Subject: NewsFlash - Therapy Update from the AAN meeting in Boston

From: Paul Bruce <[email-masked]>
Date: Tue, 29 Apr 1997 16:01:49 -0400

Everyone,
This was posted by [email-masked]  Jean Sumption
 Director,[email-masked].

Paul Bruce

In a message dated 97-04-29 15:21:46 EDT, Jean Sumption wrote:

<< Subj:        NewsFlash
 Date:  97-04-29 15:21:46 EDT
 From:  [email-masked]
 Sender:        [email-masked]
 To:    [email-masked]

 Therapy Update from the AAN meeting in Boston.

 Boston, MA.  This year's recipient of the prestigious Frank H. Netter
 Lecture, Barry G. W. Arnason, MD, told the audience at the Presidential
 Plenary Session that, after more than a century without an effective
 therapy for multiple sclerosis, neurologists now find themselves with
 three drugs that have recently been approved for the treatment of this
 demyelinating disease.  Moreover, all three agents--Avonex, Betaseron,
 Copaxone--exert a beneficial effect on the attack frequency of multiple
 sclerosis.  Allowing for differences in patient groups, study end points,
 and other parameters in the published pivotal trials, all three drugs
 reduce the relapse rate by about on third.

 However, sad Dr. Arnason of the University of Chicago, where he was
 chairman of the Neurology Department for 20 years and is currently the
 James Nelson and Anna Louise Raymond Professor of Neurology, "a 30%
 reduction in attack frequency, while substantial and highly significant,
 is nonetheless not good enough."  Dr. Arnason noted that this may actually
 understate the efficacy of these treatments, since for Betaseron at least,
 the reduction in major attacks was 50% and there was a 60% reduction in
 the number of days patients spent experiencing attacks.  Nevertheless,
 according to Dr. Arnason, there is a need to do better.

 Dr. Arnason suggested that one approach to better treatment might be
 combination therapy to potentiate the ability of interferon-beta to
 correct certain immune system abnormalities exhibited by patients with
 multiple sclerosis, such as decreased suppressor cell function, which is
 partially restored by Betaseron both in vitro and in vivo.  One such
 co-agent to test would be transretinoic acid, an approved drug for the
 treatment of psoriasis, which has a different side effect profile than
 that of Betaseron.  When combined with IFN-B in vitro, this agent
 synergistically potentiates the ability of IFN-B to augment suppressor
 cell function.  Based on this synergism, Dr. Arnason's group is now
 combining transretinoic acid with Betaseron in a pilot clinical trial.

 Immune function in patients with multiple sclerosis before and after
 treatment with IFN-B was also the focus of four additional presentations,
 three of which dealt with neutralizing antibody (NAb) formation.  Richard
 A. Rudick, MD, Cleveland Clinic Foundation, presented results obtained
 with a new method for detecting NAbs in patients treated with Avonex, some
 of whom had previously been treated with Betaseron.    Using a cutoff
 titer of >20 to define NAb positivity, the incidence of NAbs against
 Avonex after 1 year in this open-label study was <10%, considerably lower
 than the rates in the published double-blind, phase III trial.  However,
 at titers >20, NAbs persisted in serial serum samples 90% of the time if
 patients were continued on open label Avonex.  Reanalysis of the phase III
 samples using the new immunoassay suggests a trend toward reduced clinical
 and MRI efficacy in patients with titers >20.  Furthermore, Dr. Rudick
 reported that there was a significant reduction in NAb positivity when
 patients were switched from Betaseron to Avonex.  However, Peter A.
 Calabresi, MD, National Institutes of Health, Bethesda, Maryland, then
 presented data showing that, with Betaseron, >50% of NAb-positive patients
 revert to negative while being maintained on Betaseron, and NAbs to
 Betaseron persisted in only 15% of patients.  He believes that the
 correlation between the effectiveness of the treatment and the presence of
 antibodies was not clear-cut.

 Data presented by Joel J. F Oger, MD, University of British Columbia,
 Vancouver, British Columbia, suggest that there may be a biological
 difference between patients who form antibodies and those who do not.
 Those who form NAbs may have a more vigorous immune system, as
 demonstrated by high IgG secretion in the response to mitogen stimulation
 in vitro, and may be less responsive to current therapies.  Another
 potential mechanism for treatment failure was presented by John H. Uhm,
 MD, University of Montreal, Montreal, Quebec, who discussed the role of
 tissue inhibitor of metalloproteinase in reducing T-cell migration.

 Commenting on these presentations, Donald W. Paty, MD, University of
 British Columbia, Vancouver, British Columbia, stated that although
 considerable data are being generated to suggest that NAbs have an effect
 on the ability to treat multiple sclerosis with the interferons, it is not
 a consistent effect.  Some patients who form antibodies to IFN-B remain
 responsive to the drug, while some who do not form antibodies are
 unresponsive to IFN-B.  Thus, Dr Paty believes, there are still many
 unanswered questions regarding the biologic effect of NAbs.

 From another clinician's point of view, Jack S. Burks, MD, Denver
 Colorado, believes that until there is further clarification of the
 conflicting data regarding responsiveness to therapy in both the presence
 and absence of NAbs, antibodies should not be the single factor that
 determines whether a patient's therapy should be continued or switched.
 Patients doing poorly should have their medication switched even in the
 absence of NAbs, but if they are doing well they should be continued on
 the same medication.  After all, said Dr. Burks, neurologists "must treat
 the patient, not the antibody."  Although antibodies and other mechanisms
 leading to treatment failure remain debatable issues, the focus of the
 experts at the meeting was on the now established value of the three
 approved agents for the therapy of relapsing forms of multiple
 sclerosis.

 Yours in hope and good thoughts,

 Jean Sumption
 Director                                 Smile and Warm the World
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