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Treatment
revolution in store
for ulcerative colitis
By
Diana Swift
Banff,
AB—Biologic
agents are on the verge of transforming the outlook for ulcerative
colitis patients who do not respond to standard treatment with corticosteroids
and 5-ASA, or to purine antimetabolites. “These new therapies
will be coming to the clinic in the next two or three years,”
Brian Feagan, MD, Professor of Medicine, Epidemiology and Biostatistics
at the Robarts Clinical Trials, University of Western Ontario, London,
ON, said.
In a cohort of UC patients from Olmsted County, MN, who received
corticosteroids, 84 per cent had a complete or partial response,
according to data from the Mayo Clinic. But 16 per cent were primary
failures who required surgery, and one year later 51 per cent of
this cohort were corticosteroid-resistant or in a poor state of
health requiring surgery.
“Indeed, steroid resistance is one of the first clinical prognosticators
of poor-prognosis bad biology,” he said. “At the end of
a year of steroid treatment, 30 per cent of Olmsted patients required
surgery.”
As for the conventional alternative, the purine antimetabolites,
flawed early trials from the late 1970s and early 1980s showed no
difference in clinical symptoms with these agents, but did show
a modest reduction in steroid requirements.
A pivotal trial conducted by Derek Jewell at Oxford 30 years ago
looked at 80 steroid-dependent or -resistant patients randomised
to receive azathioprine at effective doses or placebo for one year.
With outcomes set as complete withdrawal from steroids and remission
(defined by an activity index), 36 per cent responded in the treatment
arm versus 22 per cent on placebo. “This is not statistically
significant, but it is the best trial we have,” Dr. Feagan
said.
In the early 1990s Hawthorne conducted a withdrawal rather than
an induction trial of 79 patients who were already responding to
AZA or 6-MP and differentially withdrew them with either placebo
or an antimetabolite. “Some of these had already been in remission
for up to four years on AZA but, that notwithstanding, there was
a statistically significant benefit of more than 24 per cent associated
with the purine antimetabolites.”
Studies of equal size and quality, however, have shown no benefit.
Analysing 50 patients randomised either to prednisolone and AZA
or to sulfasalazine, prednisolone, and placebo, Sood found no difference
in corticosteroid requirements after one year (Ind J Gastro,
2000;19[1]:14-16).
Similarly, an Israeli trial by Oren found no benefit with low-dose
oral methotrexate (Gastroenterology,1996;110[5]:1652-656).
“We need trials using higher doses given by the parenteral
route,” Dr. Feagan said.
Under investigatation
The weakness of the evidence supporting standard agents points to
the need for newer, more effective agents. Currently under investigation
are some promising monoclonal antibodies, as well as epidermal growth
factor.
Compared with infliximab, which is a 25 per cent murine and 75 per
cent human chimerized antibody, the new generation of monoclonal
antibodies is more humanized—on the order of six per cent murine
and 94 per cent human.
“It may surprise you that the first trial of infliximab was
not in Crohn’s disease, but was a small, prematurely terminated
study in the U.S. of ulcerative colitis,” Dr. Feagan said.
Two years ago, a German group presented an inconclusive randomised,
controlled trial of 42 patients with steroid-resistant UC at Digestive
Disease Week (Probert et al, Gastroenterology,2002;122:A772).
The authors reported no statistical difference at two weeks in rates
of response as measured by the modified Baron’s score in patients
taking infliximab or placebo (14 per cent versus five per cent).
“You could argue, however, that this was an underpowered trial
and that the three-fold difference might be clinically meaningful.”
Definitive answers may come from two large, randomised trials expected
to finish the maintenance stage by the end of this year. “I
am optimistic that infliximab will prove as effective for UC as
it is for CD,” he said.
Natalizumab
Dr. Feagan moved on to promising new anti-leukocyte adhesion molecules,
such as natalizumab and MLN-02. These target the interaction between
proteins on tissues and white blood cells in the vascular endothelium
that allow the flow of inflammatory white blood cells into gut tissue
and prevent normal repair. The primary adhesion molecule on the
vascular endothelium is MAdCAM-1, which interacts with the T-cell
integrin alpha4 and beta7, a heterodimer adhesion molecule.
