Andrew P Desbois University of Stirling, Institute of Aquaculture, School of Natural Sciences, Marine Biotechnology Group, Stirlingshire, FK9 4LA, UK .
Drug discovery from marine organisms has been underway for > 60 years and there have been notable successes in discovering, developing and introducing clinical agents derived from marine sources. Such examples include: the analgesic ziconotide and the anti cancer compound trabectedin. However, in light of the pressing need for new drugs, particularly those with anti-infective and anticancer properties, there is strong justification for increased exploration of marine organisms as sources of novel compounds. This article considers approaches that might enhance our chances of delivering new medicines from marine-based drug discovery efforts. Consideration is given to the organisms and habitats deserving of more attention and how we might make best use of these marine genetic resources. In particular, the opportunities offered by synthetic biology are highlighted because these methods allow drug discoverers to explore pathways in ‘non-culturable’ species and turn on natural product biosynthesis genes that are difficult to activate under laboratory conditions (so-called ‘silent’ gene clusters).
10 junio 2014
PM01183 en " Forbes " . Under The Sea: PharmaMar's Lurbinectedin Beats Topotecan In Platinum Resistant Ovarian Cancer .
Pharma & Healthcare 6/10/2014 @ 6:32AM .
Sifting through puddles from the firehose of last week’s American Society of Clinical Oncology annual meeting brought to my attention some promising news from the world of ovarian cancer. This early efficacy study with a synthetic drug based on a naturally-occurring molecule also demonstrates the continued value of prospecting the planet to harvest chemical diversity for the relief of human suffering.
PharmaMar, a Madrid-based marine natural products pharmaceutical company and division of Zeltia, conducts what I call “ocean-to-bedside” drug development. Their first marine-derived drug for cancer, Yondelis® (trabectedin, ET-743), is approved in the European Union and Japan.
The current study builds on this work with the semi-synthetic analogue, lurbinectedin (PM01183; brand name pending).
Lurbinectedin is a second-generation analogue of trabectedin (Yondelis). Known previously as ecteinascidin-743, or ET-743, trabectedin is derived from the Caribbean sea squirt, Ecteinascidia turbinata. Credit: PharmaMar.
Andres Poveda, MD, a gynecological oncologist at Instituto Valencieno de Oncologia, presented the results on behalf of a team of European Union investigators who assessed the anticancer activity of lurbinectedin in women with ovarian cancer that had become resistant or refractory to platinum-containing drugs, such as carboplatin or cisplatin (formerly BMS drugs, now available as generics).
An aside: I had always thought that “resistant” and “refractory” were synonyms when used to describe cancer responsiveness to drugs. But not so in the case of patients whose cancer no longer responds to platinum drugs. Patients with platinum-refractory cancer are those whose disease continues to grow while receiving a platinum drug. Patients with platinum-resistant cancer are those whose disease progresses within 6 months of cessation of platinum therapy. Therefore, platinum-refractory patients are considered to have more aggressive disease. This distinction is essential in appreciating the results of the trial.
This two-part, 81-patient Phase II study first established the anticancer activity of lurbinectedin in a cohort of 22 ovarian cancer patients. Those data were presented on their own at the European Society of Medical Oncology in 2012. The newly-reported data at the 2014 ASCO meeting come from another group of 59 patients randomized 1:1 to receive either lurbinectedin or topotecan (Hycamtin®; GlaxoSmithKline).
Lurbinectedin superior to topotecan in platinum-resistant ovarian cancer .
Overall response rate (ORR), the primary endpoint together with safety, was 22% with lurbinectedin and 0% with topotecan. Lurbinectedin was more effective in platinum-resistant patients (30%) than in patients with the more challenging platinum-refractory cancer (6%).
Lurbinectedin was also statistically superior with regard to median progression-free survival: 3.9 months for lurbinectedin versus 2.0 months for topotecan. When subclassified by previous platinum sensitivity, those patients with platinum-resistant disease fared even better: 7.1 months for lurbinectedin versus 1.7 months for topotecan. Unfortunately, patients with platinum-refractory cancer showed no statistical difference in progression-free survival between the two drugs.
