APM Health Europe: Healthcare Business News for European Pharmaceutical Markets

by Luu-Ly Do Quang at the AAN congress

BOSTON, May 3 (APM) - The failure of factor VIIa NovoSeven (eptacog alpha) developed by Novo Nordisk in Phase III in intracranial haemorrhage appears to be linked to significant comorbidities in the patients included in the study, according to data presented at the American Academy of Neurology (AAN) meeting in Boston which leaves open a possibility of further development.

Novo Nordisk had announced in February the failure of the FAST (rFVIIa in Acute Haemorrhagic Stroke Treatment) trial: no improvement had been obtained with the recombinant activated factor VII (rFVIIa) in comparison with the placebo in terms of the primary endpoint - mortality and disability at three months from the occurrence of the haemorrhage.

The Danish group had said that it would not submit the dossier to the health authorities to obtain an indication extension for NovoSeven.

Dr Stephan Mayer from the Columbia Presbyterian Medical Center in New York, the main author, presented the results of the preliminary analyses of the study on Tuesday during the "Late-Breaking Science" session.

In the trial, 821 patients were recruited within the three hours following an intracranial haemorrhage then randomised in double blind between a placebo, the rFVIIa at 20mcg/kg or factor VII at 80mcg/kg. The treatment was administered within four hours at the latest following the onset of symptoms.

After three months of follow-up, the rate of death or severe disability (score of 5 or 6 on the modified Rankin scale) was 24% in the placebo group, 26% in patients treated with the factor VIIa at 20mcg/kg and 29% in those receiving the 80mcg/kg dose.

The death rate alone at three months was not significantly different either between the three groups, being respectively 19%, 18% and 21%.

However, other elements were in favour of the rFVIIa, confirming the encouraging results from the Phase II study, in particular the increase in the volume of haemhorrage which was significantly lower with the 80mcg/kg dose in comparison with the placebo - 11% compared with 26%.

The researchers wished to understand why the reduced growth of the hematoma is not associated with a clinical impact.

Dr Mayer therefore emphasised that the analysis of the patient characteristics shows in particular that in the placebo group for the FAST trial, there was a greater number of individuals with a higher Rankin score at inclusion than in the Phase II.

The patients in the FAST trial were also elderly, with significant comorbidities, which probably affected the impact of the treatment on the primary endpoint, Dr Mayer believed.

A significant difference on the primary endpoint having been observed at the 15th day of follow-up, the researchers analysed the data for those under 70 years and noted a significant difference in the rate of death or severe disability among patients treated with NovoSeven, of 30% with 20mcg/kg and 33% at 80mcg/kg, compared with 38% in the placebo group.

A clear advantage also appeared on the 15th day among patients who were treated within two hours following the onset of symptoms, with a rate of death or severe disability of 33% with the drug dosed at 80mcg/kg, compared to 47% in the placebo group.

At three months, however, this benefit was no longer observed either with the sub-population of elderly patients nor among those treated within two hours.

Overall, these results appear to suggest that factor VII could be beneficial among patients under 75 years, if it is administered within two hours, Dr Mayer concluded.

He told APM that he still believed in the potential of rFVIIa but that its future depended on Novo Nordisk.

In response to questions from APM, Howard Levy, the Executive Director of Clinical Research-Hemostasis at Novo Nordisk, said he believed that it was necessary to wait for the final results of the data analysis to find out if other studies were feasible and in which indications.

ld/co/mjg/rw

luuly.doquang@apmnews.com
[6543] 03/05/2007 05:48 GMT - NEURO

LONDON, May 3 (APM) - Sanofi-Aventis on Thursday reported 2.6% lower adjusted net income during the first quarter of 2007 to 2.12 billion euros, as the French group suffered a 1.3% fall in European sales to 3.11 billion euros mainly because of difficult French and German markets.

In a statement, Sanofi said its overall sales performance was helped by growth in the U.S. where sales jumped 16.4% to 2.49 billion euros.

There was also a positive performance from other countries around the world, where sales improved by 10.9% to 1.57 billion euros.

Group net sales overall rose by 6.9% to 7.18 billion euros, but the impact of currency movements was largely responsible for reducing that growth to 2%.

Sanofi's adjusted earnings per share (EPS) over the quarter fell 3.1% to 1.57 euros, but it is raising its guidance for the full year 2007 and now expects adjusted EPS excluding one-off items, to grow by about 9% compared with a previous forecast of 6% growth.

R&D expenditure over the period grew by 3.3% to 1.08 billion euros, while group deb declined sharply to 4 billion euros at the end of March compared with borrowings of 5.8 billion euros at the end of Dec 2006.

EUROPEAN DISAPPOINTMENT

In Europe, the healthcare reforms introduced in France and Germany during 2006 continued to depress sales.

"Germany again reported a sharp fall, as parallel imports of Plavix and Lovenox continued. France is also experiencing negative growth, but was helped by winter pathologies," the company said.

The gradual introduction of Eloxatin generics across Europe accounted for 1% of the first-quarter decline in the region's net sales.

SALES

Sanofi reported that sales of its top 15 pharma products grew by 10.5% to 4.48 billion euros, but its smaller sellers suffered a 1.8% decline to 2.13 billion.

A notable disappointment was its antibiotic Ketek, which almost halved to 30 million euros because of restrictions on its indications.

The company said sales of Acomplia achieved sales of 15 million euros in the quarter. The weight loss drug has been available in France since March 2007 and is available in a total of more than 10 European countries.

It is waiting U.S. approval and the action letter from the Food and Drug Administration is due on July 26 this summer.

Of its top sellers, blood thinner Plavix grew overall by a modest 0.2% to 1.23 billion, with sales in Europe up 5.4% to 448 million euros.

