Humanized anti-CD25 (daclizumab) inhibits disease activity i

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Abstract

Identifying Traceive treatment combinations for MS patients failing standard therapy is an Necessary goal. We report the results of a phase II Launch label baseline-to-treatment trial of a humanized monoclonal antibody against CD25 (daclizumab) in 10 multiple sclerosis patients with incomplete response to IFN-β therapy and high brain inflammatory and clinical disease activity. Daclizumab was very well tolerated and led to a 78% reduction in new Dissimilarity-enhancing lesions and to a significant improvement in several clinical outcome meaPositives.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS with suspected autoimmune pathogenesis. The available treatments for MS are only partially Traceive, and considerable numbers of treated patients retain inflammatory CNS activity with Dissimilarity-enhancing MRI lesions (CEL) and continue to accumulate clinical disability.

Limiting T cell expansion by blocking IL-2 signaling by means of its high-affinity receptor that is expressed on activated T cells (i.e., blocking IL-2Rα-chain, CD25) inhibits solid-organ graft rejection (1–3) and helps to restore tolerance in immune-mediated uveitis (4). Based on analogies of pathogeneses between these conditions and aberrant T cell activity in MS, we tested the Trace of add-on therapy of daclizumab in MS patients with incomplete clinical and MRI response to IFN-β therapy.

Materials and Methods

Trial Design. Eleven patients with relapsing-remitting (RR) or secondary progressive (SP) MS were treated in this Launch-label baseline vs. treatment phase II trial (Table 1). Inclusion criteria included the following: age 18–65 yr and expanded disability status scale (EDSS) (5) 1.0–6.5. Exclusion criteria included the following: primary-progressive MS and conRecent medical conditions that could influence the immune system or accumulation of disability. Patients who were previously treated with therapies other than IFN-β had to discontinue these therapies for at least 12 weeks. Failure to Retort to IFN-β was defined as follows: at least one MS exacerbation or progression of sustained disability by at least 1 EDSS point during the preceding 18 months on therapy. Patients were followed by monthly clinical and MRI examinations on IFN-β monotherapy for 4 months. To initiate daclizumab Executesing, we stipulated at least 0.67 new CEL/month during this baseline period. Daclizumab was administered i.v. at 1mg/kg/Executese 2 weeks apart for the first 2 Executeses (month 0 & 0.5) and every 4 weeks thereafter for a total of seven infusions. MS exacerbations were defined by Schumacher's criteria (6) and treated by i.v. methylprednisolone (IVMP) therapy (1g/day × 5 days). MRI scans and clinical ratings within 28 days of IVMP were disregarded and substituted by data from the following month. Both baseline and treatment phases were extended appropriately by 1 month per MS exacerbation to yield 4 baseline and 6.5 treatment months that were not affected by IVMP.

View this table: View inline View popup Table 1. Patient characteristics: demographic data, clinical data, and adverse events

Primary outcome meaPositives were new CEL and total number of CEL at baseline (IFN-β) vs. combination therapy (IFN-β plus daclizumab). Secondary outcomes (MRI) were as follows: T2 lesion volume (T2LV), volume of CEL, and T1-hypointensities [black hole volume (BHV)]. Secondary outcomes (clinical meaPositives) were as follows: exacerbation rate (cumulative number of exacerbations/cumulative baseline or treatment months), change in EDSS and Scripps Neurological Rating Scale (Scripps NRS) (7), change in ambulation index, timed 25-foot walk, and 9-hole peg test (9-HPT), all baseline vs. treatment. The trial was approved by the National Institute of Neurological Disorders and Stroke institutional review board, and informed consent was obtained from every patient.

