From the Ectrims site:

http://www.akm.ch/ectrims2006/

Incidence and effects of neutralising antibodies in patients with multiple sclerosis treated with Avonex® or Rebif® in PROOF

T.J. Murray, A. Minagar for the PROOF Study Investigators

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Sustained benefits from interferon beta (IFNB) products used to treat relapsing multiple sclerosis (RMS) require adherence (affected by tolerability and convenience) and clinical efficacy, which can be reduced when neutralizing antibodies (NAbs) are present.

PROOF, a phase IV, retrospective and prospective, open-label study was conducted to evaluate the efficacy and tolerability of intramuscular (IM) IFNB-1a 30 mcg once weekly compared with subcutaneous (SC) IFNB-1a 44 mcg three times weekly in RMS patients.

The goal of this pre-specified endpoint was to determine the incidence of NAb formation and their effects on clinical and MRI endpoints. Prior to enrollment, subjects received IM or SC IFNB-1a for 12 to 24 months without switch or interruption and had an EDSS of 0.0-5.5.

NAbs were evaluated at study enrollment and month 6. 123 patients (n=59, IM; n=64, SC) were evaluated for NAbs. At study enrollment, 0% and 21% of patients treated with IM IFNB-1a and SC IFNB-1a were NAb+. Persistent NAbs (positive at month 0 and 6) were present in 19% of patients, all treated with SC IFNB-1a.

Compared with NAb- patients, NAb+ patients had significantly more new or enlarging T2 lesions (36.4% vs 59.3% with 0 lesions; p=0.003), total number of Gd+ lesions (54.5% vs 75.6% with 0 lesions; p=0.04), and trended towards a higher Gd+ lesion volume (0.31 vs 0.05, p=0.02 at month 0; 0.21 vs 0.04, p = 0.06 at month 6).

Disease progression (EDSS) from study enrollment to month 6 increased significantly more in NAb+ patients compared with NAb- patients (p=0.02).

Compared with patients treated with IM IFNB-1a, patients treated with SC IFNB-1a were more likely to have persistent NAb+ titers. NAb+ patients had significantly more signs of disease as shown by new or enlarging T2 lesions, total Gd+ lesions, and increased EDSS after 18 to 30 months on therapy.

A longitudinal 36 monthly imaging study on the effect of NAb in patients with multiple sclerosis

A.W. Chiu, M. Ehrmantraut, N. Richert, J. Ohayon, F. Cantor, J. Frank, H. McFarland, F. Bagnato (Bethesda, USA)

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The clinical impact of neutralizing antibodies (NAb) in Multiple Sclerosis (MS) patients undergoing therapy with interferon beta (IFNB) remains controversial. To address this issue, both cross-sectional and longitudinal studies should be performed in the same cohort of patients. To our knowledge, monthly longitudinal assessment of NAb and its effect in MS patients has yet to be examined.

Fifteen consecutive relapsing remitting MS patients were treated with IFNB-1b (250 micro g, subcutaneous, every other day) for 3 years. Patients were followed with monthly (6-month pretherapy phase [PTP] and 36-month therapy phase [TP]) magnetic resonance imaging (MRI) and clinical exams as well as bimonthly NAb evaluations. MRIs were performed on a 1.5 Tesla magnet.

T2-weighted spin echo (SE) and T1-W images SE before and within 15 minutes of a 0.1 mmol/kg injection of gadopentate dimeglumine were obtained at each session. NAb evaluation was performed using the Myxovirus-A protein inhibition assay. Patients with NAb titres >=1:20 in at least 2 consecutive samples were considered NAb+. The relationship between NAb and contrast-enhancing lesion (CEL) activity is presently analyzed.

Of the 15 patients enrolled, 5 developed NAb. Of those 5 NAb+ patients, 2 developed NAb activity at low (e.g. <= 1:47) and transient titres, present only for no more than 6 measurements. However, both patients had consistent CEL activity throughout the entire TP.

One of these patients progressed into secondary progressive MS. The remaining 3 patients exhibited NAb titres between 1:24 – 1:2703 during the first 2 years of therapy that was coincident with the presence of CELs.

Although all 3 patients showed waxing and waning of NAb activity throughout TP, the NAb activity of 1 patient waned completely by month 19 while the NAb titre of the remaining 2 patients only began to decrease at month 20. CEL levels were concomitant with NAb titres in the former patient whereas CEL activity remained high in the latter 2 individuals. Notably, CEL activity was high in all three patients prior to the occurrence of NAb.

