1.
`
`Introduction
`
`2. Methods and results
`
`3. Discussion
`
`4.
`
`Expert opinion
`
`For reprint orders, please
`contact:
`Ben.Fisher@informa.com
`
`Key Paper Evaluation
`Is fingolimod an advancement in
`the treatment of multiple
`sclerosis?
`
`Evaluation of: KAPPOS L, ANTEL J, COMI G. et al.: Oral fingolimod (FTY720)
`for relapsing multiple sclerosis. N. Engl. J. Med. (2006) 355:1124-1140.
`
`Sheila A Doggrell
`Charles Darwin University, School of Science, Faculty of Education, Health Sciences and Science,
`Darwin, NT0909, Australia
`
`Fingolimod is an agonist at sphringosine-1 phosphate receptors that reduces
`circulating T lymphocytes. Experimental autoimmune encephalomyelitis is
`often used as an animal model of multiple sclerosis (MS), and fingolimod
`prevents or reverses this encephalomyelitis. In subjects with relapsing MS,
`fingolimod reduced the total number of gadolinium-enhanced lesions
`detected by MRI, and the total volume of these lesions at 6 months. The
`annualised relapse rate was 0.77 in the placebo group, and was lowered to
`0.35 and 0.36 in the 1.25- and 5.0-mg fingolimod groups, respectively.
`However, there was no difference in Expanded Disability Status Scale score
`between untreated MS patients and those treated with fingolimod. After
`the 6-month core study, all subjects were treated with fingolimod. The
`annualised relapse rate remained low and the Expanded Disability Status
`Scale score remained steady for up to 24 months. Fingolimod decreased heart
`rate and blood pressure. Given the modest clinical benefits reported to date
`with fingolimod, long-term safety studies need to be undertaken with
`fingolimod to determine whether the benefit/risk profile justifies the routine
`use of fingolimod in subjects with relapsing MS.
`
`Keywords: encephalomyelitis, fingolimod, relapsing multiple sclerosis
`
`Expert Opin. Pharmacother. (2007) 8(3):383-386
`
`1.
`
`Introduction
`
`Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease of
`the CNS. Patients with MS commonly present with an individual mix of
`neuropsychological dysfunction, which tends to progress over years to decades. In
`the US, the incidence of MS is 0.5 – 1.0 per 1000 people. Approximately 70% of
`patients suffer from relapsing-remitting MS, which is characterized by acute
`exacerbations with full or partial remissions. Subjects with relapsing-remitting MS
`are treated with methylprednisolone during exacerbations, and with (cid:69)-IFNs or
`glatiramer acetate (a synthetic form of myelin basic protein) to reduce relapses [101].
`Despite treatment with (cid:69)-IFN or glatiramer, many MS patients still have relapses.
`In MS, CD4+ T cells destroy oligodendrocytes, which synthesise and maintain
`axonal myelin sheathes in the CNS. In autoimmune diseases such as MS, subjects
`harbour, rather than eliminate T cells that can become activated by self-antigens. A
`recent immunotherapeutic approach to treating MS is natalizumab – a monoclonal
`antibody that blocks the adhesion of the (cid:68)4 integrin-dependent adhesion of
`blood-borne encephalitogenic T cells and macrophages to microvessels in the CNS
`(reviewed in [1]). Natalizumab has been trialled in MS and shown to decrease the
`lesions, but JC polyomavirus, a progressive, multifocal leukoencephalopathy has
`developed in three subjects [2].
`
`10.1517/14656566.8.3.383 © 2007 Informa UK Ltd ISSN 1465-6566
`
`383
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2036
`
`

`

`Is fingolimod an advancement in the treatment of multiple sclerosis?
`
`is
`immunotherapeutic approach to MS
`Another new
`fingolimod. Fingolimod
`(FTY720, 2-amino-2-(2-[4-octyl-
`phenyl]ethyl)-1,3-propanediol hydrochloride) is a chemical
`derivation of myriocin, a metabolite of the fungus Isaria
`sinclairii, used in Chinese traditional medicine [1,3]. In the
`bloodstream, fingolimod is phosphorylated and resembles
`lysophospholipid sphingosine-1 phosphate (S1P) [1,3]. S1P has
`at
`least
`five receptors and has roles
`in neurogenesis,
`cardiovascular development, vasoregulation, endothelial-cell
`function and leukocyte migration [1,3]. S1P1 is expressed
`on lymphocytes
`and
`regulates
`lymphocyte migration.