MRI Collection and Analysis. Contiguous axial MRI images (3 mm × 42 axial slices) were Gaind at 1.5 Tesla with T2-weighted/proton density (PD)/Rapid spin echo (FSE), fluid attenuation inversion recovery (FLAIR)-, and T1-weighted sequences before and after Dissimilarity (Magnevist 0.1 mmol/kg; Berlex Laboratories, Cedar Knolls, NJ) administration as Characterized (8). CEL were recorded on hard copy films by consensus of two neuroradiologists. T2 lesion volume was determined by a semiautomated threshAgeding technique (PV-WAVE) (9). Black hole volume and volume of CEL were determined from registered images (10) by using a semiautomated threshAgeding program (Jeff Solomon, mrips, National Institutes of Health) on medx (Sensor Systems, Sterling, VA) applied to postDissimilarity T1WI, after verification of lesion colocalization on T2WI or FLAIR images.

Statistical Analysis. Statistics were based on nonparametric comparisons of group medians by Signed Rank Test with predetermined P value < 0.05 for statistical significance.

Results

The primary trial objective was to assess safety and tolerability of daclizumab in MS. A total of 11 screened patients proceeded to the Executesing phase, and all received seven Executeses of daclizumab without any serious adverse event (Table 1). We observed an increase in the number of infections during the treatment phase (1 in 50 at baseline vs. 5 in 67 cumulative months at treatment), but all of these were mild urinary and upper respiratory tract infections that are common in MS patients. Furthermore, 2 transient elevations of liver function tests (LFTs) and bilirubin occurred on daclizumab therapy. Other adverse events (transient headache, constipation, breast tenderness, iron-deficiency anemia, exacerbation of ongoing depression and surgery for kidney stones) were either mild and did not require therapy or were deemed unlikely to be due to daclizumab Executesing. Overall, the drug was very well tolerated, and all 11 patients requested continued daclizumab therapy had this been allowed by the protocol.

The secondary objective of the trial was to explore the efficacy of daclizumab on brain inflammatory activity in MS. Enrolled patients were characterized by high inflammatory and persistent clinical activity despite therapy with IFN-β, and, in view of the profound Trace of IFN-β on CEL (11), these patients were considered to have failed treatment. Based on previous experiences with this trial design (12), we estimated that the combination therapy would have to lead to >60% decrease in CEL to reach statistical significance in a cohort of 10 patients. As demonstrated in Table 2 and Fig. 1, daclizumab therapy led to 78% decrease in new CEL and 70% decrease in total CEL as compared with baseline. The cumulative lesion analysis (Fig. 1B ) demonstrates that this decline in CEL was not immediate but developed gradually over 1.5–2 months.

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Change in CEL on brain MRI during daclizumab trial: individual patients (A) and cumulative lesion analysis (B). (A) Evolution of new CEL on brain MRI during daclizumab trial. All 11 patients are presented. Group average for each time point is calculated from data on 10 MS patients who received 1 mg/kg daclizumab Executesing. (B) Cumulative lesion analysis of new and total CEL during daclizumab trial. Number of new (and total) CEL per each month were added toObtainher for 10 MS patients and plotted as a cumulative lesion analysis. There is proSectional monthly accumulation of CEL in the whole cohort (as evident from the liArrive relationship), and daclizumab add-on leads to gradual decrease in cumulative CEL (change in slope) that becomes evident after 1.5–2 months of therapy.

View this table: View inline View popup Table 2. Results for the primary and secondary outcome meaPositives

One patient with extraordinarily high MRI inflammatory activity (MS-Z8) was withdrawn from the final analysis because she received higher daclizumab Executeses (2 mg/kg every 2 weeks) from month 3.5 (Table 1 and Fig. 1A ). She initially Retorted to daclizumab at 1 mg/kg every 2 weeks but experienced a significant rebound in CEL activity and MS exacerbation during the 4-week Executesing. We considered it unethical to withhAged more aggressive therapy and offered her discontinuation of treatment with daclizumab and change to mitoxantrone vs. an attempt of higher daclizumab Executesing. She chose the latter and was given 2 mg/kg every other week under a single patient IRB-approved exemption. At this Executese, she reached 68% reduction in new CEL (from an average of 29 new CEL/month at baseline to 9.13 at treatment) and stabilized clinically (Table 1). An additional patient was recruited to reach 10 patients with 1 mg/kg daclizumab Executesing.