One approach to blocking this interplay is natalizumab, a humanized
antibody to alpha4. Two years ago, a study by Drosch in the New
England Journal of Medicine found natalizumab to be effective against
alpha4 beta7 and alpha4 beta1 in CD patients. “There was a
nice treatment effect with no dose response,” Dr. Feagan said.
Now a Phase II study involving more than 400 patients has reached
its primary endpoint with a positive result. “This molecule
will likely be the next approved drug for IBD. It hasn’t yet
been studied in UC, but I think it will be effective for UC.”
Natalizumab has had dramatic results in multiple sclerosis, completely
blunting the progression of new white-matter lesions.
Dr. Feagan’s group in London has investigated the targeting
of MLN-02, another vascular molecule that interacts with alpha4
beta7 and facilitates the gut-specific egress of white blood cells
into tissue. An original murine monoclonal antibody ACT-1 that interacted
with the heterodimer alpha4 beta7 raised the possibility of gut-specific
immunomodulation.
In 2003, a large, multicentre Canadian study reported to DDW on
the use of an MLN-02 antibody in 181 patients with active UC who
failed to respond to 5-ASA. Patients received placebo or the antibody
at two different dose levels. With about 60 patients in each group,
both treatment groups were twice as likely as the placebo group
to enter remission, although, as with natalizumab, there was no
dose response.
On endoscopy, some patients showed a complete remission of neutrophil
and lymphocyte infiltration after just two doses. “This is
very potent biological proof that the concept behind natalizumab
and MLN-02 works. This will be the next class of molecule to come
to the clinic,” he said.
Daclizimab
Daclizimab is a CDR-grafted monoclonal that interacts with the interleukin
receptor and is used in the transplant setting as adjuvant therapy.
“In a pilot study this was both effective and well-tolerated,
and data from a Phase II study should be available within the next
few weeks,” he said.
Dr. Feagan’s therapeutic review included recombinant human
epidermal growth factor. He referred to a small, but notable, randomised
trial that reported a dramatic benefit with epidermal growth factor
versus placebo in left-sided UC and proctosigmoiditis (Sinha et
al, NEJM, 349;4:350-57). “All patients responded,
so the results were statistically significant with just 24 participants.
This is a different approach—rather than blocking inflammation,
the drug promotes healing.”
Despite gains in treating mild-to-moderate UC, severe disease remains
a difficult area. Over the past decade, clinicians have tried treating
with cyclosporine, but in a small and hard-to-interpret trial of
cyclosporine versus placebo, D’Haens found similar results
in both arms (Gastroenterology, 2001;120:1323-1329).
More recently, Amsterdam researchers led by Van Asche compared 2
mg/kg of cyclosporine versus 4 mg/kg and found no difference in
response. “There might be a type 2 error here, but I think
it’s probably OK to use the lower dose,” he said.
He cautioned that physicians administering this immune suppressant
must inform patients that it will increase their vulnerability to
opportunistic infections such Pneumocystis carinii. “Most series
with cyclosporine report some deaths, and there’s a trade-off
between saving colons and saving lives.”
Visilizumab
With the need for more effective new treatments clear, the most
promising agent is visilizumab, a potent humanized monoclonal antibody
that binds to the T-cell receptor. In vitro, it modulates T-cell
function and activates the apoptotic mechanism. “It differs
from OKT3 in that you don’t get complete lysis and cytokine
release syndrome; you kill the cells gradually, so there’s
less of a problem.”
The effects on active T-cells are much greater with this monoclonal
than with OKT3. In a study appearing last year in Gastroenterology,
Mayer reported a marked benefit, with scores in all patients coming
down into the remission zone. Visilizumab is being studied in a
North American Phase II trial for patients with severe UC.
“We hope this will be a potent new molecule, but remember that
your T-cells are there for a reason and we might face the same problem
as with cyclosporine: trading off induction of remission against
placing the patient at risk for opportunistic infections.”
The treatment of severe ulcerative colitis with a combination of
medical therapy and surgery is one of medicine’s true success
stories, he said pointing to the Oxford experience of mortality
over five decades. In 1950, the death rate was 25 per cent; by the
mid-1990s it had come down to one in 1,000. “But this a curve
we have to keep watching. We don’t want to see that as we’re
saving colons, mortality is rising into the two per cent region.”
“I am very optimistic that in two years’ time we will
have dramatic data to show you. In the meantime, get to know your
surgeon!” Dr. Feagan concluded.
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