Expert Commentary & Five-year View
More than 64,000 patients have received NATA in the post-marketing setting so far. There is now good evidence that NATA treatment over 2 years is safe and well tolerated in most RRMS patients, with no previously unrecognized, statistically significant, threatening AEs having occurred so far. This adds confidence to the clinical use of NATA over 2 years. Nevertheless, according to post-marketing data, a risk of PML as recognized in the Phase III program is clearly associated with NATA therapy, even if it is lower during the first 2 years than anticipated based on the clinical trials. The risk of PML increases with increasing treatment duration, with a possible peak in the third year of treatment. Further data on patients having received NATA for more than 2 years are needed. The risk of PML currently requires a permanent and careful benefit–risk assessment in each individual patient receiving NATA, including a scrupulous reassessment after 2 years of treatment based on an in-depth discussion with the patient. A wider use of NATA might be boosted by the development of markers allowing individual risk assessment before and during NATA therapy, by novel, prospectively validated and effective treatment strategies for PML, and by favorable safety data over a longer period of time than currently available. In particular the availability of a novel serological assay that was announced for 2010 might boost a wider use of NATA in patients testing negative with this assay, if a prospective validation (results to be expected for 2013) confirms retrospective data that negative-testing patients are at a dramatically reduced risk of PML. On the other hand, NATA might still be used in a proportion of positive-testing individuals based on an individual benefit–risk assessment, as according to current knowledge the NATA-associated PML risk might be increased approximately twofold in these patients in comparison to the overall population currently being treated with NATA. This would translate into a PML risk within the approval-relevant risk frame of the clinical studies over 2 years, while it might possibly exceed this frame in the third year of treatment. This simple calculation does not take into account additional risk factors, such as immunosuppressive pretreatment, which might possibly help to stratify positive-testing patients regarding their individual PML risk to some extent. Particularly when considering the potential use of NATA in negative-testing patients it should be kept in mind that long-term safety data for NATA are still not available. As NATA might compromise immune surveillance owing to its mechanism of action, potential carcinogenicity in the long run remains a safety concern. However, despite case reports of melanoma or primary CNS lymphoma during NATA therapy,[147–150] there is currently no established clinical evidence for a carcinogenic effect of NATA. Finally, large clinical trials evaluating the safety and efficacy of NATA in patients with secondary progressive MS and evidence for inflammatory disease activity might be a worthwhile task, while the drug is currently not approved and should not be used in this cohort of patients. A Phase II safety study is running (NCT00559702).
Rituximab looked promising in trials including RRMS patients, and even in some of the patients with PPMS in the OLYMPUS trial. While RTX is currently not being further developed for MS therapy, newer anti-CD20 mAbs undergo Phase II trials for RRMS. According to their modes of action and late Phase III data from RA trials, OCRE and OFA might show comparable therapeutic efficacy in RRMS patients, with OFA possibly showing a superior safety profile. For reasons explained earlier in this article, OCRE might theoretically induce less infusion reactions than OFA despite being humanized instead of fully human, as OFA is. However, if true this should not significantly limit the use of OFA in comparison to OCRE, as it would mainly affect only the first infusion. However, in contrast to OFA, OCRE was associated with serious and/or opportunistic infections in the running Phase III program for RA, which might indicate a significant disadvantage of the drug. Nevertheless, as both mAbs show a profound immunosuppressive effect, probably affecting the safety and tolerability of the drugs, they might find a place as a second- or third-line treatment for RRMS. By contrast, these mAbs show theoretical potential to become a first-line therapy for younger patients with PPMS plus MRI and CSF inflammation. Even if this cohort accounts for a small proportion of MS patients, further evaluation in a clinical trial might not only be desirable for these patients at high risk for permanent disability, but also of some potential interest to the pharmaceutical industry in the increasingly crowded market of disease-modifying MS therapy. There is no other treatment strategy having shown similar promise in PPMS patients in a clinical trial to date. Only one Phase III trial investigating a disease-modifying drug in patients with PPMS is currently running. FTY720 in Patients with Primary Progressive Multiple Sclerosis (INFORMS; NCT00731692) studies the oral agent fingolimod (FTY720, Novartis, Basel, Switzerland) in comparison to placebo, and first results are to be expected for 2014.
Among all agents in advanced clinical development, ALEM currently remains the potentially most potent agent for the treatment of RRMS. The 3- and 4-year data from the CAMMS223 trial suggested that the impressive clinical efficacy of ALEM is sustained over at least 2–3 years after the last infusion. This long-lasting effect alone may argue for its use as a third-line strategy behind NATA (the same holds true for some of the new oral agents), as according to NATA post-marketing data the use of NATA after ALEM – even after a gap of years – would pose severe safety concerns related, but not restricted, to the possible occurrence of PML. However, a significant safety gap would also be advisable vice versa, as with every other strong immunosuppressant used after NATA, if the disease course of the patient allows for such a gap. In addition, the frequent occurrence of autoimmune adverse effects will restrict the use of ALEM. Should IL-21 diagnostics be further successfully validated as a prognostic marker for thyroid autoimmunity in MS patients, this might help to mitigate this problem to some clinically relevant extent. Carcinogenicity of ALEM remains a concern due to its mode of action, with no unequivocal evidence to date in a rather small cohort of MS patients. Given that the safety profile of ALEM does not significantly change in the Phase III program, the treatability of most of the autoimmune phenomena in a setting of clinical vigilance would nevertheless place ALEM before the approved agent mitoxantrone, which is probably less effective than ALEM, but is cardiotoxic and bears a previously underestimated risk of leukemia, which can be fatal in a significant proportion of patients.