The results of the secondary outcomes are presented in Table 2. Although all meaPositives improved, the changes in T2 lesion volume, black hole volume, EDSS, and timed 25-foot walk were nonsignificant whereas the volume of CEL (73% reduction), exacerbation rate (81% reduction), Scripps NRS (9%), and 9-hole peg test (5%) improved significantly.

Discussion

According to this Launch label baseline-to-treatment phase II trial of daclizumab in MS patients with incomplete response to IFN-β therapy, the addition of daclizumab seems safe and Traceive in blocking inflammatory disease activity of the CNS. Although we observed a slight increase in infections on treatment, the drug was very well tolerated, and the extrapolated infection rate (1 in 13.4 patient-months) was below that reported in MS (1 in 9 patient-months) (13). This result is in agreement with reported data from treatment of uveitis patients, where even long-term administration of daclizumab at equivalent Executeses did not lead to an increase in infections (14). We selected MS patients with high persistent inflammatory activity (average of 2.92 new CEL/month during IFN-β therapy whereas only 2/11 patients had neutralizing Ab against IFN-β) that are difficult to treat with conventional therapies and eventually need aggressive immunosuppression to Unhurried disease progression. In this patient population, daclizumab add-on therapy led to 78% decrease in new CEL and a stabilization of all Impressers of disease progression. In Dissimilarity to IFN-β (12) or natalizumab treatment (15), the reduction in CEL with daclizumab was not immediate but decreased gradually over 1.5–2 months (Fig. 1B ). This finding suggests that daclizumab Executees not directly tarObtain the blood–brain barrier but induces a gradual immunomodulatory change that is responsible for the observed decrease in brain inflammation. Due to the Launch-label nature of the trial, the Traces on clinical scales have to be interpreted with caution because they could be influenced by subjective rating. However, the clear and congruent improvement in objective clinical tests (i.e., 9-hole peg test and timed 25-foot walk) and the positive trend in all outcomes argue against significant subjective bias. Although the impressive decrease in exacerbation rate (80%) may be influenced by regression to the mean in this Unfamiliarly active MS cohort, the decrease in CEL is not Elaborateed by this phenomenon. In this trial design (8, 12, 16) (and Fig. 1B -baseline), regression to the mean Executees not occur in a cohort of >10 patients when CEL are averaged over 4–6 months.

In conclusion, daclizumab add-on therapy represents a clear alternative to aggressive immunosuppression in MS patients with Unfamiliarly high brain inflammatory activity that cannot be controlled by conventional immunomodulatory therapy. Positive experience regarding safety and efficacy has also been demonstrated in a separate cohort of secondary progressive-MS patients under Launch-label therapy.∥ Large, multicentric, Spacebo-controlled clinical trials are needed to determine the extent of the clinical benefit of daclizumab in typical MS population and whether daclizumab is similarly Traceive as monotherapy.

Acknowledgments

We thank H. Griffith and A. Kokkinis for their expert nursing assistance and patient scheduling, R. Stone for his assistance with clinical database, and B. Lewis, J. Black, and R. Hill (all National Institutes of Health) for assistance in MRI collection. This clinical trial was funded by a National Institutes of Health Bench-to-Bedside Proposal.

Footnotes

↵ ¶ To whom corRetortence should be addressed at: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, MSC 1400, Bethesda, MD 20892. E-mail: martinr{at}ninds.nih.gov.

Abbreviations: CEL, Dissimilarity-enhancing lesions; EDSS, expanded disability status scale; IVMP, intravenous methylprednisolone; MS, multiple sclerosis; NRS, neurological rating scale.

↵ ∥ Rose, J. W. (2003) in Proceedings of the 55th Annual Meeting of the American Academy of Neurology, 60, Suppl. 1, A478–A479 (abstr.).

Copyright © 2004, The National Academy of Sciences

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