APM Health Europe: Healthcare Business News for European Pharmaceutical Markets

PARIS, April 3 (APM) - Allergies and asthma which stimulate inflammation seem to have a protective effect against brain tumours, whilst antihistamines which control inflammation could eliminate this protection, according to a study presented on Sunday at the 97th Annual Meeting of the American Association for Cancer Research (AACR) in Washington.

First generation antihistamines cross the blood-brain barrier and have significant sedative effects. H1 receptors targeted by these drugs are found on glial cells and seem to have an effect on the neural inflammatory response, say Dr Michael Scheurer and his colleagues from the MD Anderson Cancer Center in Houston, Texas.

The researchers based their study on recent findings which suggested that inflammatory activity in the brain could protect against the development of brain tumours and that people suffering from allergies and asthma had a reduced risk of developing gliomas.

They analysed data from a cohort of 830 patients with brain tumours and 831 controls. The group included 339 cases of glioblastoma multiform, the most aggressive and lethal form of brain tumour, 117 cases of anaplastic astrocytoma and 154 cases of low-grade gliomas.

The researchers found that a history of asthma and allergy was significantly protective against these three types of brain tumour. The risk of developing a glioblastoma was reduced by 35%, of anaplastic astrocytoma by 51% and of low-grade glioma by 36%.

They also found that study participants who took antihistamines had a higher risk of developing a brain tumour. The risk of developing anaplastic astrocytoma was multiplied by three and low-grade glioma by two. The risk of glioblastoma was also increased (by 26%), but not significantly.

"Brain tumours are exceedingly rare, and many, many people use antihistamines, so we certainly are not suggesting a direct connection between the two," said the study's lead author, Prof Melissa Bondy.

What the results show is rather that "allergies and asthma produce enough inflammation in the brain to keep immune system cells active, and that this surveillance works to eliminate cancer beginning to develop in the brain," Dr Scheurer explained.

In people who were susceptible, those who have allergies or asthma and do not take antihistamines could be protected to a certain extent against brain tumours. But those who take antihistamines could reduce this protection and thus increase their risk of brain tumour, he added.

The researchers also asked participants if they had had chickenpox ,as latent infection is known to stimulate low level inflammation in the brain, which could also provide protection against tumour development. They found that people who had had chickenpox had a significantly reduced risk of anaplastic astrocytoma. For the other two tumours, the effect was not significant.

Finally, they also analysed the use of anti-inflammatory drugs (COX-2 inhibitors) and found a significant reduction of 31% in the risk of glioblastoma in users. However, COX-2 inhibitors were not found to protect against the other two types of brain cancer.

There are several ways to produce inflammation of the brain and COX-2 inhibition could be beneficial, the study authors note.

The objective is now to find which genes are involved and to see if certain people are genetically predisposed.

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sylvie.lapostolle@apmnews.com
[2029] 03/04/2006 06:22 GMT - CANCER NEURO RESPIR

PARIS, April 3 (APM) - Hundreds of thousands of counterfeit Viagra tablets seized by French customs at Paris' Charles de Gaulle airport in February and March contained the right amount of sildenafil although they were easy to recognise as fakes, Pfizer has told APM.

Between February 28 and March 14, customs officers at the airport made five seizures of counterfeit Viagra, a total of more than 360,000 tablets. The drugs were all in transit from India and destined for South America and Africa.

"The analysis shows that there are about the same quantities of sildenafil [as Viagra], but the appearance of the tablets was not the same," a Pfizer spokesperson told APM.

The boxes of counterfeits had "fanciful names," she added. Customs officials had already said when they announced the seizures that these were "crude imitations" rather than sophisticated copies.

The Pfizer spokesperson said that the company systematically carried out analyses on counterfeit drugs seized by customs - which are then destroyed.

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marie.julien@apmnews.com
[2030] 03/04/2006 06:27 GMT - GYNAECO

PARIS, April 3 (APM) - A study which found a high level of uterine perforation in women using Schering's levonorgestrel-releasing IUD, Mirena, is "tainted by important methodological biases, the German group has told APM.

As reported last week, Belgian and Dutch researchers reported in the journal Contraception results of a survey of hospital gynaecologists from the Dutch province of Limburg. The authors estimated the incidence of uterine perforation linked to Mirena insertion at 2.6 per 1,000 - twice as high as that reported for copper IUDs.

"It is a non-comparative study and the data gathered only concerns one type of IUD; the authors' attempted comparison is based only on a review of published research," Schering said.

"Moreover, the available data do not include certain important elements - such as the size of the uterine cavity - for all patients (9 cases out of 21)".

Schering also says that the method of calculating perforation incidence "does not appear to be pertinent nor rigorous, as the data-gathering period (1999-2002) does not coincide with the reference period estimating the number of products inserted - a different and shorter period, from mid-2000 to 2002".

The company emphasises that it actively monitors and analyses all reported data concerning adverse effects of these products.

"The incidence of perforations notified worldwide for the LNG IUS [levonorgestrel-releasing intrauterine system] for the same period is 0.18 per 1,000 insertions," says Schering.

