FDA Grants Nuvion(R) Fast Track Status in Patients With
Corticosteroid-refractory Ulcerative Colitis
FREMONT, Calif., Sept. 29 /PRNewswire-FirstCall/ -- Protein Design Labs,
Inc. (PDL) (Nasdaq: PDLI) today reported interim results from the Phase I
dose-ranging portion of a Phase I / II clinical trial of its Nuvion(R)
(visilizumab) antibody product in patients with severe ulcerative colitis that
is refractory to treatment with intravenous steroids. Dr. Axel Dignass of the
Dept. of Gastroenterology and Hepatology, Charite Medical School, Berlin,
Germany presented the data at the 12th Annual United European Gastroenterology
Week meeting in Prague, Czech Republic.
The ongoing Phase I portion of the Phase I / II trial is designed to
explore four dose levels of Nuvion given at 5, 7.5, 10 or 12.5 micrograms/kg
administered intravenously on days 1 and 2 as a bolus injection. Up to
20 patients per dose cohort will be enrolled, with up to an additional
20 patients to be enrolled in the Phase II portion of the trial, for an
expected total of approximately 100 patients treated. The interim data
reported today assessed a total of 50 patients for safety across the
5, 7.5, 10 and 12.5 micrograms/kg doses. In the 5, 7.5 and 10 micrograms/kg
doses, 30 patients were also evaluable for efficacy at study day 30. Both
Epstein Barr Virus (EBV) positive and negative patients assessed for efficacy
were in the cohorts that had completed accrual of EBV positive patients. PDL
continues to enroll the initial cohort of EBV positive patients into the
12.5 micrograms/kg dose cohort.
Steven Benner, M.D., Senior Vice President and Chief Medical Officer, PDL,
said, "We have previously seen substantial clinical activity at higher doses
of visilizumab in a completed Phase I study, and we therefore designed this
Phase I / II trial to study a range of lower doses. We have now seen clinical
responses at all dose levels tested to date. Our preliminary analysis
suggests that in ulcerative colitis the optimal dose for planned future
studies will be at the higher end of doses tested to date, based on the
previous Phase I experience and the lack of differences in safety or activity
among the current doses studied in the ongoing trial. As in our Phase I
study, visilizumab was generally well tolerated and demonstrated an
appropriate safety profile in this setting of severely ill patients, for whom
there are no approved alternative treatments."
At the 5, 7.5 and 10 micrograms/kg doses, 63% of the patients evaluated at
day 30 had an improvement in their mucosal score as measured by flexible
sigmoidoscopy to a score of 0-1, representing a normal or only mildly abnormal
finding. In addition, activity was evaluated by the Modified Truelove and
Witts Severity Index (MTWSI) score, with a clinical response defined as
achievement of an MTWSI score of less than 10 at 30 days following treatment,
and remission defined as achievement of an MTWSI score of less than four at
30 days. Assessed under MTWSI, 87% of patients achieved a clinical response
and 27% achieved remission. PDL anticipates that further discussions with
the FDA regarding future studies in ulcerative colitis will be required in
order to define primary endpoints in registrational trials.
Transient symptoms consistent with cytokine release syndrome (CRS) were
observed in 78% of patients. CRS is a known effect from biologics which
induce any significant reduction in a patient's T cells, and is typically
characterized by fatigue, nausea, chills and headache. To date, CRS observed
in both studies of visilizumab indicated that the symptoms were transient,
were seen less frequently in patients following the second day of treatment
and were typically resolved within 24 hours following the second treatment.
The study was also designed to discern potential differences in patient
responses from those patients who are EBV positive versus those who are
EBV-negative. Among the patients treated to date, the treatment appears to
have a similar side effect profile in both patients with undetectable EBV
levels and in patients with EBV-detectable counts at baseline, up to
5,000 copies per ml. Importantly, no observed opportunistic infections were
reported in the study to date, in either the EBV-positive or negative patient
groups. As a result, the company anticipates that patients with detectable
levels of EBV will be included in all the future trials of visilizumab in
ulcerative colitis, thereby increasing the number of patients likely to be
eligible for future clinical studies.
PDL has previously stated that it will seek to initiate the Phase II
portion of this study from the data stemming from the ongoing dose-ranging
study. PDL expects to complete the overall Phase I / II study and present
overall findings in the second half of 2005. In addition, the company will
seek to meet with the FDA in the fourth quarter this year to present further
findings as well as proposed plans for further clinical studies.