In the U.S, sales of Plavix fell by 7.4% to 603 million euros, due to the continuing effects of the launch last summer of a generic clopidogrel version in the United States by Apotex. A court battle is underway there to try to resolve the patent dispute.

In other regions around the world, Plavix sales improved by 18.1% to 183 million euros.

Vaccines enjoyed growth of 16% to 567 million euros, although sales of influenza vaccines tumbled 17.1%. Sales at Sanofi Pasteur MSD, the joint venture with Merck & Co in Europe, rose 3.5% to 149 million euros.

One of the joint venture's biggest hopes is Gardasil, the vaccine to guard against human papillomavirus. That is being marketed in 18 European countries.

Q1 PRODUCT SALES

:: Lovenox 634 +8%

:: Plavix 569 (-1%)

:: Stilnox/Ambien 606 +49%

:: Taxotere 449 +10%

:: Eloxatin 393 (-3%)

:: Lantus 458 +27%

:: Copaxone 289 +18%

:: Aprovel 264 +8%

:: Tritace 211 (-6%)

:: Allegra 201 +22%

:: Amaryl 94 (-19%)

:: Xatral 82 (-10%)

:: Actonel 78 (-10%)

:: Depakine 76 (-)

:: Nasacort 79 +22%

:: Vaccines 567 +16%

nh/rw

nick.hudson@apmnews.com
[6544] 03/05/2007 06:15 GMT - INDUSTRY

BOSTON, May 3 (APM) - The addition of the antibiotic minocycline for patients with Amyotrophic Lateral Sclerosis (ALS) treated with Sanofi-Aventis' Rilutek (riluzole) has aggravated their condition, according to the Phase III results presented at the meeting of the American Academy of Neurology (AAN) in Boston.

These results were particularly awaited because there is no other treatment for ALS apart from riluzole which only has a moderate effect on survival.

This Phase III was launched even though the Phase II results were already suggesting a risk of deterioration in patients even if the minocycline was well tolerated.

However, as Dr Paul Gordon from the University of Columbia in New York noted during an oral session on Tuesday, minocycline had shown neuroprotective and anti-inflammatory properties in an animal model of ALS and had even increased survival up to 16%. Dr Gordon is the study's primary author.

The Phase III study was carried out in 31 U.S. centres where 417 patients receiving riluzole were included then randomised in double blind between the addition of minocycline (up to 400mg/day) or a placebo for nine months.

At the end of the study, the results show that the patients who received the minocycline deteriorated more quickly than in the placebo group, with an increase of 1.3 points on the ALFRS-R (ALS Functional Rating Scale-Revised) compared with a 1.04-point reduction in the placebo group, i.e. a deterioration of 24%.

The forced vital capacity (FVC), however, of the patients receiving minocycline improved by 3.48%, compared with a reduction of 3.01% in the placebo group.

The muscular force was reduced in the two groups in an equivalent manner, by -0.30 points with minocycline and by -0.26 points in the placebo group.

The quality of life deteriorated in an equivalent manner in the two groups.

There was no significant difference either in survival between patients treated with minocycline and those who received the placebo, with 18.2 months and 22.1 months respectively.

The safety data show that the incidence of adverse events was similar, the most commonly observed with minocycline being gastro-intestinal effects (constipation) and neurological ones (dizziness, headaches).

These results show that minocycline aggravated the patients' functional condition, Dr Gordon concluded, lamenting the fact that once again, a treatment that was effective in animals had failed in humans.

He said that the preclinical approach for ALS would need to be considered and also the impact of mincycline evaluated in other diseases.

In response to questions from APM on these results, Professor Vincent Meininger from the Pitié-Salpêtrière hospital in Paris, the national coordinator for the ALS reference centres, believed it would be necessary to analyse this data more thoroughly to determine the reasons for this failure and to reflect on the possibility of continuing the evaluation of minocycline.

It will in particular be necessary to determine whether the dose of minocycline was too high, whether the minocycline interacted with the riluzole or if it has a pernicious effect in itself. We need to ask ourselves these questions before going any further, he concluded.

ld/co/mjg/rw

luuly.doquang@apmnews.com
[6545] 03/05/2007 06:38 GMT - NEURO

LONDON, May 3 (APM) - More than 130,000 patients in Europe are taking Sanofi's anti-obesity drug Acomplia (rimonabant) - but nearly half have to pay for it themselves, the company's head of pharmaceutical operations said on Thursday.

Mr. Hanspeter Spek told a Q1 results' conference call: "Approximately 40% of patients pay for the drug out of their own pocket."

This high percentage explains why Sanofi is dismissive of official figures showing a low uptake of Acomplia in the reimbursed sector.

Spek pointed out that a recent report showing the NHS in England spent less than 1.5 million pounds (2.2 million euros) on 23,500 prescriptions of Acomplia in the six months to Dec. 31, 2006 did not show the full picture.

Spek added that sales in France had got off to a "very good start".

Overall, Sanofi reported sales of Acomplia of 15 million euros in the first quarter.

Spek said the drop out rate was significantly lower than the 40-50% seen during the clinical trials. "We estimate it at 20% to 40% depending on the reimbursement situation."

In the United States, rimonabant is on the agenda for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting to be held on June 13. The FDA action letter is due on July 26.

rw

richard.woodman@apmnews.com
[6546] 03/05/2007 07:45 GMT - INDUSTRY

LONDON, May 3 (APM) - Roche announced on Thursday that Herceptin (trastuzumab) has been granted European approval for use in combination with an aromatase inhibitor for treating HER2 and hormone receptor-co-positive metastatic breast cancer.

