Editorial. Future Neurology

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1 For reprint orders, please contact: Recent developments in oral medications for the treatment of multiple sclerosis Currently available disease-modifying drugs require long-term parenteral administration, which imposes a burden on patients and can lead to non-adherence and possible poorer long-term outcomes. Gavin Giovannoni Queen Mary University of London, Blizard Institute of Cell & Molecular Science, Barts & The London School of Medicine & Dentistry, 4 Newark Street, London, E1 2AT, UK Tel.: Fax: [email protected] Future Neurology Editorial Currently available disease-modifying drugs (DMDs) have favorably altered the course of multiple sclerosis (MS) for many patients [1]. However, all approved DMDs (IFN-b-1a and -1b, glatiramer acetate, natalizumab and mitoxantrone) require long-term parenteral administration, which imposes a burden on patients and can lead to non-adherence and p ossible poor long-term outcomes [1]. A number of oral agents (cladribine tablets [Merck Serono], fingolimod [Novartis AG], teriflunomide [Sanofi-Aventis], laquinimod [Teva/ Active Biotech] and BG00012 [Biogen Idec]) are in the later stages (Phase III) of clinical development for MS. These agents utilize a range of mechanisms to target different parts of the inflammatory response, and it seems likely that several of them will become available within a few years. The benefit risk profiles of these drugs remain to be determined but, if approved, it is anticipated that they will improve adherence and expand the treatment options available to MS patients. Cladribine is a purine analog that is resistant to breakdown by adenosine deaminase [2]. Cladribine is phosphorylated inside cells to form the active compound 2-chloro-2 -deoxy-b-d-adenosine triphosphate (2-CdATP), which is preferentially activated in T and B lymphocytes, causing sustained reductions in peripheral T and B cell populations, whilst sparing other immune cells and hematologic components [2 4]. A parenteral formulation of cladribine (Leustat ; Janssen- Cilag) is indicated for hematologic malignancies [5], and Phase II/III proof-of-concept studies have assessed the efficacy of parenteral cladribine for MS [6 8]. Cladribine tablets, the oral formulation of cladribine, shows acceptable bioavailability [9] and is under investigation in Phase III trials in MS using a short-course dosing regimen [3]. Pivotal to the clinical development of cladribine tablets is the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, a randomized, 96-week, Phase III trial in patients with relapsing remitting multiple sclerosis (RRMS). In CLARITY, patients (n = 1326) received two or four short courses of cladribine tablets or matched placebo in the first 48 weeks (starting at study day 1 and weeks 5, 9 and 13; or study day 1 and week 5), and then two short courses at weeks 48 and 52 (both groups). Each course (0.875 mg/kg/course) was administered over 4 or 5 consecutive days in consecutive 28-day periods resulting in 8 20 days of treatment in the first 48-week period and 8 10 days of treatment in the second 48 weeks; over 96 weeks, patients received c umulative doses of 3.5 or 5.25 mg/kg [10]. Compared with placebo, cladribine tablets at both dose levels conferred significant improvements in annualized relapse rate (ARR; relative reduction 58 and 55%, both p < 0.001), proportion of relapse-free patients (80 and 79% vs 61% with placebo; both p < 0.001) and risk of sustained 3-month disability progression (33 and 31% relative reductions; p = 0.02 and p = 0.03, respectively) [10 12]. Cladribine tablets also suppressed active inflammatory lesions visualized by MRI (p < 0.001) [12,13]. Approximately 90% of patients in all groups completed treatment [12,13]. Overall, the frequency of adverse events (AEs) in CLARITY was comparable between the treatment arms, but with a higher incidence of lymphopenia with cladribine tablets (27%) versus placebo (2%), as expected based on its mechanism of action [12,14]. A total of six deaths occurred during the study, which were equally distributed across the treatment groups; these deaths included one patient randomized to the 5.25 mg/kg group who received a single course of treatment and died part of /FNL Future Medicine Ltd Future Neurol. (2010) 5(2), ISSN

