As concerns grow over Elan's drug Tysabri, Joe Armstrong asks what now for sufferers of MS?
Following the high profile rise and fall of Elan's Tysabri drug - with yet another diagnosis of a serious brain disorder linked to the drug announced last week - where do treatment hopes lie for multiple sclerosis (MS) sufferers? What is the best approach to managing this progressive illness?
According to Dr Niall Tubridy, consultant neurologist at St Vincent's Hospital, Dublin, when a patient presents with acute MS attacks (also known as relapses or flare-ups), such as weakness, visual problems or unsteadiness, they may be put on an intravenous one-to-two hour a day course of steroids for three to five days. This reduces the inflammation around the area in question and expedites recovery. Intravenous steroids do not, however, alter the long-term disease course.
If that doesn't work, occasionally another acute treatment is plasma pheresis. This involves having a drip in the arm for two or three hours a day for up to five days, the intention of which, in simple language, is to strain the blood of bad things. Since MS is a disease of the brain and spinal cord, the consultant would consider drugs to address the site of the flare up. For instance, baclofen could be administered for spasticity of the legs.
As an aside, Tubridy notes that one sometimes hears calls for the legalisation of cannabis to "cure" MS. In fact, there is no cure for MS, although cannabis might help relieve one or two of its symptoms.
MS can affect the bladder, causing urinary problems. Anticholinergic drugs might be offered to address urinary frequency and urgency, while urinary retention, that is, wanting to urinate but being unable to do so, can be treated with intermittent catheterisation to empty the bladder.
Physical therapy would also be availed of for treating some of the symptoms such as leg stiffness.
Beyond addressing only the symptoms, there are several immuno-modulatory therapies, also known as disease-modifying agents. These are used to decrease the frequency and severity of MS attacks.
There are three interferons: Rebif, Avonex and Betaferon (known as Betaseron in the US). These reduce the relapse rate for people with Relapsing-Remitting MS (RRMS). Some 85 per cent of MS patients have RRMS. They have relapses causing acute worsening of neurological function, followed by partial or complete recovery periods.
According to Tubridy, interferons reduce relapse rates by about one-third. "In some cases, they are thought to reduce disease progression, although the evidence for this isn't as clear-cut," he says.
A fourth immuno-modulatory therapy, glatiramer acetate, works in a slightly different manner but has similar efficacy, says Tubridy.
Mitoxantrone, a chemotherapy drug, can be used in more severe cases if interferons don't work. But it's a harsh treatment. It is given by intravenous injection (a needle in the vein) every three months but the total lifetime dose a patient may receive is limited.
The Elan drug Tysabri was not widely available in Ireland but it was used on a named patient basis. Fewer then 10 patients in Ireland would have used it. It was given every two weeks by intravenous injection. In February 2005 it appeared that two patients taking Tysabri (not in Ireland) in combination with Avonex had developed PML, a rare and serious brain condition. One patient died. Subsequently, a third case (and second fatality) came to light but, because PML is so rare, it had been initially misdiagnosed.
Last Thursday, it was reported that a fourth patient may have contracted PML. As in two of the previous three cases, this latest case, if confirmed, also involved Tysabri being taken with Avonex. (The patient who wasn't taking Avonex had Crohn's disease, not MS.)
A spokesperson for Elan said that the company wouldn't be commenting "on individual cases until the safety evaluation is completed". This refers to the safety review being carried out on all 3,000 patients who have used Tysabri, expected to be completed this summer.
However, if the fourth case is confirmed, Elan will have to announce this to the stock market.
Tysabri was voluntarily removed from the market last February, although Kelly Martin, chief executive of Elan, recently expressed his confidence that the drug would come back on the market. His confidence may be tempered by the emergence of the unconfirmed fourth case of PML.
Tubridy says there may have been a synergistic effect between Avonex and Tysabri. The latter had appeared to be working well, according to one-year trial data before that. If interferons reduced attacks by one-third, Tysabri reduced them by about two-thirds. Also, MRI exams showed that Tysabri reduced the number of lesions or white spots on scans.
Speaking at a recent symposium on MS held in Malta attended by some 500 doctors and neurologists, Randall T. Schapiro, clinical professor of neurology at the University of Minnesota , said that the prevention or postponement of long-term disability is the most important therapeutic aim of disease-modifying treatments in MS.
Noting that long-term disability in MS evolves slowly over many years, he said there is a paucity of data on the long-term effects of immunomodulating treatments for MS.
There is a current 16-year long-term follow up study to evaluate patients who were treated in the first pivotal trial with Betaferon. Its objectives are to investigate the long-term safety and effectiveness of Betaferon over 16 years. It will provide information for the longest controlled study ever conducted in MS.
Preliminary results show that 50 per cent of patients who used 250 mcg Betaferon in the initial trial are able to walk unaided or using aids compared to 41 per cent who used a placebo for the first two years. Some 6 per cent of patients who used Betaferon have died compared to 18 per cent who used a placebo.
However, Tubridy's view is that these findings, while important, are not spectacular. The placebo was taken for only two years. For the past 14 years, everyone has been on drugs, he observes.
Schapiro maintains that even before clinical symptoms are present, irreversible axonal loss (nerve damage) occurs due to inflammation.
He argues that neuroprotection potential is strongest at the earliest stages of MS and that interferon may protect the myelin layers and axons from further injury.
Noting that "Drugs don't work in patients who don't take them" and that, on average, half of patients prescribed drugs for chronic conditions stop taking them after a year, Schapiro called for a multidimensional approach involving neurologists, MS nurses, family doctors, neuro-psychologists, ergonomic therapists, physical therapists and social workers.
Schapiro said that adherence after 12 months was some 90 per cent with the support of MS nurses, compared to only some 65 per cent for patients remaining on therapy without nurse support. In this regard, Tubridy notes the crucial role MS nurses play in Ireland, which has a direct benefit for patients and their carers.
Schapiro said that all the treatments work but some patients cannot tolerate side effects of certain drugs, such as injection site reactions or flu-like symptoms. What is prescribed depends on the individual patient.
Ann Strunks, campaign and communications manager with MS Ireland, said: "We are cautiously optimistic that Tysabri will come back. It would be great if it did. It doesn't stop MS but it holds progression of the disease. Trials were spectacular. This rests entirely now in the hands of the FDA. Will there be more cases of PML to be uncovered? So people should keeping taking their current medication and/or therapies."
Joe Armstrong is an author and journalist specialising in health issues.