Drug Update from Eular 2007
Taken from NRAS magazine, Summer 2007
Early use of corticosteroids with methotrexate
A trial presented by rheumatologist Ernest Choy, from King’s College London, showed that taking corticosteroids as well as methotrexate during the early stages of rheumatoid arthritis could provide more protection than methotrexate alone against joint damage.
467 people diagnosed with RA during the previous two years were divided into four groups. The first was treated with methotrexate alone, whilst the three others also received either prednisolone, immunosuppressant cyclosporine A or both.
Compared to methotrexate alone, the three other treatment strategies were linked to a decrease in new joint damage of around 50% at two years, with no significant differences between the groups.
The drugs differed in terms of their speed of action. Methotrexate and cyclosporine A acted slowly on the incidence of erosions and the decrease was mainly observed during the second year. Prednisolone achieved similar results from the first year, with stabilisation during the second year.
The tritherapy was found to be superior to the other regimens in terms of disease activity and patient quality of life, defined by the disease activity score (DAS) and the Health Assessment Questionnaire (HAQ) respectively.
The decrease on the DAS seemed to be mainly due to the prednisolone and much less to the cyclosporine A, despite the latter's effect on erosions.
Dr Choy concluded that a methotrexate-glucocorticosteroid combination was more effective than methotrexate alone in slowing subsequent disease progression as long as it was administered early enough, during the "window of opportunity".
Could Increased Alcohol Intake be Associated with a Decreased Risk of Developing Rheumatoid Arthritis?
New data presented suggests that alcohol may protect against rheumatoid arthritis, with three units a week showing protective effects and ten units a week being more protective still. An alcohol consumption of three units per week or more also reduced the risk associated with smoking or genetic predisposition to RA. The findings could improve understanding of the effects of lifestyle on the risk of developing RA and pave the way for new potential treatment approaches based on the apparently beneficial effects of alcohol.
Professor Tore Kvien, President of EULAR, said, "These are very interesting findings and are the first observation, from epidemiological data, which now should be confirmed by further clinical studies before a firm conclusion can be achieved. Furthermore, we assert the need for caution in the interpretation of these data. The misuse of alcohol is associated with a number of social and medical problems and any positive implications of alcohol must be coupled with the importance of moderation in alcohol consumption in accordance with standard national guidelines."
Cimzia (certolizumab pegol) Effective in Reducing Signs and Symptoms of Rheumatoid Arthritis
New pivotal data from two Phase III studies called RAPID 1 and RAPID 2 showed that CIMZIA (certolizumab pegol) which is the first PEGylated, Fc-free anti-TNF (another anti-TNF drug not yet licensed in the UK which works differently to the three anti-TNF drugs already in use in the NHS), combined with methotrexate therapy had a rapid and significant effect in reducing the signs and symptoms of active rheumatoid arthritis compared with methotrexate alone.
RAPID 1 and RAPID 2 demonstrated that effective results could be achieved with a 200 mg every other week dose of certolizumab pegol. Certolizumab pegol was also shown to work very quickly.
"These results are significant” commented Professor Edward Keystone, Professor of Medicine, University of Toronto, Canada. "The consistency of the RAPID data confirm that certolizumab pegol may provide a valuable new treatment option for patients with this condition."
The safety and tolerability profile of certolizumab pegol in both studies was consistent with that expected of an anti-TNF agent.
In another study presented at the meeting, the efficacy of certolizumab pegol at 400 mg every four weeks as monotherapy was compared with that of placebo in treating the signs and symptoms of RA in patients who had previously failed on one or more courses of a DMARD. The ACR20, ACR50 and ACR70 responses (ACR 20 etc. is a scoring mechanism used in clinical trials – we have reported on this in previous newsletters) were significantly higher in the certolizumab pegol treated arm than in the placebo treated arm.
"These data show the potential of certolizumab pegol to safely and effectively treat patients who have previously failed disease modifying antirheumatic drug treatments," added Prof Josef Smolen, Chairman of the Department of Rheumatology, Medical University of Vienna, Austria. "In addition, certolizumab pegol could provide a valuable option in patients who are unable to take or cannot tolerate methotrexate."
Preparation for a regulatory submission for Cimzia in the treatment of RA is ongoing, with filing planned by the end of 2007.
More good news for when ‘I want to work…’
With the publication in May of NRAS’s own “I want to work…” survey, the public learned what people living with RA have known for a long time: that one in three people with RA in the UK lose their jobs after developing the condition and a staggering 86 per cent of respondents experienced, or expected, barriers to staying in their job.
But there is good news for people wanting to stay in work, underscored in new data from studies presented at the meeting of the European Leagues against Rheumatism congress (EULAR) in June in Barcelona.
