Make it personal
van Kempen, Z.L.E.
2020
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citation for published version (APA)
van Kempen, Z. L. E. (2020). Make it personal: natalizumab in relapsing remitting multiple sclerosis.
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GENERAL INTRODUCTION
The first cases of multiple sclerosis (MS) were reported in the early 19th
century but it wasn’t until 1869 that the disease was first recognized and described.1 Since then, we have travelled 1.5 centuries in time and made
countless discoveries regarding this devastating disease. Even in 2019, there is still much unknown regarding etiology, pathogenesis, genetics, immunology and neurobiology of MS. From a patient and clinician point of view, the treatment of MS might be the one research area which is of greatest interest. As MS is the most frequent disabling neurological disease in young adults, it is needless to say that patients, in the prime of their lives, justly demand the best treatment for their individual MS. In the last three decades, treatment options have risen exponentially and quality research regarding new therapeutic options is published almost monthly. For the MS specialized neurologist, it is important to keep track of new developments and use shared decision making regarding treatment options. All disease modifying treatments registered for MS are approved by the EMA/FDA in a set dose and treatment regimen. But when thinking about efficacy, side effects, complications, convenience, costs and quality of life, a ‘one size fits all’ treatment could (and should) be getting out of fashion, making way for personalized treatment in MS.
In the first chapter of this introduction, a background on MS including epidemiology, cause, pathogenesis, clinical manifestations, disease course, diagnosis and treatment will be outlined. In the second chapter of the introduction the development and working mechanism of natalizumab, the subject of this thesis, will be introduced. At the end of the second chapter the aims and outline of this thesis will be presented.
Epidemiology
Globally, approximately two to three million people worldwide suffer from MS.2 In general, MS is most common in countries more distant from the
Figure 1. Global prevalence of multiple sclerosis
Source: “The MS International Federation’s Atlas of MS, 2013”. Reproduced with permission.
In the Netherlands, currently approximately 17.000 people are living with MS, meaning 1 in 1.000 individuals is affected by this disease. In comparison, approximately 1 in 10.000 individuals in the Netherlands is affected by ALS and 1 in 100.000 individuals develops a glioblastoma.
Multiple sclerosis predominantly affects young adults and the diagnosis is most commonly made between 20-40 years of age. For unknown reasons, women are more frequently affected than men in a 2-3:1 ratio.4 Women
are most commonly affected within child bearing age. MS disease activity decreases during pregnancy (lowest in the third trimester). Unfortunately, the risk of MS activity increases threefold in the puerperium.5 Children, mostly
girls, can also be affected by MS.6
Cause of multiple sclerosis
When diagnosing a patient with multiple sclerosis, the question ‘why did I develop this disease’ is asked almost without exception. The answer is not unequivocal as multiple factors play a causal role. There are several known environmental risk factors, the most important being low vitamin D levels and smoking.7, 8 Vitamin D levels are associated with exposure to sunlight
but it is unknown if vitamin D supplementation is protective of MS evolution.
The risk of developing MS increases with duration and intensity of smoking. This risk is higher in men than in women. Another environmental risk factor is obesity in early life.9 Obesity is associated with a twofold increased risk of
developing MS. Furthermore, there is evidence that infectious agents might be involved in the cause of MS. Especially the Epstein-Barr Virus is associated with developing MS when individuals go through an infection as a young adult instead of an infection earlier in life.10
MS is familial; the risk of MS increases to 2-5% when a first-degree family member is affected and to approximately 30% for a monozygotic twin (see figure 2).3 Children who are adopted do not have an increased risk of MS when
non-biological relatives are affected with MS.11
Figure 2. Recurrence risks for multiple sclerosis in families
Pooled data from population-based surveys show age-adjusted recurrence risks for different relatives with multiple sclerosis. Error bars indicate the estimated 95% confidence intervals. Source: “Multiple sclerosis” by A. Compston and A. Coles. Lancet 2008; 372: 1502-1517. Reproduced with permission.
