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`
`Natalizumab: o4-integrin
`antagonist selective adhesion
`molecule inhibitors for MS
`RichardA Rudick' andAlfred Sandrock
`Natalizumab (Antegren™, Elan Corp.plc.; Biogen Idec.)is the first o4-integrin antagonist in
`the class of selective adhesion moleculeinhibitors andis in PhaseIII clinicaltrials for the
`
`IPR2023-00480 Drug Profile
`
`treatmentof multiple sclerosis. After a 300 mg intravenousinfusion, natalizumab has an
`elimination half-life of 6 to 9 days, but «4-integrin receptors expressed on the surface of
`peripheral blood leukocytes are more than 80% saturated approximately 1 month
`postinfusion. Therefore, natalizumab is given as a 300 mg dose administered monthly.
`Preliminary efficacy results showed a marked reduction (~90%)in the formation of new
`gadolinium-enhancinglesions and reduced the numberof patients with relapse by 50% in
`patients with relapsing-remitting or secondary progressive multiple sclerosis receiving
`natalizumabversus those receiving placebo over a 6-monthperiod.In clinical studies,
`natalizumab has demonstrated a favorable safety profile. Pivotal PhaseIII studies of
`natalizumab as monotherapy and in combination with intramuscularinterferon-f-1a are
`underwayin patients with relapsing-remitting multiple sclerosis. Natalizumab may be an
`important addition to the therapeutic armamentarium for multiple sclerosis.
`
`Expert Rev. Neurotherapeutics 4(4), 571-580 (2004)
`
`Multiple sclerosis (MS) is a chronic disease of
`the CNS which causes various symptoms
`including
`sensory
`disturbances,
`unilateral
`optic neuritis, diplopia, limb weakness, clum-
`siness andgait ataxia [1]. Eventually, more trou-
`blesome
`complications
`such as_
`cognitive
`impairment,
`spasticity,
`dysphagia, vertigo,
`pain, sensory loss and sexual dysfunction may
`also appear. The pathological hallmark of MS
`is multiple foci of inflammation accompanied
`by demyelination and varying degrees of
`axonal transection. The presence of gadolin-
`ium-enhancing (Gd+)lesions on magnetic res-
`onance imaging (MRI) indicates current sites
`of presumed inflammatory demyelination [1].
`Goals of pharmacotherapy in MS include
`symptom relief during acute relapses, and the
`prevention of future relapses and disease pro-
`gression. Since a first clinical demyelinating
`event is associated with the developmentofclin-
`ically definite MS when MS-like lesions are
`present on brain MRI scans [2], early interven-
`tion is important and should be considered at
`the timeofthefirst neurological event, especially
`
`© Future Drugs Ltd. All rights reserved. ISSN 1473-7175
`
`in patients with an unfavorable prognosis [3].
`Corticosteroids are standard therapy for the
`treatment of acute relapses due to their immu-
`nomodulatory and anti-inflammatory effects.
`They shorten the duration of the relapse and
`allow for faster recovery [3]. In the Optic Neuri-
`tis Treatment Trial, treatment with intravenous
`methylprednisolone (Medrone®, Pfizer
`Inc.)
`1000 mg/day for 3 days followed by 1 mg/kg of
`oral prednisonefor 11 days was associated with a
`significantly faster recovery compared with oral
`prednisone alone or placebo for 14 days [4,5].
`After 2 years of follow-up, patients treated with
`intravenous methylprednisolone demonstrated a
`decreased risk of subsequent attacks compared
`with patients treated with prednisone alone [6].
`However, it is unknown whether corticosteroids
`affect the long-term course ofthe disease[3].