2 Editorial Giovannoni 6 months post-treatment following reactivation of latent tuberculosis. Three isolated malignancies occurred in patients treated with cladribine tablets, including malignant melanoma, pancreatic carcinoma and ovarian carcinoma [12,14]. One case of cervical carcinoma in situ (considered precancerous) was recorded during the study and one case of choriocarcinoma was recorded during post-study surveillance, both in the 5.25 mg/kg dose group [12,14]. Herpes zoster infections were reported in 20 patients receiving cladribine tablets, including one case of herpes zoster oticus (Ramsay Hunt syndrome) in the cladribine tablets 5.25 mg/kg dose group; none of these patients developed disseminated i nfections and all of them recovered [12,14]. A number of oral agents (cladribine tablets, fingolimod, teriflunomide, laquinimod and BG00012) are in the later stages of clinical development for MS it is anticipated that they [oral agents] will improve adherence and expand the treatment options available to patients. The safety profile of any medication is paramount, and a long-term safety study with cladribine tablets is ongoing. This randomized, placebo-controlled, 96-week, Phase IIIb CLARITY EXTENSION study will provide safety and tolerability data up to 4 years; final results are expected in 2011 [15,101]. Cladribine tablets is also being evaluated in a combination regimen. The 96-week, Phase II Oral Cladribine Added-On to IFN-b in Patients with Active Relapsing Disease (ONWARD) study is assessing the safety and tolerability of cladribine tablets as an add-on therapy to IFN-b [15,102]. Patients (n = 198) with RRMS or secondary progressive MS experiencing relapses with IFN-b are randomized 1:2 to placebo or a 3.5 mg/kg cumulative dose of cladribine tablets. A 96-week extension study is currently enrolling patients who completed the ONWARD study; patients previously receiving placebo treatment will be invited to switch to cladribine tablets treatment [15,103]. In addition, the Phase III Oral Cladribine in Early MS (ORACLE MS) study is assessing the efficacy of cladribine tablets in delaying conversion to MS in patients (n = 642) with early disease who have experienced a first clinical demyelinating event and are at high risk of converting to MS [15,103]. Patients are randomized 1:1:1 to placebo or cladribine tablets to a c umulative dose of 3.5 mg/kg or 5.25 mg/kg. Based on CLARITY data, it is possible that cladribine tablets will become the first oral agent to be approved for RRMS. Furthermore, selective and sustained reduction of T and B lymphocytes by cladribine tablets may enable patients to receive effective year-long treatment, with only 8 20 days of dosing per year. Whilst cross-trial comparisons of agents should be undertaken with caution, the rapid and significant improvements in clinical outcome measures with cladribine tablets appear to compare favorably with those for approved therapies, with clinical trials reporting ARR reductions of 55 58% with cladribine tablets, 32 34% with IFN-b and 29% with glatiramer acetate [10,12,16]. The oral agent fingolimod (FTY720), a sphingosine-1-phosphate (S1P)-receptor modulator, is also in the advanced stages of clinical development for MS. Fingolimod downregulates S1P-receptor expression on lymphocytes, causing sequestration in the lymph nodes and preventing migration into the CNS. Fingolimod may also target the blood brain barrier and cell populations within the CNS [17 23]. The S1P S1P receptor system has been implicated in a number of physiologic processes and the S1P receptor subtypes targeted by fingolimod are widely distributed [21]. This wide distribution may account for a range of non-immune AEs associated with fingolimod, including heart rate reduction, changes in blood pressure and respiratory side effects [21]. These properties also suggest that fingolimod may exhibit a range of therapeutic mechanisms [21]. Selective and