One clinical path closes and another opens

Rheumatoid arthritis and multiple sclerosis

Note: This section contains material collected from interviews conducted by Lara Marks with patients who took Campath-1H for multiple sclerosis (MS) during trials. Pseudonyms are used for these patients. All the experiences described are unique to each patient and are not necessarily reflective of those of other patients who took the drug during the clinical trials.

Based on the positive results gathered in the treatment of patients with vasculitis, Waldmann and his colleagues began to investigate the possibility of using Campath-1H to treat other autoimmune disorders known to be driven by an over-activity of T-lymphocytes or T-cells which the monoclonal antibody was designed to delete. Their interest extended beyond use of the drug to prevent the rejection of organ transplants to exploring its possibilities for treating other autoimmune diseases like Type I diabetes, rheumatoid arthritis and MS. The theoretical framework for this line of thinking was outlined in H. Waldmann, 'Manipulation of T-cell responses with monoclonal antibodies', Annual Review of Immunology, 7 (1989), 407-44.

This shows John Isaacs, a specialist in rheumatology. Credit:John Isaacs.

In 1991, John Isaacs, a clinical research fellow in Waldmann's group, began a collaboration with Brian Hazelman, a consultant at the Rheumatology Unit at Addenbrooke's Hospital, to assess the utility of Campath-1H in the treatment of rheumatoid arthritis. The first trial used a monoclonal antibody produced in the Therapeutic Antibody Centre in Cambridge. It was published in J.D. Isaacs et al., 'Humanised monoclonal antibody therapy for rheumatoid arthritis', Lancet, 340 (1992), 748-52.

Initial clinical responses to the drug were promising. Based on the results, Wellcome Biotech, the subsidiary of Burroughs Wellcome, sponsored several clinical trials using various doses and routes of administration in patients with active, refractory rheumatoid arthritis in Europe and the USA. These trials confirmed the benefit of Campath-1H. The duration of benefit varied between patients, but in some cases lasted beyond 6 months. While repeated treatment with the drug was shown to be effective, the therapy-caused abnormally low levels of lymphohocytes in the blood (lymphopenia) which lasted beyond the period of benefit. The complication was attributed to the fact that the trials were conducted in patients who had already taken a number of drugs before, which in general reduced their overall lymphocyte counts and immunity. Nonetheless, the observation of lymphopenia in rheumatoid patients taking Campath-1H discouraged Wellcome from pursuing any further development of the drug for the disease in described in the section changes hands. Click here to see impact of Campath in patient with rheumatoid arthritis.

For more information on the rheumatoid arthritis trials see M.E. Weinblatt, et al., 'Campath-1H, a humanised monoclonal antibody in refractory rhematoid arthritis', Arthritis & Rheumatism, 38/11 (Nov 1995), 1589-94; E.L. Matteson, et al., 'Treatment of active refractory rheumatoid arthritis with humanized monoclonal antibody Campath-1H administered by daily sub-cutaneous injection', Arthritis & Rheumatism, 38/9 (Sept 1995), 1187-93; J.D. Isaacs, et al., 'Campath-1H in rheumatoid arthritis – an intravenous dose-ranging study', British Journal of Rheumatology, 35/3 (March 1996), 131-40.

Just at the time that Wellcome abandoned its development of Campath-1H, the drug, however, was beginning to make head way in the treatment of MS. Today, more than 2.1 million people are estimated to have MS worldwide. With onset typically in the second or third decade of a person's life, it is the most common potentially disabling neurological disease of young adults, being slightly more common in women than men. The term MS refers to scars (scleroses or plaques or erosions) particularly in the white matter of the brain and spinal cord which is mostly made up of myelinated nerve fibres. Damage to the myelin sheath can result in almost any neurological disorder, ranging from unsteady gait, tremors, changes in sensation such as loss of sensitivity or tingling, pricking or numbness, muscle weakness, speech defects, through to paralysis, incontinence and cognitive impairment. At first the symptoms might come and go for several years. This stage is known as the relapse-remitting phase. In time, however, such symptoms can become more permanent and cause disability. This is known as the secondary progressive phase of the disease.