`Disease-modifying agents
`(DMAs)
`include
`interferon
`(INF)-B-la
`(Avonex®, Biogen;
`Rebif®, Serono), IFN-B-1b (Betaseron®, Scher-
`ing-Plough), glatiramer acetate (Copaxone®,
`Teva Pharmaceutical
`Industries) and mitox-
`antrone (Novantrone®, Lederle). These agents
`
`Merck 2020
`Merck 2020
`Hopewell v Merck
`Hopewell v Merck
`IPR2023-00480
`
`571
`
`

`

`Rudick & Sandrock
`
`act to prevent or slow the primary events of MS [1,3], with varied
`effects on exacerbation rates, progression of disability, and
`inflammation in the brain as seen on brain MRIscans [7]. In the
`USA and Europe, IFN-B is used as first-line standard clinical
`therapy for relapsing—-remitting MS, galatiramer acetate is also
`used, although not always asfirst-line therapy [1,8]. These agents
`have been shown to reduce the development of new Gd+ lesions
`on MRI and reduce the frequency of new relapses, and IFN-B
`has been shown to decrease the progression of disability [9-14].
`Additional treatment options include immunoglobulin, azathi-
`oprine (Imurek®, GlaxoSmithKline), methotrexate, cyclosporin
`and
`cyclophosphamide
`(Endoxana®, Baxter Oncology),
`although noneof these agents have received marketing approval
`for the treatment of MS from regulatory agencies. These drugs
`are generally considered for patients with relapsing—remitting
`disease who have not responded to IFN-B or glatiramer acetate
`therapy [3]. Many compoundsare in development for MStreat-
`ment, including natalizumab (Antegren™, Elan Corp.plc.; Bio-
`gen Idec.; o4-integrin antibody), alemtuzumab (MabCampath®,
`Schering-Plough;antileukocyte antibody), statins (currently used
`in lipid lowering) and extraneousestrogen [15].
`There is little evidence on which to base treatment deci-
`sions for patients with continued MSdisease activity despite
`the use of currently available DMAs. Although new therapies
`have been introduced in the last 10 years, additional effective
`treatments are needed to slow disease progression, reduce dis-
`ability, and limit
`lesion evolution and irreversible tissue
`destruction [16].
`
`Introductionto natalizumab
`
`Adhesion molecules are involved in the inflammatory demyeli-
`nation process in the CNS. Adhesion molecules and ligands
`expressed on endothelial cells and leukocytes (underthe control
`of proinflammatory cytokines) mediate the entry of activated
`T- and B-lymphocytes and monocytes into the CNS[17]. The
`glycoprotein o4B, integrin (also known as verylate antigen 4) is
`one such adhesion molecule and is expressed on lymphocytes,
`monocytes, mast cells, macrophages, basophils and eosinophils
`but not neutrophils [16]. The expression of o4$1 integrin has
`been shown to be increased after T-cell activation [18]. The
`expression of vascular cell adhesion molecule (VCAM)-1, the
`major ligand for o4B,
`integrin,
`is increased in active CNS
`plaques [18].
`Natalizumab is a recombinant humanized a4-integrin anti-
`body derived from a murine monoclonal antibody (mAb) to
`human o4B, integrin [19]. The murine mAb was humanized by
`complimentarity determining region grafting of the hypervaria-
`ble region of the gene encoding the murine antibody onto a
`human immunoglobulin G4 framework (FIGURE 1)
`[19]. Natali-
`zumabis thefirst &4-integrin antagonist in the class ofselective
`adhesion molecule (SAM) inhibitors.
`Natalizumab binds to o4-integrin on the surface of activated
`T-cells and other mononuclear leukocytes, preventing cellular
`adhesion between the T-cell and the endothelial cell. The disrup-
`tion of cell adhesion molecule interactions results
`in the
`
`leukocyte migration across the
`prevention of mononuclear
`endothelium and into the parenchyma, with a subsequent reduc-
`tion in proinflammatory cytokines [BIOGEN IDEC, DATA ON FILE]. A
`further mechanism of natalizumab may be the suppression of
`ongoing inflammatory reactions in diseased tissues by inhibiting
`the binding of o4-positive leukocytes with osteopontin and
`fibronectin. There are three potential modes ofaction:
`¢ Blockade of migration by blocking adhesion to endothelial
`cells and interaction with extracellular matric proteins
`(eg., fibronectin)
`¢ Blockade of priming by interaction with osteopontin and
`VCAMexpressed on microglial cells and monocytes in situ
`* Induction of apoptosis by blocking interaction of o4-inte-
`gren bearing leukocytes with extracellualr matrix proteins
`(eg., fibronectin)
`Thus, natalizumab may have dual anti-inflammatoryeffects:
`inhibition of recruitment of immunecells into inflamed tissue
`
`and suppression of existing inflammatory activity at the disease
`site. Since natalizumab inhibits the migration of leukocytes
`into gut tissue [BIOGEN IDEC, DATA ONFILE], it is also being inves-
`tigated in inflammatory gastrointestinal conditions such as
`Crohn's disease andulcerative colitis [20-22].
