ZEL.MC and FDA - Page 10

7,90$ again.¿Will break 8€ today? Maybe

Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of

Cancer Chemother Pharmacol. 2007 Oct 9; : 17922277
Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment.
[My paper] Gerald Fetterly , Joel Owen , Kim Stuyckens , Julie Passarell , Peter Zannikos , Arturo Soto-Matos , Miguel Izquierdo , Juan Perez-Ruixo
PURPOSE: Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients. PATIENTS AND METHODS: Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024-1.8 mg/m(2)) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts </= 1), and body weight (36-122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors on the time course of ALT and the effectiveness of the dose reduction strategy. RESULTS: A precursor-dependent PKPD model described the temporal relationship between ALT elevation and trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALT(o)) and t (1/2) in plasma were 31.5 (5.1) IU/L and 1.5 days, respectively. The magnitude of the trabectedin stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of trabectedin-induced ALT release from hepatocyte by 63% (P < 0.001). Model evaluation showed that the model predicted incidence of grade 3/4 transaminase elevation was similar to the observed values. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade >/=3 toxicity by 13 and 39% following two and four cycles of therapy, respectively. CONCLUSIONS: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis following trabectedin treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy based on the serum concentration of liver enzymes will enhance the safe use of trabectedin in the clinic.

http://lib.bioinfo.pl/pmid:17922277

Next week

22-26 October 2007 -San Francisco (USA)
Conference
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer
http://www.aacr.org/home/scientists/...-calendar.aspx



22-26 Octubre 2007 - San Francisco, USA.
Congreso
NCI-EORTC-AACR
http://www.aacr.org/home/scientists/...-calendar.aspx



25/10/2007
RESULTADOS TRIMESTRALES
Resultados Tercer Trimestre 2007 - Antes de la apertura del Mercado
ZELTIA, S.A. se reserva el derecho a modificar el mismo, comprometiéndose a informar de ello puntualmente al mercado.

If you spek Spanish you can listen president here:
http://estrategiasdeinversion.com/vi...verdes_en_2009

New Abstract USA to PharmaMar

Dehydrodidemnin B

Publication number: USRE39887E
Publication date: 2007-10-16
Inventor: RINEHART KENNETH L (US); LITHGOW-BERTELLONI ANNA M (ES)
Applicant: PHARMA MAR SA (ES)
Classification:
- international: C07K7/00; C07K7/00;
- European:
Application number: US20050145507 20050602
Priority number(s): GB19890022026 19890929; US19940280110 19940725; WO1990GB01495 19901001; US20050145507 20050602


Abstract of USRE39887E

Dehydrodidemnin B with useful biological activity has formula (1). It can be isolated from natural sources or synthesized, and it forms active derivativ

Upcomings events

22-26 October AACR-NCI-EORTC International Conference on Molecular Targets and Cancer


Official congress website
San Francisco, USA
01-03 November Connective Tissue Oncology Society (CTOS).


Official congress website
Seattle , USA
08-11 November Mount Sinai XXIV Chemotherapy Symposium.


Official congress website
New York , USA


http://www.pharmamar.com/en/press/upcoming.cfm

Today ZEL.MC 3rd Quarter Results -Before the Stock Market Opens

DATA ON THREE PHARMAMAR COMPOUNDS PRESENTED AT THE AACR-NCI-EORTC MEETING

http://www.pharmamar.com/en/press/ne...=175&year=2007

Madrid, October 26th 2007: PharmaMar, a biopharmaceutical company of the Zeltia Group (ZEL) specialized in the development and commercialization of marine derived drugs against cancer, has sponsored studies from which new data have been presented on three of its compounds at the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC) Conference held between October 22nd and 26th, 2007 in San Francisco, CA.

A summary of preclinical results was presented in which the activity of Zalypsis® and Aplidin® in vitro and in vivo models was evaluated. The results confirm the activity of both compounds in preclinical evaluation models different than those tested previously.

