New Class of Treatment for Overactive Bladder Demonstrates Efficacy and Tolerability Across Three Separate Studies

ASTELLAS PHARMA EUROPE Ltd., European subsidiary of Tokyo-based Astellas Pharma Inc. today announced results from three separate clinical trials that further support the efficacy and tolerability of mirabegron. Mirabegron, a beta3 adrenoceptor agonist, is the first in a new class of treatment to be submitted for regulatory approval, using a novel mode of action for the treatment of OAB
The results, presented for the first time at the 27th annual congress of the European Association of Urology (EAU) in Paris demonstrate:
- Efficacy and tolerability of mirabegron in patients who have previously discontinued antimuscarinics - the current standard of care for OAB - Safety and efficacy of mirabegron in OAB patients over a 1 year period - Ocular safety of mirabegron with chronic use

In a sub-group, post-hoc analysis of the Phase III European-Australian trial, patients were randomised to mirabegron 50 or 100mg, tolterodine ER 4mg (a licenced antimuscarinic therapy) or placebo. Mirabegron was found to be effective in reducing the mean number of incontinence episodes/24 hours and micturitions/24 hours in antimuscarinic-naive patients as well as those who had discontinued prior antimuscarinic therapy, regardless of the reason for discontinuation. However, in patients who had discontinued prior antimuscarinic therapy due to lack of efficacy, only mirabegron demonstrated improvement in OAB symptoms - efficacy of tolterodine ER 4mg was similar to placebo.[1] For more information on the data, please see the 'notes to editors' section later in this release.
The results of a large physician / patient survey also presented at the EAU support the findings that mirabegron could be an important development for patients who have failed on previous antimuscarinic therapy due to lack of treatment response. In this survey of 519 physicians, (regarding 5,316 patients), pooled data across France, Germany, Spain and the UK found that the most common reason for switching antimuscarinics was lack of efficacy alone, accounting for 36% of 1,067 patients who switched therapy.[4]
"We have waited 30 years for a completely new mechanism of drug action to treat OAB," commented Dr Vik Khullar, head of the Department of Urogynaecology at St. Mary's Hospital, London, United Kingdom, and Principal Investigator of the European-Australian Phase III trial. "These results demonstrate that mirabegron can benefit many patients, but in particular, will offer hope to those patients who have discontinued antimuscarinic therapy due to lack of efficacy, who currently have no other treatment options."
As a first-in-class drug, long term safety and tolerability is important to establish. In a 12 month Phase III safety and tolerability study 2,444 patients were randomised to receive mirabegron 50mg, mirabegron 100mg or tolterodine ER 4mg. The study found that both mirabegron and tolterodine improved key symptoms of OAB, with improvements in efficacy from the first measured time point (month 1) and maintained throughout the one year treatment period. Overall reported adverse events were similar across all groups; mirabegron 50mg (59.7%), mirabegron 100mg (61.3%) and tolterodine ER 4mg (62.6%). However, the incidence of dry mouth, the most common and bothersome side effect associated with antimuscarinics, was considerably higher with tolterodine ER 4mg than with mirabegron 50mg or mirabegron 100mg (8.6%, 2.8% and 2.3% respectively).
"Dry mouth is a very common and troublesome side effect for patients on treatment with antimuscarinics, which often leads to problems with eating, speaking and general quality of life," commented Professor Christopher Chapple, Consultant Urological Surgeon at Sheffield Teaching Hospitals and Lead Investigator of the 12 month safety and tolerability study. "In fact, a number of patients find that this leads to them wishing to discontinue therapy. This study confirms that mirabegron, which represents a new class of oral agents, offers similar potential efficacy to an antimuscarinic, but without the same burden of dry mouth seen with antimuscarinics. This therefore provides an alternative potential option for patients who are unable to achieve the right balance of efficacy and tolerability with currently available antimuscarinic therapy for overactive bladder."
Antimuscarinics are not recommended for OAB patients with uncontrolled narrow-angle glaucoma because of their potential for mydriasis (prolonged dilatation of the pupil). Mydriasis may increase intraocular pressure (IOP).[3] Results of a Phase Ib study of 305 healthy volunteers presented at the EAU demonstrated that mirabegron 100mg was non-inferior to placebo with regard to effect on IOP. This was based on a non-inferiority margin of 1.5mmHg.[3] The adjusted mean change in IOP from baseline to day 56 was -0.3 mmHg for patients taking mirabegron and -0.2 mmHg for patients taking placebo [95% CI -0.4 to 0.3].[3] Clinically, these results demonstrate that mirabegron does not increase IOP after chronic administration in healthy volunteers over 8 weeks and supports the ocular safety and tolerability of mirabegron.[3]
Astellas Pharma Europe Ltd. is an established leader in urology in Europe, committed to improving the lives of patients with urological conditions. Its current urology portfolio includes treatments for benign prostatic hyperplasia (BPH) and overactive bladder (OAB). With a strong emphasis on research and development, Astellas is dedicated to finding new treatments to meet unmet medical needs and has a number of treatments for urological conditions in late stage development. As part of its ongoing commitment to the field, Astellas also provides and supports a wide range of educational opportunities for those working in the field of urology, designed to progress professional expertise and improve patient outcomes.