Roche said it is the first combination of targeted therapies for any cancer to receive approval worldwide.

The Swiss group in a statement said the European Commission has approved the use of Herceptin in combination with an aromatase inhibitor for the treatment of postmenopausal patients with HER2 and hormone receptor co-positive metastatic breast cancer.

The approval is based on data from the international Phase III TAnDEM study which showed that the addition of Herceptin to hormonal therapy doubled the median progression-free survival from 2.4 months to 4.8 months.

William Burns, CEO division Roche Pharmaceuticals said: "Herceptin consistently benefits patients regardless of whether it is given in the early- or advanced-stage settings, or whether it is in combination with chemotherapy, hormonal therapy, or as a single agent."

The company said comprehensive reviews have suggested that about two thirds of breast tumours are hormone receptor positive.

Of these, a significant percentage (up to 25%) are also HER2-positive. TAnDEM is the first randomised study to show that this specific subset of patients with 'co-positive' disease (both HER2- and hormone receptor-positive) are at an increased risk of relapse, "making the positive results with Herceptin even more meaningful", the company said.

Herceptin is currently approved for the treatment of early and metastatic HER2-positive disease, and has demonstrated a survival benefit in both settings.

This new approval will also allow Herceptin to be used in combination with hormonal therapy for advanced breast cancer, Roche said.

TAnDEM STUDY

TAnDEM, conducted by Roche, is a randomised Phase III trial which evaluated Herceptin in combination with the hormonal therapy anastrozole versus anastrozole alone as first-line therapy (or second-line hormonal therapy) in postmenopausal women with metastatic HER2-positive and hormone receptor-positive (ER-positive and/or PR-positive) breast cancer.

Enrolment began in 2001, and 208 patients with HER2 and hormone receptor co-positive disease were randomised at 77 centres in 22 countries across the world.

Median progression-free survival, the primary endpoint of the trial, was 4.8 months for patients who received the combination compared to 2.4 months for patients who received hormonal therapy alone (p = 0.0016).

Patients in the combination arm also responded significantly better to treatment (overall response rate was 20.3% versus 6.8%; p = 0.018). There was also a positive trend in median overall survival (28.5 months versus 23.9 months; p = 0.325); this is despite the fact that in the hormonal therapy alone arm, more than half of patients (58/104) crossed over to receive Herceptin during the trial when their disease had progressed, and an additional 15 (out of 104) patients received Herceptin at a later time point.

Overall safety data in both arms of the trial were acceptable given the known safety profile of each of the drugs in the advanced breast cancer setting. Patients in this study will continue to be followed for side effects.

HERCEPTIN

Herceptin received European approval for use in metastatic HER2-positive breast cancer in 2000 and for early HER2-positive breast cancer in 2006.

In the advanced setting, Herceptin is approved for use as a first-line therapy in combination with paclitaxel where anthracyclines are unsuitable, as first-line therapy in combination with docetaxel, and as a single agent in third-line therapy.

In the early setting, Herceptin is approved for use following standard chemotherapy. Herceptin is marketed in the United States by Genentech, in Japan by Chugai and internationally by Roche.

To date, nearly 400,000 patients with HER2-positive breast cancer have been treated with Herceptin worldwide.

nh/rw

nick.hudson@apmnews.com
[6547] 03/05/2007 07:51 GMT - CANCER

PARIS, May 3 (APM) - Cephalon has announced a net profit of $75.2 million in the first quarter of 2007, compared with $3.6 million a year ago, when the group had recorded high charges.

Last week, Cephalon had announced that its quarterly result would be about 50% higher than forecast due to increases in sales of its pain medication.

In a statement late on Tuesday the U.S. group announced that Q1 sales climbed 23% to $423.9 million, with pain drug sales up 12% to $131.4 million.

Sales from the group's central nervous system (CNS) franchise increased by 35% to $217.5 million. Cephalon's flagship product, sleep disorder drug Provigil (modafinil) also gained 35% to $201.3 million.

Cancer pain drug Actiq (transmucosal fentanyl) lost 44% with sales of $65.7 million. At the same time Cephalon launched a new formulation of this drug, Fentora, in the U.S., with quarterly sales reaching $31.7 million.

Sales of other products increased by 12% to $74.9 million.

Cephalon is maintaining its sales objectives for 2007 of between $1.68 billion and $1.73 billion and is expecting a 2007 net result (without exceptional charges) of between $292 and $298 million.

In 2007 the group is expecting between $925 million and $950 million in sales of CNS drugs and between $425 million and $450 million in sales of pain medication.

mp/rtrs/so/co/clg/nh

marc.preel@apmnews.com
[6548] 03/05/2007 08:25 GMT - INDUSTRY

LONDON, May 3 (APM) - UK drug delivery devices specialist Bespak suggested on Thursday that sales of its inhaler for Pfizer's insulin Exubera might fall short of expectations.

In a brief trading update of its financial year to April 27 and ahead of publication of its official financial results on July 11, the company said its performance over the past 12 months will match or marginally exceed expectations, with strong trading in both its inhaled drug delivery and anaesthesia and respiratory care business divisions.

While it said it has continued to benefit from demand for the Exubera inhaler to support its global launch, "there are uncertainties about short-to medium-term sales volumes".

The company did not elaborate further on those sales. In the summer of 2006, the company said it had stepped up production as the medication started to be rolled out across the world.

Since then, the uptake of Exubera has been slower than expected, and some analysts have halved their 2010 sales estimates for Exubera, which had reached as high as $1.8 billion when the drug was first approved.

In Thursday's statement, Bespak said inhaled drug delivery continued the strong organic growth, reflected in the first half with record sales of CFC-free valves and dry powder inhalers.

