the encouraging results from this pilot study and the good tolerance of the drug, provide the impetus to consider a large placebocontrolled trial with repeated infusions to assess the long-term benefits keeping in mind the safety concerns raised in the recent multiple sclerosis trial (the CAMMS233 Trial, 2008).
Wait a minute. This article needs to be read carefully. There are some issues with the statistics. For example, although these numbers are reported as being very significant, it's hard to see how this conclusion is supported by such a low sample size. In addition, about half of the cases showed improvement and about half did not. Further, we need to differentiate statistical significance from clinical. The threshold for success of this study was only a 10% improvement so even if there was a significant improvement based on this criteria, it is questionable whether this would produce a clinical or practical improvement in one's function. While one could argue that any improvement is important it is also important not to be misled by the way this research is presented.
[The generic name for Campath is alemtuzumab. Campath is a monoclonal antibody designed to latch onto cells expressing CD52 thereby killing them. CD52 is a type of protein known as a leukocyte antigen, expressed on the surface of several types of white blood cells (leukocytes) including lymphocytes (which include T cells), macrophages, monocytes and thymocytes (immature lymphocytes). Campath has been shown to be very effective at destroying T-cells. After one infusion with Campath, the body's T cell population may take years fully to regenerate.]
Annals of Neurology
Published Online: 14 Jul 2008Editorial
Marinos C. Dalakas, MD
In primary inflammatory or autoimmune neurological disorders, such as primary or secondary progressive multiple sclerosis and chronic inflammatory neuropathies and myopathies, the chronic persistent inflammation leads to degeneration and irreversible cell loss. In other disorders considered neurodegenerative, such as Alzheimer's disease or amyotrophic lateral sclerosis, there is andquot;neuroinflammationandquot; characterized by gliosis, macrophage activation, and cytokine upregulation. Although in most of these conditions inflammatory mediators coexist even from the outset with cell stress and degeneration, the interrelationship between inflammatory and degeneration-associated molecules has not been studied in vivo, and the clinically relevant markers connected with disease progression remain unclear.
Perhaps one of the typical human neurological disorders in which inflammation and degeneration coexist from the outset is inclusion body myositis (IBM), the most common acquired myopathy for individuals older than 50 years.[1-3] The muscles of IBM patients have the following characteristics: (1) clonal expansion of CD8+ cells that invade major histocompatibility complex class I (MHC-I)-expressing muscle fibers; (2) persistent upregulation of cytokines, chemokines, adhesion molecules, and MHC-I, which induces cell stress; (3) vacuolization; (4) mitochondrial and nuclear abnormalities; (5) promiscuous deposits of degeneration-associated molecules, identical to those seen in Alzheimer's disease, such as andbeta;-amyloid, tau, ubiquitin, presenilin, andalpha;-synuclein, and apolipoprotein E; and (6) involvement of the ubiquitin-proteasome system, including the disposal of unwanted proteins by macroautophagy, as seen in neurodegenerative disorders.[4] Because of these features, the IBM muscle is a useful tool to investigate in vivo the interplay between inflammatory and degenerative molecules.
. . . these two new studies[5][6] provide strong evidence that in IBM proinflammatory cytokines not only correlate with the intramuscular accumulation of amyloid, phosphorylated tau, ubiquitin, and andalpha;B-crystallin,[6] but also induce tau phosphorylation and amyloid aggregates.
.
Viral or inflammatory triggers lead to clonal expansion of CD8+ T cells and T-cell-mediated cytotoxicity via the perforin pathway. The released cytokines upregulate major histocompatibility complex (MHC) class I molecules and increase levels of the MHC-peptide loading complex, because the abundance of generated peptides cannot be conformationally assembled with the MHC to exit the endoplasmic reticulum (ER).
Because effective antidegenerative agents as treatment options are not in the offing, focusing on antiinflammatory mediators is more realistic. The results from the trial with alemtuzumab, a T-cell-depleting monoclonal antibody against CD52, in the treatment of IBM patients, support this view.[17] Alemtuzumab significantly reversed disease progression, improved the strength of some patients, and reduced the inflammatory and degeneration-associated molecules in the patients' muscles.[17] The observations are encouraging and necessitate further study.
