To anyone recently diagnosed with multiple sclerosis it probably sounds too good to be true: a drug that not only halts the progression of the disease but also seems to repair the damage. Little wonder then that alemtuzumab is gaining a reputation among some doctors as a kind of miracle cure — so much so that some clinicians are reportedly starting to prescribe it to their patients before it has even been approved.

Precisely how prudent this is remains to be seen. In autumn 2011, the results of two large, randomised phase III trials called CARE-MS I and CARE-MS II were made public, and, as widely expected, they were pretty positive. But even though alemtuzumab is now being fast-tracked by the US Food and Drug Administration (FDA), it could still take another year or more for the drug to pass through the regulatory authorities and become generally available.

Fingolimod was the first oral treatment for MS. It traps T cells in the lymph nodes, moderating the autoimmune response that damages the nerves. Several other oral MS drugs are now in trials. Credit: Novartis

Given that multiple sclerosis (MS) is a degenerative disease, it's hardly surprising that some patients and doctors are unwilling to wait — after all, time is not on their side. That some are prepared to risk taking an unapproved drug is an indication of how desperate and frustrated they have become with existing MS treatments, which at best merely slow the progression of the disease. Alemtuzumab brings fresh hope — and it is just one of an assortment of new drugs that might not only slow or stop the progression of MS, but may even reverse its effects.

Targeting immunity

One of the problems in developing treatments for MS is that, despite decades of research, we still don't truly understand the disease. The disabling symptoms are clearly the result of nerve damage, which in turn is caused by erosion of the myelin sheath, the fatty layer that normally protects the nerves and speeds up neurological signals. This demyelination is believed to be the result of an inflammatory autoimmune response, but this is a chicken-and-egg scenario, says Sha Mi, a researcher at Biogen Idec in Cambridge, Massachusetts, a biotech company that makes two of the main treatments for MS. “We don't know if the inflammation causes the degeneration, or the degeneration causes the inflammation,” she says.

The two front-line MS therapies are interferon-β and glatiramer acetate. Both target inflammation, although by very different mechanisms. Interferon-β-1a and interferon β-1b are proteins that resemble interferon, which the immune system produces naturally in response to MS. They are known to help fight viral infections and to prevent inflammation as well as demyelination. Glatiramer acetate is also thought to reduce inflammation, but because of its similarity to myelin proteins, it is believed to act like a decoy, drawing the immune response away from the myelin sheath.

Both drugs are well tolerated and relatively safe, but they are only moderately effective, reducing annual relapses by only about 30%. Until recently this was the best patients could expect. These limited returns prompted criticism that the drugs are too expensive compared with those used to treat other chronic diseases. But the risk–reward balance is changing, says Jeffrey Cohen, director of experimental therapeutics at the Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research in Ohio. “There are a sizeable number of other drugs that look promising,” he says.

One reason for this is a shift in focus away from anti-inflammatories towards treatments that more directly affect the immune cells. In 2010, fingolimod, a small molecule originally developed as an immunosuppressant for use after organ transplants, became the first oral treatment for MS. It works by targeting T cells, a type of white blood cell or lymphocyte, produced by the immune system, and trapping them in the lymph nodes. This lessens the autoimmune response against the myelin, says Paul O'Connor, director of MS research at St Michael's Hospital in Toronto, Canada, who was involved in the phase III studies of the drug. The results of these trials, which involved more than 1,000 participants, show that fingolimod reduces relapses by up to 60% (ref. 1). It also reduces the number of brain lesions by more than 70% (refs 1,2).

The oral option

The development of fingolimod spurred the search for other non-protein-based drugs that can be taken orally. Taking a pill may seem pretty basic, but for patients with multiple sclerosis it is a revolution. Until recently, the only drug treatments available for MS had to be administered through regular injections.

Historically this has been a sore point with patients, says Cohen. “People strongly dislike it.” Besides the unpleasantness of having to prick oneself with a needle, it can cause a host of undesirable side effects, from flu-like symptoms to skin ulcerations.

But this is more than just a question of patient suffering, Cohen says — it can also influence efficacy. “Self-injection affects compliance,” he says. Earlier this year, a study involving 682 MS patients found that over a two-year period only 44% of participants stuck to their drug regimen. O'Connor, who carried out the study3, says: “After two years, more than half the patients in my province stopped injecting, because they don't like the process, the pain of the injections, or the side effects of injecting oneself.”

Developing oral medications has proved maddeningly difficult, however. The problem is that both interferon-β and glatiramer acetate are protein-based drugs, says O'Connor. There was an attempt to make an oral version of interferon, “but it didn't work”, he says, because the proteins are broken down in the stomach when ingested.