The transition in the U.S. market to CFC-free asthma formulations is progressing more
successfully than anticipated.

Bespak said it has also won a number of new valve and dose counter development programmes during the year.

Last month Bespak announced the two-step acquisition of Emergent Respiratory Products of Irvine, California.

It said the deal will expand Bespak's access to the growing pre-hospital emergency medicine
market segment where its existing airway management products "have considerable potential".

nh/rw

nick.hudson@apmnews.com
[6549] 03/05/2007 08:27 GMT - DIABETE

LONDON, May 3 (APM) - Sanofi-Aventis refused to be drawn on Thursday on its possible interest in acquiring U.S. marketing partner Bristol-Myers Squibb.

Asked by APM if the company still saw any logic to such a merger, the group's head of finance, Jean-Claude Leroy, said in a results' conference call: "We don't comment on this."

There were widespread rumours earlier this year that a bid for the U.S. company, which has a market value of close to $60 billion, could be immiment, though speculation has since cooled.

Some analysts believe Bristol-Myers's recent decision to strike a new drug alliance with Pfizer makes a tie-up with Sanofi less likely.

rw

richard.woodman@apmnews.com
[6550] 03/05/2007 08:49 GMT - INDUSTRY

LONDON, May 3 (APM) - Swedish specialty pharma company, Meda, on Thursday reported a 36% increase in sales to 1.8 billion kronor (196.9 million euros) in the first quarter which benefited from after the acquisition of 3M's European pharma division in January.

The increase in sales was largely attributed to 3M's Tambocor (flecainide acetate) for heart arrhythmia, Minitran (glyceryl trinitrate) for prevention of angina pectoris and Aldara (imiquimod) for actinic keratosis, basal cell carcinoma and genital warts.

Sales in western Europe soared 59% to 774.6 million kronor (84.7 million euros) while northern Europe sales grew 16% to 227.3 million kronor (24.9 million euros) and central and eastern Europe sales rose 34% to 478.2 million kronor (52.3 million euros).

Despite the sales' increase, profits were flat compared to the first quarter of 2006 for the company focusing on cardiology, dermatology, respiratory, pain and inflammation, and gastroenterology, with a recorded net income of 175.4 million kronor (19.2 million euros), down 1.2%.

Cash and cash equivalents at the end of March were down 17% to 153.6 million kronor (16.8 million euros) from the corresponding period last year.

The Meda share jumped 4% to 257.50 kronor following the release of the results but later fell to 246.50 - 1.50 below the opening price.

kl/rw

kari.larsen@apmnews.com
[6551] 03/05/2007 09:32 GMT - INDUSTRY

LONDON, May 3 (APM) - Nycomed announced on Thursday that it has taken its inhaled corticosteroid Alvesco (ciclesonide) for asthma back from Sanofi-Aventis.

Sanofi-Aventis was Nycomed's co-development and marketing partner for the U.S. market.

A spokesperson at Nycomed, told APM on Thursday, that: "This was a mutual agreement between Nycomed and Sanofi-Aventis," but he declined to reveal the reason behind the decision.

"We have agreed not to go public with that," he told APM.

Nycomed said in a statement: "Nycomed will search for a suitable partner for commercialisation of Alvesco in the U.S."

The drug is already under assessment from the U.S. Food and Drug Administration, and Nycomed expects to file additional data during 2007.

This does not mean a complete break with Sanofi-Aventis, as the collaboration over the development and commercialisation of a combination product of ciclesonide and formoferol in the U.S. will continue.

Alvesco was acquired by Nycomed when it bought Altana's pharmaceuticals unit for 4.5 billion euros in September 2006. The drug is approved in 44 countries and is on market in 26.

kl/rw

kari.larsen@apmnews.com
[6552] 03/05/2007 09:40 GMT - INDUSTRY

PARIS, May 3 (APM) - Ipsen on Thursday announced 7% sales growth in the first quarter of 2007 to 226.7 million euros, fuelled by sales outside its French home market and specialist drugs.

The 4.8% decrease in French sales to 84.8 million euros was compensated by strong sales in Italy (+10.6% to 18.6 million) and the UK (+26.2% to 9.8 million). In the major western European markets, sales were stable at 138.8 million (-0.1%).

In other European countries, quarterly sales growth was 17.3% to 52.6 million euros, and in the rest of the world sales were 35.2 million euros, a 26.1% increase.

"The strong performance in the first quarter of 2007 is consistent with our full-year sales growth objective," said CEO Jean-Luc Bélingard in a press release on Thursday. When Ipsen presented its annual results in March it had forecast between 6.5% and 7.5% growth in 2007.

Targeted therapeutic areas were up 12.8% to 121.2 million euros, whilst primary care was down 0.6% to 96.8 million.

In oncology, sales of prostate cancer treatment Decapeptyl (triptorelin) stood at 61.1 million euros, a 10.1% increase.

In neuromuscular disorders, sales of Dysport (botulinum toxin type A) increased by 6% to 28.5 million euros.

In endocrinology, sales were 31.5 million euros (+26.3%): Somatuline (lanreotide) was up 15.9% to 25.2 million and sales of growth hormone NutropinAq (9900 (somatropin) doubled to 5.8 million euros.

Primary care drug sales were affected by the 2.6% decrease in sales of vasodilator Tanakan (gingko biloba) to 31 million euros and the continued drop in sales (-26.2%) of vascular product Ginkor Fort (gingko biloba) to 8.4 million euros.

Ipsen says that without taking into account Ginkor Fort, whose price and reimbursement rate were reduced by the French authorities in February 2006, group sales would have increased by 8.9% in the first quarter.