The fact that MS is familial supports the hypothesis of a genetic role in the development of MS. The HLA region on chromosome 6 has been associated with MS as well as with many other auto-immune diseases.12 Over 200 allelic
variants in genes, many within the HLA-DRA locus, have been identified as risk factors for developing MS.13-15 The more variants an individual has, the
predict disease characteristics.17 Interestingly, smoking, obesity and EBV
infection interact with these genetic loci at the HLA region.18
Pathology
The pathology of multiple sclerosis exclusively involves the central nervous system (CNS). A complex interaction between the immune system, neurons and glia result in inflammation and destruction of CNS tissue. Three major pathological processes underlie this process within the CNS: demyelination, neuronal loss and astrocytic gliosis.
In early MS, immune cells migrate to the CNS to start an inflammatory cascade, but the trigger for this phenomenon and why this response is maintained or repeated is still unclear. Two different hypotheses are 1. an intrinsic trigger from within the CNS which leads to CNS antigen release in the periphery, and 2. An extrinsic trigger from outside the CNS leading to an immune response against the CNS.19 Demyelination is the breakdown of
myelin and its supporting cells, the oligodendrocytes, and in this process B and T cells (the adaptive immune system) are key players. Myelin is most abundant in the white matter, but is also present in the gray matter and demyelination occurs in both areas.20 The invasion of B and T cells results in
active demyelinating lesions with blood brain barrier leakage.21 Remyelination
does occur in white and gray matter lesions, but the degree of remyelination is variable between patients.22
As the first stage of the disease is characterized by focal inflammatory demyelinating lesions within the CNS, later in the disease, more diffuse pathology takes over with neuronal loss of chronically demyelinated axons and damage and gliosis of astrocytes and activated microglia.19 This is
characteristic of the progressive phase of MS, in which diffuse injury to normal appearing white matter of the brain and spinal cord is extensive. Neuronal loss affects gray and white matter23 and neurodegeneration in the white
matter is aggravated because of slow Wallerian degeneration in response to neuronal loss in the gray matter.24
Clinical manifestations and disease course
Eighty percent of MS patients present with a semi-acute attack of neurological symptoms arising from one, or sometimes several, areas of inflammation within the central nervous system. Symptoms typically increase in an episode of days to weeks after which they will, completely or incompletely, reside
within weeks to months. Such an episode is referred to as a relapse or clinical MS exacerbation (or as most Dutch patients would say a ‘schub’). The majority of patients have an initial relapse originating from the optic nerve, brain stem or spinal cord.19 An optic neuritis presents (in the large majority of cases)
as mono-ocular loss of vision, accompanied by decreased seeing of colors and pain localized to the affected eye. Optic neuritis develops in 70% of MS patients,25 however an optic neuritis can also be a manifestation of other
auto-immune diseases. Patients presenting with optic neuritis have a 25-72% chance of developing MS, with an increase of this risk in case of presence of demyelinating brain lesions at time of the optic neuritis.26 A relapse resulting
from inflammation in the brainstem will commonly induce symptoms of diplopia with an internuclear ophthalmoplegia being a frequently encountered manifestation. A spinal cord syndrome will often result in (ascending) sensory symptoms, walking disability and bladder, bowel and sexual dysfunction. In MS, clinical manifestations can vary extensively as all sites within the central nervous system can be affected. The most common neurological complaints during the disease involve motor, sensory and visual symptoms.3 However,
coordination difficulty and tremors, bladder and bowel dysfunction including incontinence, diplopia, cognitive impairment, fatigue and sexual dysfunction are all frequently reported symptoms in MS patients. There are a few signs and symptoms relatively specific for the disease, like Lhermitte’s sign which is an electrical sensation running down the spine or limbs upon ante flexion of the neck and Uhthoff phenomenon which is a transient worsening of previous symptoms when the body temperature rises, for instance after exercise or a hot shower.
