Bob, Panretin (alitretinoin) 9-cis-ra - and APL --- issue #4
4) You raise the Panretin capsules for APL and leukemia issue.
Ligand has Orphan Status for P. Capsules for APL (acute promyelocytic leukemia )
-- our only such candidate "at this time."
Bob, I confirm what you say here. The remission response to Panretin was terrific:
>> Panretin Capsules, in a small Phase I/IIa trial had a remarkable efficacy record against APL, a rare form of Leukemia -- 80% complete remission in newly diagnosed patients, and 33% complete remission in relapsed patients.
Ligand started Phase III trials, but had to cancel them because of lack of enrollments. So, they then targetted KS.
Approval for Panretin Capsules for KS opens the door for off-label APL, and possibly other more common Leukemias. But, it is a shame that Ligand has to sit on a probable Leukemia cure because ... <<
========================================================
Bob, I started reading about this one, and was surprised how much I discovered.
For starters, learn tons about retinoids, in fairly simple English, with drawings
at www-new.moffitt.usf.edu
This site increased my general understanding of the whole picture -- the context:
-- ATRA (All-Trans-Retinoic-Acid) and its isomers (such as Panretin)
-- how retinoids work, in general and variations
-- toxicity issues, especially RAS (R A Syndrome, a serious issue with ATRA therapy)
-- cure vs remission, how long remission lasts
-- chemotherapy linked with RA therapy
-- conventional therapy for APL
From here, I want to really understand what special advantages Panretin and Targretin bring to the RA picture -- what CLINICAL advantages over other retinoids?
========================================================
A bit of history: There is a current therapy on the market - ATRA
Panretin is an isomer of ATRA
o 1988 - early studies
NCI Citation regarding APL (acute promyelocytic leukemia ) treated by all-trans retinoic acid (ATRA) -- also called Vesanoid (tretinoin) -- a Roche drug
oncolink.upenn.edu
Median time to achieve remission was 38 to 44 days
Huang M, Ye Y, Chen S, et al.: Use of in the treatment of acute promyelocytic leukemia. Blood 72(2): 567-572, 1988.
Twenty-four patients with (APL) were treated with all-trans retinoic acid (45 to 100 mg/m2/day). Of these, eight cases had been either nonresponsive or resistant to previous chemotherapy; the other 16 cases were previously untreated. All patients attained complete remission without developing bone marrow hypoplasia.
-----------------------------------
o 1992 - oncolink.com
Serious complication of APL treatment with ATRA - retinoic acid syndrome
Early recognition of the symptom complex of fever and dyspnea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome
-----------------------------------
o November 28, 1995 - Roche's Vesanoid (tretinoin) approved by FDA
os.dhhs.gov
--------------------------------------------------------------------
o 1998 - oup.co.uk
Arsenic Trioxide as an Inducer of Apoptosis and Loss of PML/RAR Protein in Acute Promyelocytic Leukemia Cells...
Background: Retinoids, which are derivatives of vitamin A, induce differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients.
However, APL cells develop resistance to retinoic acid treatment. Arsenic trioxide (As2O3) can induce clinical remission in patients with APL, including those who have relapsed after retinoic acid treatment
-----------------------------------------------------------------
Excerpts from the 1995 FDA approval article:
NOTE: this paper also explains the bases on which leukemias are categorized.
FDA Approves All-Trans Retinoic Acid for Treating a Rare Leukemia
The FDA has approved the use of the first successful differentiating agent for the treatment of patients with a rare form of leukemia -- ushering in a novel approach to cancer that has long intrigued cancer researchers. The drug, all-trans retinoic acid, is a vitamin A derivative that works by prodding malignant leukemic cells to differentiate or "mature" into normal blood cells, which subsequently die
The FDA approved Vesanoid (tretinoin) for patients with acute promyelocytic leukemia (APL) who have failed or are resistant to conventional chemotherapy.
The drug is also being studied for its usefulness in the treatment of newly diagnosed patients with this leukemia. Vesanoid will be marketed in the United States by Hoffman-La-Roche.
... all-trans retinoic acid is not a cure for APL, and may in fact work best in combination with chemotherapy.