PDL currently expects to present additional preclinical and clinical
information regarding visilizumab and the Nuvion clinical development plan at
its R&D Update, scheduled for 8:00 a.m. on Friday, Oct. 15 in New York City.
That event will be webcast.
FDA Grants Fast Track Status
PDL additionally announced that the FDA has granted Fast Track status to
the investigation of visilizumab in patients with corticosteroid-refractory
ulcerative colitis.
Designation as a Fast Track product indicates that the FDA will facilitate
the development and expedite the review of a new drug that is intended to
treat a serious or life-threatening condition, and that demonstrates the
potential to address an unmet medical need. However, fast track designation
does not mean that the FDA will expedite approval of any application for the
product or guarantee approval of the product.
"We are pleased with the FDA's action, and believe it is consistent with
our view that visilizumab potentially addresses an important unmet medical
need," Dr. Benner added.
Visilizumab Prior Phase I Results in Severe Ulcerative Colitis
As reported in May 2004, 32 patients were enrolled in the previously
reported Phase I clinical trial of visilizumab for patients with severe
ulcerative colitis that is refractory to treatment with intravenous steroids.
A total of 8 patients were treated in the initial dose cohort
(15 micrograms/kg). All 8 patients achieved remission. The most commonly
reported adverse events comprised mild-to-moderate constitutional symptoms
consistent with the cytokine release syndrome and were observed in all
8 patients. The symptoms were transient in nature, typically 2 to 3 hours in
duration, and were associated primarily with the initial infusion. T cell
recovery occurred over a period of 2 to 6 weeks.
In the second dose cohort of 10 micrograms/kg, 17 patients achieved a
clinical response and of these, 11 achieved remission. Symptoms consistent
with the cytokine release syndrome were observed in 13 of 18 evaluable
patients. The symptoms again were transient in nature and associated
primarily with the day 1 infusion. T cell recovery occurred over a period of
2 to 8 weeks with a mean of 3.25 weeks for the 15 micrograms/kg group and
2.7 weeks for the 10 micrograms/kg group. There were no reported
opportunistic infections.
About Visilizumab
Visilizumab is a humanized non-FcR binding monoclonal antibody directed at
the CD3 antigen on activated T cells. Increasing evidence implicates T
lymphocytes as the primary immune cells mediating the induction and
progression of inflammatory bowel disease. While the mechanism of action of
visilizumab in ulcerative colitis is still being characterized in ongoing
studies, early research has demonstrated that visilizumab induces selective
apoptosis of activated, but not resting human T cells in in vitro cell biology
experiments. If these observations are established in vivo, it may provide an
explanation to the rapid therapeutic benefit in ulcerative colitis. Research
studies continue on Nuvion's effects on the resting T cell populations that
appear not susceptible to in vitro apoptosis. Findings from recent studies
conducted by PDL were presented during sessions at UEGW, and summary
information from these will be included in the upcoming Oct. 15 R&D Update.
About Protein Design Labs
Protein Design Labs is a leader in the development of humanized antibodies
to prevent or treat various disease conditions. PDL currently has antibodies
under development for autoimmune and inflammatory conditions, asthma and
cancer. PDL holds fundamental patents for its antibody humanization
technology. Further information on PDL is available at http://www.pdl.com.
This press release contains certain forward-looking statements that
involve risks and uncertainties and PDL's actual results may differ materially
from those discussed above. Factors that may cause such differences are
discussed in the Company's Annual Report on Form 10-K for the year ended
December 31, 2003, and in its quarterly report on Form 10-Q for the period
ended June 30, 2004, and in other SEC filings. In particular, there can be no
assurance that the data from the Phase I study of visilizumab in ulcerative
colitis are indicative of additional results to be obtained in the ongoing
Phase I / II study, nor can there be any assurance that we will complete the
Phase I / II study or that all future studies of visilizumab will include
patients with detectable EBV levels. There also can be no assurance that the
Fast Track designation will either expedite FDA review, or improve the
potential success rate, of further clinical studies of visilizumab in severe
ulcerative colitis.
NOTE: Protein Design Labs, Nuvion and the PDL logo are registered U.S.
trademarks of Protein Design Labs, Inc.
SOURCE Protein Design Labs, Inc.
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Related links:
http://www.pdl.com
CONTACT:
James R. Goff, Senior Director, Corporate
Communications of Protein Design Labs, Inc., +1-510-574-1421, or
jgoff@pdl.com
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