can
establish, expeditiously, whether the medicine is safe and effective.” CLEAR
READOUTS As a consequence, uncommon but welldefined
diseases may be used to provide the first clear, preliminary readouts on new Novartis
drugs. This is in distinction to the past, when evaluation of efficacy often began
with trials in the more heterogeneous patient population that ultimately might
use the medicine. “We believe that studies in well-defined
diseases expedite the transition of a new medicine to and through early clinical
trials,” Dr. Fishman says. “We examine a new medicine in the right patients quickly
and nimbly, and decide whether the drug works and is likely to be safe. Then,
once we thoroughly understand the mechanism, we can extend testing of the drug
to more complex diseases, with broader populations, where the results of proof-of-concept
studies often are less clear because only a subset of patients are likely to respond
well.” There are initial signs that the new research
paradigm is accelerating discovery of new medicines and their advancement to early
clinical trials. In addition, there is the salutary possibility that these proof-ofconcept
studies might expedite treatment of some rarer and neglected diseases.
In an article last year in the journal Nature, Fishman and NIBR colleague Jeffery
Porter wrote: “Historically, pharmaceutical companies have not concentrated on
these [rare genetic] diseases. Yet the development of therapies for such patients
would not only serve a medical need – but often could be readily extrapolated
to a wide population.” The rationale is that such trials help |
| to
pinpoint which subsets of the broader, more heterogeneous population might benefit.
PLOTTING PATHWAYS Fine-tuning NIBR’s research model
extends back to the earliest stage of drug discovery – target identification –
where scientists increasingly look to fundamental signaling pathways for openings
to disrupt disease. In their Nature article, Dr. Fishman and Dr. Porter described
how a few dozen of these signaling pathways, conserved throughout most of the
animal kingdom, control many of the basic cellular functions of life. These
pathways propagate signals that activate genes and thus affect a cell’s behavior,
such as its ability to grow or to differentiate. “Perturbation of the essential
processes driven by these pathways is the cause of many diseases such as diabetes
and heart disease,” Drs. Fishman and Porter added. To
be sure, most pathways are interconnected, and a vast amount of biological research
remains to be done before all nodes are unraveled and identified – and the roles
of the pathways in complex diseases fully understood. However, novel insights
into pathway biology have already contributed to several discovery programs under
way at Novartis. One of NIBR’s most exciting proof-ofconcept
studies in 2005 involved ACZ885, a monoclonal antibody targeting interleukin-
1 beta (IL-1 beta). IL-1 beta is a cytokine, a key weapon in the body’s immune
system defenses. Excessive production of IL-1 beta is believed to play a major
role in diseases ranging from rheumatoid arthritis and asthma to chronic obstructive
pulmonary disease (COPD) – as well as certain rare genetic disorders. |
| ACZ885
binds IL-1 beta circulating in the blood, neutralizing its action and shutting
down further production of the cytokine, thereby alleviating inflammatory symptoms.
“IL-1 is part of the body’s immediate immune response
against infection – with a broad range of biological effects,” says Hermann Gram,
Preclinical Research leader for ACZ885 and a senior NIBR investigator in rheumatoid
arthritis research in Basel, Switzerland. “Whenever something disturbs the [immune]
system, then this IL-1 response kicks in and since it’s so potent, with such diverse
effects on gene expression, it has to be controlled by the body very well,” Dr.
Gram adds. There are two versions of the IL-1 protein
– called alpha and beta, respectively. Each is produced and cleared so rapidly
from the body that the proteins are exceptionally difficult to locate and measure.
While IL-1 alpha and the IL-1 receptor were targets already under investigation
by pharmaceutical companies, Novartis scientists bucked conventional wisdom by
choosing IL-1 beta as their primary target for discovery of new drugs to treat
inflammatory diseases.
MUCKLE-WELLS SYNDROME At
the time ACZ885 entered development, Novartis planned to look at asthma and COPD,
and then go into rheumatoid arthritis. “But we didn’t have any idea of which subsets
of patients to target in those diseases,” Dr. Mundel says. “We just started small
studies and hoped for the best.” However, Tim Wright,
M.D., Head of Translational Medicine for NIBR’s Immunology group, proposed another
indication unfamiliar to most of his colleagues. |
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