Additionally, data on the activity of the compound PM02374 both as a single agent and in combination with erlotinib (Tarceva®) were presented for different non-small cell lung cancer (NSCLC) cell lines. Overall, these results indicate that the combination of PM02374 and erlotinib shows a pharmacological synergy against NSCLC. This finding provides a rationale for exploring this combination in the clinical setting.

The study of the combination of Aplidin® and gemcitabine also showed a synergism of both compounds in pancreatic cancer, providing a rational base for the development of this combination in the clinical setting.

Key points of each of the presentations are detailed below:

Poster: Evaluation of antitumor efficacy of Aplidin® (plitidepsin) in 72 patients derived tumor xenographts using a clonogenic assay and determination of a predictive gene signature. The compound was tested against 72 patient derived representatives of 13 different tumors, both solid and non-solid. The main conclusions were:

• Plitidepsin is active against a broad panel of different tumor types, being the most sensitive hematological (leukemias and lymphomas), pleural mesothelioma, pancreas, non-small cell lung carcinoma and breast tumors.
• A signature of 23 gene transcripts that may predict sensitivity towards plitidepsin has been preliminary identified.

Poster: Aplidin® potentiates antitumor effect of gemcitabine in a preclinical model of pancreatic cancer. Present data of the synergism of the combination in pancreatic cancer providing a rational base for the development of this combination in the clinical setting. The main conclusions were:

• There is an in vitro synergism between Aplidin® and gemcitabine in pancreatic cell lines.
• Aplidin® potentiates antitumor effect of gemcitabine in an in vivo model of pancreatic cancer, without remarkable toxicities for the combination.

Poster: Preclinical evaluation of Zalypsis® (PM00104) to support the selection of tumour indications for clinical studies. The compound was in vitro evaluated in a broad panel (72 different cell lines) of human derived tumours. Following in vitro evaluation, the compound was evaluated in vivo in several human-derived tumours xenotransplanted in mice. The results demonstrated strong inhibition of the tumor growth in breast, prostate, gastric, melanoma and head and neck.

Poster: Antitumor activity of Zalypsis® (PM00104) in experimental models of bladder, gastric and liver cancer. The compound was in vitro and in vivo evaluated in a panel of bladder, gastric and liver human tumour cell lines. PM00104 demonstrated strong in vitro cytotoxic activity against representatives of these tumour types. Zalypsis® treatment in established xenograft tumors of gastric, bladder and liver origin resulted in significant reduction in the tumour size.

Poster: Synergism between PM02374 and erlotinib in human non-small cell lung cancer cell lines. The activity of PM02734 - alone and in combination with erlotinib- against nine non-small cell lung cancer cell lines was tested. The main conclusions were the following:

• PM02734 sensitivity correlates with the expression levels of ErbB3 receptor.
• There is a synergism between PM02734 and erlotinib at pharmacological concentrations, even in erlotinib resistant non-small cell lung cancer cell lines.
• The simultaneous administration of the two compounds is the most effective schedule in inhibiting in vitro cell growth. In addition, data were presented from two lines of investigation on marker identification to predict which types of patients could benefit more from Yondelis®. The studies addressed the level of efficiency in the DNA repair and the use of cellular proteins as potential surrogate markers of benefit from treatment.


Important note PharmaMar, based in Madrid, Spain, is a subsidiary of Grupo Zeltia (Spanish Stock Exchange, ZEL) that is quoted in the Spanish Stock Exchange since 1963 and the Spanish continuous market since 1998. Grupo Zeltia is currently part of the Ibex Nuevo Mercado (New Market). This document is a press release, not a brochure. This document does not constitute nor is part of any offer or invitation to sell or issue any application of purchase, offer or shares subscription of the Society. Likewise, this document nor its distribution is part or can be of base for any contract or investment decision and does not constitute any kind of recommendation in relation with the shares of the Company. :::::::::::::::::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::::::::::::::: ::::::::::::::::