In gastroenterology, sales of Smecta (diosmectite) increased by 7.6% to 22.9 million euros. Antihypertensive Nisis/Nisisco (valsartan) rose 7.1% to 11.8 million euros.

mp/eh/clg/rw

marc.preel@apmnews.com
[6553] 03/05/2007 09:45 GMT - INDUSTRY

MADRID, May 3 (APM) - Spain's health ministry has defended its funding of most new anti-cancer drugs approved by the European Medicines Agency (EMEA) in answer to a report by oncologists criticising limited access to the medicines.

"The ministry has included the public financing of all new oncology drugs approved by the EMEA so Spaniards can have access to the newest cancer treatments," the ministry said in a statement.

According to the report, by the Spanish Oncology Medical Society (SEOM), there are regulatory, economic, scientific-technical and operational obstacles which restrict equal access to the drugs as a result of Spain's new medicines law passed last year.

"These barriers result in different levels of access to oncological treatments among the various regions despite the fact that for cancer patients, quick access to the best and most efficient therapy for their disease is fundamental," said SEOM president Alfredo Carrato.

But in its sharply worded riposte to the charges, which it described as "insubstantial" and "not backed up with data", the ministry maintained that the new law "only restricts public financing for those medicines which are not innovative in respect to drugs that are already on the market".

"All anti-cancer treatments approved by the EMEA have been incorporated into the public financing system," the statement reiterated.

According to the SEOM report, entitled "Access Barriers to Oncological Pharmaceuticals," the chief regulatory hurdle to new drugs being approved rapidly is the bureaucratic problem of regulations and implementation in each of Spain's 17 regions.

But the ministry argued that once new therapies receive the green light from the EMEA, authorisation is passed on to the ministry which informs the health authorities in the regions.

Then a pricing commission determines the funding and the price. The ministry said the average time span for pricing authorisation has dropped from 119 days in 2005 to 70 days this year.

"Including a medicine in the National Helath System allows doctors in all regions to prescribe it to their patients when considered necessary", the statement said.

SEOM recommended setting up a national committee of experts linked to all the regions which would "elaborate clinical protocols and treatment guides".

In its report, the oncology medical society claimed that while the new treatments were expensive, the number of patients needing these medicines was lower than estimated. Therefore, total treatment costs were less than regional officials believed.

"The true cost represents only 3.5% of the entire pharmaceutical spend in the country," SEOM said.

The report also urged increased spending for anti-cancer research by hospitals.

bj/rw

benjamin.jones@apmnews.com
[6554] 03/05/2007 10:00 GMT - CANCER

by Arjen Peters

BERLIN, May 3 (APM) - Local health insurance offices (AOK) in Germany are discussing discounts with patented medicines manufacturers, a spokesman for the AOK federation has told APM.

The medicines concerned include products whose patents will soon expire and others which have the same indication as off-patent and generic drugs.

"We are taking patent expiry dates into account in our negotiations," he said, without going into further details.

Preferential price contracts for patent-protected medicines are a second phase in the WSG reform for competition in health care, which came into effect on April 1. Before this, discount agreements could only be made for generic drugs.

The AOK already signed contracts with 11 generics manufacturers for 43 drugs in February.

Under the WSG reform, only health insurance providers can negotiate discounts with pharmaceutical manufacturers. They can also sign agreements with pharmacists, doctors and hospitals.

At the end of April, AOK Rhineland/Hamburg signed a first "second phase" agreement with Janssen Cilag (Johnson & Johnson group) for antipsychotic drug Risperdal (risperidone).

The contract will initially take effect retroactively from April 1 and last until the end of December 2007. It may be used by all the other AOK offices in Germany, the AOK federation spokesman told APM.

"The advantage is twofold: Janssen Cilag is protected from competition from reimported products and AOK clients continue to receive the same product and don't have to keep changing to get the cheapest version. Pharmacists are also relieved that they only have to stock one product," he explained.

DOCTORS WANT MORE COMPETITION

Patented "me too" products for which generic drugs are available in the same indication are a second area where the statutory health insurance regime can make savings, said Leonhard Hansen, president of the North Rhine statutory health insurance doctors association (KV Nordrhein).

He was speaking at a conference held in Berlin on Wednesday by the German Generics Association (DGV) on the consequences of the WSG reform.

MARKET WORTH 13 BILLION EUROS

In 2006, the German off-patent and generic medicines market accounted for 13.1 billion euros and 514.8 million prescriptions.

Discounting agreements with generics manufacturers produced a maximum of 20% savings in expenditure on off-patent medicines - 2.6 billion euros, according to KV Nordrhein estimates.

Hansen said that at the same time, health insurance expenditure on "me too" products had reached 3.9 billion euros for 42.3 million prescriptions.

Substituting "me too" products with generic drugs approved in the same indication had produced 45 million euros of savings for KV Nordrhein in 2006.

In 2005, the year before this strategy was implemented, KV Nordrhein expenditure had increased by 13%, he emphasised.

CAUTION OVER PATENTED MEDICINES MANUFACTURERS' INTENTIONS

Birger Rostalski, an economics expert from VdAK health insurance providers, warned that signing discount agreements with patented medicines manufacturers could create commercial advantages which are not justified in therapeutic terms.

"We have contracts with 26 generics manufacturers for nine drugs and with Actavis for all its products. But we hesitate to take the plunge for patent-protected medicines. Most are still more expensive than their generic rivals which have a comparable therapeutic effect," he told APM.

The AOKs' initiative is being closely watched as the moratorium on medicines prices, which came into effect in April 2006, will expire on March 31 2008.

