Abstract
Objective: A double-blind, placebo-controlled phase II study was conducted in 168 patients, most with relapsing-remitting MS, to evaluate whether lenercept would reduce new lesions on MRI.
Background: Tumor necrosis factor (TNF) has been implicated in MS pathogenesis, has been identified in active MS lesions, is toxic to oligodendrocytes in vitro, and worsens the severity of experimental allergic encephalomyelitis (EAE) in animals. Lenercept, a recombinant TNF receptor p55 immunoglobulin fusion protein (sTNFR-IgG p55), protects against EAE.
Methods: Patients received 10, 50, or 100 mg of lenercept or placebo IV every 4 weeks for up to 48 weeks. MRI scans and clinical evaluations were performed at screening, at baseline, and then every 4 weeks (immediately before dosing) through study week 24.
Results: There were no significant differences between groups on any MRI study measure, but the number of lenercept-treated patients experiencing exacerbations was significantly increased compared with patients receiving placebo (p = 0.007) and their exacerbations occurred earlier (p = 0.006). Neurologic deficits tended to be more severe in the lenercept treatment groups, although this did not affect Expanded Disability Status Scale scores. Anti-lenercept antibodies were present in a substantial number of treated patients; serum lenercept trough concentrations were detectable in only a third. Adverse events that increased in frequency in treated patients included headache, nausea, abdominal pain, and hot flushes.
Conclusions: Lenercept failed to be beneficial, but insight into the role of TNF in MS exacerbations was gained.
MS is believed to be an inflammatory autoimmune disorder of the CNS with unknown myelin components as target. A number of findings have suggested that tumor necrosis factor (TNF) contributes to propagating the inflammatory response and to tissue injury in MS. In autopsy specimens, TNF has been demonstrated within active MS foci.1 TNF has been shown to have a direct toxic effect against oligodendrocytes and a proliferation-inducing effect on astrocytes in in vitro studies.2,3 In patients with MS, elevated TNF levels in the serum and CSF have been correlated in some studies with disease progression.4,5 Blood mononuclear cells from MS patients, studied just before an exacerbation, secrete greater amounts of TNF in response to mitogen stimulation than at other times.6 Blood mononuclear cells from MS patients with active disease express higher levels of TNF mRNA than do cells from MS patients with stable disease or healthy controls.7,8
Studies of experimental autoimmune encephalomyelitis (EAE) have profoundly shaped views of MS pathogenesis. EAE is an autoimmune disease with pathologic features reminiscent of those seen in MS. TNF treatment worsens EAE,9 and TNF neutralization by anti-TNF antibody treatment consistently protects animals from EAE.10-12 Similarly, TNF capture by lenercept, a TNFα receptor–immunoglobulin G (IgG)1 fusion protein, protects in EAE.13 The above indicates that TNF functions in EAE as a proinflammatory mediator and suggests that TNF depletion might be protective in MS. The hypothesis that neutralization of TNF may reduce or halt MS progression was evaluated in a phase II randomized, multicenter, placebo-controlled study of three doses of lenercept (sTNFR-IgG p55). Lenercept is a dimeric recombinant protein molecule built from two copies of the 55 kDa TNF receptor extracellular domain fused to a fragment of the human immunoglobulin IgG1 heavy chain.14,15 In accordance with recently published recommendations, efficacy was assessed by means of MRI.16
Methods.
Patients.
A total of 168 patients with clinically definite or laboratory supported definite MS were enrolled in a double-blind, placebo-controlled study. The study was approved by the institutional review boards of the participating centers, and all subjects gave informed consent. At enrollment, patients were between the ages of 18 and 55 years and had an Expanded Disability Status Scale (EDSS) score ≤5.5. For patients with an EDSS score ≤3, the history of MS was limited to a maximum duration of 10 years. All patients had at least two exacerbations within the previous 2 years, but were clinically stable for 4 weeks before the screening MRI and during the 4 weeks between screening and study entry. With the exception of glucocorticoids, any prior administration of agents with a putative effect on MS (including interferons, cyclophosphamide, or azathioprine) led to exclusion. Treatment with glucocorticoids was not permitted within a 4-week period before the screening visit or between screening and baseline. Other exclusion criteria included the diagnosis of primary progressive MS and inability to undergo MRI scanning. A randomization list with treatment blocks (four patients per block) was computer generated by Hoffmann–La Roche (Basel, Switzerland) for each investigation site. During the conduct of the study, the randomization list was available only to the Safety Review Board (SRB) members (see below). A limited number of Roche staff were unblinded at the time of the first analysis of efficacy as defined in the protocol. On study termination, each investigational site was provided with the site-specific randomization code.