Another secondary endpoint, and perhaps the one most important to patients and their loved ones, was overall survival. Lurbinectedin won out with overall median survival of 10.6 months relative to 5.7 months for topotecan. Again, patients with platinum-resistant disease fared best. In this subset, topotecan’s median overall survival was 7.0 months but it could not yet be calculated for lurbinectedin because more than 50% of these patients were still alive when the data were compiled. That’s an impressive result in this patient population.
Lurbinectedin was, of course, not without side effects. A total of 85% of patients receiving lurbinectedin experienced severe drops in white blood cell counts (grade 3-4 neutropenia) but this was predictable and reversible. The study authors recommended that the neutropenia could be prevented with the blood stimulating factor, G-CSF.
Other adverse events included febrile neutropenia (23%), thrombocytopenia (Grade 3-4, 29%), nausea & vomiting (Grade 3-4, 16%), and fatigue (Grade 3, 37%).
Remember that while we’re talking in terms of months of increased survival, the drugs were being tested after the patients’ disease no longer responded to platinum drugs. We don’t know how lurbinectedin would perform if given to women with ovarian cancer as a first-line treatment, alone or with a platinum drug.
Limitations
At this point, the results should be considered preliminary since the study has not been peer-reviewed and accepted for publication.
I still have some questions about how the data were compiled for lurbinectedin. Sometimes the results were given for the combination of the two parts of the lurbinectedin study arms (51 total patients) and other times it was separated out (22 patients first, then 29 patients in the part where compared with another 29 patients on topotecan).
The study design also allowed for patients whose disease progressed on topotecan to be given the choice to then receive lurbinectedin. However, it’s not clear how this factor was accounted for in the overall topotecan survival data.
Nevertheless, the continued survival of many patients receiving lurbinectedin is highly promising and bodes well continuing the path to approval in the EU and elsewhere.
PharmaMar now plans a Phase III trial in patients with platinum-resistant ovarian cancer.
Sifting through puddles from the firehose of last week’s American Society of Clinical Oncology annual meeting brought to my attention some promising news from the world of ovarian cancer. This early efficacy study with a synthetic drug based on a naturally-occurring molecule also demonstrates the continued value of prospecting the planet to harvest chemical diversity for the relief of human suffering.
PharmaMar, a Madrid-based marine natural products pharmaceutical company and division of Zeltia, conducts what I call “ocean-to-bedside” drug development. Their first marine-derived drug for cancer, Yondelis® (trabectedin, ET-743), is approved in the European Union and Japan.
The current study builds on this work with the semi-synthetic analogue, lurbinectedin (PM01183; brand name pending).
Lurbinectedin is a second-generation analogue of trabectedin (Yondelis). Known previously as ecteinascidin-743, or ET-743, trabectedin is derived from the Caribbean sea squirt, Ecteinascidia turbinata. Credit: PharmaMar.
Andres Poveda, MD, a gynecological oncologist at Instituto Valencieno de Oncologia, presented the results on behalf of a team of European Union investigators who assessed the anticancer activity of lurbinectedin in women with ovarian cancer that had become resistant or refractory to platinum-containing drugs, such as carboplatin or cisplatin (formerly BMS drugs, now available as generics).
An aside: I had always thought that “resistant” and “refractory” were synonyms when used to describe cancer responsiveness to drugs. But not so in the case of patients whose cancer no longer responds to platinum drugs. Patients with platinum-refractory cancer are those whose disease continues to grow while receiving a platinum drug. Patients with platinum-resistant cancer are those whose disease progresses within 6 months of cessation of platinum therapy. Therefore, platinum-refractory patients are considered to have more aggressive disease. This distinction is essential in appreciating the results of the trial.
This two-part, 81-patient Phase II study first established the anticancer activity of lurbinectedin in a cohort of 22 ovarian cancer patients. Those data were presented on their own at the European Society of Medical Oncology in 2012. The newly-reported data at the 2014 ASCO meeting come from another group of 59 patients randomized 1:1 to receive either lurbinectedin or topotecan (Hycamtin®; GlaxoSmithKline).
