Here's the front end of the LGND review I put up on Biotech Bash:
I'll focus on LGND's science and in
particular, its Intracellular Receptor (IR) technology since it is the most mature and its
generating all of the news lately. Moreover, I even focus on a subset of that broad
technology, the retinoid/rexinoids to provide some specific examples.
This area is most appropriate because its getting to be Nobel time again, and I want to
go on record as predicting that Ron Evans will be award the Nobel Prize in Medicine
in the not too distant future.
Having said that, here's why.
Although I started LGND's parent company, Progenx, which was a cancer diagnostic
company based on monoclonal antibodies directed against synthetic peptides of
oncoproteins and growth factors, its current focus centers on two underlying
technologies developed by Ron Evans and Jim Darnell. In 1989 Progenx obtained an
exclusive license from the Salk Institute for Ron Evan's IR technology. I had
recommended Ron as a candidate for Progenx's Scientific Advisory board, and
Progenx's board decided that the IR technology was so compelling that Progenx would
change its focus from cancer diagnostics to cancer therapeutics and become Ligand
Pharmaceuticals.
The basic approach was disarmimgly simple. A panel of intracellar receptors would be
used to screen large libraries of compounds developed by various pharmacuetical
companies. Drug candidates would be selected based on a functional assay, binding to
an appropriate receptor and turning on reporter genes. This approach was particularly
appealing to drug companies, because the old "grind and bind" approach lacked
specificity and functionality and animal studies were too time consuming and
exppensive for initial screening.
The intracellar receptors were a known quantity for the drug companies. The leading
prescription drug was Premarin, a mixture of estrogens isolated from PREgnant
MARe's urINe, and the estrogen receptor(s) was a member of a huge multi-gene
family of IRs. Another big time seller was Tamoxifen, a hormonal treatment for breast
cancer, which also acted through the estrogen receptor. Contraceptives (analogs of
estrogen and progesterone) also acted through the IRs as did glucocorticoids,
androgens, thyroid hormone, TZDs, and retinoids. The retinoids included tretinoin
(active ingredient in Retin-A, Renova, Vesanoid) and isotretinoin (active ingredient in
Accutane).
Ligand had a broad panel of receptors including the first one (glucocorticoid) which
was sequenced in Ron Evan's lab in 1985. LGND's first alliance, in 1991, was with
PFE to screen estrogen analogs for the treatment of osteoporosis and breast cancer.
The anti-estrogen candidates were to have the benefits of estrogen (bone sparing and
cardiovacular) without its drawbacks (stimulation of endometrial tissue). LGND's first
candidate was Droloxifene which is currently in Phase III studies for breast cancer and
Phase II studies for osteoporosis. Its second candidate, CP-336,156 is in Phase I
trials for osteoporosis.
Ligand's second alliance was with GLX to target athrosclerosis. This alliance has
targeted TZDs and PPARs as well as AP-1. LGND's third alliance was with AGN to
target retinoids and I'll speak about that program at length below. LGND then acquire
exclusive rights to Jim Darnell's work with STATs (Signal Transduction and Activators
of Transcription) which is the polypeptide hormone (interferons, interleukins, growth
factors) version of the IR technology (which targets the non-polypeptide hormones).
LGND then did an alliance with ABT to target inflammation using IR and STAT
technology. LGND's fifth alliance was a huge women's health program targeting
estrogen and progestin agonists and antagonists. LGND's six alliance uses the STAT
technology to identify hematopoetic growth factors for SBH. LGND also acquiced
Glycomed and has an alliance with Sankyo targeting inflammation.
It would be a bit much to go into each program (and several more including two leptin
programs are expected soon), so I'll focus on the retinoid/rexinoids which is the largest
and very much in the news last week and yesterday.
The retinoid deal began as a joint venture with AGN. LGND had three retinoic acid
recpetors (RARs) and three retinoic acid X receptors (RXRs) for screening. In 1992
AGN medicinal chemist had something like 1000 retinoids synthsized. The "Retinoid
Revolution" will be continued on the next post. |