"We need to see if the conditions offered by manufacturers are truly advantageous and do not turn into hidden price increases," he said.

ap/clg/rw

arjen.peters@apmnews.com
[6555] 03/05/2007 10:04 GMT - INDUSTRY

LONDON, May 3 (APM) - Shares in Sanofi-Aventis fell nearly 2% on Thursday despite the company offering reassurance on U.S. sales of Plavix and raising its full-year EPS guidance.

Sanofi said it expects the generic stocks of Plavix, which Apotex flooded the U.S. market with last year, to run out during the second quarter of this year.

"We believe the generic stocks will be finally exhausted during the ongoing second quarter of 2007," head of pharmaceuticals Hanspeter Spek said in a Q1 results' conference call.

The French group also announced it was raising its 2007 full-year adjusted EPS growth guidance from 6% to 9% despite the end of protection for Ambien IR in the U.S. in April and the arrival of generic competition for Eloxatin in Europe.

However Sanofi underlined the fact that this guidance is based on an exchange rate of €1 = $1.25. Analysts at Lehman Brothers estimate a rate of €1 = $1.32 is more likely.

As well as Ambien losing U.S. patent protection, generic versions of Lovenox could also be approved, while a U.S. court may rule on patents protecting Plavix by the summer.

Sanofi's share price was down 1.4% at midday after earlier falls of around 1.8%.

rw

richard.woodman@apmnews.com
[6556] 03/05/2007 10:59 GMT - INDUSTRY

LONDON, May 3 (APM) - Icelandic generics group Actavis announced on Thursday it has withdrawn from the final bidding round for Merck generics.

This leaves Mylan Laboratories Inc., Teva Pharmaceutical Industries and the joint offer from private equity firms Bain Capital and Apax Partners.

Actavis stated the current price level, estimated to be 4.5 billion euros, as reason for its withdrawal, saying it "would not produce value for Actavis' shareholders".

The company stressed, however, that it was more than capable of buying Merck's generic division financially. It seems the Icelandic group found the German group's generics business too expensive compared to the potential gain.

A final decision on who will acquire Merck's generic division is expected later this month.

kl/rw

kari.larsen@apmnews.com
[6557] 03/05/2007 11:04 GMT - INDUSTRY

LONDON, May 3 (APM) - Shire said on Thursday it is on course to launch Vyvanse (lisdexamfetamine dimsylate) for treating Attention Deficit Hyperactivity Disorder (ADHD) in the U.S. in the second quarter of this year after the U.S. Drug Enforcement Administration (DEA) classified it as a Schedule II controlled substance.

The classification follows approval of Vyvanse in paediatric use by the U.S. Food and Drug Administration (FDA) in February.

Shire in a statement said the DEA schedule classification of Vyvanse represents the final step in the Federal government's administrative approval process before the company begins commercialisation of the ADHD treatment.

The company said the DEC decision had been expected. "All ADHD stimulant medications have historically been classified as Schedule II controlled substances," said Matthew Emmens, Shire chief executive officer.

"Vyvanse is the first ADHD stimulant to have the results of abuse liability studies reflected in its product label. Shire plans to continue to build the body of evidence in support of a lower abuse potential profile."

Shire is counting on Vyvanse to offset the impact of generic competition to Adderall XR, which loses patent protection in 2009. Shire believes the new drug has peak sales potential of more than $1 billion a year.

nh/rw

nick.hudson@apmnews.com
[6558] 03/05/2007 11:52 GMT - NEURO

BOSTON, May 3 (APM) - Cephalon's effervescent buccal tablet Fentora (fentanyl) is effective in breakthrough neuropathic pain, according to Phase III results presented at the American Academy of Neurology (AAN) annual meeting in Boston.

Fentora has been available in the U.S. since October 2006 for cancer pain in patients who already use long-term opioid-based therapy.

Cephalon is studying this new formulation of fentanyl in other kinds of pain, especially rheumatological pain, and at the AAN conference the group presented results for neuropathic pain.

Cephalon says in a press release that it intends to file a supplemental new drug application for fentanyl this year.

In the poster, Dr David Simpson from the Mount Sinai Medical Center in New York and colleagues explain that patients with neuropathic pain often experience breakthrough pain when using extended release opiates.

In this study, they recruited 102 patients with chronic neuropathic pain due to a variety of conditions (including diabetes, traumatic injury, complex regional pain syndrome (CRPS) and postherpetic neuralgia) and who had between one and four episodes of breakthrough pain per day despite additional treatment with a short-acting oral opioid drug.

Pain intensity was assessed on an 11-point scale (0 = no pain, 11 = worst pain); the daily average score was 5.2.

After a titration phase to find the minimum dose needed to obtain pain relief within 30 minutes in at least two of three episodes of breakthrough pain, 79 patients who were responsive to fentanyl were randomised in double-blind fashion between this dose of fentanyl and a placebo.

Efficacy was assessed over nine episodes of breakthrough pain.

The results favoured fentanyl: the sum of pain intensity differences from five to 60 minutes after taking fentanyl was 9.6 points compared with 5.7 points for the placebo.

Reduction in pain intensity was significantly greater with fentanyl from the 10th minute, and this benefit was maintained for the 120 minute measurement period.

Pain intensity was reduced by at least 33% in a significantly greater number of breakthrough pain episodes with fentanyl compared to placebo, although the proportion was not very high. After 10 minutes, there was a reduction of at least 33% in 9% of episodes in fentanyl patients and 3% of episodes in placebo patients. This rose to 23% and 14% after 15 minutes. The difference was also significant after 120 minutes but the proportions were not disclosed in the poster.

Further treatment to relieve pain was needed by 14% of patients using fentanyl compared with 36% in the placebo group - a 72% reduction with fentanyl.

