Campath-1H · MS Living Library

This article describes early alemtuzumab trials and anticipates results in 2006. Its experimental status, trial eligibility, safety statements and comparisons of harms are historical claims, not current prescribing or treatment guidance. The trial details are preserved for reference, not recruitment.

Campath-1H is an experimental drug treatment for multiple sclerosis, organ transplant rejection and several types of leukemia. The generic name for Campath is alemtuzumab.

Campath-1H works by destroying the body's T cells which are believed to be responsible for initiating the destructive process seen in multiple sclerosis. In one small trial of 27 people with Secondary Progressive MS (SPMS), the drug was found to virtually eliminate the formation of new lesions and the inflammation associated with the disease for at least eighteen months. These results were demonstrated by MRI scans.

For 14 of these volunteers, the progress of their disease initially appeared to be completely halted. In the remaining 13, however, their MS symptoms continued to worsen even in the absence of new inflammatory lesions. MRI studies have discovered that the trial subjects, whose disease continued to progress, were the ones that had the greatest amount of existing lesions and brain atrophy. Unfortunately, as time goes on, it appears that even some of those people whose progression appeared to have been arrested by the drug are now beginning to deteriorate as well. These results have led Campath's researchers to make several important inferences:

Inflammation is not the only mechanism causing disease progression in multiple sclerosis. The researchers believe that the further progression results from the earlier death of central nervous system maintenance cells, called oligodendrocytes. These oligodendrocytes normally feed the nerve cells (neurons) certain neurotrophic factors, in particular a factor called insulin growth factor-1 (IGF-1). Without IGF-1, the long extensions of these neurons, called axons, wither and die. This axonal death seems to take place long after the oligodendrocytes have died.
Campath-1H therapy is best applied early in the course of the disease.

As a result, a new clinical trial of Campath-1H taking volunteers with early relapsing-remitting MS has begun. The hope is that, if inflammation can be stopped from the outset of the disease, then the progressive phase of the disease will never happen. The trial will compare Campath-1H with Rebif, and be tested on 180 people in the USA and Europe. The trial is called CAMMS223 and more details are listed below. It is expected that preliminary results from this trial will be available in 2006.

Side-effects

Campath-1H appears to be reasonably well tolerated despite the fact that it kills T cells. In theory, this should leave people seriously immuno-compromised but, in reality, few serious infections were encountered during the trials and no one died.

One serious side-effect was that one third of the trial subjects developed autoimmune thyroid disease (Graves disease). Despite the seriousness of this condition, it is relatively easily managed with thyroxin supplementation and most people with MS would happily exchange multiple sclerosis for Graves disease.

Another noted side-effect was that most volunteers experienced a temporary worsening of their symptoms immediately following their first infusion of the drug.

How Campath-1H works

Campath-1H is something called a humanised anti-CD52 monoclonal antibody. I will try to explain what this means.

Antibodies are small proteins produced by the immune system that stick to small sections of other proteins called epitopes. Proteins containing such epitopes are called antigens. Once attached to an antigen, other aspects of the immune system destroy the cell to which it belongs. Antibodies are extremely specific to particular antigens and will usually only stick to a single one. The immune system usually targets antigens belonging to viruses, bacteria and other unwelcome invaders but it can also attack the body's own cells in autoimmune diseases.

Because antibodies are so specific, researchers have looked at engineering antibodies to disable specific cells in the human body. These are known as monoclonal antibodies and have been called "magic bullets". Campath-1H is just such a monoclonal antibody. It is designed to latch onto cells expressing a protein called CD52 thereby killing them.

CD52 is a type of protein known as a leukocyte antigen. It is 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-1H has been shown to be very effective at destroying T-cells, the cells responsible for initiating the damage in multiple sclerosis. CD52 is also expressed on the cells lining the male reproductive tract. I am unaware whether Campath-1H has any implications for male fertility.

After the initial infusion with Campath, the body's T cell population takes many years fully to regenerate. To make up for the lost immune function, reconstituted lymphocytes of a kind that weren't associated with the disease process in MS were given to the trial volunteers (Th2 cells).

