John, LGND has a clear lead in the retinoid/RXR area because they
have targetted that area fairly intensively. The had 6 receptors
for screening early on, but there are many related receptors also,
which they could also use. They did their joint venture with AGN in
1992 and screened over 2400 retinoids (and they have about 2 dozen
interesting compounds). However, I wouldn't say that that is their
sole advantage. Its really more in the core technology. Part of
the reason the receptors are related to each other is because they
use similar mechanism and interact with each other. Thus, LGND also
has a PPAR program and they discovered that activated PPARs interact
with activated RXRs. Thus, a combination of drugs (TZD plus Retinoid)
will be most effective. LGND has many programs targetting these
receptors (via small molecules that mimic the appropriate hormone)
and specificity will be best acheived with combinations. In one sense,
Targretin is much like a three legged dog. Many don't marvel at how
fast the dog can run, but they are amazed that the dog can run at all.
Targretin is involved in many process and can be used to treat or prevent
diabetes, breast cancer, and a variety of other malignacies. However,
it will be even better when combined with others that target the same
pathway. Another example is HIV treatment. Although each drug
works as monotherapy (AZT, 3TC, protease inhibitor), they are much
more effective in combination. In the case of HIV they are more
effective because they simultaneous hit the virus at three sites in its
life cycle so it is hard for the virus to come up with three simultaneous mutations
(but much easier to develop resistance if the three drugs are given
sequentially). For diabetes, the combinations don't target drug resistance
as much as they produce specifity. For insulin resistance, PPAR gamma
and one of the three RXR seem to be the critical complex. I'm sure
that different combination are important in different diseases and
LGND's technology is designed to sort out the complexities. For
treating diabetes, I don't think that LGND's first generation retinoid
(Targretin) will be more effective than the first generation TZD (Rezulin)
when used independently. However, the two together will be more effective
than either alone and LGND has already identified a second generation compound (ALRT268),
as well as another retinoid (LG100754) that forces RRAR/RXR formation.
The combinations will also cause an increase in the cost of treatment,
but the treatment will produce long term benefits in both costs and
quality of life. In general, that is the chief benefit of Biotechs.
Although the research is extremely expensive as is the treatment,
long term these drugs produce health care savings because it cost much
less to prevent a disease than to treat the complications that arrise
from the disease.
Henry |