When patients experience a relapse for the first time without a diagnosis of multiple sclerosis, we speak of a clinically isolated syndrome (CIS). If relapses re-occur, a diagnosis of relapsing remitting multiple sclerosis (RRMS) can often be made. Important risk factors for development of MS in CIS patients are the presence of oligoclonal bands in the cerebrospinal fluid (CSF) and >10 lesions on brain MRI.27 When the MRI scan in a CIS patient shows
non-symptomatic white matter abnormalities suspect for demyelination, the chance of a second relapse is 50% in the next two years and 82% in the next 20 years.28 RRMS is characterized by relapses and radiological disease
activity defined by new or enlarging T2 lesions and gadolinium enhancing lesions on brain and spinal MRI. As years pass, the relapse frequency typically decreases, and recovery of relapses is less complete. Ten to thirty percent of
RRMS patients reach a secondary progressive phase during long-term follow-up, defined as secondary progressive MS (SPMS) in which there are no more relapses but only a gradual neurological deterioration.19 Children diagnosed
with MS take longer to reach a secondary progressive phase but do so earlier than adults.29 Fifteen to twenty percent of patient do not experience relapses
at all, these patients are diagnosed as primary progressive MS (PPMS).30 PPMS
is characterized by a gradual neurological deterioration from the start of the disease and commonly manifest as slowly progressive walking disability. There is less of a female predilection in PPMS and this form of MS usually manifests at a later age. See figure 3 for a schematic overview of the different disease courses of MS.
Figure 3 Different disease courses of multiple sclerosis
MS is a chronic disease and the course develops over decades. Defining the course or the disease (RRMS, SPMS of PPMS) in a patient is not always straightforward as it is necessary to weigh the clinical course (relapses
versus disability progression) and MRI features (new/enlarging T2 lesions, gadolinium enhancing lesions and atrophy) in this decision. Consequently, uncertainties can arise in patients showing only clinical progression but with gadolinium enhancing lesions or with relapses without MRI activity. In 2014, the MS Phenotype Group proposed new definitions regarding the course of MS.31 To increase accuracy of disease course description, instead of just
defining a relapsing or progressive course, the terms active and progressive were introduced which can be used alone or together. Active disease refers to either clinical relapses or radiological presence of gadolinium enhancing lesions or new or enlarging T2 lesions. Progressive disease refers to increase of objective neurological disability without recovery or atrophy and volume of T1 hypointense lesions on MRI, but these MRI markers are not yet used in common practice.31
Besides RRMS, SPMS and PPMS, some patients present with accidental findings on MRI fitting demyelination, but without clinical symptoms. This is described as a radiological isolated syndrome (RIS).32 Risk factors for
developing MS in patients with a RIS are age <37yrs, male sex and spinal cord involvement.33 Thirty-four percent of patients with a RIS develop symptoms
fitting the diagnosis of a CIS or MS within five years.34
Diagnosis and follow-up
No diagnosis of MS can be made without the presence of clinical symptoms as described in the previous section. If symptoms do occur, the diagnosis is based on the interpretation of clinical findings, radiological evaluation of the CNS with MRI and laboratory evaluation of the cerebrospinal fluid (CSF). A CNS auto-immune response results in the finding of CSF specific oligoclonal bands, which are present in approximately 90% of MS patients.3
In the past decades, the McDonald diagnostic criteria have been developed and revised to help making a diagnosis of multiple sclerosis with a useable tool.35-38 However, the criteria should not be used to differentiate multiple
sclerosis from other diseases of the CNS. To fulfill the diagnostic criteria, there should be dissemination of the disease in time and space demonstrated by either clinical symptoms or MRI abnormalities. See table 1 for an explanation of the 2017 revisions of the McDonald criteria for relapsing remitting multiple sclerosis.38
Table 1. Explanation of the 2017 revisions of the McDonald diagnostic criteria for relapsing remitting multiple sclerosis.38
Clinical presentation Additional data needed for diagnosis ≥ 2 clinical attacks and objective
evidence of ≥ 2 lesions
None ≥ 2 clinical attacks and objective
evidence of 1 lesion
DIS: an additional attack implicating a different CNS site OR by MRI
1 clinical attack and objective clinical evidence of ≥ 2 lesions
DIT: an additional clinical attack
implicating a different CNS site OR by MRI OR CSF specific oligoclonal bands 1 clinical attack and objective
evidence of 1 lesion
DIS: an additional clinical attack
implicating a different CNS site OR by MRI AND
DIT: an additional clinical attack OR by MRI OR CSF specific oligoclonal bands Dissemination in space (DIS) by MRI: ≥ 1 T2-hyperintense lesions in ≥ 2 of 4 CNS areas: periventricular, cortical or juxtacortical, infratentorial, spinal cord.