It is thought that because the Campath-1H treatment moves the body's immune response away from a Th1 type of response, one third of the volunteers developed antibodies to a protein found in the thyroid organ (the thyrotropin receptor) and thus developed autoimmune thyroid disease.

Miscellaneous

Campath-1H has been approved by the US Federal Drug Authority for the treatment of chronic lymphocytic leukemia. It has been developed by Millennium Pharmaceuticals and ILEX Oncology. Schering AG and its US affiliate, Berlex Laboratories (the makers of Betaseron), have exclusive world-wide marketing rights.

The CAMMS223 Campath-1H Trial Protocol

Study Title: A Phase II, randomized, open-label, three-arm study comparing low- and high-dose CAMPATH® and high-dose Rebif® (interferon beta-1a) in patients with early, active relapsing-remitting Multiple Sclerosis (MS).

Study Description: This is a Phase II, randomized, open-label, three-arm study comparing low- and high-dose CAMPATH® and high-dose Rebif® in patients with early, active relapsing-remitting Multiple Sclerosis (MS) who have not been previously treated with immunotherapies other than steroids. Patients will be split equally between the three types of treatment.

Inclusion and Exclusion Criteria: The following are selected inclusion and exclusion criteria.

Please discuss your involvement in this clinical trial with your physician.

Selected Eligibility Criteria

Patients must meet all of the following criteria for admission into this study:

Signed, written informed consent
Male or non-pregnant, non-lactating female patients, 18-50 years of age (inclusive)
Diagnosis of MS per McDonald's update of the Poser criteria, including cranial MRI consistent with those criteria
Onset of first MS symptoms within 3 years prior to screening
EDSS score of 0.0 to 3.0 (inclusive) at the screening and baseline visits
At least 2 clinical episodes of MS in the 2 years prior to study entry (i.e. the initial event if within 2 years of study entry plus greater than or equal to 1 relapse, or greater than or equal to 2 relapses if the initial event was between 2 and 3 years prior to study entry.
In addition to the clinical criteria (3 to 6 above), greater than or equal to 1 enhancing lesion on any 1 of the up to 4 screening gadolinium-enhanced MRI brain scans during a maximum 3-month run-in period (inclusive of the month 0 baseline scan)

Selected Exclusion Criteria

Patients who meet any of the following criteria will be excluded from study admission:

Previous immunotherapy for MS other than steroids, including treatment with interferons, glatiramer acetate, and mitoxantrone
Personal history of thyroid autoimmune disease
Personal history of clinically significant autoimmune disease (eg, inflammatory bowel disease, diabetes, lupus, severe asthma)
History of thyroid carcinoma (previous thyroid adenoma is acceptable and is not to be considered an exclusion criterion)
History of malignancy (except for basal cell skin carcinoma in which situation the patient is eligible only if disease-free for 5 years or more)
Any disability acquired from trauma or another illness that, in the opinion of the investigator, could interfere with evaluation of disability due to MS
Previous treatment with CAMPATH
History of anaphylaxis following exposure to humanized monoclonal antibodies
Inability to undergo MRI with gadolinium administration
Female patients with childbearing potential with a positive serum pregnancy test within 2 weeks prior to randomization. (NB: Serum pregnancy testing will be performed on each occasion.)
Male and female patients who do not agree to use effective contraceptive method(s) during the study
Impaired renal function (ie, serum creatinine greater than or at least 2 times the Institutional upper limit of normal [ULN])
Untreated, major depressive disorder (MDD)
Epileptic seizures that are not adequately controlled by treatment
Suicidal ideation
Major systemic disease or other illness that would, in the opinion of the investigator, compromise patient safety or interfere with the interpretation of study results
Abnormal CD4 count or significantly abnormal thyroid function; presence of anti-TSH receptor antibodies; known seropositivity for HIV
Intolerance of pulsed corticosteroids, especially a history of steroid psychosis
Presence of a monoclonal paraprotein
Patients who, in the opinion of the investigator, have any form of MS other than relapsing-remitting.
Patients currently participating in a clinical trial of an experimental or unapproved/unlicensed therapy