`Fingolimod probably acts as an agonist at the S1P1 receptors,
`and this subsequently leads to an internalization of the receptors
`and reduced lymphocyte migration [1]. It is proposed that in
`MS, fingolimod traps newly generated encephalitogenic T cells
`in the lymph nodes, and hence prevents them from migrating to
`the CNS [1].
`first shown to reduce circulating
`Fingolimod was
`[3]. Acute experimental
`T lymphocyte
`levels
`in
`rats
`autoimmune encephalomyelitis (EAE) is an inflammatory
`disease of the CNS, which is often used as a model of MS.
`In the EAE model, where rats were immunised with an
`emulsion of bovine spinal cord, fingolimod (started at the
`same time as the immunisation) prevented the development
`of the disease [3]. In another rat model, in which EAE was
`induced with guinea-pig myelin basic protein, fingolimod
`(started at the same time as the immunization) completely
`protected against the disease [4]. The control EAE rats had
`inflammatory
`lesions
`in
`the CNS, which
`the
`fingolimod-treated rats did not have [4]. This protection was
`associated with reduced lymphocytes stained for T-cell
`receptors in the spinal cord [4]. When spleen cells from the
`control EAE rats were transferred to naive recipient rats,
`they developed EAE, whereas the transfer of spleen cells
`from fingolimod-treated EAE rats to naive recipients did not
`transfer the EAE [4].
`More importantly, fingolimod has been shown to be
`effective after the EAE has been established
`in the
`relapsing-remitting EAE model in SJL mice [5]. In this model,
`the EAE is a chronic disease with a relapsing-remitting
`fingolimod caused a
`pattern [5]. In established EAE,
`peripheral
`lymphopenia, and a reversal of changes
`in
`expression of mRNAs encoding some myelin proteins and
`inflammatory markers [5]. Fingolimod also caused a rapid and
`sustained improvement in clinical status [5].
`Recently, a clinical trial of fingolimod in relapsing MS has
`been undertaken, and shown promising results. This trial is
`the subject of this evaluation [6].
`
`2. Methods and results
`
`The methods and results of the Phase II proof-of-concept
`trial, showing that fingolimod reduced lesions in relapsing
`MS [6], are discussed in this section.
`
`2.1 Methods
`The study enroled subjects in 10 European countries, and
`Canada with relapsing MS and one of the following:
`
`(cid:129) Two or more relapses during the previous 2 years
`(cid:129) One or more relapses in the previous 1 year
`(cid:129) One or more gadolinium-enhanced lesions detected by MRI
`
`Gadolinium-enhanced lesions are markers of the active
`nature of MS, regardless of clinical symptoms. Enroled
`subjects also had to have a score of 0 – 6 on the Expanded
`Disability Status Scale (EDSS), in which 10 is the highest
`disability, and have been neurologically stable for 30 days.
`Subjects were excluded
`if
`they had recently
`taken
`corticosteroids,
`immunomodulatory therapy or
`immuno-
`suppressive treatment. Subjects were also excluded if they had
`low white cell or lymphocyte counts. The 277 enroled subjects
`had a mean age of (cid:97) 38 years and were predominantly female
`((cid:97) 70%), with a mean EDSS score of 2.6. Most of the subjects
`had suffered from MS for (cid:97) 9 years, and were having a mean of
`1 – 2 relapses/year.
`In the first 6 months (core study), subjects received either
`placebo, or fingolimod 1.25 or 5.0 mg. Fingolimod is
`administered orally. In the 6-month extension study, subkects
`taking fingolimod continued to take it, and those taking placebo
`were randomised to fingolimod 1.25 or 5.0 mg.
`
`2.2 Results from core study
`The primary efficacy end point was the total number of
`gadolinium-enhanced
`lesions per patient
`recorded on
`T1-weighted MRI, at monthly intervals for 6 months. In the
`placebo group this was a mean of 14.8, but this was reduced to
`8.4 and 5.7 with fingolimod 1.25 and 5.0 mg, respectively.