Most patients treated with all-trans retinoic acid alone, tend to relapse within several months.
The NCI is currently evaluating through its Clinical Trials Cooperative Groups all-trans retinoic acid's role relative to chemotherapy in induction or first-line therapy, and in maintenance therapy.
Other trials are examining the integration of this active retinoid in combination with chemotherapy.
First recognized in the 1950s, APL constitutes roughly 10% of adult acute myeloid leukemia in the U.S., or about 800 patients each year. The disease typically presents with a bleeding condition that is often worsened by chemotherapy, leading to a relatively high rate of early mortality.
Nevertheless, long-term survival is somewhat more favorable in APL than that associated with other acute myeloid leukemias, with 35% to 45% of patients living at least five years.
Leukemia is a cancer of the blood-forming cells, which occurs when immature or mature cells multiply in an uncontrolled manner in the bone marrow. The disease is classified as either lymphocytic or myeloid leukemia, depending on which of these white blood cells is multiplying abnormally. When the leukemia is acute, it progresses rapidly and involves primarily immature blood cells; in chronic leukemias, in comparison, the disease progresses more slowly and involves the accumulation of greater numbers of more mature blood cells.
...In patients with APL, investigators have discovered that besides a distinctive clinical presentation, there is a characteristic molecular pattern as well. Genetic material from two genes on chromosomes 15 and 17 translocate or swap places, producing abnormal "fusion" genes. Normally, the proteins coded for by these genes (so called "transcription factors") help regulate a number of critical cellular functions including cell proliferation, embryonic development, and cell differentiation.
One of these proteins -- the nuclear receptor for retinoids -- is the portal through which all-trans retinoic acid gains access to carry out its numerous functions, but in an individual with APL, it appears that such entry is somehow blocked. However, the drug apparently works by bypassing the obstruction; in fact, virtually all patients with this characteristic genetic abnormality respond to the drug, Parkinson said.
In the U.S. since 1991, NCI, in cooperation with the FDA, has treated more than 1,500 APL patients with all-trans retinoic acid on a compassionate-use basis. A large percentage have benefited from the drug, according to Parkinson.
In addition, in summary data involving clinical trials in the United States at the Memorial Sloan-Kettering Cancer Center, N.Y., and in France and China, responses were seen in 84 percent of 565 APL patients.
All-trans retinoic acid, which is taken orally in pill form, produces adverse reactions similar to other retinoids. The most common side effects are headaches, though some patients experience transient bone pain, and children appear especially prone to the drug's central nervous system effects.
Approximately 25% of patients with APL may develop Retinoic Acid Syndrome, a potentially serious complication characterized by fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, which has, in some cases, caused patients to expire. Although the cause of Retinoic Acid Syndrome is not yet known, several mechanisms have been proposed, including the release of cytokines by maturing cells. Moreover, in most patients, progression of the syndrome can be halted through early treatment with corticosteroids, so that early recognition by the treating physician is important.
==================================================================
Perhaps, with Panretin or Targraetin
o RA Syndrome is not such a problem,
o or remission lasts longer,
o or the leukemia doesn't become resistent to it so quickly
o or they've found chemotherapy that enhances the retinoid.
But I've found nothing (so far), one way or the other.
Any comments, anyone?
--------------------------
Patent issues? Henry said NO, Ligand is covered, filed earlier than others.
But I checkd the recent S8 Filing, and searched on 'Roche'
Excerpts, FWIW, from the S8:
We have learned that Hoffman LaRoche, Inc. has received a United States patent
and has made patent filings in foreign countries that relate to our Panretin
capsules and gel products ...
The Patent and Trademark Office has informed us that the overlapping claims are
patentable to us and has initiated a proceeding to determine whether we or
Hoffman LaRoche are entitled to a patent. .
While we believe that the Hoffman LaRoche patent does not cover the use of
Panretin capsules and gel for most of our planned uses, if we do not prevail, the
Hoffman LaRoche patent might block our use of Panretin capsules and gel in
certain cancers.
========================================================
Looks like short-term traders might be doing well these days.
Wish i'd done so ...
8 5/8 to 9 or so ...
Cheryl |