Eligible patients were randomized to 10, 50, or 100 mg of lenercept or to placebo, administered IV every 4 weeks. Study duration was 48 weeks, consisting of a 24-week, double-blind treatment period and a 24-week follow-up period. Of the 168 patients randomized to treatment, one patient (randomized to placebo) was identified as ineligible prior to the baseline visit; this patient did not receive treatment, have a baseline MRI scan, or return for follow-up. For the 167 patients who received treatment, compliance to treatment and study procedures was excellent. During the first 24 weeks, 99% (991/1002) of all planned doses were administered and 98% (1303/1336) of all MRI scan sets were performed.
During the follow up period (study weeks 25–48), patients could continue double-blind treatment on a voluntary basis and 130 elected to do so. Those patients who opted not to continue treatment remained in the study and were followed on an intent-to-treat basis. For the full study duration, 10 doses (median) were administered to each treatment group.
For safety purposes, three cohorts of up to 16 patients were enrolled in an ascending-dose design at approximately 6-week intervals. The first cohort was randomized to placebo or 10 mg of lenercept whereas subsequent cohorts were randomized to placebo or 50 mg and finally to placebo or 100 mg of lenercept. An independent SRB evaluated the unblinded study data before each dose escalation during the ascending dose phase of the study. Following these evaluations, the remaining patients were recruited. The SRB reviewed data at 3-month intervals throughout the study. This review included the MRI safety data but did not include a review of the MRI efficacy data.
Magnetic resonance imaging.
MRI scans were performed according to a predefined MRI protocol at screening, baseline, and every 4 weeks (before each dose) throughout the first 24 weeks of the study for a total of eight scanning time points. At each time point, three scans with a slice thickness of 5 mm were obtained: 1) proton density/T2-weighted scan, 2) T1-weighted unenhanced scan, and 3) T1-weighted gadolinium (Gd)-enhanced scan 5 minutes after the administration of Gd-DTPA 0.1 mmol/kg. All scans were analyzed according to a prospectively defined MRI analysis plan by the UBC MS/MRI Analysis Group in Vancouver, Canada. After comparison of each MRI follow-up scan with the prior scan, the number of newly active lesions was ascertained by summing the new, recurrent, or enlarging T2 lesions, and the new or recurrent Gd-enhancing lesions. Newly active lesions identified on both the enhanced T1 scan and the T2 scan were counted as single lesions. The primary efficacy measure was the cumulative number of newly active lesions identified on the six treatment scans. Definitions of new, recurrent, and enlarging lesions have been reported previously.17,18 Persistently enhancing or enlarging lesions were separately identified as persistently active lesions, a secondary measure of efficacy. In this way, new lesions could easily be separated from other types of activity. Other secondary efficacy measures included the percentage of active scans, defined as the proportion of scans with one or more newly active lesions, and the burden of disease, which was assessed as reported previously, at baseline, and at 24 weeks.17,1,8 Burden of disease was determined by outlining each MS lesion identified on the T2-weighted MRI scan. These areas were summed slice by slice for a total lesion area recorded as mm3. In addition, the total number of Gd-enhancing lesions (a measure of safety) was counted for each patient at each scanning time point on an ongoing basis to allow MRI data to be reviewed by the SRB.
Clinical assessments.
At the baseline visit and every 4 weeks thereafter for the first 24 weeks, a history was taken, physical and neurologic examinations performed, and adverse events noted. Study drug was administered at the end of each visit. Patients were encouraged to come for additional visits should exacerbations occur between visits. During the second 24-week period, two formal visits were planned at weeks 36 and 48. Whenever possible, patients who withdrew from treatment were asked to continue all study procedures including all MRI scans.
Clinical endpoints.