Un fármaco pulmonar de Almirall logra el respaldo de las autoridades de EE UU

Almirall SA y Forest Laboratories Inc. han elaborado un fármaco experimental para ayudar a los pacientes con enfermedades pulmonares crónicas a respirar con más facilidad. Doce asesores de la entidad reguladora estadounidense votaron a favor de la eficacia del medicamento y tan solo dos mostraron reticencias sobre la recomendación del bromuro de aclidinio. Esta sustancia debe ser aplicada dos veces al día y reduce las complicaciones derivadas de las enfermedades pulmonares obstructivas crónicas.
Estas enfermedades, generalmente causadas por el tabaquismo, afectan a doce millones de estadounidenses y son la tercera causa principal de muerte en todo el país, según los Institutos Nacionales de Salud. "En esta población, donde la mitad de los pacientes siguen siendo fumadores y sufren enfermedades pulmonares graves, podemos mostrar lo que la medicación puede hacer", dijo Paul Greenberger, profesor de alergia e inmunología en la Universidad Northwestern Feinberg School of Medicine de Chicago.
Forestal, con sede en Nueva York, subió un 1,1% en Wall Street, a 32,20 dólares, tras la publicación de la noticia.
Según los estudios, el medicamento inhalado mejora la función pulmonar y reduce síntomas tales como la dificultad para respirar, la sensación de pesadez en el pecho, el exceso de moco y la tos durante un máximo de 24 horas. Los riesgos cardíacos en los pacientes que tomen la dosis más alta de este fármaco podrían aumentar, aunque se realizarán estudios adicionales para confirmar la seguridad de esta medicación a largo plazo.

**Publicado en "EL PAIS"

Blood Mystery Solved: Two New Blood Types Identified

Yet this knowledge could be "a matter of life and death," says University of Vermont biologist Bryan Ballif.
While blood transfusion problems due to Langereis and Junior blood types are rare worldwide, several ethnic populations are at risk, Ballif notes. "More than 50,000 Japanese are thought to be Junior negative and may encounter blood transfusion problems or mother-fetus incompatibility," he writes.
But the molecular basis of these two blood types has remained a mystery -- until now.
In the February issue of Nature Genetics, Ballif and his colleagues report on their discovery of two proteins on red blood cells responsible for these lesser-known blood types.
Ballif identified the two molecules as specialized transport proteins named ABCB6 and ABCG2.
"Only 30 proteins have previously been identified as responsible for a basic blood type," Ballif notes, "but the count now reaches 32."
The last new blood group proteins to be discovered were nearly a decade ago, Ballif says, "so it's pretty remarkable to have two identified this year."
Both of the newly identified proteins are also associated with anticancer drug resistance, so the findings may also have implications for improved treatment of breast and other cancers.
As part of the international effort, Ballif, assistant professor in the biology department, used a mass spectrometer at UVM funded by the Vermont Genetics Network. With this machine, he analyzed proteins purified by his longtime collaborator, Lionel Arnaud at the French National Institute for Blood Transfusion in Paris, France.
Ballif and Arnaud, in turn, relied on antibodies to Langereis and Junior blood antigens developed by Yoshihiko Tani at the Japanese Red Cross Osaka Blood Center and Toru Miyasaki at the Japanese Red Cross Hokkaido Blood Center.
After the protein identification in Vermont, the work returned to France. There Arnaud and his team conducted cellular and genetic tests confirming that these proteins were responsible for the Langereis and Junior blood types. "He was able to test the gene sequence," Ballif says, "and, sure enough, we found mutations in this particular gene for all the people in our sample who have these problems."

