Cladribine in multiple sclerosis: pitfalls in a new treatment landscape

Keywords::

• cladribine
• multiple sclerosis
• purine nucleoside analogue
• relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated inflammatory and demyelinating central nervous system disorder that affects more than 2 million people worldwide and has shown an increase in both incidence and prevalence in recent years [1]. The neurodegenerative aspects of the disease with axonal and neuronal loss, brain atrophy and gray matter damage are increasingly acknowledged [2-6]. MS is a chronic disease and to date incurable, however, in the past two decades immunomodulatory treatment became available with either beta-interferons or glatiramer acetate, both injectable drugs with modest effect on relapse rate and inflammatory MRI activity [7,8]. However, it is doubtful whether these drugs may halt or slow progressive neurodenegeration [9]. In addition, adherence to these drugs is often poor owing to side effects and the necessity for a parenteral administration [10,11]. Thus, the necessity for more efficacious therapies that ideally exhibit fewer side effects and are orally applicable is unquestioned. In recent years, the MS treatment landscape has changed dramatically with the advent of natalizumab and fingolimod and will become even more multifaceted with the approval of teriflunomide and alemtuzumab expected in 2013. The general trend with new MS therapeutics is toward compounds with higher efficacy but also potentially more risks, such as progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab [12] or macular edema under fingolimod treatment [13]. The so-called risk-to-benefit ratio is not only a cornerstone in the process of decision making of patients and their neurologists [14] but also a cornerstone in the process of drug approval by the regulatory authorities. In this regard, the recent example of cladribine has shown that the new treatment landscape has some abysses that may be invisible when a new compound is brought into clinical trials. In this issue of EOOP, Comi et al. comprehensively summarize the pharmacology, clinical trial program, efficacy data and side effects of cladribine, a synthetic purine nucleoside analogue predominantly targeting lymphocytes, that had been investigated in patients with MS since the 1990s [15]. After several smaller studies had suggested a beneficial effect of cladribine on various endpoints, such as the Expanded Disability Status Scale (EDSS) [16], relapse rate or MRI activity, a large double-blind, three-arm, placebo-controlled, multicenter, 96-week, Phase III study investigated the efficacy and safety of oral cladribine in 1,326 patients with relapsing-remitting MS (CLARITY study) [17]. The primary endpoint was the annualized relapse rate at 96 weeks. Treatment with cladribine reduced the annualized relapse rate by 57.6% in the 3.5 mg/kg group and by 54.5% in the 5.25 mg/kg group (both p < 0.001 vs placebo). Cladribine was also superior to placebo regarding several secondary endpoints, such as the risk of 3-month sustained disability progression, MRI activity (T1 gadolinium-enhancing (Gd+) lesions, T2 lesions), the proportion of relapse-free patients at week 96 and the time to first relapse. Moreover, the proportion of patients in a disease-activity-free status, defined by i) freedom from relapse, ii) no sustained worsening in EDSS and iii) no active MRI lesions (T1 Gd+ or new/enlarging T2 lesions), was significantly greater in the cladribine arms compared to the placebo arm. However, it has to be acknowledged that the effects on progression of disability with a relative risk reduction of sustained progression of little more than 30% are only modest and not superior to those of approved MS medicines, such as beta-interferon and glatiramer acetate. Despite these efficacy data, the EMA refused marketing authorization of cladribine for treatment of MS, owing to safety concerns emerging from the drug's inherent mode of action such as risk of opportunistic infections and malignancies. In the CLARITY study, 21 herpes zoster infections occurred in 20 patients on cladribine but in no patient from the placebo group. Another concerning issue is the possible reactivation of latent viral or bacterial infections and the death of a patient in the high-dose cladribine group whose tuberculosis was reactivated [17]. A related problem is the long-lasting immunosuppression that cannot be reversed before its spontaneous resolution. Moreover, 10 cases of neoplasms were reported during the study in patients treated with cladribine, a malignant melanoma, a pancreatic carcinoma, a cervical carcinoma in situ, one case of myelodysplasia, an ovarian carcinoma and five leiomyomata [17,18]. Although data were insufficient to establish a clear causal link between cladribine treatment and risk of malignancy, analysis of all cladribine trials strongly suggests its potential carcinogenicity. Thus, the EMA felt that the benefits of cladribine did not outweigh its risks [19]. EMA's standpoint has made clear that with increasing efficacy safety issues are becoming more relevant especially in the long-term which makes the assessment of risk-to-benefit ratios difficult as many clinical studies are designed for observation periods of 2 years or less. From the patients' perspective, safety issues are of course indispensable, but make trial design and economic risks for pharmaceutical companies more venturous. When trying to poise risks and benefits of a new drug, another question mark arises on the side of the benefits: how do we measure benefit? Do we have the appropriate outcome measures, given that the main concern of patients may be disability progression and not only relapse rate? With the increasing recognition of MS as a progressive neurodegenerative disease from the very beginning, it is questionable whether relapse rate and inflammatory lesions on brain MRI (variables in the suggestive term ‘freedom of disease activity') that have been applied in the CLARITY study and other recent large Phase III MS trials are still adequate measures for the evaluation of new MS therapies. ‘Freedom of disease activity' disregards other relevant aspects of the disease, such as progressive brain atrophy, cognitive dysfunction, sleep disorders and fatigue [20-23] – factors that may have a substantial negative impact on the patients' quality of life [24]. New potential surrogate markers, such as optical coherence tomography, are emerging that may prove useful to monitor neurodegeneration and neuroprotection in MS trials [25,26]. It remains a challenge for MS researchers to find more objective and sensitive clinical outcome measures of progression hand-in-hand with the development of safer and more effective medicines.

Declaration of interest

F Paul has participated in clinical trials sponsored by MerckSerono and has received travel grants, speaker honoraria and research grants from Merck Serono. F Paul states no conflict of interest in the context of this work. This paper has received funding from the German Research Foundation.