One drug that has gone through phase III trials and is now under review for regulatory approval is teriflunomide, which is derived from an existing rheumatoid arthritis drug called leflunomide. Teriflunomide is a mitochondrial enzyme inhibitor that blocks the production of some T cells and prevents certain types of both T cells and B cells from dividing. It reduces MS relapses by 31%, roughly the same as interferon-β, says neurologist Ludwig Kappos of the University of Basel, Switzerland, who has been involved in the trials. It also lowers the risk of disability progression by 30%, but its main advantage is that it can be taken orally3, says Kappos.

A third oral MS drug, BG-12 (dimethyl fumarate), submitted for regulatory approval by Biogen Idec in February 2012, reduces relapses by 32%, almost as much as fingolimod. It is not entirely clear how BG-12 works, but it is believed to promote neuroprotective pathways, as well as having anti-inflammatory effects.

Yet another oral drug, laquinimod, reduces the amount of cytokines released by immune cells and so reduces inflammation. It also hampers the ability of lymphocytes to pass through the blood–brain barrier. Although laquinimod reduces relapses by only 23%, it cuts the risk of progression by 36% and roughly halves the number of brain lesions.

Old drug, new role

Alemtuzumab also targets lymphocytes but its effect is longer lasting. It is administered not orally but by intravenous infusion, says Alasdair Coles, a clinical neuroscientist at the University of Cambridge, UK, who played a major role in both the drug's phase II and III trials. “We give patients five days of treatment,” he explains. “There's a second round 12 months later, and that's it.”

In a phase II trial involving 334 patients, this pulsed treatment was found to reduce relapses by 74% over a three-year period4. The treatment also lowered the risk of the disability getting worse by 71%. Patients treated with alemtuzumab improved by roughly the same degree that those treated with interferon worsened. What's more, alemtuzumab led to an increase in brain volume, whereas those on interferon continued to experience shrinkage.

“We have shown that if you treat early you get fantastic efficacy,” says Coles. These findings — along with other studies showing a dramatic reduction in brain lesions in patients treated with alemtuzumab5 — suggest that the drug not only halts the disease but also promotes repair of the myelin and even the nerves, he says.

The data also highlight the long-lasting nature of these effects. In a follow-up study, as yet unpublished, Coles has been following a cohort of 87 patients treated with alemtuzumab more than a decade ago. “The majority are well and have less disability now than when we started treating them,” he says. So far, only two have entered the progressive second phase of the disease. “We think if you treat early we can nip it in the bud.”

Other researchers require more evidence. “I'm sceptical,” says Kappos, who has tested a wide variety of MS drugs, including alemtuzumab. “It does deplete most immune cells, and because depletion is so complete, it may allow for the renewal of the immune system if used in the early stage of the disease. But this has not yet been proven,” he says.

Originally developed at the University of Cambridge under the name Campath, alemtuzumab was the first monoclonal antibody to be developed for treatment on humans. Coles and colleagues tested the drug in 1991 on patients with the more advanced stage of the disease, known as secondary progressive MS. Although it was effective at reducing relapses in these patients, it did little to slow the progression of disability. “It did not help them,” says Coles. “They carried on getting worse.” So the drug was shelved and wasn't reconsidered for MS until 1998. This time, however, it was given to patients with the earlier stage of the disease, relapsing–remitting MS, and the results tell a very different story.

Alemtuzumab works by 'resetting' the immune system by targeting and depleting the CD52 protein, which is abundant on the surface of all mature lymphocytes. “The normal response is for the bone marrow to produce new cells, to create a new immune system,” Coles says. But for reasons not entirely understood, the immune system that emerges from the alemtuzumab treatment is different to the earlier one, and seems to encourage repair instead of demyelination.

Clues to how this happens were revealed in a follow-up study5 in 2010, which Coles performed with Cambridge colleague Joanne Jones. They showed that when the immune cells regenerate after treatment with alemtuzumab, they secrete neurotrophins, which seem to promote myelin repair. Thus the drug effectively abolishes MS activity, says Coles.

So far, the phase III trials seem to back this up by showing evidence of regeneration, says Coles. The first trial, MS-CARE I, involving 581 patients, compared the drug with high doses of interferon-β-1a. The results, revealed in October 2011, showed that 78% of patients treated with the drug remained free from relapse after two years. They also experienced half the relapse rate of those treated with the standard therapy, interferon-β-1a.