The company adds that the latest recommendations from the UK's Royal College of Obstetricians and Gynaecologists, in 2005, indicates that the risk of perforation with copper IUDs or LNG IUSs "is low, less than 0.1%".

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carole.debray@apmnews.com
[2031] 03/04/2006 08:06 GMT - GYNAECO

LONDON, April 3 (APM) - A combination of Antisoma's novel cancer therapy AS1404 and Genentech/Roche's Avastin (bevacizumab) has the potential to become a blockbuster cancer treatment, following encouraging pre-clinical data, a spokesman for the UK biotech told APM on Monday.

Shares in Antisoma rose 5% in morning trade on the London stock market after the group said the pre-clinical data showed AS1404 is much more effective than Avastin alone at inhibiting growth of colon and lung tumour xenografts.

The pre-clinical findings were presented on Sunday to the American Association of Cancer Research (AACR).

The spokesman told APM that AS1404 as a combination treatment had the potential to achieve blockbuster status.

"This is the vanguard of a whole new class of drugs. The potential market for lung and prostate cancers is huge."

Avastin already has blockbuster status as a treatment for metastatic colorectal cancer in combination with standard chemotherapy.

AS1404 is currently the focus of three ongoing Phase II trials for lung, prostate and ovarian cancers. Last October, the group announced positive preliminary Phase II data when AS1404 is used with standard chemotherapy drugs carboplatin and paclitaxel, to treat lung cancer.

Antisoma, which has an existing oncology collaboration with Roche, said the latest data supports the possibility that future trials could also evaluate a quadruplet regimen including Avastin as well as AS1404 and the two chemotherapy drugs.

The Antimsoma spokesman told APM developing AS1404 further will depend on the ongoing Phase II trials and in particular, lung cancer data of time to progression, expected in the first half of this year.

Colorectal cancer represents a potentially large indication for AS1404 that has not yet been targeted in Antisoma's clincial programme, the company said in the statement.

Dr Ursula Ney, Chief Operating Officer, said: "The very striking interaction between AS1404 and Avastin shown by these experiments is a really promising development, pointing to additional applications for AS1404, a drug which already has very substantial market potential."

AACR PRESENTATION

AACR delegates heard that AS1404 and Avastin each slowed the growth of colon and lung cancer xenografts when used alone.

"However, the combination of the two drugs was markedly more effective against both tumours," Antisoma said in the statement.

The mean time taken for tumours to quadruple in size was compared between animals receiving the drugs and untreated controls.

For the colon cancer (HT29) xenografts, Avastin added 17 days to tumour quadrupling time and AS1404 added 29.

Tumours treated with the combination took 40 days longer than conrols to quadruple in size. With the lung cancer xenografts, Avastin added 42 days (compared with controls) to the time to reach that threshold and AS1404 added 32 - the combination added 79 days.

"These findings provide new scientific evidence to support the concept of combining vascular disrupting agents (such as AS1404) that act on established tumour blood vessels with anti-angiogenic drugs (such as Avastin) that inhibit the growth of new vessels into tumours," the statement added.

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nick.hudson@apmnews.com
[2032] 03/04/2006 08:20 GMT - CANCER

BERLIN, April 3 (APM) - Germany's Merck announced on Monday that it had received approval from the European Commission for the marketing of Erbitux (cetuximab) to treat head and neck cancer.

The drug, which is already for use in metastatic colorectal cancer, is now also indicated for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in combination with radiotherapy.

It is the first targeted cancer therapy to be approved for SCCHN.

The decision follows last month's approval by the U.S. Food and Drug Administration, and in December by SwissMedic.

A Merck spokeswoman declined to discuss marketing strategy.

The approval is based on a Phase III study of 424 patients in which median survival improved by nearly 20 months and the time from treatment start to spread of the tumour beyond the head and neck improved by 9.5 months, compared to radiotherapy alone.

"Head and neck cancer is an extremely challenging cancer type, with five-year survival rates typically low," Dr James Bonner, University of Alabama, principal investigator for the study, said in a statement.

"Erbitux offers the potential for improved control and extended survival even in severe disease."
Erbitux, which was originally discovered by U.S. biotech firm ImClone Systems Inc, has already been approved in 53 countries for treatment of metastatic colorectal cancer.

Merck has the licence to market the product in Europe while ImClone's U.S. marketing partner is Bristol-Myers Squibb.

Erbitux posted sales of 218 million euros in 2005 and is considered to have a peak sales potential of $1 billion (830,000 million euros).

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vincent.landon@apmnews.com
[2033] 03/04/2006 08:49 GMT - CANCER

SAN DIEGO, April 3 (APM) - Orphan Medical/Jazz Pharmaceuticals/UCB's Xyrem (sodium oxybate) seems to relieve pain and improve sleep quality in patients with fibromyalgia, a study presented on Sunday at the annual meeting of the American Academy of Neurology (AAN) in San Diego suggests.

The study on sodium oxybate was presented in poster form at a special session on sleep disorders, the first scientific session of the AAN meeting which is expecting 10,000 attendees between now and next Saturday.