Safety data show that adverse effects more often took place during the titration stage. The most frequent effects were typical for opiate drugs: nausea (13%), dizziness (13%), somnolence (10%) and vomiting (5%).

These results suggest that breakthrough pain related to neuropathic pain in opioid-tolerant patients can be treated with effervescent fentanyl buccal tablets, the researchers concluded.

ld/co/clg/rw

luuly.doquang@apmnews.com
[6559] 03/05/2007 11:57 GMT - NEURO

by Luu-Ly Do-Quang at the AAN meeting

BOSTON, May 3 (APM) - Pfizer's Lyrica (pregabalin) seems to relieve pain in patients with fibromyalgia syndrome, according to Phase III data presented at the American Academy of Neurology (AAN) annual meeting in Boston.

Pregabalin is indicated in epilepsy and neuropathic pain, especially diabetic and post-zoster pain.

In December 2006, Pfizer filed a supplemental new drug application for Lyrica in fibromyalgia with the U.S. Food and Drug Administration (FDA) . It plans to file in other major markets too, the U.S. group said in a press release on Tuesday.

The results presented in a poster at the AAN meeting come from one of Pfizer's four Phase III trials in fibromyalgia on a total of more than 3,000 patients.

In this trial, Dr Lesley Arnold from the university of Cincinnati and colleagues enrolled 745 patients who had had fibromyalgia for an average of eight years. Patients had a baseline pain score of 6.7 on the 10-point visual analogue scale (VAS). They were randomised in double-blind fashion between a placebo and three doses of pregabalin - 300, 450 and 600 mg/day, with two weeks' dosage escalation followed by a 12-week fixed dosage.

After the trial, the results showed an average 2.05-point reduction in pain on the VAS with 600 mg/day pregabalin, a 2.03-point reduction at 450 mg/day and a 1.75-point reduction with 300 mg/day compared to baseline. This was a significant difference compared with patients in the placebo group, who had a 1.04-point reduction.

More pregabalin patients also obtained at least 50% pain relief: 30% at 600 mg/day, 27% at 450 mg/day and 24% at 300 mg/day, compared to 15% in the placebo group.

Patients' overall health status was also better with pregabalin, according to fibromyalgia impact questionnaire (FIQ) scores. There was a significant decrease at 600 mg/day (-5.34 points) and at 450 mg/day (-5.24 points), but not with the 300 mg/day dosage.

The most frequent adverse effects in patients treated with all doses of pregabalin were dizziness (36%), somnolence (18%), weight gain (13%), headache (9%) and peripheral oedema (8%).

ld/co/clg/rw

luuly.doquang@apmnews.com
[6560] 03/05/2007 12:04 GMT - NEURO

LONDON, May 3 (APM) - Lehman Brothers on Thursday issued a positive research note on Novo Nordisk, saying investors should be 'overweight' in the stock because of the Danish group's rosy outlook.

Novo Nordisk on Wednesday reported a 40% jump in net profits to 1.7 billion kroner (228.2 million euros) in the first quarter but cut its full-year guidance because of the weak dollar.

It adjusted its predicted 2007 operating profit to grow by only 6-8% rather than the previously forecast 10%. It also cut its outlook for sales growth to less than 10%.

But the U.S. investment bank in its note pointed to the fact the company marginally raised full-year 2007 guidance for underlying operating profit to "more than 15%", compared with a previous forecast of "15%".

Lehman said it was confident of Novo's short-term performance and has set a share price target of 600 kroner, compared with 538 kroner at the time of writing.

LOWER TAXES

Analysts also highlight Novo's likely two percentage point reduction in the company tax rate to 26% from 2008 onwards, following the anticipated adoption of proposed changes to Danish corporate tax, which will "add further upside to earnings".

Leham described the Q1 results as solid. "We remain confident in Novo's short term
performance. Furthermore, we see no degeneration in the long-term positive outlook for Novo's business in diabetes or bleeding."

While Novo's profits in 2006 amounted to 9 billion kroner, Lehman has raised its forecast of 2007 full-year profits from 10.15 billion kroner to 10.53 billion kroner and increased expectations of earnings per share (EPS) this year by 4.5% to 24.51 kroner.

nh/rw

nick.hudson@apmnews.com
[6561] 03/05/2007 12:34 GMT - INDUSTRY

LONDON, May 3 (APM) - A European Commission report suggesting that the pharmaceutical industry could potentially respond to patient requests for information was condemned on Thursday by the International Society of Drug Bulletins (ISDB).

In a statement, the society said: "Industry is not a source of reliable and trustworthy information and it is a mistake to confuse advertising with information. On the contrary there is a need to limit industry influence on patients and prescribers alike."

As reported by APM on April 24, the European Commission proposals are carefully worded and open for consultation until June 30. They stress that while the pharmaceutical industry could potentially respond to patient requests for information, a regulatory framework would be needed to ensure its objectivity.

However patient information is also the focus of a working group in the Pharmaceutical Forum, which was set up by the European Commission in June 2005. One of the questions the working group is examining is that of direct-to-consumer communication by pharmaceutical companies, which is prohibited for prescription medicines in Europe.

This is what appears to have particularly upset the ISDB, which accuses the Commission of "supporting the demand of the pharmaceutical industry to get direct influence on patients," adding that a legislative proposal having this effect was expected in September.

The society noted that a previous attempt to introduce direct to consumer advertising (DTCA) of prescription drugs in the European Union was voted down by parliamentarians with an overwhelming majority five years ago.

"The new move to introduce DTCA comes disguised as a means "to improve the quality of information available to the public," its statement said.