Exacerbations were defined as the appearance of a new sign or symptom or the worsening of an old sign or symptom attributable to MS, lasting at least 24 hours in the absence of fever, and preceded by a period of stability of 28 days. An exacerbation was deemed to have ended when signs and symptoms had begun to improve. For those patients with permanent deficits, the first day of a 28-day period of stability was taken as the ending of an attack. The Neurological Rating Scale (NRS)19 was completed each time the neurologic examination was performed. As in other clinical trials in MS, a decline in NRS score of 15 points or more was considered to reflect a severe change in the patient’s neurologic condition, whereas declines of 8–14 or 1–7 points were considered to reflect moderate or mild changes, respectively.17,20 A difference of 0 points was categorized as no change; an increase in the score as an improvement. The EDSS as recommended by Kurtzke21 was scored at screening and at weeks 24 and 48 by the study neurologist. In 120/167 (72%) of patients, the EDSS was performed at all time points by the same neurologist.
In accordance with the protocol, a first analysis was undertaken after all patients had completed 24 weeks of double-blind treatment and after all MRI scans had been evaluated. An increase in the exacerbation rate was noted in lenercept-treated patients. This finding resulted in the sponsor’s decision to terminate the study and to release the treatment code. All study drug administration was stopped promptly and, after a final visit, data collection was discontinued. For this reason, study data through week 48 are incomplete. The follow-up period through week 48, however, was similar in all treatment groups.
Pharmacokinetic/dynamic parameters.
Serum samples were obtained at baseline and before dosing every 4 weeks for 24 weeks and at study weeks 36 and 48. The concentration of lenercept and titers of antibodies to lenercept were determined. All samples were analyzed centrally. Lenercept concentrations were measured using an enzyme-linked immunologic and biologic binding assay (ELIBA) developed by Roche (Hoffmann-LaRoche Ltd., Basel, Switzerland); antibodies to lenercept were identified by means of a double antigen antibody test. Samples with detectable anti-lenercept antibodies were further evaluated to determine the neutralizing potential of the antibodies (Medi-Lab, Medicinsk Laboratorium A/S, Copenhagen, Denmark).
Autoantibodies.
Serum samples were obtained at baseline and at study weeks 24 and 48 and assayed for IgM–rheumatoid factor (RF), antinuclear antibodies (ANA) (Hep 2), and antibodies to dsDNA (DAKO; Carpinteria, CA) in a central laboratory (A. Wiik, Statens Seruminstitut Copenhagen, Denmark).
Statistical analyses.
The cumulative number of newly active lesions was tested with a closed test procedure based on an analysis of variance (ANOVA) of the Ln(x + 1) transformed sum of the lesions. The protocol required that the analysis of the primary efficacy criterion be performed after imputation of the median number of lesions at a specific time point so as to compensate for missing values at that time point. Of the 1,008 expected values, 34 were missing, resulting in data imputation as noted above. The results of this analysis showed no differences among the treatment groups (p = 0.417) or between the pairs of treatment groups. Data imputation was not performed for the analyses presented herein.
A closed tests procedure, based on an ANOVA with the factor “treatment” of Ln(1 + x), where x denotes the cumulative number of newly active lesions, was used to compare the cumulative number of newly active lesions between the treatment groups. The closed tests procedure was first used to compare the means among all four treatment groups (global test)22; then, to compare the means among all combinations of three of the four treatment groups; and finally, to compare the means of each lenercept treatment group with that of the placebo group. For all comparisons, F tests were performed at the same significance level (α = 0.05); however, adjusted p values are provided. The mean of a treatment group is regarded as significantly different from that of the placebo group when all comparisons that include the two relevant treatment groups result in a p value ≤0.05; i.e., the adjusted p value is the maximum of the p values of these comparisons. The procedure stops early if the global test is nonsignificant. This procedure guarantees a multiple α = 0.05. The closed tests procedure described above was also used to assess the cumulative number of persistently active lesions. Center effects were assessed using descriptive methods.
The Kruskal-Wallis test was used to compare the mean change in EDSS scores, change in the burden of disease, and percent of active scans. To assess the influence of baseline imbalances in MRI activity among the treatment groups, covariance analyses using the corresponding transformed baseline MRI values as covariate were performed.
Survival analysis methods (Kaplan-Meier estimates; i.e., product-limit estimates and logrank tests)23 were applied to analyze the time to first exacerbation and the duration of exacerbations because of right censoring at the end of the observation period. Logrank tests, with a Bonferroni adjustment of the significance level (α = 0.017), were used for the multiple comparisons among the three lenercept treatment and the placebo treatment Kaplan-Meier curves. As an exacerbation duration can only be observed in the presence of an exacerbation, we investigated the conditional distribution of their durations. After inspection of the exacerbation data, we assumed a counting process model according to Anderson and Gill24 with independent increments because the process is slow. For the same reason, exacerbation durations were assumed to be independently and identically distributed between patients and within patients for those patients who had more than one exacerbation.