-Transfusion troubles
Beyond the ABO blood type and the Rhesus (Rh) blood type, the International Blood Transfusion Society recognizes twenty-eight additional blood types with names like Duffy, Kidd, Diego and Lutheran. But Langereis and Junior have not been on this list. Although the antigens for the Junior and Langereis (or Lan) blood types were identified decades ago in pregnant women having difficulties carrying babies with incompatible blood types, the genetic basis of these antigens has been unknown until now.
Therefore, "very few people learn if they are Langereis or Junior positive or negative," Ballif says.
"Transfusion support of individuals with an anti-Lan antibody is highly challenging," the research team wrote in Nature Genetics, "partly because of the scarcity of compatible blood donors but mainly because of the lack of reliable reagents for blood screening." And Junior-negative blood donors are extremely rare too. That may soon change.
With the findings from this new research, health care professionals will now be able to more rapidly and confidently screen for these novel blood group proteins, Ballif wrote in a recent news article. "This will leave them better prepared to have blood ready when blood transfusions or other tissue donations are required," he notes.
"Now that we know these proteins, it will become a routine test," he says.

-A better match
This science may be especially important to organ transplant patients. "As we get better and better at transplants, we do everything we can to make a good match," Ballif says. But sometimes a tissue or organ transplant, that looked like a good match, doesn't work -- and the donated tissue is rejected, which can lead to many problems or death.
"We don't always know why there is rejection," Ballif says, "but it may have to do with these proteins."
The rejection of donated tissue or blood is caused by the way the immune system distinguishes self from not-self. "If our own blood cells don't have these proteins, they're not familiar to our immune system," Ballif says, so the new blood doesn't "look like self" to the complex cellular defenses of the immune system. "They'll develop antibodies against it," Ballif says, and try to kill off the perceived invaders. In short, the body starts to attack itself.
"Then you may be out of luck," says Ballif, who notes that in addition to certain Japanese populations, European Gypsies are also at higher risk for not carrying the Langereis and Junior blood type proteins.
"There are people in the United States who have these challenges too," he says, "but it's more rare."

-Other proteins
Ballif and his international colleagues are not done with their search. "We're following up on more unknown blood types," he says. "There are probably on the order of 10 to 15 more of these unknown blood type systems -- where we know there is a problem but we don't know what the protein is that is causing the problem."
Although these other blood systems are very rare, "if you're that one individual, and you need a transfusion," Ballif says, "there's nothing more important for you to know."

Las mujeres sedentarias tienen una peor sexualidad que las activas

Si no se anima a hacer deporte para mejorar su estado físico y psíquico, prevenir las enfermedades cardiovasculares, la diabetes o la obesidad, tal vez el argumento que le propone ahora la ciencia le motive más: el sexo. No sólo la buena función sexual de los hombres depende del flujo sanguíneo en los genitales, también la de las mujeres. Los problemas sexuales de la mayoría de ellas con la excitación y la respuesta sexual se deben a un flujo insuficiente en el área genital.
Sin embargo, practicar ejercicio de forma regular puede contribuir, y mucho, a mejorar el flujo sanguíneo en el clítoris y potenciar así la función sexual femenina.
Omer Faruk Karatas, de la Universidad Faith, en Ankara (Turquía), es el autor principal de una investigación que lo confirma.
En declaraciones al ELMUNDO.es asevera: "Este es el primer estudio que compara a atletas de élite y mujeres sanas respecto a la función sexual y el flujo sanguíneo del clítoris. El objetivo era evaluar los efectos de practicar ejercicio de forma regular en ambos grupos".
El clítoris es un "órgano eréctil que contribuye significativamente a la función sexual, especialmente durante la excitación y las distintas fases del orgasmo. Las medidas de su flujo sanguíneo con ultrasonido doppler (técnica especial que evalúa la circulación de la sangre a través de los vasos sanguíneos) se están llevando a cabo frecuentemente con el fin de establecer la función o la disfunción sexual femenina, por ejemplo tras el consumo de medicación o de una cirugía de genitales", declara el director del ensayo.
Pruebas de ultrasonido
Por este motivo, los científicos llevaron a cabo la prueba en 25 jugadoras de balonmano y voleibol de entre 20 y 45 años, sexualmente activas, que practicaban ejercicio regular (un mínimo de cuatro horas al día). A todas ellas las compararon con otras tantas mujeres sanas, con la misma media de edad, que realizaban dos horas de deporte a la semana, según publica 'Journal of Sexual Medicine' .