Lurbinectedin superior to topotecan in platinum-resistant ovarian cancer .
Overall response rate (ORR), the primary endpoint together with safety, was 22% with lurbinectedin and 0% with topotecan. Lurbinectedin was more effective in platinum-resistant patients (30%) than in patients with the more challenging platinum-refractory cancer (6%).
Lurbinectedin was also statistically superior with regard to median progression-free survival: 3.9 months for lurbinectedin versus 2.0 months for topotecan. When subclassified by previous platinum sensitivity, those patients with platinum-resistant disease fared even better: 7.1 months for lurbinectedin versus 1.7 months for topotecan. Unfortunately, patients with platinum-refractory cancer showed no statistical difference in progression-free survival between the two drugs.
Another secondary endpoint, and perhaps the one most important to patients and their loved ones, was overall survival. Lurbinectedin won out with overall median survival of 10.6 months relative to 5.7 months for topotecan. Again, patients with platinum-resistant disease fared best. In this subset, topotecan’s median overall survival was 7.0 months but it could not yet be calculated for lurbinectedin because more than 50% of these patients were still alive when the data were compiled. That’s an impressive result in this patient population.
Lurbinectedin was, of course, not without side effects. A total of 85% of patients receiving lurbinectedin experienced severe drops in white blood cell counts (grade 3-4 neutropenia) but this was predictable and reversible. The study authors recommended that the neutropenia could be prevented with the blood stimulating factor, G-CSF.
Other adverse events included febrile neutropenia (23%), thrombocytopenia (Grade 3-4, 29%), nausea & vomiting (Grade 3-4, 16%), and fatigue (Grade 3, 37%).
Remember that while we’re talking in terms of months of increased survival, the drugs were being tested after the patients’ disease no longer responded to platinum drugs. We don’t know how lurbinectedin would perform if given to women with ovarian cancer as a first-line treatment, alone or with a platinum drug.
Limitations
At this point, the results should be considered preliminary since the study has not been peer-reviewed and accepted for publication.
I still have some questions about how the data were compiled for lurbinectedin. Sometimes the results were given for the combination of the two parts of the lurbinectedin study arms (51 total patients) and other times it was separated out (22 patients first, then 29 patients in the part where compared with another 29 patients on topotecan).
The study design also allowed for patients whose disease progressed on topotecan to be given the choice to then receive lurbinectedin. However, it’s not clear how this factor was accounted for in the overall topotecan survival data.
Nevertheless, the continued survival of many patients receiving lurbinectedin is highly promising and bodes well continuing the path to approval in the EU and elsewhere.
PharmaMar now plans a Phase III trial in patients with platinum-resistant ovarian cancer.
Merck Adquiere por 3.580 Millones de $$ Idenix Pharmaceuticals .
Europa Press .
La farmacéutica MSD, conocida como Merck en Estados Unidos y Canadá, ha llegado a un acuerdo definitivo para adquirir Idenix Pharmaceuticals a un precio de 24,50 dólares por acción en efectivo, los que supone valorar la empresa en 3.850 millones de dólares (2.828 millones de euros).
Idenix es una compañía biofarmacéutica dedicada al descubrimiento y desarrollo de medicamentos para el tratamiento de enfermedades virales humanas, cuyo objetivo principal es el desarrollo de la próxima generación de terapias antivirales orales para tratar la hepatitis C, para lo que tiene tres medicamentos en desarrollo clínico.
Según los términos del acuerdo, aprobado por los consejos de administración de ambas compañías, Merck presentará a través de una subsidiaria una oferta para adquirir todas las acciones en circulación de Idenix Pharmaceuticals.
El cierre de la operación, previsto para el tercer trimestre de 2014, está sujeto a ciertas condiciones, entre ellas que el número de acciones que acuden a la oferta representen al menos la mitad de todos los títulos en circulación. Una vez cerrada esta oferta, Merck adquirirá todas las demás acciones a través de una fusión.