`
`Pharmacokinetic & pharmacodynamicprofile
`Natalizumab consists of recombinant humanized o4-integrin
`antibody and excipient materials (ie, sodium chloride, sodium
`dibasic phosphate heptahydrate, sodium monobasic phosphate
`monohydrate and polysorbate 80}. The current formulation of
`natalizumab is provided in a buffered solution at a concentra-
`tion of 20 mg/ml. The product is stable for 30 months when
`stored at 28°C [BIOGENIDEC,DATA ONFILE].
`
`Pharmacokinetics
`
`The pharmacokinetics of natalizumab were evaluated in a PhaseI,
`randomized, placebo-controlled, dose-escalating trial
`involving
`28 patients 19 to 55 years of age with stable relapsing—remitting
`or secondary progressive MS [19]. Patients were randomized to
`
`
`
`J CDRs \
`
`¢ CDR grafted from Ab
`¢ Human IgG4 framework
`¢ Retainsfull potency
`
`Human IgG4
`framework
`
`Figure 1. Protein structure of natalizumab.
`Ab: Antibody; CDRs: Complementary-determining regions;
`Ig: Immunoglobulin.
`
`572
`
`Expert Rev. Neurotherapeutics 4(4), (2004)
`
`

`

`natalizumab 0.03 mg/kg (n = 3), 0.1 mg/kg (n = 3), 0.3 mg/kg
`(n= 3), 1 mg/kg (n = 6), 3 mg/kg (n = 6) or placebo (n = 7).
`Maximum serum concentrations and area under the curve (AUC)
`values for natalizumab were generally proportional to the admin-
`istered dose, although there was some indication of greater than
`proportional increases at the higher doses. At the lowest dose lev-
`els (0.03 and 0.1 mg/kg), serum natalizumab concentrations rap-
`idly fell below detectable levels after the completion of the infu-
`sion. In contrast, patients receiving natalizumab 1 and 3 mg/kg
`had detectable concentrations for 3 to 8 weeks. At the 3 mg/kg
`dose, mean maximal drug concentrations (C,,,,) of 52.5 pg/ml
`were observed approximately 2h after the dose. The drug con-
`centration time curve was biphasic with a rapid distribution phase
`followed by a prolonged terminal phase. The elimination half-life
`of the 3 mg/kg dose was 4 to 5 days (108.0 + 30.1 h) [19]. The
`pharmacokinetic parameters for the six patients receiving the
`highest natalizumab dose level are summarized in TABLE 1.
`Similar results were obtained in another PhaseI trial evaluat-
`ing single doses of natalizumab 1, 3 and 6 mg/kg or placebo in
`39 patients with relapsing—remitting or secondary progressive
`MS [BIOGEN IDEC, DATA ON FILE]. Natalizumab concentrations
`increased proportionally with the administered dose. Mean
`Cyyax Concentrations were 22, 71 and 152 jig/ml for the 1, 3
`and 6 mg/kg doses, respectively.
`In a Phase II trial, 72 patients with relapsing—-remitting or
`secondary progressive MSreceived two intravenousinfusions of
`natalizumab 3 mg/kg or placebo 28 days apart [17, BIOGEN IDEC,
`DATA ONFILE]. There were no significant differences between the
`first and second doses with respect to pharmacokinetic parame-
`ters, indicating no significant accumulation of the drug. Simi-
`larly, in another Phase II study in which patients received natal-
`izumab 3 or 6 mg/kg every 28 days for 6 months, there was
`minimal accumulation of the drug with multiple dosing as
`assessed by C,,,,, and AUC values. However, the mean half-life
`was slightly higher for the 6 mg/kg dose (262 h) than for the
`3 mg/kg dose (202 h) after multiple dose administrations.