For more information: www.pharmamar.com PharmaMar and Zeltia Press Office Pedro L. González Tel: # 34 91 846 6000



More news releases

Posters AACR

http://www.aacr.org/Uploads/Document...07_posterc.pdf


C60 Preclinical evaluation of PM00104 to support the selection of
tumor indications for clinical development. Thomas Greiner1, Armin
Maier1, Niko Bausch1, Heinz H. Fiebig1, Doreen LePage2, Maria José
Guillén3, Carmen Cuevas3, Pablo Avilés3. 1Oncotest GmbH, Freiburg,
Germany; 2PharmaMar USA Inc., Cambridge, MA; 3PharmaMar S.A.,
Madrid, Spain.
PM00104 is a novel marine-derived antitumor agent, chemically related to the marine natural compounds Jorumycin and the family of
Renieramycins, obtained from molluscs and sponges, respectively. The
compound binds to DNA and is cytotoxic, however, it does not activate the
DNA damage checkpoint response. Thus, PM00104 has cytotoxic effects
dependent on DNA binding that are not associated with DNA damage.
Currently PM00104 is in late phase I clinical development demonstrating
evidence of a positive therapeutic index and the ability to control tumor
growth in pre-treated patients. Antitumor efficacy and tumor type
selectivity of PM00104 was investigated in vitro in 72 patient-derived
human tumor models using a clonogenic assay. The tumor panel
represented 17 different types of malignancies. Subsequently, the
compound was studied in vivo in mice carrying xenografts of the
clonogenic assay-sensitive tumors. In vitro PM00104 was tested at
concentrations ranging from 0.1 pM to 10.0 nM. Pronounced
concentration dependent antitumor activity (mean IC70 = 4.267 nM) and
antitumor selectivity was observed. Sensitive tumor models were on
average approximately 8-fold more sensitive than the average of all
tumors tested. The highest selectivity was observed agaInstitute tumor
models of leukemia, lymphoma, small cell lung cancer,
pleuramesothelioma, mammary cancer, and non small cell lung cancer.
In vivo the tolerability of PM00104 following single intravenous injection
and repeated dosing in two different administration schedules was
evaluated. After the most tolerable dose levels had been determined, the
antitumor activity of PM00104 was tested in nude mice bearing sc
xenografts either of the patient derived mammary carcinoma MAXF 401 or
the cell line derived prostate carcinoma PRXF 22RV1. The most effective
PM00104 therapy protocol resulted in complete remission of MAXF 401
and in a significant growth inhibition of PRXF 22RV1 (min. T/C 14.0%). In
an ongoing follow-up study PM00104 is currently being tested for
antitumor activity in a broad panel of patient derived sc tumor models
comprising bladder carcinomas, gastric cancers, melanomas and head and
neck cancers. Until today 6 tumor models have been tested and significant
growth inhibitions agaInstitute 2 melanomas (MEXF 989, min. T/C 11.5%
and MEXF 462, min. T/C 42.8%) and 1 bladder carcinoma (BXF 1218, min.
T/C 21.2%) were observed.