In this study financed by Orphan Medical, Todd Swick, the director of the Houston Sleep Center, evaluated sodium oxybate in 188 patients with fibromyalgia.

They stopped taking their fibromyalgia treatment three weeks before the beginning of the trial. During this period, pain symptoms were evaluated and patients were found to have a mean score of 65 points on a visual analogue scale (VAS) evaluating pain.

Patients were randomised in double-blind fashion between 4.5 g or 6 g sodium oxybate, administered at night, and placebo for two months. 147 patients completed the study.

The intention to treat results show that both doses of sodium oxybate significantly reduced pain compared to placebo - a reduction to 50 points (vs 58 points) on the VAS.

Sodium oxybate was also shown to be effective using the Fibromyalgia Impact Questionnaire (FIQ), which evaluates both pain and fatigue, with a decrease of about 20 points for the two doses of sodium oxybate, compared with a 10-point decrease for patients taking placebo.

Sodium oxybate's mechanism of action for pain is still badly understood, Dr Swick told APM.

Secondary evaluation criteria also suggests a benefit for sodium oxybate on quality of sleep, with an increase in slow sleep, notably phases 3 and 4 (deep sleep) and a significant decrease in the percentage of rapid eye movement (REM) sleep compared to placebo.

The most frequent adverse effects with the two doses of sodium oxybate were nausea (15% at 4.5 g and 28.4% at 6 g, compared with 9.2%) and dizziness (respectively 6.7% and 13.4% vs 1.5%).

There was no open-label extension to this study, but 70% of participants asked to continue using sodium oxybate, Swick said.

These results suggest that sodium oxybate, administered at bedtime, improves sleep architecture, with beneficial effects on daytime symptoms in patients with fibromyalgia, the researchers conclude.

Asked about further studies, Swick said that another trial had begun on about 100 patients for a period of 14 to 16 weeks, with a combined primary endpoint linked to both pain and fatigue. Depending on the results, an indication extension application might be filed.

Sodium oxybate, developed by US company Orphan Medical, which was acquired by fellow American company Jazz Pharmaceuticals last year, has been marketed in the USA since 2002 in the treatment of excessive daytime somnolence and cataplexy in patients with narcolepsy.

In Europe, sodium oxybate was approved in October 2005 in the treatment of cataplexy in patients with narcolepsy. It was launched in December 2005 in Germany by Belgian group UCB, which acquired distribution rights for the European market.

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luuly.doquang@apmnews.com
[2034] 03/04/2006 09:12 GMT - NEURO RHEUMATO

By Luu-Ly DO-QUANG

SAN DIEGO, April 3 (APM) - XP13512, a prodrug of anti-epileptic gabapentin, seems effective in the treatment of restless legs syndrome, according to a Phase II study presented on Sunday at the annual meeting of the American Academy of Neurology (AAN) in San Diego.

Prolonged-release oral medication XP13512 is a transported prodrug of gabapentin developed by U.S. biotech company XenoPort, which says that it is more bioavailable than gabapentin.

In mid-March, XenoPort announced that it had begun a first Phase III trial in 200 patients with restless legs syndrome (RLS). Preliminary results are expected by the first half of 2007. Two other Phase III trials are also planned as contributions to the US marketing authorisation application.

In the Phase II study, presented at a special oral session on sleep disorders, Dr Clete Kushida of Stanford University school of medicine and colleagues recruited 95 adults with RLS who were treatment naïve and had a mean score of 22 points on the International Restless Legs Syndrome (IRLS) scale.

Patients were then randomised in double blind fashion between XP13512 at 600 mg or 1,200 mg once daily and placebo for two weeks.

XP13512 at 1,200 mg was found to be better than placebo as of the first week of treatment, with an IRLS score of 7.7 points compared with 14.6 points for the placebo group. The benefit was maintained at the end of the study, with respective scores of 6.3 and 13.5 points, said Dr Kushida.

Over the study period, there was a decrease of 16.1 points with XP13512 compared to 8.9 points with placebo.

Secondary endpoints also generally showed the effectiveness of XP13512 at 1,200 mg, especially patient and investigator Clinical Global Impression of Change (CGI) scales, sleep quality, the number of nocturnal awakenings due to leg movement and the number of hours awake per night.

Dr Kushida reported that 34.4% of patients treated with XP13512 at 1,200 mg - compared with 3% of patients using placebo - spent the second week free from RLS symptoms. 68.8% compared with 33.3% had no nocturnal awakenings during this week.

Results were however similar for the 600 mg dose and placebo.

XP13512 was generally well-tolerated. The most frequent adverse effects were somnolence and dizziness, which occurred in 12% and 6% of patients in the 1,200 mg group, compared with 5% and 1% respectively in the placebo group.

These adverse effects were generally mild and transitory. Dr Kushida said that no serious effects were observed.

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luuly.doquang@apmnews.com
[2035] 03/04/2006 10:42 GMT - NEURO

by Philippe Wackel

BRUSSELS, April 3 (APM) - A new EU regulation which comes into effect this week will allow pharmaceutical companies to launch their products in Europe without having initially provided all the data normally required for marketing authorisation.