Immunologists had long speculated that MS was an immunological disease, based on observations in mice with a similar disease known as experimental allergic encephalitis. The disease was induced by vaccination with proteins from nerve sheaths and resulted in brain damage. Based on this work, Waldmann hypothesised early on that, as for other autoimmune diseases, Campath-1H might help treat MS.

By the late 1980s, just at the moment when Waldmann was pondering the feasibility of using Campath-1H for autoimmune diseases like MS, Alastair Compston, a neurologist whose research was focused entirely on MS, was separately coming to the conclusion that a treatment targeting T-cells in peripheral blood might influence the disease process in MS. Joining Addenbrooke's Hospital and Cambridge University, in 1988, as a foundation professor of neurology, Compston had developed his thinking based on 6 years laboratory and clinical investigations into the causes of MS with colleagues at Cardiff University. He believed that T-cells circulating in the bloodstream and migrating in increased numbers into the brain and spinal cord was the pivotal event involved in the pathogenesis of MS. Research suggested that once such T-cells entered the nervous system they prompted a release of chemicals which set off a complex sequence of events that caused inflammation and injury to the myelin sheath, an insulating substance that coats nerve fibres.

This shows a nerve cell, coloured green, with its protruding dendrites and central nucleus. The long tail of the nerve cell, known as the axon, is covered by a fatty myelin sheath. When myelin is attacked and damaged by the body's immune system, the nerve cells in the brain and spinal cord are prevented from communicating effectively with each other. This inhibits the receiving and sending of impulses between the brain and the central nervous system and is responsible for the symptoms and signs of MS. credit:Wellcome Images, N0026131.

Compston had wondered for some time how he might test his hypothesis and stop the cascade of events that leads to damage of the myelin sheath and their underlying axons. One way forward, he concluded, might be to eliminate the T-cells in the blood stream. This, he reasoned could head off the chaos such cells initiated in the nervous system that leads to damage of the myelin sheath in MS. Learning of the effectiveness of Campath-1H in treating vasculitis from Lockwood, a close personal friend, Compston realised that, in theory, the drug provided just the tool to stop the damage wreaked by T-cells on the nervous system that resulted in MS. His line of thinking was encouraged by the fact that vasculitis, like MS, is an autoimmune disorder where the body mistakenly directs T-cells against itself. With this in mind, in 1991 Compston approached Waldmann to secure some Campath-1H to treat some of his MS patients. Waldmann quickly agreed, based on the fact that he too had independently began to think that Campath-1H could be useful for treating MS. He had come to this conclusion based on his experience of therapeutic immunology rather than from a detailed knowledge of MS.

This shows Alastair Compston. Credit: Alastair Compston.

The idea of using a monoclonal antibody to treat MS was not new. In 1988, investigators based at Dana-Faber Cancer Institute and Harvard Medical School, USA, reported a pilot study of monoclonal antibodies directed towards T-cells in 8 patients with chronic progressive MS. Similarly, in 1991, a study had been undertaken with 16 MS patients using OKT3, a monoclonal antibody against T-cells granted marketing approval in 1986 for preventing patients' immune systems rejecting transplanted organs. Encouragingly, patients in this second study had shown no new clinical or MRI activity of MS during their period of treatment. These early investigations had, however, been hampered by the fact that they had been conducted with full mouse monoclonal antibodies. Patients had developed neutralising immune responses to the mouse protein. One of the advantages of Campath-1H was that it was a humanised monoclonal antibody that had reduced mouse components which reduced its chance of provoking an immune response. Indeed, the drug had been well tolerated by patients with vasculitis. Moreover, it had been demonstrated to be effective in depleting T-cells in these patients.