Dissemination in time (DIT) by MRI: simultaneous presence of a T1-gadolinium enhancing lesion and a T2-hyperintense lesion or a new T2-hyperintense or T1-gadolinium enhancing lesion compared to former baseline scan.
DIS = dissemination in space. CNS = central nervous system. DIT = dissemination in time. CSF = cerebrospinal fluid.
In case of a clinically isolated syndrome (CIS), when the first relapse and MRI are fitting with MS but the patient does not fulfill the diagnostic criteria, the patient should receive follow-up to evaluate if the CIS develops to MS. After the diagnosis, there are several tools to follow disease activity and progression necessary to (re)evaluate treatment and follow-up strategies. A clinical evaluation should always include a relapse assessment and neurological examination to establish disability. By far the most used scoring system for disability in MS is the Expanded Disability Status Scale (EDSS).39
The EDSS quantifies disability examined at the neurological examination and clinical history in eight functional systems scores of which a final EDSS score can be calculated (0 is no disability, 10 is death). Another frequently used scoring system in MS is the Multiple Sclerosis Functional Composite (MSFC); consisting of the timed 25-foot walk (T25FW), the 9 hole peg test (9HPT) and the paced auditory serial addition test (PASAT).40 Besides clinical evaluation,
the most used tool for follow-up on disease activity is brain (and sometimes spinal cord) MRI. Standardized protocols have been proposed for routine use (every six months to two years) including 3D T1-weighted, 3D FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences and a DWI sequence.41 In clinical trials MRI is often the primary outcome
measure as MRI lesions develop more often than clinical relapses and a new MRI lesion does not necessarily lead to clinical symptoms.42 Biochemically,
disease activity can be monitored by measuring neurofilament light (NfL), structural elements which are released in the cerebrospinal fluid (CSF) after axonal injury in various neurological disorders including MS.43 There is a
strong positive association with NfL in CSF and serum using a single molecule array (Simoa) assay and NfL in serum is shown to be associated with MS disease activity.44
Treatment
Up until halfway through the 90s there were no licensed disease modifying treatments (DMTs) on the market for MS. β interferons were used in RRMS since the 1970s but officially came to market in 1995 followed by glatiramer acetate in 2003. Both medications have a comparable moderate efficacy with a reduction of relapses of approximately 30% compared to placebo.45, 46 The β interferons are injectables: interferon β-1a is injected three times
per week subcutaneously or one time a week intramuscular, interferon β-1b is injected subcutaneously every other day and peginterferon β-1a (later coming to market in 2014) is injected once every two weeks subcutaneously. Glatiramer acetate is injected subcutaneously every day, but in 2015 a different dose came to market which is injected subcutaneously 3 times a week. Interferons and glatiramer acetate are both immunomodulatory (and not immunosuppressive) therapies and are still used today as first line medication. They have a well-known safety profile and favorable low risk of long-term complications. Natalizumab was introduced in 2006, has a high efficacy and will extensively be discussed in chapter 2 of the introduction. In 2011, fingolimod joined the market for RRMS. Fingolimod is a selective sphingosine-1-phosphate modulator and prevents egress of lymphocytes from lymph nodes. Is has a high efficacy with 48-53% relapse reduction compared to placebo.47, 48 Fingolimod is prescribed in a tablet once per
day. In 2013, two new drugs were introduced to market. The first one was teriflunomide, a dihydro-orotate dehydrogenase inhibitor, which reduces the proliferation of lymphocytes by blocking this mitochondrial enzyme. Teriflunomide is prescribed in once per day tablets and has a moderate
efficacy of 31% reduction of relapses compared to placebo.49, 50 The second
