From M.J. FOX Foundation (http://www.michaeljfox.org/)

Original article.....

On Monday, June 16, 2008, Israeli drugmaker Teva issued a press release reporting that Azilect (rasagiline) was on track to become the first disease-modifying treatment for Parkinson’s disease. The company has completed the ADAGIO Phase 3 clinical trial, in which Azilect tablets met three clinical endpoints demonstrating that the drug could slow progression of Parkinson’s disease.

The Michael J. Fox Foundation spoke with Karl Kieburtz, MD, PhD, Professor of Neurology and Community and Preventive Medicine at the University of Rochester Medical Center and chair of the Parkinson Study Group, about how patients should interpret the news.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.

MJFF: In the simplest terms, what is Teva reporting and why is it potentially important for people with Parkinson’s?

KK: Teva’s press release reported that rasagiline, which Teva sells under the brand name Azilect, can slow functional decline in early-stage PD patients who have not yet been treated with dopamine-replacement therapies, such as levodopa. This means that rasagiline could be the first PD treatment to receive the label “disease-modifying” from the Food and Drug Administration (FDA).
MJFF: Do we know for sure that rasagiline is disease-modifying?
KK: No, we don’t know that with certainty yet. I want to emphasize strongly that the press release was not a scientific one. Commercial entities are obligated by the Securities and Exchange Commission (SEC) to put out communications such as this when they have information that they know may affect their share prices. As of this week, the scientific data resulting from the trial have not been made public. In the future, when the data have been made public, the results of this trial may be seen differently.
The good news is that at least some scientific results should be forthcoming as soon as within the next few weeks. Some of the data from the ADAGIO trial will be presented during the week of June 23 at the Movement Disorders Society Congress in Chicago, and we would also expect to see publication in a peer-reviewed journal within a relatively short timeframe. [Editor’s note: Watch the MJFF Web site for further updates in coming weeks.]
MJFF: What kind of drug is rasagiline? Are there other similar drugs that could exert a similar effect?
KK: Rasagiline belongs to a class of drugs called monoamine oxidase inhibitors (MAO-Is). To date these drugs have typically been used alone or in combination with levodopa as a symptomatic therapy for both early- and late-stage Parkinson’s patients. Another drug in the same class is called selegiline. At this point it’s impossible to extrapolate Teva’s rasagiline results to selegiline, because selegiline has not yet been tested in the same ‘delayed start’ design. Perhaps there is some unique quality to rasagiline that allows it to potentially slow PD progression. We’ll know more when we see the data.
MJFF: Are there negative side effects or other concerns people should have before asking their doctor for Azilect? Should everyone with PD now consider taking the drug?

KK: Certainly MAO-inhibitors are not without side effects, and there are some warnings associated with prescribing them. They have possible interactions with certain other drugs, including selective serotonin reuptake inhibitors (SSRIs), which are widely prescribed to treat depression. They may interact with a chemical called tyramine found in foods including alcohol and certain cheeses, which can result in blood pressure changes. As a result, people on some of these drugs must adhere to a restricted diet, and this can be difficult. Studies suggest that rasagiline may be less prone to interact with tyramine in this way, but it is still important that patients speak with their doctors to address all the potential issues that surround starting a course of treatment with rasagiline.

MJFF: Was there earlier evidence that rasagiline could be disease-modifying?
KK: Yes, there were preliminary results which Teva was following up on with the ADAGIO study. In 2004 the Parkinson Study Group conducted the TEMPO trial on rasagiline, with results similar to the news out this week, though TEMPO’s overall duration was shorter.
MJFF: How did the researchers design the ADAGIO trial to test for disease modification?
KK: It’s important to note that the endpoints for the trial were clinical outcomes, not biochemical measures. In other words, we still don’t have a way to “look inside” a patient’s brain and check to see how well the dopamine neurons are doing. What this means is that the clinicians were assessing trial participants for observable changes in their PD symptoms — i.e., did their movement not slow as much over the course of the trial? Trial participants were measured against the Unified Parkinson’s Disease Rating Scale (UPDRS), the standard validated tool used in PD clinical trials.
The ADAGIO researchers employed a design known as a “delayed-start trial.” As recently as April 28, at a meeting co-sponsored by MJFF, the Parkinson Study Group, the Food and Drug Administration (FDA) and the American Association of Pharmacological Scientists, FDA has suggested that, in the absence of a biological marker, a delayed-start trial is the design most likely to satisfactorily demonstrate disease modification.
MJFF: What is a delayed-start trial and how does it work?
KK: A delayed start trial works like this: At the outset of the trial, participants are divided into two groups. One group receives the actual treatment, and one receives a placebo. Neither the patients nor the clinicians know which group is which. Results are carefully tracked for a certain period of time — in the case of the ADAGIO trial, 36 weeks.
When the 36 weeks have elapsed, the placebo group is switched to the actual treatment. At this point the clinicians are looking for a very specific result. If the treatment being tested is exerting a disease-modifying effect, then the improvements seen in the group that started on placebo should not be able to “catch up” with the improvements seen in the group that received actual treatment from the beginning. Even though the “delayed start” group may see some improvement once they switch from placebo to the drug, there will always be a “gap” between the two groups. If you can demonstrate that the gap exists and that it remains over an extended period of time, FDA has suggested that it’s reasonable to claim that your treatment is slowing the progression of the disease.
MJFF: Bottom line: How excited should patients and their loved ones feel about this news?
KK: Results that come out in a business-oriented press release aren’t sufficient to make a judgment on implications for patients. We need to really evaluate the science and we need to know exactly what the study found. For example, what were the side effects experienced by patients in the trial? How many dropped out? Did they have to follow a special diet? How did they feel about that?
So, while the news reported this week is potentially very exciting, it is not yet actionable. The clinical and research community awaits further understanding of the trial results in order to effectively advise patients on best next steps.

