5
BioTech Navigator, August 1997
increased neoplasia due to "immune
suppression" have not been observed,
these remain real possibilities. De-
spite these longterm safety concerns,
we believe safety concerns for Enbrel
is less than cA2 (CenTNF). In fact, a
recent study published in the July
17,1997 issue of New England Jour-
nal of Medicine (vol.337, pp141-147)
reported that twice weekly injection of
Enbrel for three months in RA pa-
tients was safe, well tolerated and as-
sociated with improvement in the in-
flammatory symptoms of RA. Im-
munex, however, is not alone in their
soluble
F
-
receptor technology.
Roche Holding Ltd. is also developing
a TNFR-Fc fusion protein based upon
a distinct and different TNFR receptor
designated "p60." This product is in
early human tests.
An equally pressing concern
is whether blockade of
F
-
is
strictly anti-inflammatory or whether
it can actually prevent further destruc-
tion of the joints. RA has both in-
flammatory and destructive compo-
nents, which can be mediated by dis-
tinct mechanisms. IL-1 has shown to
be involved in the process of joint de-
struction. Thus to counteract this
component of RA biologic agents
against IL-1 will also be required.
Amgen Incorporated is currently test-
ing an interleukin-1 receptor antago-
nist (IL-1ra), a natural protein which
binds to the IL-1 receptor that com-
petes with IL-1. Immunex can poten-
tially enter into the anti-IL-1 arena, as
they have been granted a patent on the
IL-1 receptor.
Another approach that was
in phase III clinical trials utilized
anti-T cell therapy, specifically anti-
On the following pages are featured companies and a list of pharmaceuticals and biotechnology companies who have or are developing drugs or
diagnostics for a disease(s). The list contains competing companies who are in opinion who have interesting therapeutics and may not be mentioned in our
newsletter due to lack of space. The companies are either: (a) pharmaceuticals, (b) companies having drug product(s) approved for marketing, and have growing
product revenues, (c) companies having promising drug candidate(s) in late stage clinical trials, and are expected turn profitable in the next few years and (d)
companies in pre-clinical testing or early stage human clinical trials, and are not expected to turn profitable for years. Some of these companies may not be suitable
for every account, depending on investment objective, risk-tolerance and financial situation.
The stock price of emerging biotechnology companies with no significant commercial products may appreciate in value based on significant clinical
trials progress with potential new drug therapies, not on current revenue and earnings. Depending on the clinical trials phase results, the stock performance of
emerging public biotechnology companies may appreciates several times over the company's initial offering price. This price-appreciation potential creates
significant interest among risk tolerant, growth-oriented investors.
CD4+ T cells. IDEC Pharmaceuticals
in conjunction with SmithKline
Beecham PLC were pursuing prima-
tized Mab CE9.1, against the CD4
molecule found on the surface of
CD4+ T lymphocytes. Since T cells
have been thought to play a pivotal
role in initiating and modulating hu-
moral and cellular immune responses
in RA, they seem like logical targets
for therapeutic agents. However, hu-
man trials with CE9.1 have since
been suspended by IDEC and
SmithKline as researchers at those
companies encountered worrisome
and unexplained immune-system ef-
fects with the compound.
Also in clinical trials (Phase
II) is an approach that involves vacci-
nation with peptides derived from the
T-cell receptor (TCR). There is in-
tense interest in the TCR with autoim-
mune disease, especially since several
medical researchers have found that
specific T cells isolated from synovial
fluid of RA patients express restricted
patterns of the TCR. It is thought that
vaccination with peptides specific to
these restricted patterns will eliminate
T cells involved in the inflammation
process. Both Connective Therapeu-
tics and Immune Response Corpora-
tion are independently pursuing this
technology. Biocryst Pharmaceuticals
is also targeting T cells, however their
compound, BCX-34, inhibits an en-
zyme required for T cell proliferation.
This product is in preclinical develop-
ment for RA. Immunization or elimi-
nation of T cell function by either of
these approaches must be specific, as
adversely affecting beneficial T cells
has the potential of leading to wrong-
ful immune suppression.
ISIS Pharmaceuticals in col-
laboration with Boehringer Ingelheim
are in clinical trials (Phase II) with
antisense technology against intercel-
lular adhesion molecule type 1
(ICAM-1). ICAM-1 is a cell surface
protein that facilitates the migration
of immune cells involved in both
acute and chronic inflammation.
Over-expression of ICAM-1 is specifi-
cally implicated in a wide variety of
inflammatory disorders, such as
rheumatoid arthritis. Their lead com-
pound, ISIS 2302, selectively inhibits
the cell surface expression of ICAM-
1, by blocking the synthesis of ICAM-
1. In the Phase II study of patients
with Crohn's disease (another autoim-
mune disease), ISIS 2302 demon-
strated safety and efficacy.
Lastly, another approach that
is worth mentioning in clinical trials
involves oral dosing of collagen as a
means to reduce the systemic immune
response to collagen-degradation frag-
ments found in the joints of RA pa-
tients (Autoimmune Incorporated).
Preliminary results with this approach
appear to yield statistically significant
improvement in several indicators of
disease activity. Larger clinical stud-
ies are currently ongoing to confirm
these earlier results.
Biotechnology companies are
betting that these new biologic agents
which target the underlying cellular
and molecular basis of RA should do
well against the disease. If not, the
advances in biological RA therapy are
an important step forward in therapy
and in understanding the pathogene-
sis of inflammatory arthritis.