In 1991, Compston obtained some Campath-1H to start experimentally testing the drug in patients. The first person he selected for treatment was Judith. Referred to him in 1989, Judith was a trained Inland revenue tax officer who had a position as a tax partner with an international accountancy firm. She had first developed symptoms of MS in 1988 at the age of 43. This was a year after she had been transferred from London, to her firm's office in Cambridge. Her symptoms included difficulties in walking as well as tripping and falling up stairs.

Judith had little idea of the long-term implications of having MS. Leading a very active life and having had no previous medical treatment, except for the removal of her appendix when she was 5 years old, she had no concept of what lay ahead. For the next year, she continued driving and working as before, helped by treatment with steroids and the fact that her symptoms were intermittent. In the summer of 1990, however, she awoke one morning to find she could only see in black and white and quickly realised her vision was profoundly impaired. With her husband away on a business trip, Judith had no one to turn to at that scary moment. Over the following days she began to experience other problems. Her health had deteriorated so badly by 1990 that her husband was forced to abandon his job in London to care for her.

This shows Judith at the time she began to experience her first symptoms of MS. Credit: Judith.

By the time Judith saw Compston, her condition had worsened so much she was desperate for something to help her. Adamant that it was not possible that a disease like MS had no possible treatment, Judith made it clear she was willing to try anything. Based on this, Compston suggested Campath-1H, warning that it was an entirely novel drug and that the benefits and risks were completely unpredictable. Judith quickly agreed to the treatment on the basis that she had nothing to lose and the fact that she instinctively trusted Compston's expertise and judgement. Her response reflected her underlying motto to everything she did in life which was 'why not?' Having been a non-medical representative on an Ethics Committee for a London hospital for four years, Judith also had some insight into the safeguards and procedures put into place for clinical trials for the testing of novel drugs.

Judith was given one cycle of Campath-1H intravenously for 3-4 hours for a few days. While her symptoms initially got worse for a day or two, her condition started to stabilise after 48 hours. Within a couple of weeks of completing treatment, Judith experienced a major improvement in her mobility and was able to resume her normal working life. A few months later, she was well enough to go skiing, a pursuit she loved but had had to abandon as a result of her MS symptoms. To Compston's delight, Campath-1H not only resulted in the depletion of the T-cells in Judith's bloodstream, but over the next 28 months reduced the number of new lesions forming in her brain. Importantly, Judith's improvement supported Compston's hypothesis that T-cells were a contributory factor in MS and his hunch that an effective treatment lay in targeting them in the bloodstream. Click here for Judith's follow-up story.

In 1994, Compston was joined in his efforts by Alasdair Coles, a doctoral student funded by an MRC Clinical Training Fellowship. By this time, Compston and his team had tried one cycle of Campath-1H in a further 6 MS patients, 5 with secondary progressive and 1 with primary progressive forms of the disease. Like Judith, these patients' symptoms initially but transiently worsened for a few days. Their MRI scans, however, showed a slowing down of the patients' cerebral inflammation for at least 6 months after treatment. Such results confirmed Compston's hypothesis that sustained depletion of T-cells could suppress new lesion formation in MS and reduce the number formed. Nonetheless, it remained unknown how far Campath-1H's reduction in such lesions could prevent further disability. All of the patients given the drug so far had been significantly disabled before starting treatment. More trials were needed to address this issue. Mounting such testing, however, was not going to be easy. The MS Society of Great Britain and Northern Ireland had funded the previous studies, but with the evidence so far collected with 7 patients still inconclusive, they and other charities were reluctant to continue funding such a venture.

This shows Alasdair Coles photographed after a sailing race around the Isle of Wight. Credit: Alasdair Coles.

Despite experiencing difficulties in securing funding, over the next 4 years Compston and Coles managed to test Campath-1H on 29 more patients with secondary progressive MS. This they did with the collaboration of Waldmann and his team and supplies of the drug from the TAC. The patients were given monthly scans for 3 months before and 6 months after treatment, followed by scans at 12 and 18 months, to assess the duration of Campath-1H's effect; and clinical assessments were made.