Poster AACR

C61 Evaluation of antitumor efficacy of Plitidepsin in vitro in 72
patient derived tumor xenografts using a clonogenic assay and
determination of a predictive gene signature. Armin Maier1, André
Korrat1, Heinz H. Fiebig1, Doreen LePage2, Maria José Guillén3, Carmen
Cuevas3, Pablo Avilés3. 1Oncotest GmbH, Freiburg, Germany; 2PharmaMar
USA Inc., Cambridge, MA; 3PharmaMar S.A., Madrid, Spain.
Plitidepsin is a novel marine-derived antitumor agent, originally
isolated from the tunicate Aplidium albicans and and currently obtained by
total synthesis. The compound is now in Phase II clinical trials, and clinical
activity has been noted in advanced pretreated myeloma, renal carcinoma
and melanoma. Plitidepsin’s mechanism of action is still under
investigation. The compound induces apoptosis rapidly and persistently,
inhibits VEGF secretion and blocks cell-cycle. In order to identify target
tumor types for further clinical studies based on antitumor efficacy and
tumor type selectivity, Plitidepsin was characterized for its ability to inhibit
anchorage independent growth and in vitro colony formation of tumor
cells in semi solid medium using a clonogenic assay. Further, based on
antitumor efficacy data a gene signature being specific for the
responsiveness towards Plitidepsin was determined. The compound was
tested in 72 human tumor xenografts reflecting 17 different tumor types.
Pronounced concentration dependent antitumor activity and antitumor
selectivity of Plitidepsin was observed. The mean IC70-value was
determined as 4.0 nM, which is also achievable in patients below the
clinical recommended dose. IC70-values ranged between 0.04 nM and >1.0
μM. Above average activity was observed in 28 out of the 72 test tumors.
IC70-values in these tumors were on average about 8-fold lower than the
average of all tumors tested. Sensitive tumor types were seen among
hematological malignancies (2 out of 2 leukemias, 2/2 lymphomas),
mesothelioma (2/2), pancreatic cancer (2/3), non small cell lung cancer
(7/21), small cell lung cancer (2/2), and mammary cancer (3/11).
Efficacy data of 69 tumors, for which gene expression profiles determined
by Affymetrix HG-U133 Plus 2.0 gene chip array were available, were used
for bioinformatic analysis. Subsets of tumors and their corresponding data
were randomly split into a training set (n=47) and a validation set (n=22).
Bioinformatic analysis was used to match in vitro efficacy data with the
corresponding gene expression data. A signature of 23 gene transcripts
being predictive for responsiveness was identified. The signature was
validated using the leave-one-out-cross-validation method of the training
set, and by prediction of sensitivity of the independent validation data set.
A total of 6 tumors of the validation set were predicted to be sensitive,
and 16 to be resistant. In real testing, 5 out of 6 tumors that were
predicted to be sensitive were really sensitive towards Plitidepsin (83%
correct prediction). Vice versa, 13 out of 16 tumors, that were predicted to
be resistant, were really resistant towards Plitidepsin (81% correct
prediction). A Mann-Whitney Rank Sum Test was used to compare the IC70
values of both groups. The results showed that it was possible to
significantly discriminate between sensitivity and resistance in the
validation set (p=0.01). Plitidepsin showed in vitro antitumor activity in a
variety of different tumors, as evident from the concentration-dependent
growth inhibition in these tumors. Moreover, sensitivity towards Plitidepsin
in the clonogenic assay could be predicted by biomarker analysis based on
gene expression profiling of tumors.