A chi-square was used to evaluate the number of patients with no, one, two, three, or four exacerbations in each treatment group after 24 weeks of treatment and at the end of the study (through week 48). Because of small frequencies in some cells, the table was collapsed to counting patients with and without exacerbations to allow a valid chi-square test. For the multiple comparisons the unadjusted p values should be compared with the Bonferroni adjusted α of 0.017 (0.05 ÷ 3). Chi-square tests were also used to evaluate the NRS and the rate of RF or ANA among the treatment groups. Cox regression analysis was performed to assess potential predictive factors for the occurrence of exacerbations. The data and analyses were performed on all data available, i.e., through week 48, unless otherwise stated in the text or tables. Two-tailed analyses were used throughout.
Results.
Figure 1 depicts the trial profile. The treatment groups were comparable at entry on all baseline disease characteristics and demographics (table 1). The protocol permitted enrollment of both relapsing-remitting and secondary progressive patients, and from 4 to 10 patients with secondary progression were enrolled in each group (see table 1). Prestudy MRI characteristics were likewise comparable among the treatment groups (table 2) although there was a tendency (nonsignificant) for the higher lenercept dose groups to have more MRI activity (median).
Figure 1. Profile of the lenercept MS clinical trial.
Demographic and baseline characteristics of patients entered into the lenercept MS trial
MRI measurements at baseline of patients entered into the lenercept MS trial
MRI results.
The results of the cumulative number of newly active MRI lesions, the percentage of persistently active lesions, the percentage of active scans, and the change in burden of disease over 24 weeks of treatment are shown in figure 2 and table 3. There were no significant differences between the treatment groups for any measure. The results of the analyses of the primary efficacy criterion according to the protocol specifications were similar to those presented here. Because of the tendency for higher activity at baseline in the high-dose groups (see table 2), covariance analyses using the corresponding transformed baseline MRI values as covariate were performed, but these, too, failed to show a significant difference between the groups.
Figure 2. (A) Number of cumulative newly active lesions as determined by MRI (see Methods) over the first 24 weeks of the lenercept MS trial: placebo –—, lenercept 10 mg - - - -, lenercept 50 mg — - — -, lenercept 100 mg – – – –. The vertical bars give the standard error at the four weekly intervals at which MRI scans were performed. (B) The mean number of gadolinium (Gd)–positive lesions every 4 weeks over the first 24 weeks of the trial. Vertical bars give the standard error. (C) Mean anti-lenercept antibody titers at four weekly intervals.
MRI measurements over the first 24 weeks of the lenercept MS trial
Clinical endpoints.
Exacerbations.
The number of patients who developed exacerbations by week 24 and through study week 48 were both increased in the lenercept groups as compared with the placebo treatment group as shown in table 4. A center effect was not present. Over the entire study period, a total of 36 exacerbations was reported in patients taking placebo as compared with 38, 57, and 49 exacerbations in patients taking 10, 50, and 100 mg of lenercept, respectively. Exacerbation duration showed a tendency to increase with lenercept treatment, but this did not reach statistical significance (see table 4). This assessment was limited to exacerbations with an onset date within the first 24 weeks of the study as exacerbation resolution dates were available in all but four exacerbations (one per treatment group).
Number, duration, and annual rate of exacerbations during the lenercept MS trial
Exacerbation rate.
The overall exacerbation rate in patients treated with placebo was approximately one exacerbation/patient/year (the expected placebo rate). The exacerbation rate was increased over the placebo rate by 2%, 68%, and 50% in patients treated with lenercept at doses of 10, 50, and 100 mg, respectively (see table 4). To control for a possible effect of unequal follow-up of patients between treatment groups, exacerbation rates were determined for each treatment group by 4-week intervals. The mean 4-week exacerbation rates were then converted to annual rates as presented in table 4.