One Saturday afternoon in 1998, Compston and Coles met to discuss the data they had collected from the 29 patients tested. With their mood reflecting the rain beating down on the windows outside, they concluded that the disabilities of most of their patients had got worse. This was despite the fact that MRI scans had shown substantial decrease in disease activity and they had observed a reduction in clinical relapses following treatment.

At first it looked like all their work had been to no avail. Mulling over the results they began to realise, however, that the problem they were seeing could be rooted in the fact that Campath-1H was being given to patients too late in the course of their disease, when much of the damage had already been done and the nervous system was already irreversibly damaged by the previous waves of inflammation. Based on this, the two clinicians wondered whether the benefit of the drug would be improved if given to patients earlier in the course of their disease and before the inflammatory process had set in train the cascade leading to brain atrophy and disability.

Switching to the use of Campath-1H for treating MS patients earlier in their disease was not without risk. A number of patients had developed complications, the most acute being reactions to the infusion of the drug. Moreover, a third of the patients had developed Graves' disease (an over active thyroid gland) some months after treatment. Graves' disease, also known as thyrotoxicosis, is an autoimmune disorder that results in an over-active thyroid. This side effect was particularly puzzling because few of the other 600 patients who had taken the drug for other conditions had experienced the disease. This suggested that patients with MS were uniquely susceptible to Graves' disease. Nonetheless, the complication was worrying.

Patients in the early stages of MS who were still relatively healthy had much more to lose from side effects from Campath-1H, than those in the later stages of the disease who were already profoundly disabled. Despite this, Compston and Coles decided they should risk treating patients with active relapsing-remitting MS, that is patients who were earlier in the course of their disease. Those selected for treatment were patients with a poor long-term prognosis, having had a high rate of relapse early in the course of their disease or having failed to respond to existing licensed treatments. Attracting little support from funding agencies or professional colleagues and unable to gain commercial funding, Compston and Coles were once again reliant on the collaboration of Waldmann and his team and supplies of the drug from the TAC for this work.

This shows the two key stages in the course of MS, with the progressive accumulation of symptoms represented in green. credit: A. Coles, H. Waldmann, G. Hale, 'Inducing tolerance to Campath-1H (alemtuzumab) in the treatment of multiple sclerosis', slide 4.

By 2002, Compston and Coles had collected data from 58 MS patients at different stages of MS. This totalled all patients treated since 1991. Overall, the results indicated that although Campath-1H had little effect in reducing disability in patients who were already well-advanced in their MS, it had a positive impact on those who were less-advanced. This supported the idea that intervention with the drug might indeed be a promising treatment for early relapsing-remitting MS.

While the results suggested Campath-1H had some efficacy in treating relapsing-remitting MS, far more testing was needed to fully determine its benefits. This would need to be done on a much larger scale than previously attempted and with randomisation of patients to control and treatment paths. All the research conducted thus far had been done on an open basis, which opened the potential for bias. Undertaking a randomised control trial, however, required far greater financial resources then at the disposal of the Cambridge team. In an effort to raise funds, Compston launched into 'beauty parade after beauty parade', explaining his research to different biotechnology companies in order to generate interest. His efforts, however, came to nothing.

Compston's fortunes would change when he was visited by Jeff Buchalter in 2002. Buchalter was the chief executive officer and president of Ilex Oncology, the company responsible for the clinical trials for gaining marketing approval for the use of Campath-1H in treating chronic lymphocytic leukaemia. Employed until September 2001 by Pharmacia, a large pharmaceutical company, Buchalter had been hired by Ilex Oncology to help transform what was essentially a contract research organisation, testing drugs for other companies, into a pharmaceutical company with its own portfolio of drugs. Arriving at Ilex with a strong expertise in sales and marketing, Buchalter immediately set to work to see how Campath-1H could be leveraged to help the company achieve its goal of becoming a fully integrated pharmaceutical company. At the time, Campath-1H was Ilex's only commercially viable product.