**publicado en "EL MUNDO"

Taking Back the Brain

A promising novel target for potentially treating Alzheimer's disease has been identified in mice by a team at the University of California, Davis. The researchers will present their findings at the Biophysical Society's 56th Annual Meeting in San Diego, Calif., held Feb. 25-29.
The team’s focus is on controlling cells in the brain known to be major inflammatory agents. These cells, called microglia, are activated by toxic beta amyloid proteins that accumulate as plaques in the brain and disrupt neuronal function, and they are major players in the initiation and progression of Alzheimer's disease. To turn off the microglia, and therefore stop their neurotoxic effects, the UC Davis team blocked the flow of potassium ions through a voltage-gated potassium channel on the microglial membrane.
"Our observations raise the exciting possibility that potassium channel blockers might preferentially inhibit the action of microglia related to killing neurons without affecting the beneficial functions associated with them, as such as scavenging of debris,” says UC Davis’ David P. Jenkins, first author of the study.
In their investigation, the researchers examined microglia from mice specially bred to develop a mouse-mimic of Alzheimer's disease. They found that the adult mouse brains with high levels of beta amyloid also expressed higher levels of potassium channels on their microglia compared to microglia isolated from normal mouse brains. The researchers tested the functional importance of microglial potassium channels by administering a potassium channel blocker to brain tissue specimens. Results showed that the blocker inhibited plaque-induced microglia activation and the toxicity associated with it, but that it did not interfere with the useful "housecleaning" tasks that microglia perform.
"With the rise of Alzheimer's disease,” says Jenkins, “finding a novel pharmacological target for curbing the harmful effects of beta amyloid-induced microglia activation is highly desirable in developing new therapies."
The presentation, “Microglial KV1.3 channels as a potential target for Alzheimer’s disease,” is at 10:30 a.m. on Wednesday, Feb. 29, 2012, in the San Diego Convention Center, Hall FGH. ABSTRACT: http://tinyurl.com/7t2u4f5
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This news release was prepared for the Biophysical Society (BPS) by the American Institute of Physics (AIP).

Austerity in Europe puts pressure on drug companies

Profits at pharmaceutical companies have been declining or showing little growth for the last year as austerity measures across Europe lead to cuts in health care spending. Some analysts say this trend could continue until at least 2014.
Budget cuts mean that many European governments are not willing to pay as much for pills. But new laws in some countries are also putting pressure on companies to prove their drugs are effective or risk having them dropped from the coverage list, or covered at a lower rate.
And price reductions in Europe can have a ripple effect. Profits from sales in emerging markets may also fall, because governments in emerging markets refer to the prices set in Europe to determine their own.
That would particularly hurt European pharmaceutical companies, which have been quite successful in emerging markets in the last five years. American companies, by contrast, do not rely as much on overseas revenue because of their large domestic market.
Before the recent wave of austerity measures, drug companies faced relatively low resistance from European governments when they set prices and introduced products. Countries with strong industrial bases, like Germany, France and Britain, allowed companies the most flexibility in setting prices.
“The euro crisis is forcing governments to restructure how they think about medications,” said Richard Bergström, director general of the European Federation of Pharmaceutical Industries and Associations.
Because the prices governments are willing to pay are falling, drug companies are recalibrating their strategies and considering economic factors earlier in the process of developing medicines. They are also reducing the number of new drugs in which they invest research money.
On average, West European countries spend 8 to 12 percent of their gross domestic product on health care — a proportion that has remained stable despite the crisis, according to the Organization for Economic Cooperation and Development.
The pharmaceutical sector, though, is being hit disproportionately hard because cutting prices for pills is a quick way to reduce spending, compared with alternatives like cutting money for hospitals or restructuring health care systems.
In the last year, pharmaceutical sales to pharmacies and hospitals declined 2.2 percent in France, 3.1 percent in Italy and nearly 9 percent in Spain, according to Business Monitor International, a company in London that follows the pharmaceutical industry.
Analysts say that it is difficult to predict how badly profits will be affected in the next fiscal year. Other factors, including expiring patents, mean that each company’s profit will be affected differently.
Still, “the austerity measures themselves are going to affect everyone,” Mr. Bergström said.
And the numbers are not encouraging.
Novartis, the Swiss pharmaceutical giant, posted a 7 percent decline in net income for 2011 despite a 16 percent increase in sales. AstraZeneca, based in Britain, posted full-year revenue for 2011 of $1.34 billion, down 2 percent from 2010. In 2011, net profit for the company’s West European market was down 11 percent from the previous year.
Kaushal Shah, an analyst with Business Monitor International, said the clearest way to see the effects of the euro crisis on pharmaceutical companies was in job cuts. AstraZeneca plans to cut more than 7,000 jobs in Europe, in addition to the 21,600 positions it has eliminated since 2007. Novartis, a largely European company, will cut nearly 2,000 jobs in the United States this year. Pfizer cut 6,000 jobs last May. In times of hardship, pharmaceutical companies usually lay off sales representatives and protect research and development departments, which lead drug creation. In this crisis, even research and development positions face cuts as companies strive to make these departments more efficient so as to reduce costs while maintaining a pipeline of new products.
“2011 is the first year recorded where

