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* PDLI: Incremental Phase I/II results for SMART
anti-gamma interferon in Crohn's disease appear to be
positive at higher doses (confirming the trend in the
preliminary results reported in November 2001) though the
trial was too small (n=28) to show statistical
significance.
OPINION
The abstracts for this year's annual Digestive Disease Week (DDW) meeting,
which is scheduled to take place from May 19th- 22nd in San Francisco, have
now become publicly available. We highlight some of the key pipeline
candidates for companies under our coverage universe for which clinical data
will be presented.
PROTEIN DESIGN LABS- KEY ABSTRACTS
SMART anti-gamma interferon: There is one abstract related to SMART anti-
gamma interferon that will be presented at this year's DDW. As a reminder,
this product is currently in Phase I/II clinical trials in Crohn's disease,
and in Phase I studies in psoriasis. Future indications could include
multiple sclerosis, type I diabetes and rheumatoid arthritis. This abstract
will be presented on Tuesday, May 21 from 3:00-3:15 p.m. as part of a
research forum entitled "Novel Therapeutic Approaches to IBD". The forum is
from 2:15-3:45 p.m. at the Moscone Center, Rooms 134-135.
Background: SMART anti-gamma interferon is an antibody that targets gamma
interferon, a cytokine produced by T lymphocytes and natural killer cells,
and is currently in development for several autoimmune diseases, including
Crohn's disease. Gamma interferon has been shown to be present in increased
levels in intestinal cells affected by Crohn's disease, a chronic
inflammatory disease with a prevalence of about 100 in 100,000 people, and an
incidence of new onset disease in approximately six out of 100,000 people.
As described previously, the company initiated a Phase I/II double-blinded,
randomized, placebo-controlled multi-center trial in January 2001. The two-
stage trial enrolled 56 patients with moderate to severe Crohn's disease.
The first stage is a single dose, dose escalating, dose comparison of anti-
gamma interferon versus placebo. Patients who receive and respond to active
drug will be entered into a second stage where they will receive three
additional doses or placebo for four weeks. The study will explore efficacy
as measured by the Crohn's Disease Activity Index (CDAI).
Abstract #103096: Preliminary Results of a Phase I/II study of HuZAF (SMART
anti-gamma interferon), an anti-IFN monoclonal antibody, in patients with
moderate to severe active Crohn's Disease (CD)
Study design: Twenty-eight patients with CD who had CDAI (Crohn's Disease
Activity Index) scores of greater than or equal to 250 and less than or equal
to 450 were randomized to receive one of 3 dose levels of HuZAF (0.1, 1.0, or
4.0 mg/kg) or a single dose of placebo. Study endpoints at 4 weeks post
dosing were (1) clinical response (decrease of CDAI score or greater than or
equal to 70 points from baseline), (2) remission (CDAI score of less than or
equal to 150), (3) enhanced response (decrease of CDAI score of greater than
or equal to 100 points), and (4) safety.
Study Results: Demographics and baseline disease characteristics were
comparable for the 4 groups. Seven males and 21 females reported a mean age
of 37 plus or minus 11 years (Range: 20 to 68 years), a mean disease duration
of 8.1 plus or minus 6 years, and a mean baseline CDAI score of 328 plus or
minus 64. Adverse events were evenly distributed among the four groups, the
3 reported SAEs (serious adverse events) were considered to be related to
disease. Increased doses of HuZAF correlated with higher rates of clinical
response and greater numbers of remissions though this trial was too small to
show statistical significance. Likewise the percent of patients with
enhanced response was higher as dose levels increased (Table 1). Therefore,
preliminary results indicate that HuZAF administered as a single IV dose to
patients with moderate to severe active CD is well tolerated with a good
safety profile. Increasing doses of HuZAF yielded higher clinical response
rates and greater numbers of remissions, while reported AEs (adverse events)
remained evenly distributed among the dose groups. Further clinical studies
are planned to confirm the safety and efficacy of HuZAF as a treatment for CD
(the company intends to begin a Phase II clinical trial based on these
results).
Table 1: Percent of Patients with Clinical Response and Remission at Day 29
Treatment % Response: % Remission: CDAI % Response:
Group (mg/kg) CDAI decrease score <=150 points CDAI
>=70 points (n/N) (n/N) decrease>=100
points (n/N)
Placebo (N=6) 50% (3/6) 33% (2/6) 33% (2/6)
0.1 (N=6) 50% (3/6) 0% (0/6) 17% (1/6)
1.0 (N=8) 75% (6/8) 25% (2/8) 50% (4/8)
4.0 (N=8) 86% (6/7)* 71% (5/7)* 71% (5/7)*
* No CDAI score for one patient in the 4 mg/kg treatment group at day 29 due
to discontinuation
secondary to an SAE.
Source: DDW 2002 Abstracts
Comparison with JNJ's Remicade Data in Crohn's. Although it is difficult to
compare the results from this initial dose-ranging study to another approved
biologic, Remicade, we do so only for reference purposes. JNJ's Remicade
(infliximab), a chimeric monoclonal antibody targeting TNF-alpha, is approved
for use in moderately to severely active Crohn's disease patients and in
patients with fistulizing Crohn's. Data from the package insert detail the
results from a 108 patient, placebo-controlled, double-blinded study.
Enrolled patients had CDAI scores ranging from 220 to 400 and were not
responding to first-line treatment with corticosteriods or 5-aminosalicylates
(5-ASA). Use of these agents was permitted during Remicade treatment. The
results showed that at week four, 48% (13/27) of patients given a single IV
infusion of 5 mg/kg Remicade achieved remission (CDAI score below 150),
compared to 4% (1/25) of placebo patients. Furthermore, 82% (22/27) of
Remicade-treated patients had a response (CDAI decline of 70 points),
compared to 16% (4/25) of placebo-treated patients. Response to Remicade was
typically observed within two to four weeks after treatment, and the
proportion of patients responding diminished over time. There was no evidence
of dose response, as higher doses of 10 and 20 mg/kg tested did not result in
greater response rates.
Companies Mentioned in this Report:
Johnson & Johnson -- (JNJ, $62.16, 2L, Phil Nalbone)
NPS Pharmaceuticals -- (NPSP, $33.31, V2)
Protein Design Labs -- (PDLI, $17.36, 2S)
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