Poster C62 in AACR

C62 Antitumor activity of Zalypsis® (PM00104) in experimental
models of bladder, gastric and liver cancer. Doreen J. LePage 21,
Halina Sasak 21, Maria José Guillén 12,Wendy Grant 21, Carmen Cuevas
12, Pablo M Aviles 12. 1PharmaMar Usa Inc., Cambridge, MA; 2PharmaMar,
Madrid, Spain.
Zalypsis® is a synthetic alkaloid related to Jorumycin, and the
Renieramycins. PM00104 demonstrated relevant in vitro activity
agaInstitute human solid and non-solid tumor cell lines, as well as
in vivo activity in human tumor models and is currently in Phase I
clinical development.
Zalypsis® has been assayed for in vitro activity agaInstitute a panel of
human tumor cell lines of bladder (5637, UM-UC-3, SW780, J82 and
SCaBER), gastric (Hs746T, AGS, CLS-145 and HGC-27) and liver ca. (HepG2
and SK-HEP-1). In vitro evaluation was carried out using the MTS assay.
The activity criterion for these experiments was an IC50 value ≤100 nM.
All cell lines tested met the activity criteria.
The in vivo evaluation in these histological tumor types was done with
the following tumors: transitional cell ca. of the bladder (SW-780), gastric
ca. (Hs746T) and hepatocellular ca. (HepG2). Xenografts were performed in
female athymic nude mice (n=10-15 /gr.) with cells from in vitro culture
suspended in 50% Matrigel®. Treatments were initiated when the tumor
volumes were approx. 175 ± 100 mgs. For the initial set of studies,
PM00104 was dosed intravenously at 300 ug/kg/inj. Xenograft model SW-
780, Zalypsis® was administered on a qdx5x2 schedule at 300 μg/kg/d. A
statistically significant (p=0.001) antitumor activity was seen with %
Test/Control of 41.9, 47 and 42.9% on days 24, 27 and 32 respectively.
Hs756T model, a trend toward activity was observed with statistical
significance between days 21 and day 33 with % Test/Control values of
69.8 (p<0.01), 50.8 (p<0.001), 52 (p<0.001) and 56.5 (p<0.01) on days
21, 25, 28 and 33 respectively. Later studies explored an intermittent
dosing schedule of q7d x 3 administered intravenously at 900
ug/kg/injection. The HepG2 model, Zalypsis administered as a q7d x 3
(D13, 20, 27) at 900μg/kg/day. This resulted in statistically significant
activity between days 19 and 40 with % Test/Control values of 36.7
(p<0.001), 36.6 (p=0.0017), 29.4 (p=0.003) 30.4 (p=0.001), 38.4
(p=0.002) and 57.4 (p=0.02) on days 19, 22, 26, 29, 33 and 40 respectively.
Experiments show good correlation between in vitro and in vivo results.
Further preclinical data supporting the use of intermittent dosing regimens
for PM00104 in tumor xenograft models will be presented.

Poster 179 in AACR

C179 Synergism between PM02734 and erlotinib in human nonsmall
cell lung cancer cell lines. Roman Perez-Soler1, Yi-He Ling2,Jose Jimeno3. 1Montefiore Medical Center, Bronx, NY; 2Albert Einstein
College of Medicine, Bronx, NY; 3Pharmamar R&D, Madrid, Spain.
PM02734 is a novel marine-derived cyclic peptide belonging to the
Kahaladide family of compounds currently in clinical trials with preliminary
evidence of antitumor activity. Previous studies have shown a correlation
between erbB3 expression and sensitivity to PM02734.We determined the
cytotoxic effect of PM02734 in a panel of human NSCLC cell lines. Of nine
cell lines tested, four cell lines (H322, A549, H3255-EGFR mutant-, and
H661) were highly sensitive to PM02734, with IC50 values of 0.3-1.25 μM,
two cell lines (H1299 and H1975-double EGFR mutant-) had an
intermediate sensitivity, with IC50 values of 2-2.5 μM, and the remaining
cell lines (H258, H460, and H1650-EGFR mutant-) were resistant to
PM02734 with IC50 values > 5 μM. The mechanism of cell death of
PM02734 did not appear to involve caspase activation whereas EGFR TKI
erlotinib (E) caused cytotoxicity by mitochondrial-mediated apoptosis.
Interestingly, two of the PM02734 sensitive cell lines (H322 and H3255)
were the only two cell lines sensitive to E.Western blot analysis confirmed
the correlation between erbB3 expression and cell sensitivity to PM02734.
PM02734 caused cell cycle arrest at S-phase in PM02734-sensitive H322
cells, in contrast with E, which caused G1/S phase arrest. Based on these
findings, we studied the cytotoxicity of the combination of PM02734 and
E.We treated H322, A549, H1299 and H460 cells with PM02734 alone, E
alone, or both at a 1:1 molar ratio for 72 h. Cell survival fractions were
determined by MTT assays and the combinational effects were analyzed by
the median effect method of Chou and Talalay. The combination of
PM02734 and E was synergistic in all cell lines with combination indexes
ranging between 0.59 and 0.81. To further explore the mechanism of
synergism, we examined the combinational effect of PM02734 and E on
the EGFR pathway and found that the combination was more effective in
inhibiting AKT than either single agent alone in H322 cells. In addition, we
investigated the effect of different exposure schedules of PM02734 and E
on cell growth inhibition and found that the concurrent exposure to both
agents for 72 h was more effective in inhibiting cell growth than the
sequential schedules PM02734 followed by E or E followed by PM02734.
Taken together, our results indicate that the combination of concurrent
PM02734 and E is synergistic at pharmacologically achievable
concentrations in NSCLC cell lines. This information and the lack of
overlapping toxicities between both compounds provide a rational basis
for exploring this combination in the clinic. This work was supported by
NIH Grant CA84119 and CA96515, and by Phamamar R & D.

