LGND's "Retinoid Revolution" is a remarkable acheivement from the science and
business side. For this thread, I'll focus on the science. It really begins in 1985 when
Ron Evan's lab sequenced the glucocorticoid recptor. Subsequently, a related
receptor, the thyroid hormone receptor, was sequenced in Ron's lab and it soon
became apparent that these were members of a huge multi-gene family that acted as
receptors and transcription facors for a vast array of non-polyepetide hormones.
Sequnce analysis showed that most of these receptors hads several closely related
members, as well as more distantly family members. The organizaton and homology
were sufficiently similar to allow additional members to be identified, even in the
absence of a known hormone.
Ron's lab soon targeted another family that was closely related to the Thyroid
Hormone receptors. The Retinoic Acid Receptors (RARs) were the targets of a
couple of well studied drugs, tretinoin (active ingredient in JNJ's Retin-A and Renova
as well as Roche's Vesanoid), and its molecular cousin, isotretinoin, the active
ingredient in Roche's Accutane.
It soon became clear that there were 3 members (alpha, beta, and gamma) of the RAR
group. All three reacted with tretinoin and isotretinoin. However, three more related
receptors were identified, and although they were very closely related to RAR alpha,
beta, and gamma, they did NOT react with the two well studied retinoid.
Consequently, they were named Retinoid X Receptors (RXRs) and fell into the orphan
recpetor category (they were clearly related receptors, but their natural ligand was
unknown).
In 1992, LGND scientists discovered 9-cis retinoic acid. It did react with the RXRs
and was found to be naturally produced. Consequently it became the first
non-polypeptide hormone to be discovered in 25 years. It reacted with all 3 RARs as
well as all 3 RXRs. Initially LGND called it LGD1057, then ALRT1057, then Panretin
(because it reacted with all 6 know receptors).
Shortly after its publication in 1992, Ron Evans, published a series of papers on
homodimer and heterodimer formation. The RXRs not only could form heterodimers
with the closely related RARs, but they also formed heterodimers with other IRs such
as PPAR. PPAR gamma is the target of TZDs, including Rezulin, WLA's wonder drug,
for treating the underlying cause of type II diabetes, insulin resistance. Moreover,
PPAR gamma forms a heteroduplex with RXR alpha to alter gene expression
associated with cells overcoming insulin resistance.
In the summer of 1992, LGND formed a joint veture with AGN. LGND's 6 receptors
would be used to screen AGN's library of retinoids, initially around 1000 which
subsequently grew to over 3000. The program met with huge success. Retinoid
agonists ands antagonists were identified with a wide range or recptor specificties. One
compound, LGD1069, was isolated that reacted with all three RXRs (and
subsequently calleds a rexinoid). This compound was called Targretin and it is LGND's
lead rexinoid.
The retinoid program became so successful, that it was spun off into a seperate
company, Allergan Ligand Retinoid Therapeutics. This is really just a funding vehicle (it
was one employee and LGND and AGN do all of the development and clinical trails)
that began in 1995 with a $100 million bank account. LGND received 100% of
Targretin, AGN received 100% of Tazarotene, and they split the rest (icluding
Panretin) 50/50. For the retinoids in the joint venture, LGND targeted cancer
applications while AGN focuse on skin and eye problems. An RAR specific
compound, ALRT1550 has entered the clinic, and three more compounds are slated
for INDs in 1998. However, much of the recnt news centers on the two most
advanced compounds, Targretin and Panretin.
Panretin (9-cis retinoic acid) is the most advanced compound. It entered the clinic in
two forms, topical and oral. The topical trial came first. It targeted Kaposi sarcoma.
LGND started a Phase III trial about a year and a half ago. More recently, AGN
started an International. Last week AGN announced some much needed good news
for the Biotech sector. The International trial had been halted because an interim
analysis had indicated that 42% of patients receiving Panretin responded in
comparision to 7% of those receiving the placebo. LGND is winding up the Phase III
trial in the US. It's protocol did not include interim analysis other than an independent
company's look at the placebo. In the Phase II trial an unexpectedly high percentage
(15%) of the "untreated" lesions showed improvement (for Phase II, each patient
served as his own control - some leasions were treated while some were not).
However,several of the "untreated" lesions showed signs of treatment. The Phase III
trial was a double blind placebo controlled trial and interim analysis of the placebo
group showed a response rate of the expected "10% or less". The final results should
come out in a month or two.
Yesterday, LGND provided the investment community with more "good news" on the
clinical front. The final Phase I/II data on oral Panretin was presented in Europe. The
trial was for Acute Promyelocytic Leukemia (APL) and Panretin induced a complete
remission in 4 of the 5 new patients as well as 1/3 of patients who had failed earlier
treatment, including tretinoin (Vesanoid). A Phase III trail has already begun and final
results are anticipated next year (or 1999?). This it seems rather likely that Panretin will
be available (at least in the topical form) next year, a remarkably short six years since
the discovery was published (it took Roche 30 years with tretinoin).
LGND's clinical success story doesn't end with Panretin. The topical form of Targretin
is also in pivotol Phase III trials for Cutaneous T-Cell Lymphoma (CTCL) and the oral
is in two Phase II/III trails for CTCL. The Phase II data for topical Targretin is even
stronger than the topical Phase II data for Panretin treatment of KS.
An even more exciting story however, centers on Targretin treatment of type II
diabetes. As noted above, in 1992 Ron Evans discovered that RXRs form
heteroduplexes with PPARs. PPAR alpha appears to be involved with energy and fat
metabolism, while PPAR gamma is involved with overcoming insulin resistance (and is
the target of TZDs like Rezulin).
Consequently, LGND initiated animal studies on type two diabetes. In addition to
Targretin, a more potent analogue, ALRT268 (also specific for the three RXRs) was
used to treat db/db mice (models for type II diabetes) and ob/ob mice (models for
obesity). Targretin and ALRT268 were effective in lowering glucose, insulin, and
triglyceride levels. ALRT was slightly more potent than Tragretin and on a par with a
second generation TZD, SBH's BRL49653. Moreover, as predicted from the
molecular studies, the rexinoids synergized with the TZD.
In March LGND announces the start of a European Phase II study of oral Targretin
treatment of type II diabetes. Interim results are expected soon. The initial clinical data
has been used to establish a mega-diabetes deal. Announcement which is widely
anticipated in the next month or two. The diabetes deal should transform the company
with large up front payments and "profit sharing".
Thursday, LGND begins a six conference road show for the investment community
(BioCentury, Bear Stearns, UBS, Oppenheimer, Roberston Stephens, Hambrecht &
Quist). I except SEVERL SIGNIFICANT announcements. |
