4
BioTech Navigator, August 1997
ity may limit their use to patients
whose symptoms are resistant to other
second-line agents.
Patient response to therapy is
monitored by assessing pain, func-
tional status, degree of synovial in-
flammation, and measurements of
erythrocyte sedimentation rate (ESR)
and plasma C-reactive protein con-
centration. Improvements do not ap-
pear for several weeks after starting
therapy, and response is maximal usu-
ally after many months. Failure to
respond after 4 to 6 months usually
indicates that therapy needs to be
modified. Options include increasing
the dosage, modifying the concomi-
tant NSAID or corticosteroid regimen,
switching to another second-line
agent, or adding an additional second-
line agent. Although combination
therapy is widely used in an attempt
to permit dosage reduction to reduce
toxicity, studies have not generally
shown combinations to be more effec-
tive than treatment with the individ-
ual drugs.
At one end of the spectrum, a
small number of patients achieve
complete remission. At the other end
of the spectrum is a larger group of
patients who do not respond to ther-
apy. Most patients are somewhere in
the middle, they show some reduction
in pain and an increase in mobility.
RA almost invariably recurs whenever
the second-line agent is discontinued.
Unfortunately, drug discontinuation is
necessary in a high percentage of pa-
tients because of drug toxicity or a
relapse despite therapy. Another rea-
son why the current therapeutic
agents used to treat RA show limited
efficacy is that they were not initially
developed for treating RA, and do not
significantly reduce the destructive
component of RA. However, some
such as methotrexate can alter the
natural history of RA.
Biologic Agents for
treating RA.
The biologic agents that are
actively being pursued different from
the current therapeutic agents in that
they attempt to address the underlying
cellular and molecular basis of RA.
The last several years have witnessed
an explosion in the number of agents
being investigated, in part because of
advances in understanding the patho-
genesis of RA and in the arena of
biotechnology. As a result of this
progress, a number of biologic agents
have been developed that are targeted
against specific components of the
immune system, such as specific T
cell subsets, cytokine production or
action, or adhesion cell surface recep-
tors. In addition, attempts to induce
tolerance to antigens by Mabs, vacci-
nation, or oral administration of anti-
gen are being pursued. These ap-
proaches are generating a consider-
able amount of excitement , although
preliminary results with some were
not as successful as anticipated. Nev-
ertheless, these approaches still repre-
sent a viable and profitable approach.
For example, a study reported in 1996
with the intended to evaluate the po-
tential costs of hypothetical biological
agents compared to current therapeu-
tic agents, methotrexate and intra-
muscular gold, concluded that the to-
tal cost per person for six month ther-
apy were: methotrexate, $5,430; intra-
muscular gold, $5,725; and biological
agent, $9,411. The primary cost
drivers for methotrexate and intra-
muscular gold were the indirect costs
of RA and monitoring. In contrast,
total costs of the biologic agent were
driven predominately by medication
costs. With this in mind, the potential
revenue biotechnology companies can
generate with effect biological agents
against RA could be over a billion
dollars a year.
Presently there are two clear
leaders at bringing biological agents
to the RA market. Both companies
target
F
-
, although with slightly
different approaches. Therapy di-
rected at
F
-
, include the use of
Mabs or soluble receptors that bind to
F
-
and block its biologic activity,
leading to rapid improvement in RA
patients' sense of well being, followed
by decreases in joint swelling and ten-
derness and morning stiffness over
the treatment period. Immunex Cor-
poration, has genetically engineered a
portion of the
F
-
receptor which
contains the extracellular domain of
the protein that is required to bind to
F
-
. This recombinant molecule,
referred to as TNFR p75-Fc or Enbrel,
effectively competes with the cellular
F
-
receptor, for
F
-
, thereby
reducing the biologic activity of
F
-
. Centocor Incorporated, has devel-
oped a chimeric Mab, referred to as
cA2 or CenTNF, which is also spe-
cific to
F
-
. This chimeric Mab
contains the constant regions of hu-
man immunoglobulin G, linked to the
variable regions of a mouse anti-
human TNF Mab. The human por-
tion of the chimeric Mab is required
to "humanize" the molecule to mini-
mize the production of neutralizing
antibodies against the chimeric Mab.
Of the two anti-TNF ap-
proaches, we favor Enbrel. This con-
clusion is based upon the fact that sol-
uble
F
-
receptor has been found
in synovial tissue. And second, the
level of soluble
F
-
receptor is
increased in serum and synovial fluid
in RA and in many other autoimmune
and inflammatory conditions. This
suggests that soluble
F
-
receptor
is involved in regulating
F
-
ac-
tivity. A major concern in Mab ther-
apy is the potential for patients to de-
velop antibodies that neutralize the
therapeutic agent, limiting its
longterm usefulness or causing aller-
gic reactions on retreatment. Another
concern is the effect elimination of
F
-
will have on the patients. Be-
cause
F
-
evolved to serve specific
biological functions, near elimination
of the molecule could have unpre-
dictable, untoward side effects. Al-
though opportunistic infections and