Regulation 507/2006, which concerns specific categories of medicines, was published in the Official Journal of the European Union (EU) on March 30 and comes into effect three days after publication. It forms part of the 2004 reform of EU pharma legislation.

Conditional marketing authorisation takes its inspiration from measures sometimes known as "compassionate use" which already exist in certain EU member states, such as France's authorisation for temporary use (ATU).

The new text stipulates that for certain categories of medicines, it may be necessary to grant conditional marketing authorisation, by centralised approval procedure, based on data which is less complete than that normally required.

These categories are: medicines for the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases; medicines intended to be used in emergency situations in response to public health threats recognised either by the World Health Organisation (WHO) or the European Community; and orphan medicines.

The risk-benefit balance must be positive, and the public health benefits of making the medicine immediately available should outweigh the risk inherent in the fact that additional data are still required.

COMPANY OBLIGATIONS

The holder of a conditional marketing authorisation is required to complete or initiate certain studies aiming to confirm that the risk-benefit balance is positive and to resolve any questions relating to the quality, safety and efficacy of the medicine.

Conditional marketing authorisation is different from marketing authorisation granted in exceptional circumstances, as laid down in the 2004 regulation reforming European pharmaceutical legislation.

Thus, conditional marketing authorisation is granted before all data are available, but is not intended to remain conditional indefinitely. Once the missing data is provided, it is replaced by normal marketing authorisation.

In contrast with this, it is normally never possible to assemble a full dossier for a marketing authorisation granted in exceptional circumstances.

Conditional marketing authorisation is valid for one year on a renewable basis. Application for renewal must be made six months before the expiry of the marketing authorisation and the European Medicines Agency's opinion, which is published, must be adopted within 90 days of receipt.

The EMEA will immediately inform the European Commission of conditional marketing authorisation requests and will make the specific obligations and the timeframe for their completion publicly available.

Clear information must be provided to patients and healthcare professionals on the summary of product characteristics and on the packaging leaflet as to the conditional nature of the authorisation.

Enhanced pharmacovigilance for products with conditional authorisation is provided for in existing EU legislation.

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philippe.wackel@apmnews.com
[2036] 03/04/2006 11:10 GMT - GENERAL

LONDON, April 3 (APM) - GlaxoSmithKline and Sirna Therapeutics announced on Monday a tie-up to develop therapeutics for respiratory diseases which could involve the U.S. biotech group receiving milestone payments of more than $700 million.

In a statement, GSK said the companies have agreed an exclusive alliance focused on discovery, development and commercialisation of novel RNA interference (RNAi)-based therapeutics for respiratory diseases. RNAi is a natural, selective process for turning off genes.

San Francisco-based Sirna will receive an initial payment of $12 million, made up of cash and the purchase of Sirna shares at $ 8.36 a share.

Under the agreement, Sirna may also receive milestone payments in excess of $700 million for collaboration and clinical development events, as well as royalties on worldwide sales of products which emerge from the alliance. In addition, Sirna will be eligible to receive contract manufacturing revenues, the statement added.

Dr Garth Rapeport, Senior Vice President at GSK's respiratory & inflammation drug research centre, said the alliance would "expedite the development of novel therapeutics with potential use in a number of respiratory diseases such as asthma and COPD".

Under the terms of the agreement, Sirna will provide GSK optimised and formulated siRNAs against targets identified by Sirna and GSK.

GSK will assume responsibility for the further preclinical and clinical development of these compounds as well as worldwide commercialisation of products resulting from the alliance.

Sirna is active on several fronts including anti-virals, dermatology, metabolism, neurology, ocular, oncology and respiratory.

According to the company's web site, the respiratory team is exploring the potential for local delivery of siRNAs to the lungs for the treatment of asthma, COPD and respiratory viral infections.

"The team has successfully demonstrated extended lung exposure (suitable for once a day dosing), with limited systemic exposure, following lung administration of formulated, chemically modified siRNAs.

"In the asthma program, potent and efficacious siRNAs have been developed which target the inflammatory cytokines responsible for driving the airway inflammation which underlies airway hyper-responsiveness in patients with asthma.

"Using in vivo models measuring airway hyperresponsiveness - one of the hallmarks of asthma - and targeting the interlukin 4 receptor, studies have demonstrated an 80 percent inhibition of airway hyperresponsiveness," the company said.

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nick.hudson@apmnews.com
[2037] 03/04/2006 12:49 GMT - RESPIR

By Luu-Ly DO-QUANG

SAN DIEGO, April 3 (APM) - Sleeping drug indiplon, co-developed by Neurocrine Biosciences and Pfizer, seems effective at three months in the treatment of primary insomnia, according to new Phase III data presented on Sunday at the annual meeting of the American Academy of Neurology (AAN) in San Diego.

This trial is part of a Phase III programme which is evaluating both an immediate-release gel capsule formulation and a prolonged-release tablet in a total of 5,682 patients with chronic or transitory insomnia. The dossier has been submitted to the U.S. Food and Drug Administration, which must give its decision by May.