`The effect of coadministration of natalizumab and intramuscu-
`lar IFN-B-1a on the pharmacokinetics and pharmacodynamics of
`both drugs was evaluated in an open-label study of 38 patients
`with relapsing—remitting MS [BIOGENIDEC, DATA ON FILE]. Patients
`were required to have received intramuscular IFN-f-1a forat least
`3 months and to be negative for antiJFN-B-la antibodies.
`Patients received a single intravenous infusion of natalizumab
`3 mg/kg (n = 15) or 6 mg/kg(n = 23). After coadministration of
`natalizumab and intramuscular
`IFN-B-la, pharmacokinetic
`parameters (e.g., AUC,C,,,,, and half-life) for natalizumab were
`similar to those observed in other pharmacokinetic analyses of
`natalizumab monotherapy. In addition, pharmacokinetic (AUC
`and C,,,,,) and pharmacodynamic (8-2 microglobulin and neop-
`terin) parameters for intramuscular IFN-B-la before and after
`administration of natalizumab were not significantly different.
`These results suggest that the pharmacokinetics of natalizumab
`are not altered in the presence of intramuscular IFN-B-la and
`that natalizumab does not affect
`the pharmacokinetics or
`pharmacodynamics of intramuscular IFN-B-1a.
`
`Natalizumab
`
`Table 1. Pharmacokinetic parameters of natalizumab
`after a single intravenous 3 mg/kg dosein six patients
`with relapsing—remitting or secondary progressive
`multiple sclerosis [19].
`
` Parameter Value (mean + standard deviation)
`AUC... (gsh/mi)
`9899.00 + 1285.00
`
`AUCiast (ugeh/ml)
`
`Cmax (ig/ml)
`
`Trax (H)
`
`Clearance (mi/h/kg)
`
`9778.00 + 1380.00
`
`52.50 + 12.00
`
`2.07 + 1.25
`
`0.30 + 0.00
`
`Veg (ml/kg)
`67.10 + 17.10
`Half-life (h) 108.00 + 30.10
`
`
`
`AUC:Area underthe curve; C,,,,: Maximum plasma concentration;
`Tmax: Time to maximum plasma concentration;
`V,: Volumeofdistribution at steady state.
`
`
`
`Pharmacodynamics
`Single natalizumab doses of 1 to 6 mg/kg produce maximal
`saturation (defined as >80% saturation) of o4-integrin recep-
`tors on the surface of lymphocytes 24 h after administration
`[BIOGEN IDEC, DATA ON FILE]. Approximately 90% of patients
`achieve over 80% saturation of o4-integrin receptors after
`natalizumab doses of 3 and 6 mg/kg. Receptor saturation is
`maintained for 1, 3-4 and 6 weeks with natalizumab 1, 3 and
`6 mg/kg, respectively.
`against natalizumab was
`Development of antibodies
`observed in both Phase I and II studies, as may be expected
`with a monoclonal antibody product
`[16,19]. Among the
`21 patients receiving natalizumab in a dose-ranging study,
`noneofthe patients in the lowest dose levels (0.03, 0.1, 0.3,
`1 mg/kg) developed antinatalizumab antibodies [19]. In con-
`trast, three out of six patients receiving natalizumab 3 mg/kg
`developed low and transient antibody levels. In a Phase II
`trial, antibodies against natalizumab were detected in 15 out
`of 142 patients (11%) receiving natalizumab 3 or 6 mg/kg
`[16]. The clinical impact of binding or blocking antibodies
`against natalizumab is currently not known.
`Natalizumab produced increased levels of circulating white
`blood cells
`(i.e.,
`lymphocytes, monocytes and eosinophils)
`although the mean values did not exceed the normal range [16].
`The increase began within the first month of treatment, persisted
`throughoutthe treatment period and subsided after treatment was
`discontinued. This effect is consistent with the mechanism of
`
`action of natalizumab-inhibition of the migration of leukocytes to
`areas of inflammation by binding to o4-integrin receptors. The
`increase in white blood cells did not exceed the upper limit of the
`normal range and does not appear to adversely affect safety.