`Secondary MRI end points included the total volume of
`gadolinium-enhanced lesions per patient and this was 1418 mm3
`in the placebo group, and 715 and 530 mm3 with fingolimod
`1.25 and 5.0 mg, respectively. The proportion of patients with
`gadolinium-enhanced lesions was (cid:97) 50% at baseline, and after
`6 months this had increased to 62% in the placebo group, but
`decreased to 36 and 37% with fingolimod 1.25 and 5.0 mg,
`respectively. The total number of new lesions per patient on
`T2-weighted images, over the 6 months, was 6.4 in the placebo
`group, but only 3.0 and 1.9 with fingolimod 1.25 and 5.0 mg,
`respectively. The change in lesion volume on T2-weighted images
`was an increase of 129 mm3, whereas there was a decrease of 113
`and 627 mm3 with fingolimod 1.25 and 5.0 mg, respectively.
`Relapse was defined as the occurrence of new symptoms or
`worsening of previously stable or improving symptoms, lasting
`> 24 h, and accompanied by an increase of 0.5 in the EDSS
`score, or 1 point in the functional systems. Clinical end points
`included the number of patients remaining free of relapse at 6
`months, which was 66% in the placebo and 86% with both
`fingolimod 1.25 and 5.0 mg. The annualised relapse rate was
`0.77 in the placebo group, and this was lowered to 0.35 and 0.36
`in the fingolimod 1.25- and 5.0-mg groups, respectively. There
`
`384
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`Expert Opin. Pharmacother. (2007) 8(3)
`
`

`

`was no difference in EDSS scores between untreated MS,
`subjects and those treated with fingolimod.
`The first dose of fingolimod caused a decrease in heart rate
`of 13.8 and 16.6 bpm in the 1.25- and 5.0-mg groups,
`respectively. This effect decreased with subsequent doses.
`Mean blood pressure was initially decreased by 5 – 6 mmHg
`with fingolimod, but increased by 4 – 6 mmHg after 2
`months of treatment. Pulmonary function tests showed a
`reduction in forced expiratory volume at 1 s (FEV1) of 1.9,
`2.8 and 8.8% in the placebo, fingolimod 1.5- and 5.0-mg
`groups, respectively.
`Both doses of fingolimod caused increases in concentration
`of alanine aminotransferase in 10 and 12% of subjects (with
`1.25 and 5.0 mg, respectively), compared with 1% of subjects
`in the placebo group. This effect of fingolimod decreased with
`continuing treatment, and reversed when fingolimod was
`stopped. Fingolimod caused a 20 – 30% reduction in
`peripheral-blood lymphocyte counts. No serious infections
`were reported.
`Fingolimod 5.0 mg, but not 1.5 mg, increased the
`incidence of nasopharyngitis (placebo, 15%; fingolimod
`5.0 mg, 28%), dyspnea (13 versus 1%), diarrhea (12 versus
`2%), nausea (11 versus 2%). One patient, given fingolimod
`5.0 mg for 10 weeks, developed posterior encephalopathy
`syndrome, which did not resolve completely when fingolimod
`was stopped. The subject was left with a right homonymous
`hemianopia (loss of half vision), associated with left occipital
`hyperintensity, and mild ataxia (loss of coordination)
`remaining at 15 months.
`
`2.3 Results from extension study
`Of the 277 subjects who completed the core study, 250
`continued to the extension study, and continuing benefits
`were observed with fingolimod. Thus, the number of
`gadolinium-enhanced lesions remained low in those treated
`with fingolimod, while falling in those previously treated with
`placebo for 6 months and then fingolimod for 6 months. The
`proportion of patients with gadolinium-enhanced lesions
`continued to fall to 15% and 12% of subjects at 12 months,
`with fingolimod 1.25 and 5.0 mg, respectively. EDSS scores
`did not change over the 12 months.
`The overall incidence of adverse effects was lower in the
`extension study. However, one subject, who changed from
`placebo to fingolimod 5.0 mg, developed facial herpes zoster,
`and another, who changed from placebo to fingolimod 1.5 mg,
`developed enterocolitis.
`
`2.4 Results to 24 months
`The subjects in the fingolimod trial have been followed for
`a further 12 months, and a summary of the results have
`been presented [102]. After 24 months, the number of
`subjects with gadolinium-enhanced lesions remained low
`at 9 – 21% [102]. The annualised relapse rate (0 – 24
`months) remained low in all groups at 0.29 – 0.38 [102].