References used:
5 Kitazawa. Ann Neurol 2008; 63.Annals of Neurology Vol 62 (suppl 11) page: S60
2007 ANA and CNS Meeting Programs ANA T1-T136
doi:10.1002/ana.11641
Abstract
T-45. Alemtuzumab (CAMPATH 1-H) Therapy in Sporadic Inclusion Body Myositis
(sIBM) Alters Disease Progression and Suppresses Endomysial Inflammation Marinos
C. Dalakas, Goran Rakocevic, Beverly McElroy, Mohammad K. Salajegheh, Jens Schmidt,
Michael Harris-Love, Joseph Shrader, Ellen Levy, and Allen D. Kirk;
Bethesda, MD
In this study we examined the effectiveness of Alemtuzumab in suppressing endomysial inflammation and arresting sIBM progression. Alemtuzumab is a humanized monoclonal antibody against CD52 that causes severe PBL reduction up to 6 months. Thirteen sIBM patients with a 12 month natural history were treated with 0.3 mg/kg/day Alemtuzumab for 4 days. Primary end-points were the disease stabilization or increased strength 6 months after treatment. During a 12 month observation, patients' total strength had declined by a mean of 14.9% on QMT, while six months after therapy, only by 1.9 % (p less than 0.002). Six of 13 patients improved by 15.7% (4 - 35%); the other 7 declined by 6% (-1.5 - 15%). Total MRC scores declined during observation by 13.8% but improved after 6 months by 11.4 % (p less than 0.001). PBL depletion persisted for 6 months after treatment, with naive CD45RA+ CD62L+, but not effector CD45RA+CD62L-, cells affected. Repeated muscle biopsies showed CD3 lymphocyte depletion by a mean of 50 % (p less than 0.008). Only mRNA of Fas, Mipa and alphaB-crystallin, were significantly reduced in muscle. In sIBM, Alemtuzumab causes peripheral and endomysial lymphocyte reduction and halts disease progression up to 6 months.
also see The original meeting poster of this report
Source
American Academy of Neurology
59th Annual Meeting, Boston, April 28 - May 5, 2007.
[S 57.001] Alemtuzumab (CAMPATH 1-H) Therapy in Sporadic Inclusion Body Myositis
(sIBM): A Treatment Trial in Patients with Established Natural History Data
Marinos Dalakas, Goran Rakocevic, Beverly McElroy, Mohammad Salajegheh, Michael
H. Love, Joseph Shrader, Ellen Levy, Allan D. Kirk
OBJECTIVE: Describe the effect of Alemtuzumab in a cohort of sIBM patients selected
based on natural history data. BACKGROUND: sIBM is characterized by inflammation
and vacuolar degeneration. Even though the endomysial T cells are clonally expanded
and antigen-driven, sIBM is resistant to immunotherapies. Alemtuzumab is a humanized
monoclonal antibody against CD52 that causes an immediate depletion or severe
reduction of peripheral blood lymphocytes (PBL), lasting at least 6 months.
Alemtuzumab is effective in transplantation and appears promising in autoimmune
disorders. DESIGN/METHODS: This is a proof-of-principle study designed to examine
if Alemtuzumab depletes not only PBL but also endomysial T cells and alters
the natural course of sIBM. 13 sIBM patients with 12-month natural history data,
were treated with 0.3 mg kg/day Alemtuzumab for 4 days. The primary end-points
were disease stabilization compared to natural history, or an increase strength,
6 months after treatment initiation. Lymphocytes, cytokines and other autoimmune
markers were serially monitored in the blood and the repeated muscle biopsies.
RESULTS: During a 12-month observation period, the patients total strength had
declined by a mean of 14.3% on QMT measurements. Four months after therapy,
the mean strength of all patients had improved by 8%, and at 6 months by 4%
from baseline. Six of 13 patients had improved by 15.7% ( 4-35%) and reported
increased ADL; the other 7 declined by 6% (-1.5-15%). The MRC data provided
similar information. Depletion of PBL was noted 2 weeks after treatment and
persisted up to 6 months. Repeated muscle biopsies showed lymphocyte depletion,
most prominent in the improved patients. Immunopathologic correlations between
responders and non- responders will be reported. CONCLUSIONS/RELEVANCE: Preliminary
analysis of this proof-of-principle study, concludes that in sIBM an aggressive
lymphocyte depletion, as induced by Alemtuzumab, can improve strength or halt
disease progression up to 6 months after therapy. Supported by: NINDS.