There was a dose-dependent decrease in the time to first exacerbation as shown in figure 3 (logrank test: global, p = 0.0006; 10 mg versus placebo, p = 0.498; 50 mg versus placebo, p = 0.0006; and 100 mg versus placebo, p = 0.006). The comparisons with unadjusted p values for 50 and 100 mg of lenercept as presented above remain significant when Bonferroni adjusted (α of 0.017, i.e., 0.05 ÷ 3).
Figure 3. Proportion of patients remaining exacerbation free over the course of the lenercept MS trial: placebo –—, lenercept 10 mg - - - -, lenercept 50 mg- – - –, lenercept 100 mg – – – –. Times of termination for individual patients are shown as vertical bars.
The severity of exacerbations was assessed indirectly by computing the difference between the best pretreatment NRS score (highest value at baseline or screening) and the worst score recorded at any time during the study, i.e., through week 48. Although a trend for increasing severity with lenercept treatment can be perceived (table 5), this difference did not reach statistical significance.
Change in the NRS and the EDSS during the lenercept MS trial
Exacerbations did not appear to occur more frequently immediately before or after study drug administration, but this may reflect no more than difficulties in determining exacerbation onset dates with precision.
Predictors of exacerbations.
A Cox regression was performed. None of the following was identified as predictive of exacerbations: age, sex, MS category, number of exacerbations within 2 years before the study, baseline EDSS score, or baseline number of newly active lesions.
EDSS.
There was no difference in EDSS score changes between the treatment groups after 24 weeks of treatment or at the last assessment (table 5). Sixty-seven percent of patients in the placebo group reported new or worsening MS symptoms during the study as compared with 77%, 90%, and 93% of patients treated with lenercept in the 10-, 50-, and 100-mg dose groups, respectively. Symptoms that increased in frequency or severity with lenercept treatment included sensory complaints, limb weakness, visual impairment, fatigue, vertigo, and spasm (table 6).
Safety.
Six patients withdrew from treatment during the study as a result of an adverse event. Depression worsened in one patient in the placebo group; development of a rash after the first injection led to the withdrawal of two patients, one in the 10-mg dose group and the other in the 100-mg dose group. Three additional patients withdrew from the 100-mg dose group, one due to the occurrence of a transient episode of flushing, dyspnea, and gastralgia after the fifth dose and two because of exacerbation-related symptoms after the fifth and seventh doses, respectively. Ninety-five percent of patients treated with placebo had at least one adverse event reported as compared with 87%, 90%, and 95% of patients treated with 10, 50, and 100 mg of lenercept, respectively. Adverse events that increased in frequency with active treatment included headache, hot flushes, nausea, and abdominal pain (see table 6). A transient episode of dyspnea associated with the administration of lenercept at doses of 50 and 100 mg occurred in six patients.
Patient complaints over the course of the lenercept MS trial
Laboratory.
RF (IgM) and ANA were present in 1% (2/162) and 20% (33/161) of patients at baseline, respectively. During the study, five patients developed a positive IgM-RF (all in the lenercept treatment groups) and 15 patients developed ANA, 14 of whom were receiving lenercept. One patient on lenercept developed both antibodies. Thus, new occurrences of RF or ANA were more frequent in lenercept-treated than in placebo-treated patients (18/124 versus 1/43; chi-square p = 0.03). Clinical manifestations of rheumatoid arthritis or systemic lupus erythematous were not observed, and dsDNA was consistently negative in all patients in whom ANA positivity was detected.
Total serum IgM had increased in a dose-dependent fashion in lenercept-treated patients after 24 weeks of treatment by an average of 0.6, 0.9, and 1.0 g/L in the 10-, 50-, and 100-mg dose groups. For those patients in the 100 mg dose group who remained on treatment beyond 24 weeks, the mean increase reached 1.2 g/L. Total serum IgG concentrations had increased by an average of 0.5 g/L at 24 weeks on treatment in patients receiving 100 mg of lenercept; for those patients who remained on treatment in the 100-mg dose group, this increase ultimately reached 1.2 g/L. Serum IgG concentrations were not increased in the other groups.
Pharmacokinetics.
