801

BULLETIN BOARD

ISSN 1475-070810.2217/1475-0708.5.6.801 © 2008 Future Medicine Ltd Therapy (2008) 5(6), 801–805

BULLETIN BOARDHighlighting the latest news and research in therapy

in the news...Adalimumab may be an effective

treatment for JIA

Neuroblastoma: fi rst example of

pediatric cancer oncogene foundpg 802

New research suggests that use of

antipsychotic drugs is associated with a higher risk of stroke pg 802

Approved antihistamine may be used

to treat Alzheimer’s disease pg 803

The careHPV test shows promise as a

primary screening method for cervi-cal cancer prevention in low-resource regions pg 804

Recent drug approvals pg 805

Results from a new study suggest that adali-mumab may be an effective treatment for children suffering from juvenile rheumatoid arthritis. Juvenile rheumatoid arthritis, also known as juvenile idiopathic arthritis, is the most common form of arthritis affecting children. It is an autoimmune disorder characterized by joint swelling, stiffness and occasionally reduced motion. As the tumor necrosis factor has been shown to have a pathogenic function in juvenile rheuma-toid arthritis, the researchers assessed the effectiveness and safety of adalimumab, a TNF inhibitor derived from a fully human monoclonal antibody, in children.

The study included 171 patients aged 4–17 years suffering from active juvenile rheumatoid arthritis. All of the patients had been prescribed nonsteroidal anti-infl am-matory drugs previously. After stratifying the patients according to methotrexate use, they were given 24 mg of adalimumab (brand name Humira®) per square meter of body surface area subcutaneously every other week for a total of 16 weeks. At this point, patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response were randomized to receive either adalimumab or placebo in a double-blind manner every alternate week for up to 32 weeks. This response measure is an indication of the improvement in symptoms of the patient.

In the group not receiving methotrexate, 74% of the patients were found to have an ACR Pedi 30 response at week 16, whereas in the group who had been treated with methotrexate, 94% had an ACR Pedi 30 response at this time point. The patients who had an ACR Pedi 30 response were the ones who had shown an improvement in the symptoms and were eligible for the next phase of the study. The researchers found that amongst the patients who did not receive methotrexate, 43% of those treated with adalimumab and 71% of those given

placebo reported disease fl ares. The latter was the main outcome measure of the study. In the other group consisting of the metho-trexate-treated patients, 37% of those treated with adalimumab experienced disease fl ares, as did 65% of those given placebo. These results were statistically signifi cant.

After 48 weeks of treatment, the scien-tists found that the percentages of patients amongst the methotrexate-treated group, who had an improvement in their symp-toms (as indicated by the ACR Pedi 30, 50 or 70 responses) were signifi cantly greater for those treated with adalimumab compared with those receiving placebo. The differ-ences between those receiving adalimumab and those receiving placebo in the group of non-methotrexate-treated patients were not statistically signifi cant. The response rates were maintained for 104 weeks of treat-ment. A total of 14 serious adverse events, out of which half were serious infections, that could be related to adalimumab were reported in the study.

Owing to insuffi cient sample size and duration, the researchers could not estab-lish the risks for rare adverse events. In addition, they were also unable to identify differences between patients treated with methotrexate and those not receiving it due to insuffi cient power of the study.

“Adalimumab, alone or in combination with methotrexate, appears to be an effi ca-cious option for the treatment of children with polyarticular juvenile rheumatoid arthritis. Responses were sustained through two years of continued treatment,” the authors stated.

Source: Lovell DJ, Ruperto N, Goodman S et al.;

Pediatric Rheumatology Collaborative Study

Group; Pediatric Rheumatology International

Trials Organisation: Adalimumab with or without

methotrexate in juvenile rheumatoid arthritis. N.

Engl. J. Med. 359(8), 810–820 (2008).

Adalimumab may be effective treatment for juvenile rheumatoid

arthritis, report suggests

The autoimmune disorder juvenile rheumatoid arthritis may be effectively treated with the TNF inhibitor adalimumab

Therapy (2008) 5(6)802 future science group

BULLETIN BOARD

Scientists at the Children’s Hospital of Philadelphia, USA, have discovered the group of genetic mutations responsible for the development of the inherited aggressive childhood cancer neuroblas-toma. The mutations have also been implicated in the high-risk form of spo-radic neuroblastoma, the most common type of the disease. Germline mutations in the anaplastic lymphoma kinase (ALK ) gene were detected in several cases of familial neuroblastoma under investigation at the Children’s Hospital, with researchers drawing on data accu-mulated worldwide. This current study also represents the fi rst account of a childhood cancer caused by oncogenic mutations, and helps to further estab-lish ALK as a crucial neuroblastoma oncogene.