Based on an unpublished interim analysis of 150 patients participating in the Phase II SELECT monotherapy trial, it was decided to move daclizumab monotherapy to Phase III in patients with RRMS, including a large active comparator trial. DAC previously showed a favorable adverse-effect profile in the Phase II CHOICE trial where it was combined with IFN-β; however, according to recent open-label data, autoimmune phenomena occurring in some MS patients under DAC treatment becloud its otherwise favorable adverse-effect profile. In favor of the drug, measurement of CD56bright natural killer cells, as confirmed in two independent patient cohorts, might serve as an efficacy biomarker. It is too early to speculate about the potential market position of DAC before more safety and efficacy data are available.
According to the view presented here, most mAbs in current clinical development will play roles as valuable second- or third-line agents for the treatment of RRMS. So are there new true first-line agents on the horizon? Clearly, drugs that could be administered orally might be attractive candidates for a first-line therapy. Recently, first Phase III data became available for the purine nucleoside analogue cladribine (EMD Serono, Geneva, Switzerland) and for the sphingosine-1-phosphate receptor agonist fingolimod (FTY720). In large placebo-controlled trials, both cladribine (CLARITY) and fingolimod (Fingolimod Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis [FREEDOMS]) showed impressive relative treatment effects on clinical and MRI parameters. However, rather low disease activity within the control groups – following a general trend of recent MS trials – complicates the interpretation of these encouraging trials.[153,154] For fingolimod, efficacy-related superiority over a current disease-modifying first-line agent, that is, IFN-β1a 30 µg once-weekly intramuscularly (Avonex®), has directly been demonstrated in a short head-to-head trial over 1 year (Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis [TRANSFORMS]). However, as 47.6% of the IFN-β1a patients had been pretreated with an IFN-β formulation, a subgroup analysis stratified according to pretreatment will aid the further interpretation of this trial. Both cladribine and fingolimod posed some safety concerns. Cladribine is a powerful immunomodulator causing a long-lasting and marked reduction of lymphocyte subpopulations. In the 96-week CLARITY trial, five malignant solid tumor cases in different organ systems were diagnosed in the cladribine groups (n = 884), but none in the smaller group of placebo patients (n = 435), which represented a low absolute rate but needs further evaluation, particularly as cases of benign uterine leiomyoma were diagnosed significantly more often in cladribine (n = 5) than in placebo patients (n = 0). Dermatomal herpes zoster occurred in 20 patients receiving cladribine. Overall, the drug was well tolerated. Some potential safety problems were also identified in the Phase II and III fingolimod clinical trial program for MS, including but not limited to malignant skin cancers and severe infections.[153,155,158] Overall, the drug was also well tolerated. Both agents were tested at two different dosages, with the higher dose not being more effective than the lower one in both cases. With the exception of pending FDA filing for cladribine as of February 2010, both agents were filed for FDA and EMEA regulatory approvals at the better tolerated lower doses. The anti-proliferative and anti-inflammatory pyrimidine synthesis inhibitor teriflunomide, which is currently being tested in Phase III trials for RRMS (first results to be expected for 2010), was superior to placebo and generally well tolerated in two short Phase II MS trials as a monotherapy or when combined with IFN-β. Among other adverse effects, liver toxicity, upper respiratory tract infections, back pain and hair loss were more frequently observed under teriflunomide than under placebo in both trials.[159,160] In animal studies, the compound showed teratogenic potential, as with some of the other oral agents currently in Phase III development. The immunomodulator laquinimod, which is also currently being tested in Phase III trials for RRMS (first results to be expected in 2011), showed slight liver toxicity in a RRMS Phase II trial, but none of the serious adverse effects (i.e., myocardial infarction, pericarditis and serositis) of its mother substance roquinimex (linomide). BG00012, a fumarate derivative for oral administration, showed moderate efficacy and a favorable adverse-effect profile in a 24-week Phase II MS trial, and first Phase III results are to be expected for 2011. Depending on future Phase III and longer-term safety results, some of these agents might become a true first-line therapy.
However, despite a number of new disease-modifying drugs, potentially entering the MS market within the next years, there will be an ongoing demand for current first-line therapies. Despite probably modest efficacy in comparison to some of the drugs in clinical development, which first has to be demonstrated in well-designed head-to-head trials for most of these agents, current first-line agents allow stabilization of disease activity in a significant number of patients. A favorable safety track record spanning back nearly 20 years is their main advantage over powerful, but also potentially harmful new agents. Given the limited financial resources in most healthcare systems, the availability of lower-priced generics within the next years will add to the attractiveness of current first-line agents, and in particular allow broader access to them in less wealthy countries. Nevertheless, new agents will valuably add to the proven armamentarium, be promoted by the pharmaceutical industry and, in particular, novel oral agents will be requested by many patients owing to their mode of administration. With an increasing number of always less than perfect therapeutic options, measures allowing risk and efficacy prediction of an individual drug in an individual patient – as currently on the horizon for NATA, DAC and ALEM – might be key to determining the success of a drug.
Financial & competing interests disclosure
This work was supported by grant A-57 from Interdisziplinäres Zentrum für Klinische Forschung (IZKF) at the University of Würzburg, Germany. Mathias Buttmann received research support from Merck Serono and Teva/Sanofi-Aventis, and travel grants and lecture fees from Bayer Schering Pharma AG and Merck Serono. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Expert Rev Neurother. 2010;10(5):791-809. © 2010 Expert Reviews Ltd.
Cite this: Treating Multiple Sclerosis with Monoclonal Antibodies: A 2010 Update - Medscape - May 01, 2010.