Indiplon is a hypnotic agent which acts by binding to a specific site on a subtype of the GABA-A receptor, said Robert Farber of Neurocrine, who presented the study for oral discussion at a special session on sleep disorders.

The study was conducted on 702 adults who had had primary insomnia, according to DSM-IV criteria, for at least three months. These patients had average sleep latency of 55 minutes and total sleep averaging five hours, more than three nights per week.

After three weeks when all patients received placebo, they were randomised in double-blind fashion between indiplon gel capsules at 10 mg or 20 mg and placebo.

After a month of treatment, sleep latency was already significantly less with indiplon at both doses compared with placebo - about 35 minutes compared with 48 minutes. The effect was maintained at three months, with 30 minutes' latency with indiplon compared with 40 minutes with placebo.

Total sleep was increased with both doses of indiplon, to six hours, compared with five and a half hours with placebo.

On secondary endpoints, Faber reported that total time spent awake during the night after three months of treatment decreased from 75 minutes to 40 minutes with indiplon, compared with 65 minutes with placebo.

These patient-reported improvements seem to be confirmed by doctors' evaluations.

The most frequently observed adverse effects were somnolence (3% at 10 mg and 7.3% at 20 mg) and headache (8.5% and 9%), compared with 1.3% and 6.9% in the placebo group. Amnesia was also reported in 1.3% and 6.4% of patients using indiplon, compared with none in the placebo group. About 20% of the patients treated with 20 mg indiplon left the study because of adverse effects (5.2% in the placebo group).

The results of two other studies of indiplon will be presented by poster on Tuesday at the AAN meeting. This data will concern a two-week evaluation, with one study specifically on elderly people.

ROZEREM AND LUNESTA EVALUATIONS

At the ANN session on sleep disorders, results for Takeda's Rozerem (ramelteon) and Sepracor's Lunesta (eszopiclone) were also presented.

Louis Mini from Takeda reported the results of the post-hoc analysis of a double-blind, placebo-controlled trial of ramelteon in 269 patients. After five weeks, 66% of patients treated with ramelteon experienced an improvement of at least 50% in sleep latency, compared with 48% of patients in the placebo group.

According to the researcher, the not inconsiderable results observed in the placebo group are explained by advice on healthy living and relaxation given to all patients.

James Walsh, of the Sleep Medicine and Research Center in Saint Louis, Missouri, presented the results of a study aiming to confirm the long-term effects of eszopiclone. In this study, 830 patients were randomised in double blind fashion between eszopiclone and placebo.

After six months, sleep latency was 24 minutes with eszopiclone compared with 44 minutes with placebo.

"VERY SIMILAR" RESULTS

Invited to discuss all these results, Prof Sonia Ancoli-Israel of the University of California in San Diego - who was a consultant for the three pharma companies involved in the studies - said that, according to the data presented, all three medicines were effective in the short-term treatment of insomnia, but that long-term data was only available for eszopiclone.

The results presented for the three drugs, which are current or future competitors of Sanofi-Aventis' Ambien/Stilnox (zolpidem) are "very similar," she said, even though the criteria measured in the ramelteon study were different from those in the two other studies. The most frequent adverse effects of all three drugs were headache and somnolence, she added.

Moreover, when treatment was stopped suddenly, none of the three drugs seemed to induce sleep rebound or withdrawal syndrome.

Referring to the conclusions of a US National Institutes of Health (NIH) conference which took place in June 2005, Prof Ancoli-Israel said that hypnotics should generally be used over a period of 7-10 days, as mentioned on the summary of product characteristics (SPC).

She did not talk specifically about indiplon, which is set to be the next non-benzodiazepine insomnia treatment to be approved, following ramelteon in July 2005, eszopiclone in December 2004, zaleplon in 1999 (Jones Pharma's Sonata) and zolpidem in 1992.

Direct comparative studies need to be carried out for all these medicines and also for OTC treatments and cognitive behaviour therapy. Comparative costs also should be evaluated, the psychiatrist said.

She added that it was also important to evaluate the effectiveness of these medicines in specific patient populations, especially children and the elderly, and on specific criteria, such as falling and cognitive capacity.

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luuly.doquang@apmnews.com
[2038] 03/04/2006 13:01 GMT - NEURO

BERLIN, April 3 (APM) - The German market for OTC medicines sold exclusively in pharmacies increased 2.4% to 6.2 billion euros in value and 3.2% to 740 million units in volume in 2005, according to the German pharmaceutical market statistics agency Insight Health.

There are three standard sizes of medicines packaging in Germany. In a news release, Insight says that almost half of sales of these products were of medium-sized packs, one third of small packs and a quarter of large packs.

The pharmacy OTC market seems to be slowly recovering from measures introduced in 2004 under which these products were no longer reimbursed, except when intended for paediatric use and in certain specific indications, such as aspirin in the prevention of cardiovascular disease. These measures had caused the market to plunge 70%.

The return to growth in 2005 is due to products bought directly by consumers, up 6.7% to 4.5 billion euros.