“This discovery enables us to offer the fi rst genetic tests to families affected by the inherited form of this disease,” said pediatric oncologist Dr Yael P Mossé, of The Children’s Hospital of Philadelphia, PA, USA, the fi rst author of the study. “Furthermore, because there are already drugs in development that target the same gene in adult cancers, we can soon begin testing those drugs in children with neuroblastoma.”

Neuroblastoma is the most com-mon solid tumor of early childhood, accounting for approximately 8% of all childhood cancers, but is, however, responsible for 15% of all cancer deaths

in children owing to the aggressive nature of the disease.

The current study performed a genome-wide scan of DNA samples from 20 families with familial neuro-blastoma, with the initial identifi cation of a signifi cant predisposition locus at chromosome bands 2p23–24. Further investigation of that region on chromo-some 2 revealed three separate germline missense aberrations in the tyrosine kinase domain of the ALK gene com-mon to eight of the families under observation.

Next, the researchers focused on whether ALK mutations could be somatically acquired in the more common occurrence of noninherited neuro blastoma. Tumor samples from 194 high-risk cases of the sporadic form of the disease were analyzed, and ALK mutations were found in over 12% of cases.

These discoveries thus offer amenable therapeutic drug targets for the inhibi-tion of tumors, and several pharma-ceutical companies are currently devel-oping ALK inhibitors, with one already undergoing early-phase adult clinical trials.

Source: Mossé YP, Laudenslager M, Longo L

et al.: Identifi cation of ALK as a major familial

neuroblastoma predisposition gene. Nature

doi:10.1038/nature07261 (Epub ahead of

print) (2008).

Neuroblastoma: fi rst example of pediatric cancer oncogene found

New research suggests that use of antipsychotic drugs is associated with a higher risk of stroke

A recent study from the London School of Hygiene and Tropical Medicine, UK, has investigated the association between the use of typical and atypical antipsychotic drugs and the incidence of stroke in patients with and with-out dementia. Published in the British Medical Journal, the results suggest that all antipsy-chotics are associated with an increased risk of stroke, and that the risk may be higher in patients receiving atypical antipsychotics com-pared with those receiving typical antipsychot-ics. In addition, people with dementia appear to be at a higher risk of an associated stroke compared with those without dementia.

Participants included in the study were identifi ed with the use of UK-based electronic primary care records of more than 6 million patients from over 400 general practice clin-ics. A total of 6790 patients (905 of whom had received an atypical antipsychotic) with a recorded incident stroke and at least one pre-scription for any antipsychotic drug before the end of 2002 were included in the analysis. At the time of fi rst drug exposure, the median patient age was 80 years and 64% were women.

The results demonstrated that use of any antipsychotic drug was associated with a rate ratio for stroke of 1.73. In addition, the rate ratio for stroke among patients taking typical antipsychotics was 1.69 compared with 2.32 among patients taking atypical anti psychotics. In patients receiving any antipsychotic drug, the rate ratios were 3.50 for those with demen-tia compared with 1.41 for those without dementia

“This implies that the use of antipsychotics might be acceptable in elderly patients without dementia, although as with all treatment choices, a wider consideration of all potential risks and benefi ts would need to be taken into account,” comment the researchers.

Source: Douglas IJ, Smeeth L: Exposure to antipsychot-

ics and risk of stroke: self controlled case series study.

Br. Med. J. (2008) (Epub ahead of print).

About the Bulletin BoardThe Bulletin Board highlights some of the most important events and research in medicine.If you have newsworthy information, please contact:Charlotte Barker, Managing Commissioning Editor, Therapy, Future Medicine Ltd, Unitec House, 2 Albert Place, London N3 1QB, UK; Tel.: +44 (0)20 8371 6090; Fax: +44 (0)20 8343 2313; c.barker@futuremedicine.com

www.futuremedicine.com 803future science group

BULLETIN BOARD

Approved antihistamine may be used to treat Alzheimer’s disease

Dimebon, a drug once approved as an anti-histamine in Russia, has now been shown to improve cognitive decline in patients with Alzheimer’s disease. Lead author of the study, Dr Rachelle Doody, profes-sor of neurology at the Baylor College of Medicine in Houston, TX, USA, is encouraged by the results.