`
`Pharmacokinetic modeling
`A population pharmacokinetic modeling assessment deter-
`mined that the clearance of natalizumab was only weakly
`
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`
`573
`
`

`

`Rudick & Sandrock
`
`related to body weight over the range of 40 to 100 kg [BIOGEN
`IDEC, DATA ON FILE]. Pharmacodynamic data also indicate that
`the 3 and 6 mg/kg monthly doses maintain adequate saturation
`of the a4-integrin receptor in approximately 90% of patients
`with MS.In addition, this analysis found that there is a plateau
`effect for efficacy at total doses of 300 mg or more. Based on
`these data, the mg/kg dosing schedulesusedin early clinical tri-
`als were considered unnecessary. Therefore, ongoing PhaseIII
`trials use a fixed 300 mg dose. In a pharmacokinetic study of a
`single dose of natalizumab 300 mg administered by intravenous
`infusion over 60 minin healthy volunteers (n = 65), mean con-
`centration of natalizumab and o,4-integrin receptor saturation
`over time were similar to those observed with mg/kg dosing
`(FIGURE 2) [BIOGEN IDEC, DATA ONFILE].
`
`Clinicaltrials
`Phase | studies
`
`Four dose-ranging Phase I studies were completed aspart of the
`natalizumab MSclinical development program to gather data
`on the pharmacokinetic, pharmacodynamic andsafety profile
`of the drug. One study was conducted in healthy volunteers
`while the other three evaluated natalizumab in patients with
`either relapsing—remitting or secondary progressive MS.Intra-
`venous doses of natalizumab 0.03-6 mg/kg were assessed. A
`published Phase I study reported that natalizumab waswell-tol-
`erated, with no serious adverse events reported during the study
`[19]. Although the study was not designed to assess efficacy,
`there were no in-study disease exacerbations or any increase in
`disease activity as assessed by MRI.
`
`A
`
`7
`
`0
`
`7
`
`14
`
`21
`
`28
`
`Days postinfusion
`
`90
`go_|
`70
`60
`50
`40
`30
`20
`10
`0
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`
`
`
`Meanconcentration
`
`(ug/ml)
`
`
`
`
`
`Meanpercentagesaturation
`
`{
`
`
`
`Overall, Phase I trials found that natalizumab was very well-
`tolerated, with an overall adverse event profile that did not dif-
`fer significantly from placebo. Pharmacokinetic and pharmaco-
`dynamic results from these studies also helped to identify the
`most appropriate natalizumab doses for use in subsequent
`Phase II and III MStrials.
`
`PhaseII studies
`
`Overall, Phase II studies have demonstrated significant reduc-
`tions in inflammatorylesions, as visualized by MRI, and fewer
`patients with relapse during natalizumab treatment compared
`with placebo. The results of the published Phase II trials are
`summarized in TABLE 2 [16,17].
`In the first randomized, double-blind, placebo-controlled, par-
`allel-group, Phase II study, the safety andefficacy of natalizumab
`was evaluated in 180 patients with relapsing—remitting or sec-
`ondary progressive MS [BIOGEN IDEC, DATA ONFILE]. Patients were
`randomized to a single intravenous infusion of natalizumab
`1 mg/kg (n = 57), 3 mg/kg (n = 60) or placebo (n = 63) during
`the early phase of an acute exacerbation (within 96 h of onset)
`and observed for 14 weeks post treatment. There was nosignifi-
`cant difference in the rate or degree of recovery from the exacer-
`bation, as measured by the Expanded Disability Status Scale
`(EDSS). This finding is not unexpected due to the short treat-
`ment period and is consistent with other studies showing that
`natalizumab doesnotaffect the duration of enhancementin pre-
`existing lesions. A posthoc analysis showeda significant reduction
`in the volume of Gd+lesions in the natalizumab 3 mg/kg group
`and the combined 1 and 3 mg/kg group compared with placebo.
`Given the role of ay integrins in T-cell
`migration and lesion formation and the
`MRI changes produced by natalizumab in
`this trial, further clinical studies evaluating
`multiple
`doses
`of natalizumab were
`considered warranted.
