I looked back at the two previous Ligand 10Ks in order to find out more about
Targretin cancer trials, mostly to examine the size of the various trials, and
to search for an explanation of why we hadn't heard anything about the trials.
Instead, I found some very interesting info on Panretin Capsules, which may
shed some light on the lack of news from the Targretin trials.
For instance, Panretin Capsules, in a small Phase I/IIa trial had a remarkable
efficacy record against APL, a rare form of Leukemia. It showed 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. If Ligand gets approval for
Panretin Capsules for KS, it 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 they can't afford the large trials for the more
common forms of Leukemia, IMHO, and has to use the "Orphan Drug" route.
Also, in one of the trials for moderate to severe plaque psoriasis, Panretin Capsules showed that 50% of the patients who got the "optimal dose level" achieved a 50% or greater improvement. So, as soon as Panretin Capsules hopefully get approved for KS, it could open the door for psoriasis. But, Ligand still has not chosen between Targretin and Panretin for psoriasis.
Here is the Panretin Capsule extract from the 1997 10K:
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In completed Phase I/IIA human clinical trials, Panretin Capsules were well
tolerated at doses as high as 140 mg/m(2)/day (milligram per square meter of
body surface, per day), the maximum tolerated dose ("MTD"). At the MTD level,
side effects, including headaches, elevated triglyceride levels, hypercalcemia
and mucocutaneous irritation, were dose limiting toxicities.
Memorial Sloan-Kettering Cancer Center ("Sloan-Kettering") interim data
indicate that nine of 39 patients with advanced or otherwise untreatable cancer
treated with Panretin Capsules experienced no disease progression for periods
ranging from 14 to 28 weeks. The Phase I/IIA clinical data also indicate that
Panretin Capsules have good bioavailability. Patient exposure to Panretin
Capsules is proportional to the administered dose of the compound over a broad
range of doses.
United States and international Phase II trials have been launched with
Panretin Capsules in a number of cancer indications, including kidney cancer
(in combination with interferon alpha), ovarian cancer (with cis-platin), KS,
prostate cancer, non-Hodgkin's lymphoma and multiple myeloma.
In June 1997, kidney cancer, non-Hodgkin's lymphoma and multiple myeloma trials
were discontinued due to insufficient activity. A Phase III trial with Panretin
Capsules at a dose of 140 mg/m(2)/day in APL was initiated in the fourth
quarter of 1996.
In September 1997, the final analysis of a Phase I/IIA trial of Panretin
Capsules in APL showed that 4 of 5 newly diagnosed patients achieved complete
remission and 4 of 12 relapsed patients also experienced complete remission.
The FDA approved an application by Ligand, to have Panretin Capsules
designated an "Orphan Drug" for the treatment of APL. In February 1998, the
Company announced the restructure of the slowly accruing APL program by
terminating the ongoing Phase III studies.
Panretin Capsules entered a Phase II trial for psoriasis in the United States
in September 1995, a Phase II trial for myelodysplastic syndrome in Europe in
the second quarter of 1996 and a Phase II trial for proliferative vitreo-
retinopathy, which was discontinued in July 1997 due to inability to accrue
patients in this small patient population. In July 1997, the Company reported
interim results of a Phase II study for Panretin Capsules in KS showing that
Panretin Capsules has an acceptable safety profile and a sufficient number of
positive responders to continue full accrual of the trial by the Aids
Malignancy Consortium.
In February 1998, Ligand announced favorable results in two Phase II trials
with Panretin Capsules in patients with KS. The two studies were similar in
design, with one conducted by the AIDS Malignancy Consortium ("AMC") sponsored
by the National Cancer Institute ("NCI") and the other conducted directly by
Ligand. In the studies, Panretin Capsules were administered once daily at doses
increasing from 60 mg/m(2) to 100 mg/m(2)/day. Study participants had to have
biopsy proven KS associated with AIDS and at least five to six skin lesions
that were assessed every two weeks for response. Response was determined by
applying standard ACTG criteria for complete and partial response based on the
indicator lesions. The protocol-defined evaluation period was 16 weeks.
The study conducted by the AMC has enrolled 66 patients at eight sites. The
overall response rate at final analysis through the 16-week evaluation period
for patients meeting the criteria for evaluation was 38% (19 of 50) including
one complete responder. Drug side effects were generally manageable, with some
patients requiring dose reductions with headache, dry skin, rash, alopecia,
peeling/flaking and hyperlipidemia as the most common events.
The study conducted by Ligand enrolled 57 patients at five study centers. The
overall response rate for all patients (21 of 57) was 37%, and for patients who
met the protocol defined criteria for evaluation, the overall response rate was
57% (21 of 37). One patient demonstrated a complete response. Almost all
patients were on highly active antiretroviral therapy (HAART), including at
least one protease inhibitor, prior to the start of Panretin Capsules therapy.
The side effect profile was similar to that in the AMC study.
A 50-patient Phase II trial of Panretin Capsules in psoriasis has been
completed and Panretin Capsules appear to be well-tolerated in patients with
moderate to severe plaque psoriasis. In this study, 50% (5 of 10 patients) who
received the optimal dose level of 0.9 mg/kg administered daily, achieved a 50%
or greater improvement based on the Physician's Global Evaluation.
There is currently substantial interest among oncologists in the potential of
retinoids, as evidenced by the existence of over 60 open protocols at the NCI
to examine the effects of retinoids on a variety of cancers. A Phase I/II study
is currently being conducted by the NCI to evaluate the safety and efficacy of
Panretin Capsules in children with malignancies, and the Phase II trials are
underway sponsored by the NCI to evaluate the safety and efficacy of Panretin
Capsules in patients with lung cancer, cervical cancer and those with breast
cancer.
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