El presidente de Merck Research Laboratories, Roger Perlmutter, destacó que Idenix ha creado una "prometedora cartera" de medicamentos candidatos para la hepatitis C que completan sus terapias en desarrollo y ayudarán a lograr avances en su trabajo para desarrollar un tratamiento eficaz que tenga una duración lo más corta posible para los millones de pacientes que existen en el mundo.
...
La farmacéutica MSD, conocida como Merck en Estados Unidos y Canadá, ha llegado a un acuerdo definitivo para adquirir Idenix Pharmaceuticals a un precio de 24,50 dólares por acción en efectivo, los que supone valorar la empresa en 3.850 millones de dólares (2.828 millones de euros).
Idenix es una compañía biofarmacéutica dedicada al descubrimiento y desarrollo de medicamentos para el tratamiento de enfermedades virales humanas, cuyo objetivo principal es el desarrollo de la próxima generación de terapias antivirales orales para tratar la hepatitis C, para lo que tiene tres medicamentos en desarrollo clínico.
Según los términos del acuerdo, aprobado por los consejos de administración de ambas compañías, Merck presentará a través de una subsidiaria una oferta para adquirir todas las acciones en circulación de Idenix Pharmaceuticals.
El cierre de la operación, previsto para el tercer trimestre de 2014, está sujeto a ciertas condiciones, entre ellas que el número de acciones que acuden a la oferta representen al menos la mitad de todos los títulos en circulación. Una vez cerrada esta oferta, Merck adquirirá todas las demás acciones a través de una fusión.
El presidente de Merck Research Laboratories, Roger Perlmutter, destacó que Idenix ha creado una "prometedora cartera" de medicamentos candidatos para la hepatitis C que completan sus terapias en desarrollo y ayudarán a lograr avances en su trabajo para desarrollar un tratamiento eficaz que tenga una duración lo más corta posible para los millones de pacientes que existen en el mundo.
...
¿Qué pruebas de imagen aumentan más el riesgo de cáncer? .
MARÍA VALERIO /// Madrid 10/06/2014 .
En niños con graves problemas cardiacos, sus primeros años de vida pueden ser una sucesión de pruebas médicas con las consiguientes dosis de radiación. Aunque estos procedimientos no están exentos de riesgo, por el incremento del riesgo de tumores que pueden suponer en su vida adulta, un amplio análisis publicado en la revista Circulation lanza un mensaje tranquilizador.
Científicos de la Universidad de Durham (en Carolina del Norte), han analizado los historiales médicos de 337 niños menores de seis años que se habían sometido a algún tipo de operación por problemas de corazón (el 70% de ellos padecía algún tipo de cardiopatía congénita).
En estos pequeños, el uso de pruebas de imagen que funcionan con radiación (desde las radiografías hasta los TAC o los procedimientos de cateterismo que se siguen mediante un contraste desde el exterior) suele ser habitual antes y después de pasar por el quirófano; y de hecho la media de exámenes de estos pequeños ascendía a 17 pruebas por cabeza.
...
En niños con graves problemas cardiacos, sus primeros años de vida pueden ser una sucesión de pruebas médicas con las consiguientes dosis de radiación. Aunque estos procedimientos no están exentos de riesgo, por el incremento del riesgo de tumores que pueden suponer en su vida adulta, un amplio análisis publicado en la revista Circulation lanza un mensaje tranquilizador.
Científicos de la Universidad de Durham (en Carolina del Norte), han analizado los historiales médicos de 337 niños menores de seis años que se habían sometido a algún tipo de operación por problemas de corazón (el 70% de ellos padecía algún tipo de cardiopatía congénita).
En estos pequeños, el uso de pruebas de imagen que funcionan con radiación (desde las radiografías hasta los TAC o los procedimientos de cateterismo que se siguen mediante un contraste desde el exterior) suele ser habitual antes y después de pasar por el quirófano; y de hecho la media de exámenes de estos pequeños ascendía a 17 pruebas por cabeza.
...
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