sustained reduction of T and B lymphocytes by cladribine tablets may enable patients to receive effective year-long treatment, with only 8 20 days of dosing per year. Fingolimod is in Phase III development for the treatment of RRMS [ ]; the 0.5 mg dose is expected to be filed for approval in In the recently completed, parallel-group, Phase III Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS (TRANSFORMS) trial, patients (n = 1292) received intramuscular IFN b-1a (30 µg once-weekly) or oral fingolimod (0.5 or 1.25 mg/day) for 12 months [17 20]. The study compared the treatments in terms of efficacy (ARR, MRI end points and disability), safety and tolerability. 168 Future Neurol. (2010) 5(2)

3 Recent developments in oral medications for the treatment of multiple sclerosis Editorial TRANSFORMS data showed significant improvements with fingolimod at both low and high doses compared with intramuscular IFN b1a in terms of relapse-related parameters (relative ARR reduction, 52% and 38%, respectively [p < 0.001]; proportion of relapsefree patients, 83 and 80 vs 69%, respectively [p < 0.001]) and MRI lesion activity (number of new lesions over 12 months, 1.7 and 1.5 vs 2.6, respectively, p = and p < 0.001) [20]. Mean change from baseline in Expanded Disability Status Scale scores showed no significant difference in the time to progression or in the proportion of patients with confirmed progression among the study groups (-0.08 and vs +0.01, respectively; p = 0.06 and 0.02) [20]. Rapid and significant improvements in clinical outcome measures with cladribine tablets appear to compare favorably with those for approved therapies. In contrast to intramuscular IFN-b-1a therapy, fingolimod treatment was not associated with influenza-like illness. AEs of interest reported with fingolimod included cases of bradycardia, atrioventricular block, macular edema and hypertension, and an elevation in liver enzyme levels. Due to the design of the study, lymphopenia was not reported often as an AE, although treatment with fingolimod produced reductions in peripheral lymphocyte counts of approximately 75%. 12 cases of malignancy (including three cases of malignancy melanoma and five cases of basal cell carcinoma) were reported in the fingolimod treatment groups compared with one case in the IFN-b-1a group. Two deaths in the treatment group that received fingolimod 1.25 mg were caused by disseminated primary varicella zoster infection and herpes simplex encephalitis [19,20]. Two 24-month, placebo-controlled, Phase III studies (Fingolimod Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis [FREEDOMS and FREEDOMS II]) have been undertaken to assess the efficacy and safety of fingolimod 0.5 or 1.25 mg/day in RRMS patients [21,104]. The FREEDOMS study showed significant improvements in ARR with fingolimod 0.5 mg and 1.25 mg (54% and 60%, respectively; p < 0.001) compared with placebo, and significant benefit with both doses of fingolimod in terms of 3-month disability progression (p < 0.05) and MRI end points (p < 0.001) [21,105]. AEs of interest associated with fingolimod treatment included several cases of bradycardia and atrioventricular block, cases of macular edema, an increased incidence of lower respiratory tract and lung infections, and an elevation in liver enzyme levels. Fingolimod treatment produced similar reductions in peripheral lymphocyte counts to those reported in TRANSFORMS [21,105]. FREEDOMS II is ongoing and extension studies are planned for both trials; however, based on the results of the TRANSFORMS and FREEDOMS studies, further investigation of the 1.25 mg dose in relapsing forms of MS has been halted. In addition, the placebo-controlled Phase III INFORMS study will evaluate the ability of fingolimod 1.25 mg/day to delay time-to-disability progression in patients with primary progressive MS [106]. No studies are currently assessing fingolimod in c ombination therapy regimens in MS. Three additional oral agents (teriflunomide, laquinimod and BG00012) are undergoing Phase III trials for MS, with anticipated regulatory submission in 2011/2012. Teriflunomide the active metabolite of