The study, which was conducted at 11 sites in Russia, enrolled 183 patients with mild-to-moderate Alzheimer’s dis-ease. Patients were randomized to receive either oral dimebon, 20 mg twice-daily or placebo. The effects of dimebon were analyzed over a 12-month period, where patient progress was assessed on fi ve dif-ferent outcomes: thinking and memory

ability, overall function, psychiatric and behavioral symptoms, and ability to per-form daily activities. During this time, the researchers observed a continued improve-ment in patients. “What we saw in the clin-ical trial is that people on the medication continued to improve over time. Those on placebo continued to decline”, said Doody. “Usually at this point in a drug’s develop-ment, we are happy to see improvement in one of the outcome measures, we saw improvement in all fi ve.”

The data suggests that dimebon is safe, well-tolerated and has caused signifi cant improvements in the clinical course of patients suffering from mild-to-moderate Alzheimer’s disease. Currently, the safety,

tolerability and effi cacy of dimebon is being evaluated in an ongoing Phase III study in several international locations, including the USA.

“As we continue research, we hope to replicate these results,” Doody said. “My belief is that this drug will turn out to be useful for Alzheimer’s disease, regardless of the stage of the disease.”

Source: Doody RS, Gavrilova SI, Sano M et al.:

Effect of dimebon on cognition, activities of daily

living, behaviour, and global function in patients

with mild-to-moderate Alzheimer’s disease: a

randomised, double-blind, placebo-controlled

study. Lancet 372(9634), 207–215 (2008).

The careHPV test shows promise as a primary screening method for cervical cancer prevention in

low-resource regionsA new rapid screening test for the human papillomavirus (HPV), created for use in developing countries, has been tested recently on a group of local women in the Shanxi province in eastern China and has been shown to be 90% accurate in detect-ing precancerous cervical disease.

The test in question is called the careHPV, and was designed by Attila Lorincz, a Professor of Molecular Epidemiology at Barts and The London School of Medicine and Dentistry, UK. It can be used to carry out screening in rural areas by personnel with minimal training. The test is able to detect 14 high-risk types of carcinogenic HPV and it can be per-formed in approximately 2.5 h.

Countries in the developed world have the necessary infrastructure to provide cytologic screening, which has led to a 50–80% decrease in mortality. However, to date it has been diffi cult to use cyto-logic screening in low-resource settings;

there have been problems with taking smears and analyzing them correctly.

Research into the development of a rapid, simple and cheap HPV DNA screen-ing test that could be used in rural and low-resource regions was carried out in collabo-ration with the Program for Appropriate Technologies in Health (PATH, Seattle WA, USA) and funded by the Bill and Melinda Gates Foundation.

“The new test needs to be studied in many countries to confi rm its suitability

for cervical cancer screening on the global stage.”

The test is modifi ed from the Hybrid Capture test, the gold-standard routine HPV DNA test, which was created by Lorincz for use in developed countries. It is a signal amplifi cation assay that can be per-formed in a small bench-top work space.

There is no requirement for mains electric-ity or running water. The short assay time of approximately 2.5 h allows testing and clinical follow-up on the same day.

Using the prototype careHPV test, a total of 2388 women between the ages of 30 and 54 years, from the Shanxi province in China, were screened. The sensitivity of the test to detect precancerous cells was found to be 90%. “The clinical performance of my new HPV test in China appears promising – it is based on decades of research and I hope it will be employed widely to save the lives of millions of women. The new test needs to be studied in many countries to confi rm its suitability for cervical cancer screening on the global stage,” commented Lorincz.

Source: Qiao YL, Sellors JW, Eder PS et al.: A new

HPV-DNA test for cervical-cancer screening in

developing regions: a cross-sectional study of clini-

cal accuracy in rural China. Lancet Oncol. (2008)

(Epub ahead of print).

Therapy (2008) 5(6)804 future science group

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