The segment of OTC drugs prescribed by a doctor and reimbursed decreased by 7.6% to 1.7 billion euros, of which 807 million euros were reimbursed by private health insurance companies (-9.4%) and 793 million euros by insurance providers for the obligatory scheme (-5.7%).

The market share of OTC products reimbursed by private companies thus fell two points to 14% and that of OTC products reimbursed under the obligatory scheme by one point to 13%. The other 73% was for non-reimbursed OTC products, up three points.

DOWN IN JANUARY AND FEBRUARY DUE TO LACK OF FLU

In the first two months of 2006, the pharmacy OTC market was down another 4.7% to 1 billion euros in value and down 5.6% to 128 million units in volume.

This decline is due to the absence of a flu epidemic which at the beginning of 2005 had led to rises of 14.4% in value and 18.4% in volume, Insight says.

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arjen.peters@apmnews.com
[2039] 03/04/2006 13:29 GMT - INDUSTRY

by Frank Powley

COPENHAGEN, April 3 (APM) - Iceland's Actavis appears to be making new headway in its bid to acquire the Croatian pharmaceutical company Pliva now that Deutsche Bank has jumped in to facilitate the negotiations as a third party.

Halldor Kristmannsson, corporate communications manager, told APM on Monday that Actavis expected to hear positive news from Pliva about Actavis' proposed merger of the two companies.

"We hope to hear something this week. We are gaining support (for the merger proposal) among key shareholders," said Kristmannsson.

Up to now, Pliva's CEO, Ziljko Covic, had been resisting the merger, which could create the world's third largest generics company.

"The CEO is now saying he is willing to discuss our proposal with a third party, but at a higher price," said Kristmannsson. "Deutsche Bank has been supporting the company's (Pliva) evaluation," he added.

Actavis had valued Pliva, among the top 12 generics companies, at 1.6 billion dollars (1.32 billion euros), and was willing to pay 570 Croatian kuna (77.8 euros) per share, offering a 35% premium over the average Pliva share price during the last three months and a 48% premium to Pliva's average 12-month share price.

The deal would be subject to standard due diligence and discussions with management, Actavis said in a statement.

"The all-cash preliminary proposal provides investors with an immediate and tangible return on their investment and in Actavis' evaluation the price recognises expected future growth in sales and revenues," the Reykjavik-based company said.

But Pliva's management rejected the bid, saying in a statement that the proposal did not "adequately reflect the fundamental value and future prospects of the company" since it had divested its loss-making proprietary drug business along with a production plant in Germany.

Kristmannsson said that Actavis based its offer on Pliva's current prospects, which look less positive for 2006.

Following nearly a year of unfruitful talks with Covic, Robert Wessman, President and CEO of Actavis travelled to Zagreb a week ago to argue for the Group's acquisition proposal, and to discuss the possibility of Actavis being listed on the Zagreb Stock Exchange.

EASY INTEGRATION

"Pliva and Actavis complement each other in almost every respect. They have complementary geographic coverage, therapeutic focus and a product pipeline with minimal overlap. This will make the integration process very straightforward and the benefits of the combination immediate," said Wessman in a statement issued in Zagreb.

Wessman stressed that Actavis' offer "is friendly in every respect", adding that he is "encouraged by Covic's most recent statements".

It was last Thursday that Pliva let it be known that Deutsche Bank was involved in the merger proposal.

On 13 March, Wessman had sent a letter outlining Actavis' proposal to Pliva's board. This was leaked to the Croatian media, making it necessary according to Icelandic stock exchange regulations for Actavis to issue its own press release.

Actavis, with a market capitalization of over 2 billion dollars (1.65 billion euros), as of December 2005 and over 600 products on the market worldwide, has grown rapidly in recent years through its acquisitions, including Alpharma's human generics business, Amide Pharmaceuticals and most recently, Sindan's oncology business.

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frank.powley@apmnews.com
[2040] 03/04/2006 13:45 GMT - INDUSTRY

LONDON, April 3 (APM) - GlaxoSmithKline said on Monday it has halted enrolment into its Phase III trial of its potential blockbuster Tykerb (lapatinib) with Xeloda (capecitabine) for breast cancer following positive data and plans to file the combination treatment in Europe and U.S. in the second half of the year.

In a statement, GSK said enrolment of the Phase III trial to evaluate the Tykerb and capecitabine combination compared with capecitabine alone was stopped on a unanimous recommendation of an Independent Data Monitoring Committee (IDMC).

All women already enrolled in the trial will continue to be followed and those who are receiving capecitabine alone will be offered the option of switching to the combination therapy of capecitabine and Tykerb in consultation with their physician.

Tykerb is an oral, once-daily dual kinase inhibitor for breast cancer and potentially other tumours. It targets ErbB1 (EGRF) and ErbB2 receptors associated with cancer cell growth and proliferation.

In November, GSK's former R&D chairman, Tachi Yamada said Tykerb was one of four products linked to oncology which would become blockbusters. He predicted the global cancer market would rise from $42 billion in 2004 to $70 billion by 2009.