Trough serum concentrations of lenercept were detectable in only a third of the patients in all dose groups and tended to relate to the anti-lenercept antibody profile. Thus, patients without antibodies had persistently detectable lenercept trough serum concentrations, whereas patients with high antibody concentrations had consistently undetectable trough levels. Antibodies to lenercept at a concentration greater than 20 ng/mL, as determined by the double-antigen screening assay, were detected in the majority of patients on treatment (5% [2/43] of patients on placebo, as compared with 98% [43/44], 88% [35/40], and 100% [40/40] of patients in the 10-, 50-, and 100-mg dose groups, respectively.) Antibody concentrations varied considerably from patient to patient and over time; generally, a dose-dependent peak occurred after the first dose, followed by a relatively stable level that persisted for as long as the patient continued to receive lenercept (see figure 2).
Discussion.
Lenercept treatment in the phase II study reported here increased MS attack frequency. There was also a suggestion that lenercept increased attack duration and worsened attack severity as judged by the extent of changes noted on the NRS. The lenercept effect was more pronounced at the two higher doses employed (50 and 100 mg) than at the lowest dose (10 mg). An increase in attack frequency was noted in lenercept-treated patients within the first month on drug and persisted throughout the period during which drug was given. The magnitude of the treatment effect on exacerbations could be biased because the trial was stopped early. We believe this is unlikely as the results of the second 24-week study period were consistent with those found during the first 24 weeks.
Despite the seemingly deleterious clinical effects of lenercept, no meaningful difference between treatment groups was noted in terms of worsening of the EDSS score. Whereas MS attack frequency and subsequent development of disability have correlated in large patient series studied over many years, no such correlation was noted in the current study, perhaps because of the relative insensitivity of the EDSS and the prompt cessation of the study following the interim monitoring analysis.
It is important to remember that had the current study shown a positive treatment effect, the results would have had to be validated in a second trial. Prudence dictates that similar caution be applied to the detrimental clinical effect noted in the current trial, particularly in view of the seemingly discordant MRI data. Setting caution aside, it is reasonable to conclude that lenercept is probably contraindicated in MS based on the internal consistency of the clinical results presented here and the untoward results obtained in a preliminary study of two patients administered a humanized mouse monoclonal anti-TNF antibody.2,5 The dissociation seen between a significantly increased clinical activity and, at best, a slight trend toward an increase in MRI-measured activity was surprising. It may be due to the lack of a robust correlation between MRI and clinical outcome, although it is generally perceived that MRI changes, in particular newly active lesions, are sensitive measures of disease activity. In the current study, more than 90% of the newly active lesions measured were Gd-enhancing, a reflection of enhanced blood–brain barrier (BBB) permeability. To date, a reduction in Gd-enhancing MRI lesions has been shown to be unequivocally associated with clinical benefit only for the beta interferons.
Could TNF neutralization have enhanced the inflammatory CNS process without affecting BBB permeability? If such occurred, our selection of newly active MRI lesions as the outcome measure for this study may have been ill suited for the assessment of this particular drug. Alternatively, failure to demonstrate an increase in MRI activity may have depended on technical factors. MRI scans over the course of the current trial were obtained immediately before dosing; i.e., 4 weeks after the preceding dose. In two MS patients treated with anti-TNF antibody, increased numbers of Gd-enhancing lesions were observed shortly after drug administration, with return to baseline within 2 to 3 weeks.25 Had a similar early and transient increase in MRI activity occurred in the current trial, it would not have been detected.
Selection of MRI endpoints for a therapeutic study of any novel agent in MS may have to be individually determined for that agent. This may require a survey of the effects of the drug on MRI dynamics over days or weeks as a prelude to protocol design for a phase II study. Novel therapeutic agents assessed solely by currently recommended MRI methodology could potentially be deemed inert even if associated with deleterious clinical effects, as was seemingly the case in this study. The same could hold for beneficial effects. This study cautions against an overly broad interpretation of MRI results in the absence of corroborating clinical data.
EAE is widely employed as an animal model for MS and is thought to entail at least some of the same pathways of tissue injury as does MS. Lenercept has repeatedly shown potent preventive and therapeutic effects in various EAE protocols13 and thus the EAE results were not predictive of lenercept’s effect in MS. Recently, inordinately severe EAE has been reported in mice lacking TNF following immunization with myelin oligodendrocyte glycoprotein,26 suggesting that even within EAE models results may differ depending on the model system.
Why lenercept failed is unknown; it could relate to some property unique to the lenercept molecule independent of its TNF neutralizing capacity. Antibodies to lenercept develop promptly in a substantial number of patients who receive it, and although the antibodies do not neutralize TNF binding, they do accelerate elimination of the drug. Furthermore, lenercept contains the Fc-like portion of IgG. It is conceivable that formation of immune complexes and activation of Fc receptors on lymphoid cells may have had a role in enhancing the inflammatory process.