leflunomide is a small immunomodulatory molecule licensed for use in rheumatoid arthritis. Terif lunomide inhibits pyrimidine synthesis by binding to the enzyme dihydro-orotate dehydrogenase in T cells, which inhibits the proliferation of lymphocytes and other rapidly dividing cell populations [26,27]. In trials, teriflunomide is being administered daily at a dose of 7 or 14 mg/day [27]. Four ongoing Phase III studies are assessing the activity of teriflunomide in the treatment of RRMS, MS with a relapsing course (with or without progression) and clinically isolated syndrome [ ]. Data from a 6-month, Phase II study suggest that the main AEs associated with teriflunomide are related to immunosuppression, including reduced leucocyte counts and upper respiratory tract infections [28]. Data from a number of Phase II and III trials have been published concerning the novel oral MS therapies... it is hoped that these new treatments will expand the future therapeutic armamentarium in MS. Laquinimod is thought to target antigen presentation, inhibit CNS infiltration by autoreactive immune cells and promote a Th2- biased immunologic response [1,29]. Data from a 24-month Phase IIb study demonstrated that 169

4 Editorial Giovannoni laquinimod 0.6 mg/day was well tolerated and reduced relapse rates and disability progression in RRMS patients [30]. Three ongoing Phase III studies are currently evaluating laquinimod 0.6 mg/day in RRMS [ ]. Oral BG00012 (BG-12 or dimethyl f umarate), is thought to have anti-inf lammatory and immunomodulatory properties [31]. BG00012 is a fumaric acid ester that activates nuclear-factor-e2-related factor-2, a transcription factor in a major cytoprotective and anti-inflammatory pathway [32,33]. Fumaric acid esters have been approved in Germany for the treatment of p soriasis since The mechanism of BG00012 makes it a potential candidate for combination regimens in MS [30]. In a Phase IIb study in patients with RRMS, BG00012 m onotherapy reduced brain MRI activity and exhibited an acceptable safety profile [33]. Phase III trials are investigating BG00012 at a dose of 240 mg two- or three times daily in RRMS patients [114,115]. Data from a number of Phase II and III t rials have been published concerning the novel oral MS therapies. The completion of additional studies will provide further insights into the benefit risk profiles of these agents. It is hoped that these new treatments will expand the future therapeutic armamentarium in MS, o ffering patients more individualized therapy with improved efficacy, safety, acceptability and convenience. Financial & competing interests disclosure Professor Giovannoni was principal investigator in the CLARITY study and first author of the paper about the study published recently in the New England Journal of Medicine. He has received consulting fees from Bayer Schering Healthcare, Biogen Idec, Eisai, Genzyme, GlaxoSmithKline, Five Prime, Merck Serono, Novartis, Protein Discovery Laboratories, Teva-Aventis, UCB Pharma and Vertex; lecture fees from Bayer Schering Healthcare, Biogen Idec, Pfizer, Teva-Aventis and Vertex; and grant support from Bayer Schering Healthcare, Biogen Idec, GW-Pharma, Ironwood, Merck Serono, Merz, Novartis, Teva- Aventis and UCB Pharma. 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 m anuscript apart from those disclosed. Editorial assistance and medical writing support were provided by ACUMED (Tytherington, UK), funded by Merck Serono S.A. Geneva, Switzerland, an affiliation of Merck KGaA, Darmstadt, Germany. Bibliography Papers of special note have been highlighted as: of interest of considerable interest 1. Cohen BA, Rieckmann P: Emerging oral therapies for multiple sclerosis. Int. J. Clin. Pract. 61(11), (2007). Reviews current unmet needs in multiple sclerosis (MS) and the importance of treatment adherence, and overviews novel oral agents in development for MS. 2. Beutler E: Cladribine (2-chlorodeoxyadenosine). Lancet 340(8825), (1992). 