Here's more info from the "Metabolic Disease" section of the Annual Report:
Scientists have known for several years that retinoids that bind the RXR family deliver their
therapeutic effects through partnered intracellular receptors (IRs). However, more recently
researchers have discovered that RXRs are necessary or "obligate" partners in these IR pairs
through all tissues. These IR pairs consist of one RXR and one of a variety of other IRs, such
as RARs, PPARs (peroxisome proliferator-activated receptors), or thyroid hormone
receptors. While RXRs are widely expressed, their IR partners are more discreet, being
expressed in selective tissues, such as liver, fat or muscle. As a result, compounds that bind
RXRs offer the unique potential to be broadly active compounds that can treat a variety of
metabolic diseases.
In animal models of type II diabetes, RXR agonists appear to stimulate the physiological
pathways responsive to RXR-PPAR receptor partners expressed in key target tissues that are
involved in glucose metabolism. As a result, a discrete set of genes is activated in these tissues
resulting in a decrease in serum glucose levels, triglycerides and insulin. Developing drugs that
utilize this unique mechanism of action may offer more 'gentle' therapies than conventional
insulin-stimulating drugs.
RXR Heterodimer Biology
Once activated, RXR receptors exist as a heterodimer complex, partnered with a variety of other
intracellular receptors (IRs). RXR receptors can act as obligate partners with these IRs, resulting in
potential clinical utility in type II diabetes, other metabolic diseases or cancer depending on their partner.
Nature Article on RXRs in Diabetes
Early in 1997, Ligand scientists published an article in the journal Nature discussing the
antidiabetes activity of RXR compounds such as TargretinTM and ALRT268, another potent,
RXR-selective agonist (an ALRT compound). The antidiabetic activity of Targretin and
ALRT268 were compared in two well-studied rodent models (ob/ob and db/db mice) with a
second generation thiazolidinedione (TZD) (a new class of antidiabetes drugs which are potent
PPAR agonists) and a control group. There were 15 mice in each treatment group. Glucose,
triglycerides and insulin levels were monitored throughout the duration of the treatment.
Studies performed indicate that both Targretin and ALRT268 decreased blood glucose by
approximately 40%. Targretin reduced triglycerides by 30% and insulin by 20%. ALRT268
reduced insulin levels by more than 50% compared to control animals. Targretin, as a single
agent, was as effective as TZD, and additive therapeutic effects were obtained when it was
administered with TZD. Co-administration of ALRT268 and TZD decreased blood glucose
levels by nearly 50%. Targretin maintained its antidiabetic activity and was well-tolerated
during the course of therapy. These data suggest that Targretin and ALRT268 may be
promising oral therapeutics for treatment of type II diabetes.
Sidebar RXR Heterodimer Biology Once activated, RXR receptors exist as a heterodimer
complex, partnered with a variety of other intracellular receptors (IRs). RXR receptors can
act as obligate partners with these IRs, resulting in potential clinical utility in type II diabetes,
other metabolic diseases or cancer depending on their partner.
Oral TargretinTM in Phase II Human Clinical Trials in Diabetes
A Phase II multi-center trial in type II diabetes in Europe was initiated with Targretin Oral
Capsules in the first quarter of 1997. US trials are expected to begin in 1997. The clinical
studies have two main objectives: to study the safety and tolerability of different dose levels of
Targretin in type II diabetic patients, and to determine the potential for this RXR-agonist to
have positive metabolic effects on carbohydrate and/or lipid metabolism in this population. If
Phase II studies are successful Ligand expects to enter full development on a registration track
during 1998. Ligand's goal is to initiate a significant pharmaceutical partnership in type II
diabetes in 1997 to conduct this development and subsequent commercialization.
A New Tool For Identifying Novel Obesity Drugs
Ligand's basic research programs in gene signal transduction and intracellular signaling have
yielded exciting findings that may provide new drug discovery tools for identifying novel drugs
for the treatment of obesity. In collaboration with researchers from the prestigious Institute
Pasteur de Lille, Ligand's scientists discovered the region of DNA, called the promoter, that is
responsible for controlling expression of the protein leptin by the human obesity gene, or leptin
gene. Leptin, or ob protein, plays a key role in controlling appetite and metabolism.
The identification of the leptin promoter is significant because it provides a vehicle for
researchers to identify novel small molecule drugs that modulate the leptin gene's expression,
and in turn, treat obesity. The Company is now integrating this promoter into its proprietary
high throughput screening assays to identify new drug candidates that can be administered
orally, unlike proteins which require injection. To protect its proprietary rights to this genetic
tool, Ligand submitted a patent application to the US Patent and Trademark Office covering
this and related inventions. |