Perhaps lenercept failed because of a flaw in the rationale for TNF neutralization. Consistent with this formulation is the result of a study of two patients with rapidly progressive MS in which increased activity was noted after administration of an anti-TNF antibody.25 Cytokines are pleiotropic factors and act in a complex network. Certain actions of TNF may be viewed as proinflammatory and others as anti-inflammatory; the latter may contribute to “off” signals in MS. If the on/off balance of TNF-mediated signals is relevant to MS, then removal of TNF could, contrary to widely held perceptions, potentiate disease. Interferon (IFN)–γ administration provokes MS attacks.27 TNF induces interleukin (IL)-10 and prostaglandin E2 production and these acting jointly inhibit IL-12 production and, hence, IFN-γ production.28 Thus, mechanisms may exist by which TNF blockage could augment those immune responses that contribute to MS pathogenesis.
Although lenercept failed in MS, it did reduce signs and symptoms of rheumatoid arthritis in phase II studies.29 This finding suggests a final caution. An agent that demonstrates a beneficial effect in one autoimmune disease should not be presumed to have beneficial effects in another.
Appendix
Multiple Sclerosis Study Group: The Lenercept Multiple Sclerosis Study Group comprises the following participating institutions, principal investigator (in italics), and investigative teams (in alphabetical order by principal investigator; team members in alphabetical order).
University of Chicago, IL: B.G.W. Arnason, MD; G. Jacobs, RN; M. Hanlon, RN; B. Harding Clay; A.B.C. Noronha, MD. Health Sciences Center and Misericordia General Hospital (Winnipeg, Manitoba): A. Auty, MA, BM, BCh; B. Davis, BN; A. Nath, MD. Höpital de l’Enfant-Jésus (Québec City, Québec): J.P. Bouchard, MD, FRCPC; C. Belanger, MD, FRCPC; F. Gosselin, RN; M. Thibault, MD, FRCPC. Höpital de Notre-Dame (Montreal, Québec): P. Duquette, MD, FRCPC; P. Bourgoin, MD, FRCPC; R. DuBois, RN; M. Girard, MD, FRCPC. University Hospital (London, Ontario): G.C. Ebers, MD, FRCPC; G.P.A. Rice, MD, FRCPC; M.K. Vandervoort, BscN, MSCN. Montreal Neurological Institute (Montreal, Québec): G.S. Francis, MD; L. Duncan, MD; Y. Lapierre, MD. Ottawa General Hospital (Ottawa, Ontario): M.S. Freedman, MD, FRCPC(C); S.N. Christie, MD, FRCPC(C); H.E. Rabinovitch, MD, FRCP(C). Foothills Hospital (Calgary, Alberta): L.M. Metz, MD, FRCPC; D. Patry, MD, FRCPC; W.F. Murphy, MD, FRCPC; S. Peters, BN; S.D. McGuiness, MN. Dalhousie MS Research Unit (Halifax, Nova Scotia): T.J. Murray, MD; V. Bhan, MD; C.E. Maxner, MD; R. Van Dorpe, MD. University of British Columbia (Vancouver, British Columbia): J.J. Oger, MD, FRCPC; J. Nelson, RN; W. Morrison, RN; N. Bogle; S. Beall, MD; G. Vorobeychick, MD. F. Hoffmann-LaRoche, Ltd., Basel, Switzerland: A. Valerie Hiltbrunner, MD, MPH; J. Bock, Dr. Habil; W. Lesslauer, MD. The University of British Columbia MS/MRI Analysis Group: D.K.B. Li, MD, FRCPC; D.W. Paty, MD; G.-J. Zhao, MD. Publication Committee: B.G.W. Arnason, MD, Chairman; G.S. Francis, MD, Co-Chairman; G.C. Ebers, MD; T.J. Murray, MD; D.W. Paty, MD; A.V. Hiltbrunner, MD; J. Bock, Dr. Habil.
Acknowledgments
Acknowledgment
The authors thank Madeline Murphy for editorial assistance and for typing the manuscript.
Footnotes
- Received September 11, 1998.
- Accepted April 8, 1999.
References
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