one is alemtuzumab which is given intravenously in two (or more when necessary) courses of 5 and 3 days, given one year apart. It is an anti-CD52 therapy which induces B and T cell depletion. Alemtuzumab has a high efficacy with a reduction of relapses of approximately 50% compared to interferon β-1a.51 Unfortunately because of recent reports of serious
adverse events,52 including fatal cases due to cardiac and vascular problems,
prescribing alemtuzumab is restricted to exceptional cases while the EMA safety committee researches the safety profile. In 2014 dimethyl fumarate was approved. Dimethyl fumarate activates the nuclear factor E2-related factor-2 pathway, which protects against oxidative stress related neuronal death and damage to myelin in the CNS. Is has a high efficacy with a 44-53% reduction of relapses.53, 54 Daclizumab, an IgG1 monoclonal antibody, was approved
for RRMS in 2016 after clinical randomized trials showed a high efficacy of 50-54% relapse reduction compared to placebo55 and 45% relapse reduction
compared to interferon β-1a.56 However, in 2017 the EMA restricted its use
due to hepatotoxicity and in March 2018 the drug was suspended because of reports of serious inflammatory brain disorders.57 In 2017 cladribine was
introduced to the market. Cladribine is a synthetic deoxyadenosine analogue which depletes B and T cells. It has a high efficacy with a 58% reduction of relapses compared to placebo.58 The drug is prescribed in tablets based on
body weight and is administered in a few day courses given in two consecutive years. Ocrelizumab is a humanised monoclonal antibody against the B cell surface antigen CD20 and causes b cell depletion. It came to market in 2017 and is administered intravenously every six months with a high efficacy with 47% relapse reduction and 94% of reduction of gadolinium enhancing lesions on MRI compared to interferon β-1a.59 All treatments currently on the market
target a section in the inflammation cascade and consequently are approved for RRMS in which inflammatory lesions result in relapses and disability. However, ocrelizumab is the first to slow progression in PPMS patients and is now the only DMT approved for this form of MS.60 Approved treatments
have risen exponentially the last decades and the expectation is that this trend will continue (see figure 4).
Figure 4. Disease modifying treatments and the year they came to market.
Note: Daclizumab was drawn from the market in 2018 because of reports of serious adverse events.
Consequently, with new more effective treatments, the bar has been raised regarding the desired effect of treatment. In light of this, no disease activity was introduced as an outcome measure,61 which was later renamed as NEDA
which stands for no evident disease activity. No evident disease activity (or NEDA-3) is reached when there is no MRI activity (new/enlarging T2 lesions and gadolinium enhancing lesions), no relapses and no disability progression (mostly measured by EDSS).62 Additionally, NEDA-4 includes the rate of
cerebral atrophy.63 NEDA is used in clinical trials but is also used in current
practice, where annual brain MRI and clinical follow-up is recommended.31, 62
Besides the pursuit of NEDA, a discussion is ongoing whether a patient should be treated with a moderate effective DMT only switching to a more effective DMT when there is disease breakthrough (escalation strategy) or starting with high efficacy drugs in the pursuit to prevent as much disease activity as possible (induction strategy).64 In general, the more effective DMTs carry a
higher risks of complication, so a choice has to be made per individual if the risks outweigh the benefits.
Besides disease modifying treatment, relapses can be treated with steroids with the aim of faster recovery. In many hospitals the standard steroids regimes is comprised of a 3 days intravenous methylprednisolone course (1gr/day), however a multicenter study shows that an oral course of steroids (500mg for 5 days) is non-inferior to intravenous steroids.65 In the Netherlands,
oral high dose of methylprednisolone is not routinely available.
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65. Le Page E, Veillard D, Laplaud DA, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet 2015; 386: 974-981.