Looking at the sales figures then coming in for Campath-1H, Buchalter quickly realised the product was not doing as well as anticipated. One of the reasons that it seemed to be struggling in the cancer market was the fact that the drug, because it depleted a patient's T-cells, increased their susceptibility to infections. In part this was a reflection of the very high dose of the drug that needed to be administered to treat CLL. It was not helped by the fact that CLL is itself a very immunosuppressive disease. Alerted to the toxicity of Campath-1H in cancer patients, Buchalter was very surprised to discover that Compston was testing it. Indeed, Buchalter considered the idea crazy. He was not the only one with such thoughts. Many oncologists around him shared such misgivings. What they failed to appreciate was the fact that Campath-1H was being administered in much lower doses to MS patients, so carried far less risk of generating the negative immunosuppressive effects that had been observed in CLL patients.

Despite his reservations about Compston's work, Buchalter was intrigued to find out more. His motivation was driven, in part, by his experience of marketing Intron-A, a genetically engineered form of interferon, when employed at Schering-Plough some years before. Like Campath-1H, Intron-A had started life as a treatment for leukaemia and had subsequently been developed as a treatment for other indications. Buchalter realised that if Ilex could develop Campath-1H for MS, then it could become as lucrative as Intron. Based on this thinking, Buchalter set up a meeting with Compston.

This shows Jeff Buchalter, chief executive officer of Ilex Oncology. Credit: Jeff Buchalter.

By the time Buchalter arrived at Addenbrooke's Hospital, Compston had become so jaded by the process of trying to persuade pharmaceutical executives to fund his work, he was highly dubious that anything would come of the meeting. His attitude was not helped by the fact on meeting Buchalter initially seemed sceptical about the local clinic-based results and appeared to be checking his watch to see when the meeting would end.

The atmosphere between Buchalter and Compston was to radically change when Compston walked Buchalter to the hospital's exit for what seemed the conclusion of their meeting. By sheer coincidence, the two men happened to meet one of Compston's patients, Imogen, returning for a check-up. Having listened to Imogen's story (click here for Imogen's description of her experience), Buchalter asked to see the medical records Compston had collected. Stunned by how much progress Imogen had clearly made with Campath-1H, Buchalter quickly cast aside all his doubt about the drug's potential. He was further bowled over by the positive results he saw from the Compston's other MS patients. Having viewed the data, Buchalter decided there and then to find the necessary funds for more trials. He calculated this would come to at least $90 million.

On returning from Cambridge, Buchalter set about the task of convincing LeukoSite and its investors to support the development of Campath-1H for MS. This was not an easy job given the fact that much of the company's focus was then on cancer and it had little expertise in MS. His challenge was compounded by the fact that most of the clinicians the company had worked with until this point were oncologists. They had no knowledge of Compston and his work and were highly sceptical that a drug with such a toxic profile in cancer was suitable for use in patients with MS. Most of the company's executives and its investors were also very wary of Buchalter's proposed project, viewing it as a high risk best avoided.

The key thing that Buchalter and Compston needed to persuade their critics once and for all was to design a convincing clinical trial. To this end, they focused their energies on the construction of a phase II trial that would provide a comparison of the efficacy of Campath-1H with interferon beta-1a (Rebif), a drug already on the market for the treatment of relapsing MS. Interferon beta-1a was particularly important as a comparator, because clinicians regarded it as the golden standard for treatment. The drug was known to reduce the number of attacks attributable to MS even though there was no evidence that it changed the long-term course of the disease or limited the accumulation of disability.

In 2002, Compston and Coles, backed by Ilex, launched a phase II trial. Designated CAMMS223, this trial targeted patients with early, relapsing-remitting multiple sclerosis who had received no previous treatment. Those selected for treatment had to have scores of 3 or less on the Expanded Disability Status Scale and the onset of their symptoms had to have occurred no more than 36 months before the time of their screening. They also had to have experienced at least 2 clinical events in the previous 2 years.