The trial evaluated women with refractory advanced or metastatic breast cancer who have documented ErbB2 (HER2) overexpression and whose disease progressed following treatment with trastuzumab (Herceptin) as well as other cancer therapies.

A pre-planned interim analysis of 321 patients in the study yielded statistically significant results, exceeding the primary endpoint, GSK added.

According to the study protocol, the pre-planned interim analysis was reviewed by the IDMC, which unanimously recommended halting enrolment in the study because it exceeded its primary endpoint of time to disease progression (TTP) for women receiving the combination of orally-administered Tykerb and capecitabine.

ENCOURAGING DATA

Paolo Paoletti, Senior Vice President of GSK's oncology medicine development center, said: "We are extremely encouraged by these data which suggest that Tykerb may offer significant benefit as an oral medication in combination with chemotherapy for patients with advanced or metastatic ErbB2 positive breast cancer, and whose disease has progressed on previous treatment regimens, including Herceptin."

He added: "On the basis of this and other data we now plan to file in the US and Europe during the second half of 2006."

PHASE III TRIAL

The Phase III trial is an international, multicentre, randomised, open-label study to evaluate and compare TTP in patients with documented ErbB2 (HER2) overexpressing refractory advanced or metastatic breast cancer treated with Tykerb in combination with capecitabine versus capecitabine alone.

The primary endpoint of the study was to detect a 50% increase in TTP in the combination arm compared with the capecitabine alone arm.

A total of 392 patients have been enrolled in the study of which 321 were included in the analysis (160 in the combination arm and 161 in the monotherapy arm). The most common drug-related adverse events in the combination arm of the study were diarrhea and nausea.

nh/rw

nick.hudson@apmnews.com
[2041] 03/04/2006 14:12 GMT - CANCER

LONDON, April 3 (APM) - Pfizer's COX-2 inhibitor Celebrex (celecoxib) may be effective in prevention for colorectal cancer in high-risk patients, according to studies presented on Monday at the American Association for Cancer Research conference.

However the two studies, which were presented at the Washington event and were partly funded by Pfizer, also reinforced evidence that the drug increased the risk of cardiovascular events.

In a statement Pfizer said it had provided regulatory agencies globally with data from the trials and it would also submit any final reports. The company did not say if it intended to file for an extension of indication for the drug based on the new data.

Researchers said over-expression of the COX-2 enzyme is related to the growth and spread of colorectal tumours. Therefore the inhibitor may reduce the occurrence of precursor, colorectal adenomas in patients with a family history of the disease, as well as the development of sporadic colorectal tumours.

In the Adenoma Prevention with Celecoxib (APC) study researchers randomised 2,035 patients to twice daily doses of either placebo (679), celecoxib 200mg (685) or celecoxib 400mg (671).

Average patient age was 60 and all were at high risk of developing colorectal cancer and had undergone polyp removal.

A follow up colonoscopy was conducted in 89% of patients after one year and 76% after three years.

Incidence of one or more benign tumours was 61% in those taking placebo but this figure was reduced by 45% in the therapy group.

Relative risk of advanced neoplasms, adenomas of more than 1cm or those showing tubolovillous or villous features, severe dysplasia or invasive cancer were also greatly reduced in the therapy arms. There were 66% fewer of these tumours in the treatment groups compared to placebo.

Monica Bertagnolli, associate professor of surgery at Harvard University concluded: "The results of this study show that patients at high risk for developing colorectal cancer have dramatically fewer pre-malignant tumours when they take celecoxib."

In a second study, Israeli researchers seeking to establish if celecoxib reduced the incidence of sporadic colorectal adenomas, enrolled 1,561 patients who had undergone polypectomy. Average age was again 60.

In the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) study, patients were randomised in a 3:2 ratio to receive either celecoxib (400mg once daily) or placebo.

Of the international sample, 88.7% were followed up with colonoscopy at one year and 79.2% at year three.

The PreSAP study was stopped when the ARC study (above) showed at 33 months a two-to-three-fold increase in serious adverse cardiovascular events.

At the time ARC announcement of the increased risk was made, PreSAP data showed a hazard ratio of 1.2 for those taking celecoxib compared with placebo for death from cardiovascular events and non-fatal heart attack or stroke.

However this study also found positive data for the drug in colorectal cancer with three year follow up showing the incidence of adenomas was 49.3% in the placebo group but significantly lower at 34% in the therapy arm.

Prevalence of adverse events was similar in placebo (74%) and celecoxib (76.8) but patients taking the drug had a higher risk of cardiovascular events compared to placebo (7.5% versus 4.6%).

Nadir Arber, head of the Integrated Cancer Prevention Center in Tel Aviv said in a statement: "For patients at high-risk of developing colorectal cancer, celecoxib may be considered while weighing the risk of potential cardiovascular events. "

He added: "Regular Non-Steroidal Anti-Inflammatories (NSAIDs), such as prescription-strength ibuprofen and naproxen, may also work, but at the high doses needed in cancer prevention trials, there would be an unacceptable patient risk for GI complications. The high doses of Celebrex in these studies had minimal effects on the entire gastrointestinal tract."