3. Leist TP, Vermesch P: The potential role for cladribine in the treatment of multiple sclerosis: clinical experience and development of an oral tablet formulation. Curr. Med. Res. Opin. 23(11), (2007). Overviews the clinical development of cladribine tablets, examining data from early trials on the parenteral formulation and recent studies on the oral agent in MS. 4. Soelberg-Sørensen P, Comi G, Cook S et al.: Effects of cladribine tablets on haematological profiles in patients with relapsing remitting multiple sclerosis in the 96-week, Phase III, double-blind, placebo-controlled CLARITY study. Presented at: 25th Congress of the (Poster P472). 5. Leustat (cladribine) Summary of Product Characteristics. Janssen-Cilag Ltd. UK, July Beutler E, Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J: The treatment of chronic multiple sclerosis with cladribine. Proc. Natl Acad. Sci. USA 93(4), (1996). 7. Rice GP, Filippi M, Comi G: Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 54(5), (2000). 8. Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J, Beutler E: Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 344(8914), 9 13 (1994). 9. Liliemark J: The clinical pharmacokinetics of cladribine. Clin. Pharmacokinet. 32(2), (1997). 10. Giovannoni G, Comi G, Cook S et al.: Clinical outcomes with cladribine tablets in the 96-week, Phase III, double-blind, placebo-controlled CLARITY study in patients with relapsing remitting multiple sclerosis. Presented at: 25th Congress of the (Poster P470). 11. Giovannoni G, Comi G, Cook S et al.: Disease-free status achieved with cladribine tablets in the 96-week, Phase III, double-blind, placebo-controlled CLARITY study in patients with relapsing remitting multiple sclerosis. Presented at: 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany, 9 12 September 2009 (Poster P471). 12. Giovannoni G, Comi G, Cook S et al.: A randomized, placebo-controlled trial of cladribine tablets for relapsing-remitting multiple sclerosis. N. Engl. J. Med. 362(5), (2010). Presents final efficacy and safety data from the Phase III Cladribine Tablets Treating Multiple Sclerosis Orally 170 Future Neurol. (2010) 5(2)

5 Recent developments in oral medications for the treatment of multiple sclerosis Editorial (CLARITY) study of cladribine tablets in patients with relapsing remitting MS (RRMS). 13. Comi G, Cook S, Giovannoni G et al.: Reductions in MRI activity in relapsing remitting multiple sclerosis achieved with cladribine tablets in the 96-week, Phase III, double-blind, placebo-controlled CLARITY study. Presented at: 25th Congress of the Dϋsseldorf, Germany, 9 12 September 2009 (Poster P469). 14. Cook S, Vermersch P, Comi G et al.: Safety and tolerability of cladribine tablets in relapsing remitting multiple sclerosis during the 96-week, phase III, double-blind, placebo-controlled CLARITY study. Presented at: 25th Congress of the Dϋsseldorf, Germany, 9 12 September 2009 (Oral 88). 15. Viglietta V, Greenberg S, Mikol D et al.: Clinical development plan for cladribine tablets, an oral immunomodulator, for the treatment of multiple sclerosis. Presented at: 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany, 9 12 September 2009 (Poster P439). 16. Comi G: Individualised treatment in MS: More than one option. Presented at: 19th Meeting of the European Neurological Society. Milan, Italy, June 2009 (Oral presentation, plenary hall). 17. Cohen J, Pelletier J, Kappos L et al.: Oral fingolimod (FTY720) versus interferon β-1a in relapsing remitting multiple sclerosis: results from a Phase III study (TRANSFORMS). Presented at: 61st Annual Meeting of the American Academy of Neurology. Seattle, WA, USA, 25 April 2 May 2009 (Poster S21.004). 18. Cohen J, Pelletier J, Kappos L et al.: Oral fingolimod (FTY720) significantly reduced relapse rate compared with intramuscular interferon b-1a in relapsing remitting multiple sclerosis: clinical results from a 12 month Phase III study (TRANSFORMS). Presented at: 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dϋsseldorf, Germany, 9 12 September 2009 (Poster P456). 19. Kappos L, Cohen J, Pelletier J et al.: Safety findings from a 12 month phase III study (TRANSFORMS) comparing oral fingolimod (FTY720) and intramuscular interferon b-1a for relapsing remitting multiple sclerosis Presented at: 25th Congress of the (Poster P807). 