Thaks, Stefaan.
Here is the full release as well as the abstract. I have had a chance to read the paper, and bottom line is that dEPOb did better in this preclinical model than taxol just about everywhere (dramatically so in taxol resistant strains), and also better than one of the BMS variants (aza-EPOb) in clinical trials. Further, the half-life in humans will probably be better than in mice, and so one of the reasons you can't always extrapolate from a nude-mice model to humans doesn't apply. (Lots of others still remain of course). Note that this is still a very long way from an approved drug (4-5 years at least if all goes very well).
Kosan Collaborator Finds Epothilone D to be Superior to Paclitaxel in
Animal Models
Head-to-Head study published in The Proceedings of the National Academy of
Sciences
HAYWARD, Calif., Jul 3, 2001 (BW HealthWire) -- Kosan Biosciences
Incorporated (Nasdaq: KOSN chart, msgs) announced today the publication of
extensive experiments by its collaborators at the Sloan-Kettering Institute
for Cancer Research indicating that Epothilone D is an efficacious
anti-tumor agent with a broad therapeutic spectrum and wide safety margin in
animal model systems. In this head-to-head study, it was demonstrated that
the therapeutic effects of Epothilone D are superior to paclitaxel as well
as some other currently used cancer therapeutics. Paclitaxel is the active
ingredient in the leading anticancer agent Taxol(R).
Epothilones are polyketide natural products that inhibit cancer cells by the
same mechanism as paclitaxel, and also are effective against most
paclitaxel-resistant tumors. Epothilone D, also known as desoxyepothilone B,
is in pre-clinical development by Kosan Biosciences and Sloan-Kettering.
The paper describes experiments in cell cultures and in animal models
comparing Epothilone D to paclitaxel, certain other anticancer agents, and
15-desoxy-15-aza-epothilone (aza-EpoB), an epothilone currently undergoing
clinical evaluation by Bristol-Myers Squibb. The paper describing "The
Synthesis, Discovery and Development of a Highly Promising Class of
Microtubule Stabilization Agents: Curative Effects of Desoxyepothilones B
and F Against Human Tumor Xenografts in Nude Mice" appears in the July 3,
2001 issue of The Proceedings of the National Academy of Sciences. In an
earlier paper (Proc. Nat. Acad. Sci. 95, 9642:1998) it had been demonstrated
that Epothilone D has a superior therapeutic index to Epothilone B in
animals.
The lead author of the paper is Dr. Ting-Chao Chou of the Sloan-Kettering
Institute. The senior author is Dr. Samuel Danishefsky, Director of the
Laboratory for Bioorganic Chemistry at the Sloan-Kettering Institute and a
member of Kosan's Board of Scientific Advisors. The researchers reported a
number of important findings including:
-- Epothilone D is as effective or more effective than paclitaxel
in reducing the size of paclitaxel-sensitive human tumors
implanted in nude mice.
-- Epothilone D exhibited potent or curative effects in
paclitaxel-resistant human tumors implanted in nude mice. In
the same models, paclitaxel exhibited only moderate or minor
effects, and aza-EpoB showed little therapeutic effect.
-- In all tumors tested, Epothilone D showed superior therapeutic
effects compared to other important anticancer agents such as
doxorubicin, vinblastine, camptothecin and etoposide.
-- Epothilone D was well tolerated at therapeutically effective
doses.
-- A lower frequency of multiple drug resistance occurred after
cells were treated with Epothilone D than with paclitaxel.
"We were especially pleased that Epothilone D demonstrated superior
therapeutic effects compared to several existing anticancer agents,
including paclitaxel and other epothilones in early development, said Dr.
Samuel Danishefsky, the senior author of the PNAS paper. "We were pleasantly
surprised that even at curative therapeutic doses no severe toxicity was
observed other than significant decreases in body weight," noted Dr. Chou,
the lead author. "The pre-clinical data on Epothilone D are an extremely
promising prelude to human clinical trials Kosan plans to initiate this
year," said Daniel V. Santi, M.D., Ph.D., Chairman and CEO of Kosan. "The
Sloan-Kettering results are particularly encouraging in view of the positive
responses reported in Phase I human trials for Bristol-Myers Squibb's
aza-EpoB at the recent ASCO meeting in San Francisco," added Santi.
The Sloan-Kettering Institute is the basic research arm of Memorial
Sloan-Kettering Cancer Center, the world's oldest and largest institution
devoted to prevention, patient care, research and education in cancer. The
pilot scale synthesis and chemical evaluation of Epothilone D were funded by
the National Cancer Institute through the RAID (Rapid Access to Intervention
Development) program.
Here's the abstract. (dEpoB is the KOSN drug.):
Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 14, 8113-8118, July 3, 2001
Pharmacology
The synthesis, discovery, and development of a highly promising class of
microtubule stabilization agents: Curative effects of desoxyepothilones B
and F against human tumor xenografts in nude mice
Ting-Chao Chou*, Owen A. O'Connor, William P. Tong, Yongbiao Guan*, Zui-Guo
Zhang*, Shawn J. Stachel§, Chulbom Lee§, and Samuel J. Danishefsky§,¶,
* Preclinical Pharmacology Core Facility, Department of Medicine,
Analytical Pharmacology Core Facility, and § Laboratory for Bioorganic
Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New
York, NY 10021; and ¶ Department of Chemistry, Columbia University,
Havemeyer Hall, New York, NY 10027
Contributed by Samuel J. Danishefsky, March 28, 2001
We have evaluated two synthetic epothilone analogues lacking the
12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and
12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth
inhibition (IC50) for a variety of anticancer agents were measured in
CCRF-CEM/VBL1000 cells (2,048-fold resistance to vinblastine). By using
dEpoB, dEpoF, aza-EpoB, and paclitaxel, the IC50 values were 0.029, 0.092,
2.99, and 5.17 µM, respectively. These values represent 4-, 33.5-, 1,423-
and 3,133-fold resistance, respectively, when compared with the
corresponding IC50 in the parent [nonmultiple drug-resistant (MDR)] CCRF-CEM
cells. We then produced MDR human lung carcinoma A549 cells by continuous
exposure of the tumor cells to sublethal concentrations of dEpoB (1.8 yr),
vinblastine (1.2 yr), and paclitaxel (1.8 yr). This continued exposure led
to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug,
respectively. The therapeutic effect of dEpoB and paclitaxel was also
compared in vivo in a mouse model by using various tumor xenografts. dEpoB
is much more effective in reducing tumor sizes in all MDR tumors tested.
Analysis of dEpoF, an analog possessing greater aqueous solubility than
dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and
MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious
antitumor agents with both a broad chemotherapeutic spectrum and wide safety
margins.
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To whom reprint requests should be addressed. E-mail:
s-danishefsky@ski.mskcc.org.
www.pnas.org/cgi/doi/10.1073/pnas.131153098
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