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EMBARGOED UNTIL
MONDAY, APRIL 19, 2004
Contact: Donna Krupa
703.967.2751 (cell)
703.527.7357 (office)
djkrupa1@aol.com
APS Newsroom: April 17-21, 2004
Washington, DC Convention Center
East Registration Area/Flex Unit
Telephone: 202.249.4009
Preliminary Data Confirm Use Of Pnp Inhibitor Bcx-1777
And A Corresponding Reduction Of Leukemic T-Cells
A multi-institutional study may offer
new clues for the treatment
of some autoimmune diseases
Washington, DC
– Some children lack a specific enzyme known as purine nucleoside
phosphorylase (PNP). These children have also been found to have profound
T-cells counts despite have normal B-cell concentrations. The observation
has helped establish the relationship between PNP and T-cells and led to the
development of inhibitors of PNP for the treatment of T-cell proliferative
disorders such as T-cell leukemias. Psoriasis, rheumatoid arthritis and
Crohn’s disease are also thought to benefit from a PNP inhibitor.
PNP Inhibitors and BCX-1777
BCX-1777, (1S)-1,4-dideoxy-1-C-( 4-hydroxypyrrolo[3,2-d]
pyrimidin-7-yl)-1,4-imino-D-ribitol hydrochloride [1:1] is a transition
state inhibitor of PNP. Inhibition of PNP results in elevated plasma
2’-deoxyguanosine (dGuo), which is converted to intracellular
2’-deoxyguanosine triphosphate (dGTP) in malignant T-cells and activated
T-cells. dGTP induces cell death in these cell types.
BCX-1777 is being tested in several Phase I and Phase I/II studies.
These include a Phase I/II study of intravenous BCX-1777 in refractory
T-cell malignancies, a Phase I pharmacology study of BCX-1777 in refractory
malignancies, a Phase I multi-center study of intravenous BCX-1777 in
refractory hematologic malignancies, and a Phase I/II multi-center study of
intravenous BCX-1777 in patients with refractory CTCL.
A New Study
The results of a new study entitled, “Intravenous and Oral Phamacokinetic
and Pharmacodynamic Study of BCX-1777, a Novel Purine Nucleoside
Phosphorylase Transition-State Inhibitor,” are being presented. The work is
the result of research conducted by John Michael Kilpatrick, Leigh Harman,
Deborah Phillips, Jianwen Zhang, and Philip Morris, all from BioCryst
Pharmaceuticals Inc., Birmingham, AL; Ronald Bukowski, from the Cleveland
Clinic, Cleveland, OH; and Deborah Thomas at the M.D. Anderson Cancer
Clinic, Houston, TX. The research associated with this study occurred at
M.D. Anderson, Cleveland Clinic Foundation, University of Florida/Shands
Hospital, University of Alabama at Birmingham, Mt. Sinai Hospital,
Cornell/New York. Hospital, Tufts-New England Medical Center, and Duke
University Medical Center. The authors will present their findings at the
American Physiological Society’s (APS) (www.the-aps.org)
annual scientific conference, Experimental Biology 2003, being held
April 17-21, 2004, at the Washington, D.C. Convention Center.
Methodology
This was a Phase I study, the first step in human testing of a new drug.
These trials evaluate drug safety and toxicity at different dose levels in a
small number of volunteers. This study consisted of intravenous five-day,
twice daily dosing cycles, separated by two to four weeks in patients with
cancer. The Phase I pharmacokinetic study (the movement of drugs throughout
the body) consisted of a single oral dose after four to eight days of a
single IV dose. This was followed by two days of IV dosing twice a day.
This investigation
included a determination of drug pharmacokinetics and several markers
related to drug activity or pharmacodynamics. These markers included plasma
dGuo and inosine, erythrocyte PNP activity, and intracellular dGTP.
BCX-1777, dGuo, and inosine were determined by high performance liquid
chromatography coupled with mass spectrometry detection. PNP activity was
monitored by enzymatic assay and cellular dGTP was determined by DNA
polymerase assay.
Results
Intravenous IV
administration of 10, 26, 40, 60, or 90 mg/m2 BCX-1777 to cancer
patients results in a rapid elevation of plasma dGuo, going from
£0.004 μM
prior to dosing to 2.4–34 μM
after dosing. In contrast, in normal rats, dogs, and primates the dGuo
range was smaller (1.5-4.5
mM).
The range of BCX-1777-dependent dGuo responses in cancer patients may be
related to differences in the dGuo pools due to variation of cell turnover
in these individuals. The plasma terminal half-life of BCX-1777 was 11.7
hr, but the half-life of the inhibition of erythrocyte PNP was much longer.
In vitro
experiments indicated that it might be as long as five days.
During and 7-10
days following the dosing periods, most treated patients have shown large
and rapid increase in blood levels of deoxyguanosine, rapid accumulation of
dGTP in leukemic T-cells, and a sharp drop in leukemic cell counts. Oral
administration of 10 mg/m2 BCX-1777 solution to humans also
produced an increase in plasma dGuo and inhibition of erythrocyte PNP with
an apparent bioavailability of approximately 30 percent.
Conclusions
These preliminary data confirm the hypothesis that use of the PNP inhibitor
BCX-1777 to elevate plasma dGuo results in elevation of cellular dGTP and a
corresponding reduction of leukemic T-cells. An evaluation of the clinical
efficacy is scheduled to be determined in several Phase II clinical trials.
Additionally, these data support use of PNP inhibitors in treatment of other
T-cell proliferative disorders, such as psoriasis and rhematoid arthritis.
- end -
The
American Physiological Society (APS) was founded in 1887 to foster basic and
applied science, much of it relating to human health. The Bethesda, MD-based
Society has more than 11,000 members and publishes 3,800 articles in its 14
peer-reviewed journals every year.
***
Editor’s
Note: For further information or to schedule an interview with a member of
the research team, please contact Donna Krupa at 703.967.2751 (cell),
703.527.7357 (office) or at
djkrupa1@aol.com. Or contact the APS newsroom at 202.249.4009 between
9:00 AM and 6:00 PM EDT April 17-21, 2004.
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