The CAMMS223 trial was designed so that patients could be randomised to three paths of treatment. This was necessary for enhancing the credibility of the study. The first arm, designated the control group was to be treated 3 times a week with interferon beta-1a. The second and third groups were to receive 12mg and 24 mg of Campath-1H. The first cycle of Campath-1H was to be given for 5 days, and then the second cycle, a year later, over 3 days.

From the outset, CAMMS223 aimed to capture the disability outcome of patients. Measuring clinical outcome necessitated the trial initially running for three years before results could be collated. The overall design of the trial was highly unusual. Until now, most phase II trials targeting MS were designed to measure efficacy using the surrogate marker of a reduction of lesions as seen in MRI scans of the brain over a 6 month period. The CAMMS223 trial was also unusual in setting out to compare Campath-1H with a drug that was already on the market. Most other trials testing MS drugs had used a placebo as the comparator drug. One of the reasons Campath-1H was to be compared with interferon beta-1a, was Compston's belief that all his patients deserved some form of treatment, even if this complicated the design of the study and made it more difficult to determine the impact of the treatment compared with the usual approach of testing a new drug against a placebo preparation.

By 2004, 334 patients, aged in their 20s and 30s, had been enrolled in the CAMMS223 study at 49 centres in Europe and the USA. Results from the trial indicated that Campath-1H, at both 12mg and 24mg per day, proved more effective than interferon beta-1a in reducing the risk of sustained disability among early relapse-remitting MS patients. Overall, the drug reduced the risk of sustained accumulation of disability by 71 per cent as compared with interferon beta-1a. It also reduced the risk of relapse by 74 percent. Moreover, at 3 years follow-up, 77 per cent of those on the low-dose Campath-1H and 84 per cent of those on the high-dose had suffered no relapses. This compared with 52 per cent of those who received beta interferon 1a. Later, at 5 years follow-up, nearly two-thirds of those who had last received the drug 4 years before remained free of clinically active disease. This compared with 27 per cent of those receiving beta interferon 1a. The high percentage reduction achieved by Campath-1H compared with the interferon drug was particularly striking given that in previous studies interferon based MS drugs had themselves shown benefits when compared with placebos.

This come from Figure 2, CAMMS223 Trial Investigators, 'Alemtuzumab vs Interferon Beta-1a in early multiple sclerosis', New England Journal of Medicine, 359/17 (23 Oct 2008), 1786-801. In panel C, you can see that, on average, patients with alemtuzumab (Campath-1H) experienced a diminishing of their disability while those on interferon beta-1a experienced a worsening of their disability.

While Campath-1H appeared to reduce disability in patients with early relapsing-remitting MS, the drug had caused some complications. Almost all of the patients reported at least one adverse event during the trial. Again, one of the most common complications was autoimmune thyroid-related adverse events, including Graves' disease, which affected roughly 30 per cent of the patients. Patients had also experienced flu-like symptoms after the drug was infused.

A new complication had also surfaced during the trial: a patient in America died soon after developing immune thrombocytopenic purpura. This is a disorder in which the blood is unable to clot properly. It is caused by an insufficiency of platelets. The condition is not usually fatal and generally patients can return to normal within 6 months, although it can last up to 2 years. Symptoms due to the disorder include purple bruises on the skin and in the mouth. The patient in question had experienced 2 weeks of easy bruising, nose bleeds and other bleeding, and had not sought medical attention. This was the first case of immune thrombocytopnic purpura reported with Campath-1H. Following the death, measures were put into place to identify and treat any subsequent patients experiencing this complication, which was subsequently seen in 2.8 per cent of the patients receiving Campath-1H. As a result of the death, trial patients in CAMMS223 were not given a planned third cycle of the drug between September 2005 and May 2007.