Axxonis Pharma AG announces the submission of a marketing authorisation application to the European Medicines Agency (EMEA) for Nenad(R) (lisuride transdermal patch as add-on therapy for Parkinson's Disease and for Restless Legs Syndrome, and subcutaneous (sc) lisuride infusion for advanced Parkinson's Disease) Lisuride, the active principle of Nenad(R), is a potent dopamine agonist which in its parenteral forms (transdermal patch and sc infusion) has been developed to provide continuous dopaminergic stimulation (CDS). Experts expect from CDS a new quality of treatment of Parkinson's Disease and RLS combined with ease of administration. All results obtained so far not only demonstrate strong efficacy but also a good general tolerability of Nenad(R) and an improved quality of life for those affected by these neurological conditions

">Axxonis Pharma AG anuncia la presentación de una solicitud de autorización de comercialización a la Agencia Europea de Medicamentos (EMEA) para Nenad (R) (lisuride parche transdérmico como tratamiento adicional a la terapia para la enfermedad de Parkinson y para el Síndrome de Piernas Inquietas, y subcutánea (sc) lisuride para perfusión la enfermedad de Parkinson avanzada)
Lisuride, el principio activo de Nenad (R), es un potente agonista de la dopamina que, en su forma parenteral (parche transdérmico y perfusión sc) ha sido desarrollado para facilitar la estimulación dopaminérgica continua (CDS). Expertos de CDS esperar una nueva calidad del tratamiento de la enfermedad de Parkinson y SPI combinada con la facilidad de administración. Todos los resultados obtenidos hasta la fecha no solo demuestran la firme eficacia, sino también una buena tolerabilidad general de Nenad (R) y una mejor calidad de vida para los afectados por estas condiciones neurológicas

About Nenad(R)
Nenad(R) 10 cm squared and 20 cm squared transdermal patches, which release 2.5 microgram lisuride and 5.0 microgram lisuride per hour, respectively, have been developed as a new application form of the strong dopamine agonist lisuride in order to enhance efficacy and to improve tolerability. The Nenad(R) patch works by non-invasive transport of lisuride across the skin and provides continuous dopaminergic stimulation (CDS) over two days. For Parkinson's Disease, one or two 20 cm squared patches are applied every other evening; for RLS, one or two 10 cm squared patches are applied every other morning. With these schedules, only one up-titration step is required in Parkinson's Disease with a rapid onset of action (significant after only one week treatment) with a simultaneous reduction in early adverse events. In RLS, most patients respond satisfactorily to just one 10 cm squared patch or, in severe cases, two patches of 10 cm squared, with improvement also in day-time symptomatology.

">Nenad (R) 10 cm  y 20 cm cuadrado parches transdermicos, que liberan 2,5 microgramos lisuride y lisuride 5,0 microgramos por hora, respectivamente, se han desarrollado como un nuevo formulario de solicitud de la fuerte agonista de la dopamina lisuride con el fin de mejorar la eficacia y mejorar tolerabilidad. El Nenad (R) de parches en forma de transporte no invasiva de lisuride a través de la piel y proporciona la estimulación dopaminergica continua (CDS) a lo largo de dos días. Para la enfermedad de Parkinson, una o dos parches de 20 cm cuadrados se aplican cada dos noches, por SPI, uno o dos de 10 cm cuadrados parches se aplican a todos los días por la mañana. ...........

Lisuride sc (Nenad(R) Powder for solution for sc infusion) was developed for the treatment of patients in an advanced stage of Parkinson's Disease. The continuous application of this parenteral dopamine agonist using a small portable minipump provides stable individual drug levels and thereby achieves superior therapeutic results in treatment-resistant stages of Parkinson's Disease complicated by motor fluctuations. Studies showed good therapeutic efficacy on "Off" (hypomobility) and "On" with troublesome dyskinesia (hypermobility). Lisuride also has antifibrotic and antiproliferative effects as a strong antagonist of 5- HT (serotonin) 2B receptors and therefore is expected to cause no cardiac valvulopathy as is the case with some other dopamine agonists.

">Lisuride sc (Nenad (R) Polvo para solución para perfusión sc) fue desarrollado para el tratamiento de pacientes en una fase avanzada de la enfermedad de Parkinson. La continua aplicación de la presente parenteral agonista de la dopamina mediante una pequeña mini bomba portátil proporciona unos niveles individuales estable de drogas y, por ende, logra resultados terapéuticos superiores en el tratamiento resistente a las fases de la enfermedad de Parkinson complicada por las fluctuaciones motoras. Los estudios mostraron buena eficacia terapéutica en "Off" (hipomovilidad) y "On" molestos con disquinesia (hipermovilidad).
Lisuride también tiene efectos antifibroticos y antiproliferativo como un fuerte antagonista de receptores 5 - HT (serotonina) 2B y, por tanto, se espera que no cause daños valvular como es el caso de algunos otros agonistas de la dopamina.

Fuente: Medical News Today

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