**Published in "THE NEW YORK TIMES"

Newly approved drug for metastatic melanoma nearly doubles median survival

Researchers from UCLA's Jonsson Comprehensive Cancer Center, together with scientists from 12 other sites in the United States and Australia, report for the first time that a newly approved drug for patients with metastatic melanoma nearly doubles median survival times, a finding that will change the way this deadly form of skin cancer is treated. The data comes from an international Phase II study of Zelboraf that included 132 patients followed for at least one year.
Patients with this advanced form of melanoma that has spread to other organs typically survive about nine months. Patients taking Zelboraf, which blocks a mutated BRAF protein, survived an average of 15.9 months, said study senior author Dr. Antoni Ribas, a professor of hematology/oncology and a researcher at UCLA's Jonsson Cancer Center.
"This study shows that Zelboraf changes the natural history of this disease," Ribas said. "This data is beyond what I would have expected. We're seeing a significant number of patients with durable responses to the drug, and that the whole group of treated patients is living longer. These results tell us that this drug is having a very big impact, and this changes the way we treat metastatic melanoma."
The study appears Feb. 23, 2012 in the peer-reviewed New England Journal of Medicine.
About 50 percent of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf, a pill taken twice a day, Ribas said. Of those, 53 percent have an objective response to the drug, meaning their tumors shrink by more than 30 percent. An additional 30 percent of patients have tumor responses of lesser magnitude. Only 14 percent of patients with the BRAF mutation failed to respond to Zelboraf.
The drug represents a breakthrough in treating metastatic melanoma. Prior to this, 10 percent or less of patients with this advanced form of the disease responded to any of the available conventional treatments, Ribas said.
"We knew this drug would make the melanomas shrink in a large proportion of patients and that it worked better than chemotherapy," Ribas said. "We did not know that patients taking Zelboraf were living longer until now."
The main limitation with Zelboraf is that tumors eventually become resistant. But Jonsson Cancer Center researchers are studying this resistance and have uncovered several mechanisms by which the cancer gets around Zelboraf. Cancer center scientists currently are seeking agents to target those mechanisms, Ribas said.
For Louise Belley, 60, of Santa Ana, Zelboraf has allowed her to live much longer than her doctors initially predicted, and last June she was able to see her daughter graduate from college. Belley was diagnosed with metastatic melanoma in November of 2007. In June 2009, she was among the first people to get the drug when it was in Phase I studies at the Jonsson Cancer Center.
Her first CT scan in September 2009 after joining the trial -- nearly two and a half years ago -- was clear of any cancer, she said. Her scans remain clean today.
"At first I was devastated by my diagnosis, because I realized I was in a really bad place," Belley said. "But now I feel strongly that the chances are good that I will continue to be cancer free, and I plan to live every day to the fullest."
Zelboraf was approved by the U.S. Food and Drug Administration for use in metastatic melanoma in August of 2011. About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.
"This trial shows a high rate of response to (Zelboraf) in patients with metastatic melanoma and activating BRAF mutations," the study states. "These results independently confirm the high response rate and response duration shown in a Phase I trial."

**Source: University of California, Los Angeles (UCLA), Health Sciences