While the CAMMS223 trial had again shown Campath-1H a promising treatment for early MS, some concerns remained. Importantly, the trial had not been able to assess the long-term safety of the drug. Nor had sufficient numbers of patients taken the drug to identify uncommon adverse events. With many questions still being asked about the safety of the drug and scepticism still abounding about its potential as a treatment for MS, Compston and his team realised they needed to do more trials. Indeed, this was essential if the antibody was ever to be considered for a drug licence. Launching more testing was soon agreed to by Genzyme, which, had taken over responsibility from Ilex for CAMMS223 and further development of the drug in 2004.

What was required were phase III trials with a large pool of patients. Launched in 2007, two studies were again designed as randomised control clinical trials, comparing Campath-1H with interferon beta-1a. The first, labelled CARE MS-1, was designed to treat patients who had not had any previous treatment. It was to enrol 733 patients. The second, called CARE MS-II, was structured along the same lines except that it enrolled patients who had already received a first-line therapy and nonetheless suffered at least one further relapse. It was to enrol 1,046 patients.

One of the challenges in conducting the two trials was finding patients early enough in their disease not to have received any previous treatment. Such patients were harder to recruit in North America and Western Europe, where patients have access to a wide range of treatments, than in South America and Eastern Europe, where treatment options are more limited. In the end patients were recruited from a variety of locations around the world. Initially recruitment was slow, but this picked up considerably after 2008 once results from the phase II study were officially published. In 2011, the two phase III studies were completed and the results published in The Lancet in November 2012. Overall, the trial data supported the experience gained over the previous 13 years and were very encouraging.

The CARE MS-1 trial data indicated Campath-1H significantly reduced the risk of patients having another relapse of MS. Patients allocated Campath-1H had a relapse rate of 22 per cent compared with those given interferon beta-a, who had a relapse rate of 40 per cent. Similarly, 78 per cent of patients taking Campath-1H were relapse-free for up to 2 years compared with 59 per cent of those given interferon beta-1a. Of the patients taking Campath-1H, 8 per cent had a sustained accumulation of disability compared with 11 per cent of those given the interferon drug. In terms of side effects, infections, predominantly of mild or moderate severity, occurred in 67 per cent of the patients treated with Campath-1H compared with 45 per cent of those with interferon beta-1a. Herpes infections (primarily cutaneous) were higher in the Campath-1H group, at 16 per cent, than those in the beta 1a group, which was 2 per cent. As previously observed, the Campath-1H patients also had a higher rate of thyroid-associated adverse events, 18 per cent, about a year after treatment compared with 6 per cent of those in the interferon beta-1a group; and 1 per cent of the Campath-1H group had developed thrombocytopenia compared with none in the interferon group.

Positive results were also reported for the CARE MS-II investigation. Overall, 35 per cent of patients who received Campath-1H relapsed compared with 51 per of patients who were given interferon beta-1a. Moreover, Campath-1H patients were also relapse-free at 2 years (65%) compared with those taking interferon beta-1a (47%). In terms of sustained accumulation of disability, this was reported as 13 per cent in the case of the Campath-1H patients and 20 per cent for the interferon patients, corresponding to a 42 per cent improvement in the Campath-1H group. Of the patients allocated Campath-1H, 90 per cent experienced infusion-associated reactions, and 77 per cent had infections compared with 66 per cent in the interferon group. Such infections were mostly mild-moderate and none were fatal. As expected, the Campath-1H patients also reported thyroid disorders (16%) and immune thrombocytopenia (1%).

The data from both the CARE MS-1 and MS-II trials indicated that Campath-1H was effective when used as a first-line treatment in relapsing-remitting MS, whether or not this had previously been treated with another drug. During the trials, Campath-1H was found to reduce the relapse rates significantly not only in previously untreated patients, but also in those who had relapsed after another first-line treatment. Patients previously treated and given the drug, furthermore, experienced a decrease in disability. Adverse effects reported in the trial indicated that management strategies would need to be put into place for the early identification of any secondary autoimmune disorders among those who took the drug.

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