"The main actor behind this move is the Pharmaceutical Forum, a working group without any democratic legitimacy that consists of two EU commissioners, three EU parliamentarians, Member State ministers, no less than five pharmaceutical industry associations, representatives of health professionals and insurers. Patients are 'represented' by the industry-sponsored European Patients' Forum."

rw

richard.woodman@apmnews.com
[6562] 03/05/2007 13:56 GMT - GENERAL

BERLIN, May 3 (APM) - GlaxoSmithKline's Cervarix and Sanofi Pasteur's Gardasil vaccines against cervical cancer from human papillomavirus (HPV) show "fascinating progress" according to German AVP medicines bulletin.

Gardasil obtained European approval in September 2006 and Cervarix is currently being assessed by regulators.

At the end of March, the German standing committee on vaccination (STIKO) from the Robert Koch institute (RKI) for disease control and prevention recommended systematic vaccination of 12-17 year-old girls in Germany with Gardasil or Cervarix.

The Federal Joint Committee of doctors and health insurance fund officials (G-BA) is now examining the question of reimbursement.

AVP or Arzneiverordnung in der Praxis ('Drug prescription in Practice') is an independent bulletin edited by the German medical association's drugs commission (AkdÄ). In its second edition of 2007 it also highlights the benefits of Novartis' antibiotic Cubicin (daptomycin).

Together with Pfizer's Zyvoxid/Zyvox (linezolid) and Wyeth's Tygacil (tigecycline), Cubicin offers a third option against methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE).

However, Cubicin may also elevate creatinine kinase levels and cause rhabdomyolysis when used in combination with statins, AVP adds.

The bulletin finds that Janssen-Cilag's extended release methylphenidate Concerta seems to improve compliance in attention deficit hyperactivity disorder (ADHD). This is an important consideration in this group of patients - which might justify paying eight times as much as for regular methylphenidate in certain cases, AVP considers.

However, Lilly's Strattera (atomoxetine) is only recommended in second line in ADHD as its effects are equivalent to those of methylphenidate (Novartis' Ritalin and generic versions), with a long latency period of several weeks.

AVP is also cautious about Lilly's diabetes drug Byetta (exenatide) in combination with metformin (Merck KGaA's Glucophage and generic versions) in type 2 diabetes.

Although this product reduces weight gain and hypoglycaemia, these benefits are counterbalanced by nausea, vomiting and the need for two injections daily.

AVP is more categorical in its condemnation of Grünenthal's enantiomer of racemic ibuprofen Seractil (dexibuprofen), which it finds not to be substantially better than regular ibuprofen - and four times as expensive.

AVP also reviews atypical neuroleptics Zyprexa (olanzapine, Lilly), Risperdal (risperidone, Janssen Cilag), Solian (Sanofi-Aventis' amisulpride and generic versions) and clozapine (Novartis' Leponex/Clozaril and generic versions). The bulletin concludes that they should not be first-choice treatments because of their metabolic and hormonal adverse effects.

LISTING OF GERMANY'S 25 LAUNCHES IN 2006

AVP classifies the 25 new medicines launched in Germany in 2006 in four groups:

1. Useful new active principals:

Novartis' Cubicin (daptomycin), antibiotic;

OPi's Fomepizole Opi for acute ethylene glycol intoxication;

Shire's Fosrenol (lanthanum carbonate) in the prevention of hyperphosphataemia in kidney failure requiring dialysis;

Sanofi-Aventis' Gardasil vaccine against human papillomavirus types 6, 11, 16 and 18;

Pfizer's Macugen (pegaptanib) against macular degeneration;

Genzyme's Myozyme (alglucosidase alpha) in Pompe disease;

BioMarin's Naglazyme (galsulfase) against mucopolysaccharidosis type VI;

Bayer Schering Pharma's Nexavar (sorafenib) in second line in renal cell carcinoma;

Elan's Prialt (ziconotide) against severe chronic pain;

Servier's Procoralan (ivabradine) against stable angina in patients with beta-blocker intolerance;

GlaxoSmithKline's Rotarix (monovalent vaccine) in the prevention of gastroenteritis caused by rotavirus;

Sanofi-Aventis MSD's RotaTeq (polyvalent vaccine) in the prevention of gastroenteritis caused by rotavirus;

Novartis' Savene (dexrazoxane) against anthracycline extravasation;

Pfizer's Sutent (sunitinib) against gastrointestinal tumours and refractory renal cell carcinoma;


2. Improved versions of existing active principles:

Bristol-Myers Squibb's Baraclude (entecavir) against hepatitis B virus infection;

Bioenvision's Evoltra (clofarabine) in second line against acute lymphoblastic leukaemia;

Novartis' Exjade (deferasirox) against chronic iron excess in beta thalassaemia major;

Ferring's Pabal/Duratocin (carbocetin) in the prevention of uterine atonia after caesarean section;

Bristol-Myers Squibb's Sprycel, in second line against chronic myeloid leukaemia;

Encysive's Thelin (sitaxsentan) against pulmonary arterial hypertension;

Wyeth's Tygacil (tigecycline), antibiotic;


3. Drugs not notably different from existing treatments:

Sanofi-Aventis' Acomplia (rimonabant) against obesity;

UCB's Neupro (rotigotine) patch in Parkinson's disease;

Nycomed's Preotact (recombinant parathyroid hormone) against osteoporosis;


4. Drugs which have been insufficiently studied:

Elan/Biogen Idec's Tysabri (natalizumab) against multiple sclerosis.

(AVP volume 34, 2/2007)

ap/clg/rw

arjen.peters@apmnews.com
[6563] 03/05/2007 14:27 GMT - INDUSTRY