CHAPTER 2
NATALIZUMAB
Natalizumab is a recombinant humanized IgG4 monoclonal antibody. Natalizumab targets the α4 subunit (CD49d) on the very-late antigen 4 (VLA4; α4β1) and the lymphocytes’ Peyer’s patch adhesion molecule-1 (LPAM1; α4β7). VLA4 is involved in the homing of lymphocytes to the central nervous system (CNS) and LPAM1 is involved in the homing of lymphocytes to the gastrointestinal lymphoid tissue, the latter being the reason why natalizumab is also effective in the treatment of Crohn’s disease.1 When VLA4 on
lymphocytes binds to its ligand; vascular cell adhesion molecule-1 (VCAM1) which is expressed on endothelial cells, migration of lymphocytes over the blood brain barrier is facilitated. Natalizumab blocks this pathway by binding to VLA4 and hereby reduces inflammation in the CNS. Consequently, CD4 and CD8 T cells, CD19 B cells and CD138 plasma cells are reduced in the CSF in natalizumab treated patients.2 In the periphery, after initiation of natalizumab,
the composition of immune cells change with CD4, CD8, CD19 and CD34 cell counts increasing during natalizumab treatment.3 With exceptions
to CD34 cells, other cell subsets stay within the limit of normal during natalizumab treatment.4 The change of peripheral immune composition
during natalizumab is reversible after discontinuation of treatment.5
VLA4 is expressed on different lymphocyte subsets, however expression varies per subset.6 CD19 B cells and CD14 monocytes express significantly
higher levels of VLA4 than CD3 T cells. Among T cells, CD8 cells express twice the VLA4 in comparison to CD4 cells.6 Furthermore, VLA4 expression
on different cell subsets is higher in MS patients compared to controls.7
Natalizumab influences VLA4 expression on lymphocytes,7 resulting in a
decrease of VLA4 over different lymphocyte subsets which recovers after 4 weeks (one infusion interval).6 VLA4 expression is suggested as a biomarker
for efficacy.8
VCAM1 expression on endothelial cells is promoted by pro-inflammatory factors9 and shedding of soluble VCAM1 in serum increases with the
occurrence of inflammatory lesions in MS.10 Therefore, soluble VCAM1 may
reflect the endothelial barrier, with high VCAM1 in serum reflecting a low endothelial blood brain barrier. Natalizumab decreases the concentration of soluble VCAM1.11
After natalizumab infusion, the serum concentration rises rapidly to a maximum whereafter an exponential decline sets in (see figure 1). Bound natalizumab to CD49d (the α4-subunit of VLA4), referred to as receptor saturation, is quite stable during a 4 week natalizumab cycle in most patients.12
Low natalizumab concentration and α4-saturation are correlated with disease acitivty.13
Figure 1. Mean serum concentration (A) and mean percentage of α4 saturation in healthy volunteers after 300mg natalizumab infusion.12
Source: “Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS” by R. Rudick and A. Sandrock. Expert Rev Neurother 2004; 4: 571-580. Reproduced with permission.
Natalizumab can induce antibodies which were reported in 9% of patients in the pivotal trials.14, 15 The majority of patients develop antibodies, which
are mostly transient.16 A high antibody titer is associated with persistence of
natalizumab antibodies.17 Persisting antibodies are reported in 3.5-9.4%,16, 18-20
but these number are dependent of the technique of the assay, the timing of blood sampling and the definition of persistence of antibodies. Natalizumab
antibodies are inversely correlated with natalizumab concentration and antibodies are associated with disease activity.16
Clinical trials
In 1992, antibodies against α4β1 (VLA4) were shown to reduce lymphocyte infiltration and disease activity in murine models with induced experimental autoimmune encephalomyelitis, which has similarities to multiple sclerosis.21
In 1999 the results of the first phase I trial of natalizumab were reported, in which different doses of 0.03 to 3.0 mg/kg were well tolerated in 28 stable RRMS or SPMS patients.22 Different phase II trials were performed using
natalizumab doses of 1, 3 and 6 mg/kg, showing a significant reduction in the number of T2 lesions23 and gadolinium enhancing lesions on MRI24 and
relapses.25 Two large phase III studies followed, the SENTINEL and AFFIRM
trial.14, 15 In both of these trials a set 4 weekly dose of 300mg was used, hereby
giving the large majority of patients (with body weight ranging from 50-100kg) a 3 to 6 mg/kg natalizumab dose.
In the AFFIRM trial, 942 RRMS patients were randomized to natalizumab versus placebo in a 2:1 ratio. Relapse reduction was 68% compared to placebo and confirmed disability reduction was reduced with 42% at one and 54% at two year follow-up. Active (new or enlarging) T2 lesions and gadolinium enhancing lesions were reduced with 83% and 92% respectively compared to placebo. Fatigue, allergic reactions and hypersensitivity reactions occurred significantly more frequent in the natalizumab group.