The results of MS-CARE II, which involved 840 patients and also compared the drug with interferon-β-1a, were announced in November 2011 by Genzyme of Cambridge, Massachusetts, a private company that hopes to commercialize the drug under the brand name Lemtrada. This trial revealed a 49% reduction in relapse rate compared with those on interferon-β-1a, and crucially showed a 42% reduction in the risk of disability progression.

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Benefits and risk

Even so, not everyone is as comfortable with alemtuzumab as Coles. The unease stems from the drug's potential risks, says Cohen, who is also involved in the phase III trials. After all, you can hardly expect to wipe out an entire immune system without inviting some unwelcome complication, such as infections. The risk of infection has been lower than expected, says Cohen. But he points out that the risk of developing other autoimmune diseases does seem to increase after the first year of treatment. To be precise, MS-CARE I and II showed that 18% and 16% of patients, respectively, developed an overactive thyroid gland (Graves' disease), and 3% and 1%, respectively, developed idiopathic thrombocytopenic purpura (ITP), a potentially life-threatening autoimmune disease that targets platelets. Coles notes that in 2005 one patient died from ITP during the trials. “It's a very high-risk, high-gain drug,” he says.

This is a familiar pattern for MS drugs, says O'Connor. Interferon is safe but has a low efficacy. Teriflunomide performs slightly better but still only has minor side effects. Natalizumab, a monoclonal antibody that is already available as a treatment for MS, works by binding to T cells in such a way that they are unable to pass through the blood–brain barrier and cause inflammation. It's highly effective, says Cohen, but it also carries the risk of serious complications, particularly progressive multifocal leukoencephalopathy (PML), a rare but often fatal viral infection of the brain.

The synthetic anticancer drug cladribine is another example of this connection between benefits and risk. It is used to treat hairy cell leukaemia, and works by inhibiting a metabolic enzyme in lymphocytes, causing cells to die. A phase III study of cladribine in MS patients, published in 2010, showed that the drug reduced annual relapses by 51% and brain lesions by 90% (ref. 6). The problem was a worrying association with cancer, says O'Connor. The risk led both the European Medicines Agency (EMA) and the FDA to reject it, asking for more data on the drug's safety. The time and costs associated with a new clinical trial programme, coupled with uncertainty as to whether the trial could deliver the appropriate data, proved too much for the drug's developer. In June 2011, Merck Serono withdrew cladribine as an MS treatment, even though it had already been approved in Russia and Australia.

Fingolimod has also come under the spotlight following the death of 11 patients, one of whom died just hours after taking her first dose. According to Novartis, the Swiss pharmaceutical company that sells the drug under the name Gilenya, four of the remaining ten deaths were cardiac-related and six remain unexplained. The drug is now under review to determine whether it was involved in the deaths. “There have been more than 30,000 patients who have taken this drug, so we need to keep things in perspective,” says O'Connor. “These developments suggest a need for caution pending the acquisition of more information.”

Nevertheless, despite such safety scares, Coles is still optimistic that alemtuzumab will pass the safety test. Graves' disease and ITP are serious conditions but they can both be treated. What's more, it seems that the risk of such complications do not apply equally to everyone. “We can identify in advance of treatment people who are at high risk of developing an autoimmune disease with an accuracy of about 90%,” Coles says. The process simply involves screening patients for a biomarker7, serum IL-21, he adds.

Tough choices

While great strides have been made in treating relapsing–remitting MS, the biggest challenge now lies in finding therapies for progressive MS, says O'Connor. So far, none of the treatments seem to provide much help for people with advanced MS. It's possible, he concedes, that by this stage of the disease the nerves have sustained too much damage, and remyelination will not help.

There is hope, however. Biogen Idec is developing two treatments that not only promote myelin repair, but also seem to encourage repair of the damaged nerves. What's more, because neither of the drugs modulates the immune system, they should be much safer, says Biogen Idec neurobiologist Sha Mi. One, a monoclonal antibody now in phase I trials, works by blocking a protein called LINGO-1, which is responsible for down-regulating the production of myelin8,9, says Mi. This should result in more myelin. The second treatment relates to a potential pathway involving a protein called Death Receptor 6 (DR6)10. Mi found that when DR6 was blocked by antibodies in rats, oligodendrocytes could repair the myelin and improve nerve function. She also found that blocking DR6 reduces T-cell-mediated inflammation.

All these drugs certainly offer genuine hope for MS sufferers, even if they sometimes bring certain risks. And this may mean that patients face some tough decisions about which treatments they should choose. But at least now — perhaps for the first time — they actually have options.