The raised risk of cardiovascular events shown by the studies seems to match research published in UK's Royal Society of Medicine Journal last month which concluded that Celebrex doubled the risk of heart attacks and this was consistent for a class effect for COX-2s.

However in another study from last month researchers writing in the American Journal of Medicine concluded the drug was not linked to a higher risk of heart attacks than traditional NSAIDs.

Despite the problems associated with COX-2s, Celebrex remains an important product for Pfizer and the company has predicted sales will rise from to $2 billion in 2006 compared with $1.7 billion last 2005. However 2005 sales were nearly reduced by 50% on 2004 after the safety fears emerged.

ns

nick.smith@apmnews.com
[2042] 03/04/2006 15:54 GMT - CANCER RHEUMATO

BERLIN, April 3 (APM) - New pharmacoeconomic directives have come into effect in the Netherlands defining the cost-effectiveness data to be provided by pharmaceutical companies seeking full reimbursement for their medicines.

The directives allow companies to carry out pharmacoeconomic studies without having to wait for official recommendations, the Dutch Health Insurance Board (CVZ), which conducts cost-benefit analyses of medicines, announced in a press release.

Cost-benefit analysis of medicines has existed in the Netherlands since 1999. Drugs that are therapeutically interchangeable are grouped together into clusters and comprise list 1A. The reimbursement of these products is limited to the average price of the products in the cluster.

Full reimbursement is only granted to products that are not interchangeable and thus cannot be put in a cluster. These are admitted to list 1B.

The comparative merit rating evaluation required to apply for inclusion in list 1B must in future be made in comparison to standard treatment, which is not necessarily medical.

The most important comparative criterion considered by the CVZ is whether a product achieves an improvement in quality of life (usefulness criterion) compared to standard treatment, followed by clinical performance (effectiveness criterion).

In cases where neither of these criteria is applicable, the manufacturer can present data on total costs (minimalisation criterion). These include direct and indirect costs for health insurance providers and possible paramedical expenses.

The evaluation of therapeutic effectiveness must be carried out over the same time-period as that of costs. Studies may use modelling techniques to generate long periods of observation, but models used must be based on peer-reviewed publications.

FULL REIMBURSEMENT FOR TARCEVA AND XYREM BUT NOT FOR STRATTERA

The last evaluations carried out under the old directives concern Lilly's Strattera (atomoxetine) for attention deficit/hyperactivity disorder (ADHD), Roche's cancer drug Tarceva (erlotinib) and UCB's cataplexy treatment Xyrem (sodium oxybate).

Strattera is on list 1A, in a cluster with methylphenidate (Novartis' Ritalin and generic copies). Lilly asked for it to be included in list 1B, citing the possibility of treating patients who are resistant to methylphenidate.

This argument was not accepted, as it concerns differences between individual patients rather than intrinsic product characteristics which define patient groups, the CVZ explained in another news release.

Tarceva is currently the only second-line treatment indicated in non-small cell lung cancer. This product improves patient survival by two months and can be administered as out-patient treatment, so it was admitted to list 1B.

Three months of treatment with Tarceva costs about 7,000 euros, and annual expenditure in the Netherlands for Tarceva will be about 5.9 million euros in three years' time, according to the CVZ's estimates.

Xyrem has orphan medicine status for cataplexy in people with narcolepsy. Studies presented by UCB show a significant advantage compared to standard treatment with tricyclic antidepressants, especially clomipramine, the CVZ says.

This medicine has thus also been accepted for inclusion on list 1B. About 125 people among 7,500 sufferers in the Netherlands are likely to be treated with Xyrem. Given that the cost of treatment is about 9,600 euros per year, annual expenditure for the Dutch health insurance is likely to total 1.2 million euros, according to the CVZ.

ap/clg/ns

arjen.peters@apmnews.com
[2043] 03/04/2006 16:27 GMT - INDUSTRY

PARIS, April 3 (APM) - Sanofi-Aventis told APM on Monday it had filed a case against Novo Nordisk in a New Jersey court last month, alleging the Danish company used "misleading advertising" in a U.S. promotion of its long-acting insulin analog Levemir (detemir).

The company said that in supporting documentation on Levemir given to doctors Novo "made allegations concerning Lantus (insulin glargine), Sanofi-Aventis' competing product, which we consider to be erroneous," he explained.

Novo Nordisk apparently drew comparisons between Levemir and Lantus in the advertising.

With this legal action, "we are asking for the immediate withdrawal of these documents," which have the effect of establishing "unfair competition," he added.

Sanofi-Aventis does not wish to comment any further on this case before judgment is given.

Lantus was launched in the U.S. in mid-2001. Levemir, which was approved in June 2005, appeared on the U.S. market last week.

In the U.S. the two groups are up against each other in another court case. Novo Nordisk filed a case against Sanofi in September 2005 for infringing patents relating to its insulin pen injection system FlexPen, which the French company is contesting.

so/mjg/ns

sophie.labbe@apmnews.com
[2044] 03/04/2006 16:43 GMT - INDUSTRY