In the SENTINEL trial, 1171 patients with RRMS were included and randomized for treatment with interferon β-1a plus natalizumab or monotherapy with interferon β-1a. Relapse reduction of double therapy was 54% in comparison to monotherapy at year one and two. Furthermore, an impressive 83-98% reduction of active T2 lesions and gadolinium enhancing lesions were seen in the natalizumab group compared to monotherapy of interferon β-1a. The SENTINEL study was terminated prematurely because of two reports of progressive multifocal leukoencephalopathy (PML). Natalizumab was finally approved for RRMS in 2006 after PML risk factors were identified and since then until September 2019, 202.300 patients have been treated with natalizumab in 80 countries with over 765.985 patient-years of experience (personal communication Biogen).
The sustained efficacy of natalizumab was confirmed in many trials. 26-31 However, after discontinuation of natalizumab a so-called rebound of
disease activity has been described.32, 33 There remains discussion as this
phenomenon might not be a true rebound but instead a return of disease activity not exceeding the pre-natalizumab status.34, 35
Natalizumab was also investigated in a randomized double-blind placebo-controlled trial in SPMS patients (ASCEND trial).36 In this trial no significant
reduction of EDSS progression and T25FW time was reported in natalizumab treated patients compared to placebo. However, the time on the 9HPT was reduced in the natalizumab group compared to placebo. These findings were insufficient for natalizumab to be registered for the treatment of SPMS.
Progressive multifocal leukoencephalopathy
Natalizumab is associated with a risk of the development of PML. PML is a lytic demyelinating brain infection caused by the John Cunningham Virus (JCV). The JC virus is a common polyoma virus and is presumably inhaled or ingested whereafter it resides latently in kidneys and bone marrow.37
Thirty to seventy percent of the population is infected with the JC virus38
and approximately 55% of MS patients are seropositive.39 Age is the most
important risk factor for JCV positivity.40 Interestingly, patients can convert to
seropositivity and seronegativity with changing JCV antibody titers. The rate of seroconversion (in either direction) in the general population is estimated to be 1-2% annually.38 The reason why natalizumab treated patients are at risk
for PML, is not fully elucidated. Natalizumab forces CD34(+) cells (possible carriers of the JC virus) out of the bone marrow41 and induces upregulation
of gene products that favor JCV growth.42 Both these factors could play a
role in the increased risk of PML. After a latent JCV infection in kidneys or bone marrow in a natalizumab treated patient, the JC virus might enter the brain as free virions or through an infected cell. Once in the brain, JCV infects oligodendrocytes after which an asymptomatic cellular PML exists for several months.37 Together with clinical symptoms, demyelinating plaques, bizarre
astrocytes and oligodendrocytes with inclusions are formed. Without CNS immune reconstitution, PML is generally a lethal disease. When CNS immune reconstitution takes place, an immune reconstitution inflammatory syndrome (IRIS) usually occurs, sometimes aggravating clinical symptoms with the need for treatment with corticosteroids. Immune reconstitution is induced by immediate discontinuation of natalizumab and could be hastened by plasma exchange. No antiviral therapies have yet showed to improve outcome.