`The EDSS values remained stable in all groups. The side
`
`Doggrell
`
`influenza
`effects of nasopharyngitis, headache and
`[102]. The
`remained higher with fingolimod 5.0 mg
`open-label extension is to continue, with all subjects
`receiving fingolimod 0.15 mg [102].
`
`3. Discussion
`
`Given that two patients developed serious infections and
`one developed posterior reversible encephalopathy while
`taking fingolimod, larger studies need to be undertaken to
`[6]. In addition, as
`assess the safety of fingolimod
`fingolimod
`increased
`the concentration of alanine
`aminotransferase in some subjects, further studies are
`needed to evaluate any potential liver toxicity [6].
`The authors conclude that oral fingolimod may be a
`treatment option for relapsing MS, but before this can be
`considered for general clinical use, large-scale trials of efficacy
`and safety are needed [6].
`
`4. Expert opinion
`
`4.1 Clinical outcome
`Although there is no clearcut link between gadolinium-enhanced
`lesions and the signs and symptoms of MS, several agents that
`reduce gadolinium-enhanced lesions in MS have also been shown
`to reduce or prevent the decline in EDSS (e.g., IFN-(cid:69)1a [7],
`[8], natalizumab
`[9]). Over 6 months,
`glatiramer acetate
`fingolimod reduced gadolinium-enhanced lesions, but there was
`no difference in EDSS score between untreated MS subjects and
`those treated with fingolimod. It will be of interest as to whether
`there are any long-term improvements, or prevention of decline,
`of the clinical symptoms of MS with prolonged treatment with
`fingolimod. Unfortunately, this could not be determined from
`the extension study, as all subjects were given fingolimod.
`
`4.2 Selective S1P1 agonist
`It has been suggested that the beneficial effects of fingolimod in
`MS are due to interaction with the S1P1, whereas interaction
`with the other S1Ps may underlie the side effects of reduced
`heart rate, increased mean arterial blood pressure and airway
`obstruction [1]. Thus, the ability of fingolimod to decrease heart
`rate is probably due to stimulating the S1P3/G protein-gated
`potassium channel, IKACh [10]. To overcome these side effects, it
`will be necessary to develop drugs that are selective for S1P1,
`and this is already starting to happen. KRP-203 is a selective
`S1P1 agonist being developed for use as an immunosuppressant
`in transplants [11], which did not induce bradycardia in
`the guinea-pig [12].
`
`4.3 Ongoing trials with fingolimod in multiple
`sclerosis
`Fingolimod is now in two large Phase III trials, one comparing
`the 1.25-mg dose with placebo, and the other comparing
`fingolimod with interferon in subjects with MS [102]. A lower
`dose of fingolimod is also to be evaluated [102].
`
`Expert Opin. Pharmacother. (2007) 8(3)
`
`385
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`

`

`Is fingolimod an advancement in the treatment of multiple sclerosis?
`
`4.4 Safety of fingolimod
`Fingolimod
`is also being clinically developed as an
`immunosuppressant for long-term use in transplantation [13,14].
`The safety data from the development of fingolimod for use in
`the treatment of MS and also in transplantation, may be able to
`be combined to determine the safety of fingolimod in large
`numbers of patients.
`
`4.5 Is fingolimod an advancement in the treatment
`of multiple sclerosis?
`Given the modest clinical benefits reported so far with
`fingolimod, long-term safety studies need to be undertaken
`with fingolimod to determine whether the benefit/risk
`profile justifies the routine use of fingolimod in subjects
`with relapsing MS.
`
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`Websites
`
`101. http://www.emdicine.com/emerg/topic321.h
`tm
`Lazoff M: Multiple Sclerosis. Emedicine
`from WebMD (2007).
`
`102. http:www.medscape.com/viewarticle/545804
`_print
`Fingolimod effective to 24 months in
`relapsing MS.
`
`Affiliation
`Sheila A Doggrell
`Charles Darwin University, School of Science,
`Faculty of Education, Health Sciences and
`Science, Darwin, NT0909, Australia
`E-mail: sheila.doggrell@cdu.edu.au
`
`386
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`Expert Opin. Pharmacother. (2007) 8(3)
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`