While our cohort is small, the length of the longitudinal follow-up offers a unique dataset worthy of description. While reduction in therapeutic efficacy is observed in patients with high NAb titres, those patients seem to exhibit a predisposition to poor IFNB-1b response prior to NAb occurrence. Further analyses in larger sample populations are warranted to confirm our preliminary investigation.

Developing strategies to manage neutralising antibodies – preliminary results from the RENeu study
S. Hodgkinson, L. Sedal, M. Paine, S. Siejka, D. Gorai, H. Butzkueven, E. Willoughby, K. Boundy, D. Booth, F. Mackay, A. Tabensky, L. Sartori, K. Curnow, M. Paine (Liverpool, Melbourne, Launceston, AUS; Auckland, NZ; Adelaide, Sydney, AUS)

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There are currently no clinical guidelines for management of interferon-beta (IFN) treated patients who develop neutralising antibodies (NAbs) to their IFN therapy.

The RENeu study (Recovery of IFN-beta Efficacy in RRMS with Neutralising IFN-beta Antibodies and Reduced Bioactivity) tests the hypothesis that patients who develop persistent NAbs and are unresponsive to IFN as measured by MxA mRNA can (a) become NAb- if their IFN therapy is ceased and their MS is managed by monthly pulsed methylprednisolone treatment (500 mg/day for 3 days) for up to 12 months, and (b) become responsive to IFN if they are reinitiated on the least immunogenic IFN i.e. AVONEX.

The RENeu study will also assess the clinical efficacy and safety of this treatment regimen over 2 years. We report on preliminary results for the first patients enrolled in RENeu.

Thirteen patients (of 20 planned for RENeu) have now commenced treatment with monthly-pulsed prednisolone. Their NAb titres at study entry (CPE) ranged from 40 to >4000 (upper limit of assay). Of these, six patients have received methylprednisolone for up to 12 months, all starting with NAb titres >200.

NAb titres have decreased significantly in 4 of these 6 patients, reaching <20 in one patient and 30 in three. The patient eligible for bioactivity testing (CPE <20) was found to be responsive to injected IFN by the MxA mRNA test and has remained NAb- following subsequent treatment with AVONEX once weekly for 6 months. Most importantly, this patient continues to respond biologically to AVONEX.

A recent report by Petersen et al in 2006 has demonstrated that in 18 patients with NAb titres >200 by CPE, NAb titres remained high for extended periods after discontinuing IFN therapy. The NAb titre only decreased below 100 in one patient, and this did not occur until more than 3 years after ceasing therapy. In contrast, the initial results of the RENeu study show that monthly-pulsed methylprednisolone may be effective in reducing NAb titres. Bioactivity testing is useful for clarifying whether low titre NAbs do impact on patient responsiveness to IFN.

Are neutralising antibodies against IFN-beta always harmful in MS?

P.S. Sorensen, N. Koch-Henriksen, K. Bendtzen on behalf of the Danish Multiple Sclerosis Group

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Background: Neutralizing antibodies (NAbs) against interferon (IFN)-beta is generally believed to reduce the treatment effect in multiple sclerosis (MS). However, data from pivotal trials of IFN-beta in MS have suggested that patients, who were tested NAb-positive with an in vitro assay, had an even reduced relapse rate during the first 6 to 12 months of therapy.

Patients and methods: We collected clinical data and plasma samples for in vitro NAb measurements prospectively every 6 months in 453 patients who after start of IFN-beta therapy were treated with IFN-beta for at least 24 months. NAbs were measured blindly with a cytopathic effect assay (CPE).

Results: During treatment months 0-6, patients who during the first 24 months of therapy became NAb-positive (neutralizing capacity of 20% or more) in a cytopathic effect assay (CPE) of medium sensitivity had significantly fewer relapses (annualized relapse rate 0.60) compared to patients who maintained the NAb-negative status (annualized relapse rate 0.93; p=0.006), whereas the opposite was observed in every 6 month period after month 6.

The annualized relapse rate for months 6-48 was 0.57 in the NAb-positive patients versus 0.46 in NAb-negative patients (p=0.009). Interestingly, measurements of NAbs with a more sensitive CPE assay disclosed that the majority of the patients who became NAb-positive already had measurable neutralizing activity in the blood at month 6.

Conclusion: There is concordant evidence from the present Danish study and the pivotal studies of the three different IFN-beta preparations that patients who become NAb-positive have lower relapse rates during the first 6-12 months of therapy. We hypothesize that low affinity NAbs are present early after start of IFN-beta therapy.

These low-affinity antibodies are neutralizing in vitro, but may increase the half-life of IFN-beta in vivo and, thereby, enhance the therapeutic effect. With affinity maturation, NAbs prevent IFN-beta to bind to its receptor and abolish the treatment effect reflected by increased relapse rate.