In September 2019, 825 confirmed cases of natalizumab associated PML have been reported with substantial mortality and morbidity in survivors (personal communication Biogen). The risk of PML increases with JCV positivity, higher JCV index, longer duration of natalizumab treatment and prior immunosuppressant use (see table one for a risk estimation).43
Table 1. Cumulative risk of PML in the pooled cohort reported by Ho et al.43 in JCV
positive patients without prior immunosuppressant use. Risk is indicated per 1000 patients. Number of natalizumab infusions JCV index ≤ 0.9 JCV index > 0.9 and ≤1.5 JCV index > 1.5 12 0.01 0.06 0.2 24 0.06 0.3 1.1 36 0.2 1.1 3.7 48 0.6 3.1 10.4 60 1.1 5.5 18.2 72 1.6 8.5 28.0
JCV = John Cunningham Virus
Natalizumab treated patients undergo stringent monitoring to estimate PML risk and detect PML in the pre-clinical phase. Patients should be tested every 6 months for JCV antibodies and when positive and continuing natalizumab, patients should receive frequent MRI scans (usually every 3-4 months) for early detection of PML.37 MRI findings suggestive of PML are a subcortical location
(with involvement of the U-fibres), T1 hypointensity, presence of punctate T2-hyperintense lesions and diffusion-weighted imaging hyperintensity.44 The
aim of early diagnosis of PML is to limit brain damage by initiating immune reconstitution as soon as possible. PML diagnosis should be confirmed with CSF measurement of JCV viral load, however, at an early stage of PML CSF viral load can be negative. Repeated MRI and CSF analysis are sometimes required for adequate diagnosis of PML. In some cases brain biopsy may be needed to make a definite diagnosis.43
PML is not only associated in MS patients using natalizumab. Cases of PML have also been described in patients using fingolimod and dimethyl fumarate. Over twenty cases of PML have been attributed to fingolimod,45 mostly in
is very rare with under 10 cases being reported. Dimethyl fumarate associated PML seems to be associated with prolonged lymphophenia.46
Aims and outline of this thesis
Natalizumab has proven its undeniable efficacy in the treatment of relapsing remitting MS. With over 13 years of clinical experience, extensive post-marketing data has been collected regarding safety, long-term complications and efficacy. Even though new therapies are emerging in record time, natalizumab still holds a key position in the treatment of (aggressive) RRMS. Therefore, it is of utmost importance to keep on improving this efficacious therapy with optimizing efficacy, increasing convenience and minimizing the risk of complications.
By the studies combined in this thesis, we studied natalizumab biomarkers with the aim of developing a personalized natalizumab treatment and study possible effects of such a strategy.
In part II natalizumab concentration in serum is introduced as a biomarker. In
chapter 3 we studied natalizumab trough concentrations in 80 patients. We
evaluated the inter-individual variability of natalizumab concentration and the intra-individual stability of trough concentrations. Furthermore, we studied if duration of treatment, age, weight and disease activity were correlated with natalizumab trough concentrations. In chapter 4 an unusual case with natalizumab antibodies during 8 years of treatment is presented. We studied the longitudinal natalizumab pharmacokinetic and pharmacodynamic values compared to a matched control and report on clinical follow-up after discontinuation of treatment. In chapter 5 we studied natalizumab treated patients with a pregnancy related discontinuation of treatment. We report data of a retrospective cohort of 22 cases and studied disease activity in relation to treatment gap and natalizumab trough concentration before discontinuation.
In part III, personalized extended interval dosing of natalizumab is introduced. In chapter 6 the results are reported of a prospective multi-center trial investigating personalized extended interval dosing of natalizumab, based on trough natalizumab serum concentrations in 61 stable RRMS patients. Disease activity is studied, clinically and radiologically, in a one year follow-up period and a second year extension phase. In a subgroup, the effect of personalized extended interval dosing is studied using different biomarkers, such as
receptor saturation, CD49d expression and neurofilament light. Chapter 7 elaborates on the natalizumab wearing-off effect, which is a well-known but under studied phenomenon. The wearing-off effect is described in respect to prevalence, symptoms and duration. Furthermore, possible relations are studied with patient and treatment characteristics (standard interval dosing versus personalized extended interval dosing) and natalizumab pharmacokinetic and pharmacodynamic values.
In part IV different aspect of natalizumab associated PML are studied. In
chapter 8 we studied JCV conversion in natalizumab treated patients.
We evaluated if JCV conversion might be associated with natalizumab serum concentrations. In chapter 9 we studied longitudinal natalizumab trough concentrations in patients prior to onset of natalizumab associated PML in relation to matched controls. In chapter 10 we evaluated if serum neurofilament light could be a possible biomarker in natalizumab associated PML. We studied if neurofilament ligth increases in serum prior to PML onset and at time of diagnosis. Furthermore, we evaluated if PML lesion volume on MRI is associated with neurofilament light.
In part V and chapter 11 we summarize our conclusions of this thesis with an extensive discussion of their implications for clinical practice and future studies. An outline is made regarding the future of personalized extended interval dosing with its effects on the life of the patient, economic effects and possible effects on the risk of PML.
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