Poster 294 in AACR

C294 Aplidin potentiates antitumor effect of gemcitabine in vitro
as well as in vivo. Pravin J. Mishra1, Giuseppe S. A. Longo1, Prasun J.
Mishra1, Jose Jimeno2, Miguel Aracil2, Elizabeth Poplin2, Joseph R. Bertino1,
Debabrata Banerjee1. 1Cancer Institute Of New Jersey,Robert Wood
Johnson Medical School, University of Medicine and dentistry of New
Jersey, New Brunswick, NJ; 2Pharmamar S.A., Madrid, Spain.
Each year about 32,000 individuals in the United States and more
than 60,000 in Europe are diagnosed with pancreatic cancer. Although
pancreatic cancer is responsible for only 2% of newly diagnosed cancers in
this country, it is the fourth-leading cause of cancer deaths. Gemcitabine
remains the standard of care with modest activity in pancreatic cancer
underscoring an urgent need for improvement in therapeutic management
of the disease.With this in mind we have initiated studies exploring
combination of Gemcitabine and other agents for potential use in
pancreatic cancer. Aplidin® (Plitidepsin) is a novel marine-derived antitumor
agent, originally isolated from the tunicate Aplidium albicans and
currently obtained by total synthesis, and is currently in Phase II clinical
trials. Aplidin has been shown to induce rapid and persistent apoptosis,inhibit VEGF secretion and block cells in G1 phase of the cell cycle. Our
experimental data demonstrates a profound synergy between Aplidin and
Gemcitabine in vitro agaInstitute pancreatic cancer cell lines. Greater
response was seen with combined treatment than with either agent alone
in PANC-1 cells as assessed by the Chou-Talalay combination index
analysis. Of interest Gemcitabine synergises with Aplidin® (in picomolar
range) with combination index (CI) value 0.46 at concentrations 780nM
and 7.8pM respectively. In vivo efficacy studies were carried out on
xenografted tumors (Panc-1) in nude mice. Three different doses of
Aplidin® (0.2mg/kg, 0.3mg/kg and 0.4mg/kg) were tested in combination
with Gemcitabine (250 mg/kg). After the tumors became palpable, mice
were injected in two cycles on day 1, 4 and 8, 12 and followed up to 24
days. All three combinations were more effective (T/C- 0.07, 0.17, 0.16)
than either of the drugs alone (Aplidin T/C- 0.23 and Gem T/C- 0.45)
without any significant toxicity. Interestingly, the lower dose (0.2mg/Kg) of
Aplidin® combination was more potent (T/C-0.07). As Gemcitabine and
Aplidin do not have overlapping toxicities, combination of these two drugs
may provide a higher therapeutic index. Based on the encouraging in vitro
and in vivo data, a phase 1 clinical trial is planned.

Nexy NOVEMBER 8, Mount Sinai XXIV Chemotherapy Symposium

-THURSDAY, NOVEMBER 8
. 8:30 NEW AGENTS IN OVARIAN CANCR
Carol Aghajanian, M.D.
9:45 OVERVIEW OF NATIONAL & INTERNATIONAL PHASE III
TRIALS IN OVARIAN CANCER.
William McGuire, M.D.
10:00 TRABECTEDIN IN RELAPSED OVARIAN CANCER
Carolyn Krasner, M.D.