20. Cohen JA, Barkhof F, Comi G et al.: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362(5), (2010). 21. Kappos L, Radue E-W, O Connor P et al.: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362(5), (2010). Presents 24 month efficacy and safety data from the Phase III Fingolimod Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) study of fingolimod in patients with RRMS. 22. Miron VE, Schubart A, Antel JP: Central nervous system-directed effects of FTY720 (fingolimod). J. Neurol. Sci. 274(1 2), Horga A, Montalban X: FTY720 (fingolimod) for relapsing multiple sclerosis. Expert. Rev. Neurother. 8(5), Discusses in detail the mechanism of action, immunomodulatory effects, pharmacokinetic/pharmacodynamic properties and clinical efficacy and safety data for fingolimod in MS. 24. Mehling M, Brinkmann V, Antel J et al.: FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71(16), Coelho RP, Payne SG, Bittman R, et al.: The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J. Pharmacol. Exp. Ther. 323(2), , (2007). 26. Tallantyre E, Evangelou N, Constantinescu CS: Spotlight on teriflunomide. Int. MS. J. 15(2), Discusses the mode of action and clinical efficacy and safety data for teriflunomide in the context of oral agents in development for MS and ongoing unmet medical needs in MS. 27. O Connor PW, Li D, Freedman MS et al.: A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 66(6), (2006). 28. Freedman M, Wolinsky JS, Byrnes WJ et al.: Oral teriflunomide or placebo added to interferon b for 6 months in patients with relapsing multiple sclerosis: safety and efficacy results. Presented at: 25th Congress of the (Poster P878). 29. Yang JS, Xu LY, Xiao BG et al.: Laquinimod (ABR ) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-b in Lewis rats. J. Neuroimmunol. 156(1 2), 3 9 (2004). 30. Comi G, Abramsky O, Arbizu T et al.: Long-term open extension of oral laquinimod in patients with relapsing multiple sclerosis shows favourable safety and sustained low relapse rate and MRI activity. Presented at: 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany, 9 12 September 2009 (Poster P443). 31. Fox RJ: BG00012 a novel oral therapy in development for the treatment of multiple sclerosis. Eur. Neurol. Rev. 3(1), Reviews BG00012 as a novel oral therapy for MS, overviewing its mechanism of action, outlining efficacy and safety data from clinical trials and listing ongoing clinical studies. 32. Lee DH, Linker RA, Gold R: Spotlight on fumarates. Int. MS. J. 15(1), Kappos L, Gold R, Miller DH: Efficacy and safety of oral fumarate in patients with relapsing remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled Phase IIb study. Lancet 372(9648), Presents efficacy and safety data from the Phase IIb study of BG00012 in patients with RRMS. Websites 101. Summary of the CLARITY EXTENSION NCT ?term=clarity&rank= Summary of the ONWARD study NCT ?term=onward&rank= Summary of the ORACLE MS study NCT ?term=oracle&rank=

6 Editorial Giovannoni 104. Summary of the FREEDOMS II trial NCT ?term=fingolimod&rank= Mundel T: FTY720 FREEDOMS study: initial results _spotlight-fty720.shtml (Accessed 1 October 2009) 106. A summary of the INFORMS trial NCT ?term=fty720&rank= Summary of the TENERE trial NCT ?term=teriflunomide&rank= Summary of the TEMSO trial NCT ?term=teriflunomide&rank= Summary of the TOPIC trial NCT ?term=teriflunomide&rank= Summary of the Phase III efficacy study of teriflunomide in RRMS NCT ?term=teriflunomide&rank= Summary of the LAQ/5063 extension study NCT ?term=laquinimod&rank= Summary of the ALLEGRO trial NCT ?term=laquinimod&rank= Summary of the BRAVO trial NCT ?term=laquinimod&rank= Summary of the DEFINE trial NCT ?term=define+bg00012&rank=1 (Accessed 8 June 2009) 115. A summary of the CONFIRM trial is available at clinicaltrials.gov NCT ?term=confirm+bg00012&rank=1 (Accessed 8 June 2009) Affiliation Gavin Giovannoni Queen Mary University of London, Blizard Institute of Cell & Molecular Science, Barts & The London School of Medicine & Dentistry, 4 Newark Street, London, E1 2AT, UK Tel.: Fax: [email protected] 172 Future Neurol. (2010) 5(2)