Thursday, May 3, 2007 3:45 PM Scientific Sessions: Muscle Disease (3:45 PM-5:00 PM)
also see The abstract of the poster subsequently published
Alemtuzumab to Treat Sporadic Inclusion Body Myositis: Clinical Trial Information.
http://www.clinicaltrials.gov/ct/show/NCT00079768
Alemtuzumab to Treat Sporadic Inclusion Body Myositis. This study is currently
recruiting patients. Verified by National Institutes of Health Clinical Center
(CC) January 2006
Purpose:
This study will examine the safety and effectiveness of alemtuzumab (Campathandreg;
(Registered Trademark)) for improving muscle strength in patients with sporadic
inclusion body myositis (s-IBM). The most common inflammatory muscle disease
in people over the age of 50, s-IBM progresses steadily, leading to severe weakness
and wasting of the muscles in the arms and legs. The cause of s-IBM is not known,
but it may be an autoimmune disease, in which the body's immune cells (white
blood cells) attack and destroy parts of muscle. Alemtuzumab is a laboratory-made
antibody currently approved to treat certain leukemias. It has also been used
to treat patients with autoimmune conditions such as rheumatoid arthritis, vasculitis,
multiple sclerosis, and tissue rejection associated with transplantation. Alemtuzumab
destroys white blood cells that have a protein called CD52 on their surface
and that might be among the cells attacking muscle.
Patients with s-IBM are eligible for this study.
The Rationale for using Campath in IBM:
Alemtuzumab (marketed as Campath or Campath-1H): A monoclonal antibody (MAb)
is an antibody that has been created in a laboratory. It is a kind of treatment
that is very different from chemotherapy. Most chemotherapies aimed at cancer
are chemicals that kill all rapidly dividing cells in your body. A MAb is designed
to bind to and help destroy only certain cells. Like a natural antibody, a MAb
binds to a specific antigen, much like a andquot;lock and key,andquot; and results
in the destruction of the targeted cell. In the lab, researchers can create
MAbs designed to attach to specific antigens found on certain cells. This andquot;lock
and keyandquot; or andquot;antibody to antigenandquot; binding makes MAbs a relatively
targeted and effective new treatment. An example of a MAb is Campathandreg; (alemtuzumab).
It is mainly used to treat people with a type of cancer called B-cell chronic
lymphocytic leukaemia (CLL).
Campath works by targeting the andquot;CD52andquot; antigen, a protein on the surface of the cell, one of the most common antigens found on B and T cells: Because this CD52 andquot;flagandquot; is so common, Campath treatment is quite broad (it is not specific to the problems seen in IBM). When Campath binds to this CD52 antigen, it activates your immune system to destroy the targeted cells not only in the blood but also in the bone marrow; it depletes your population of T-cells. Campath causes lymphocyte depletion for up to six months. Hopefully some of the T cells attacking muscle in IBM will show CD 52 on their surface and will be destroyed by the Campath, thereby reducing strength of the T-cell driven immune response against the muscle. So, using Campath is a more general approach to suppressing the T-cell response until a more specific antigen target can be identified that presumably causes IBM (not discovered yet). If a virus causes IBM (and presumably everyone with IBM has the same virus infection) and they can zero in on a specific antigen then they presumably could stop the effects of the virus in its tracks by using a MAb designed to attack this specific antigen.
http://www.cancerbackup.org.uk/Treatments/Biologicaltherapies/Monoclonalantibodies/Alemtuzumab
Monoclonal antibodies are used to try to destroy some types of cancer cells,
while causing little harm to normal cells. They recognise certain proteins that
are found on the surface of some types of cancer cells. Once the monoclonal
antibody recognises the protein it 'locks' onto it (like a key in a lock). This
may then trigger the bodyand#146's immune system to attack the cancer cells and
cause the cells to destroy themselves.
Campath locks on to a protein called CD52. This is found on the surface of certain
white blood cells (lymphocytes), including those affected by the leukaemia.
The leukaemic lymphocytes are known as malignant lymphocytes. MabCampath attacks
both malignant and normal lymphocytes. The body quickly replaces any normal
white blood cells that are damaged however, so the risk of side effects from
the treatment is small.
http://www.campath.com/ The corporate website.
http://users.path.ox.ac.uk/~scobbold/tig/CAMPATH/CAMPHIST.HTM From laboratory to clinic: the story of CAMPATH-1 by Geoff Hale and Herman Waldmann
http://www.path.cam.ac.uk/~mrc7/campath/campath.html Mike Clark's CAMPATH Story.
http://en.wikipedia.org/wiki/Campath From Wikipedia.