In the PROWD study, first highlighted in the Winter 2006 edition of this newsletter, significantly more patients taking methotrexate alone reported job loss and/or imminent job loss over four years compared with those treated with a combination of the anti-TNF treatment Humira ® (adalimumab ) and methotrexate. Two other studies showed that treatment with Humira and methotrexate in combination halved the number of missed workdays for both paid workers and homemakers compared to methotrexate alone, and that people on combination treatment were more likely to work longer periods and continue working, compared to patients taking a disease modifying anti-rheumatic drug (DMARD). Also, patients in the third study were more likely to achieve disease remission.
Professor Paul Emery, the lead investigator of the PROWD study said, “While the long-term efficacy, safety and convenience of adalimumab has been widely established, the studies demonstrate early treatment with adalimumab plus methotrexate reduces joint damage, slowing progress of disease and disability, which keeps RA patients at work and working longer.”
As highlighted in our survey, helping people to stay in work is currently a key priority for the UK government, and there is growing consensus that achieving this will require greater ‘joined-up’ thinking and action from different Government departments to support people appropriately and make such treatments more widely available across the UK.
Lower doses of Enbrel (etanercept) can maintain RA remission
A small study has shown that rheumatoid arthritis remission may be maintained when doses of Enbrel (etanercept) are halved. Etanercept is currently indicated at a dose of twice 25 mg/week or 50 mg once weekly, which is equally effective.
According to results presented by Leonardo Punzi from Italy, remission may be maintained with a single dose of 25 mg etanercept per week rather than two. This would lower the cost of treatment and possibly the incidence of adverse effects.
One hundred and five patients who had been in remission for at least three months with two doses of etanercept per week, were randomised into two groups. One group continued treatment at the same dose, the other only received a single 25 mg dose every week.
After six months, results were similar in both arms. 73% of the study arm patients were still in remission compared with 88.6% of control arm patients. The difference was not significant and physical function also remained unchanged. The researchers found no significant difference in terms of adverse effects.
Of the 14 patients in the study arm who did not maintain remission, nine achieved it again when they returned to the original dosage. The five others had to switch to a different anti-TNF drug.
However, the study lacked information on the safety of this strategy in terms of joint erosion.
Orencia® (abatacept), a new, novel treatment for people with moderate to severe rheumatoid arthritis
Orencia® (abatacept) was launched in June in the UK by Bristol-Myers Squibb Pharmaceuticals Limited (BMS) for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs (DMARDs) including at least one anti TNF treatment; this followed its licensing by the European Commission on May 21, 2007.
Abatacept is licensed in the UK for use in combination with methotrexate and has been studied extensively in clinical trials involving over 1,995 patients. Many of these studies were presented at EULAR this year and BMS had a large stand with much information.
“Despite significant advances in treatment, there are many patients with rheumatoid arthritis whose disease is not adequately controlled by existing treatments. The availability of Orencia is a crucial step forward in the treatment of rheumatoid arthritis. We have seen sustained clinical benefits with Orencia, including reduced joint damage and less pain, which lead to significant improvements in people’s quality of life,” said Professor Paul Emery, Clinical Director, Rheumatology, Leeds Teaching Hospitals Trust.
Abatacept has a unique mode of action and is the first treatment to selectively inhibit the activation of T-cells. T-cells are thought to initiate the inflammatory cascade in rheumatoid arthritis and are integral to the development and progression of the disease. Full activation of T-cells requires two signals: a main one and a second, co-stimulatory signal. Abatacept interrupts the inflammatory process associated with rheumatoid arthritis by selectively modulating one of the necessary co-stimulatory activation signals. It is a selective co-stimulation modulator of T-cell activation. By doing so, it results in the down-regulation of the inflammatory process, reducing the joint damage and pain.
An article by Dr Andrew Ostor on Orencia is now available on the NRAS website or by calling the NRAS office.
Additional Data on CRx-102 Presented
CRx-102 is a treatment currently in trial which is a synergistic combination of the two agents, dipyridamole and prednisolone and studies on its mode of action and efficacy in the treatment in osteoarthritis (OA) were presented in posters.
However, it is also being trialled in the treatment of RA and in a satellite symposium at Eular, Dr John Kirwan from Bristol Royal Infirmary and principal investigator in the CRx-102 rheumatoid arthritis trial, presented data indicating that CRx-102 treated patients experienced significantly less fatigue than those on placebo.
"This data on CRx-102 provides additional evidence of its clinical benefit and novel mechanism of action which will prove extremely helpful as we design future studies and more specifically define the clinical benefit of CRx-102 and its potential role within the RA and OA treatment pathways," commented Alexis Borisy, President and CEO of CombinatoRx.