`Tubridy and colleagues conducted a
`randomized, double-blind, placebo-con-
`trolled, parallel-group, Phase II study of
`the effect of natalizumab on brain lesion
`activity as detected by MRIin 72 subjects
`with active relapsing—remitting or second-
`ary progressive MS. This
`study was
`described in the pharmacokinetics sec-
`tion [17, BIOGEN IDEC, DATA ONFILE]. Inclu-
`sion criteria included EDSSscores of 2.0
`to 7.0,
`inclusive,
`two or more clinical
`exacerbations within the past 18 months
`and more than 4 weeks since onset of last
`exacerbation. Patients were excluded if
`
`35
`
`42
`
`—7
`
`0
`
`7
`
`14
`
`21
`
`28
`
`Days postinfusion
`
`they had used immunomodulating drugs
`within the past 6 months, used corticos-
`teroids within the past 4 weeks or had a
`normal T2-weighted MRI scan at base-
`line. Patients were randomized to natali-
`zumab 3 mg/kg (n = 37) or placebo
`
`Figure 2. Mean serum concentration (A) and mean percentage saturation of o4-integin
`receptors (B) over time in healthy volunteers (n = 65) after a single 60 min intravenous
`infusion of natalizumab 300 mg.
`
`574
`
`Expert Rev. Neurotherapeutics 4(4), (2004)
`
`

`

`Table 2. Summary of randomizied, double-blind, placebo-controlled, PhaseIl clinical trials evaluating natalizumabin
`multiple sclerosis [16,17].
`
`
`Study
`duration
`
`Drug/dose
`
`Efficacy
`
`
`Ref.
`
`Natalizumab
`
`Patients Patients
`Mean
`Mean
`Timepoint
`
`number of—number of withno new with
`new active
`new Gd+ Gd+ lesions
`relapses
`
`lesions
`lesions
`(%)
`(%)
`
`24 weeks—_-Placebo (n = 35) 12 weeks 3.6 3.3 73.1 NR [17]
`
`
`
`
`
`Natalizumab 3 mg/kg every 28 days x2 (n = 37}
`12 weeks
`51.8
`51.6
`583.6
`NR
`
`
`
`
`
`
`
`
`
`
`24 weeks—_-Placebo (n = 71) 24 weeks 97 9.6 32.0 38 —s[16]
`
`Natalizumab 3 mg/kg every 28 days x6 (n = 68)
`24 weeks
`580.8
`S807
`75.0
`Sig
`Natalizumab 6 mg/kg every 28 days x6 (n = 74)
`24 weeks
`S811
`581
`65.0
`Sig
`
`8p < 0.05.
`Sp < 0.001.
`GD+: Gadolinium-enhancing; NR: Not reported.
`
`
`
`(n = 35), administered as two intravenous infusions 28 days
`apart and were observed for 24 weeks [17]. During the first
`12 weeks post-treatment, the mean cumulative number of new
`active lesions (i.e., the number of new Gd+ lesions plus the
`numberor new or newly enlarging T2 lesions — the primary
`outcome measure) was significantly reduced in patients receiv-
`ing natalizumab versus those receiving placebo (1.8 vs. 3.6;
`p = 0.042). The mean number of new Gd+lesions during the
`first 12 weeks was also lower in the natalizumab group than in
`the placebo group (1.6 vs. 3.3; p = 0.017). In addition, more
`natalizumab-treated patients experienced no new Gd+ lesions
`duringthe first 12 weeks of therapy compared with the placebo
`group (83.6 vs. 73.1%; p = 0.037). However, natalizumab did
`not appearto affect the duration of enhancementoflesions that
`existed prior to treatment.
`There was nostatistically significant difference between
`natalizumab and placebo groups in the incidence of MSexacer-
`bationsin thefirst 12 weeks of the study. However there was a
`difference in the latter 12 weeks of the study (weeks 12-24) in
`favor of placebo [BIOGEN IDEC, DATA ON FILE]. The discrepancy in
`the numberof patients with relapse in the 12-week post-treat-
`ment phase was due to a reduction in relapses in the placebo
`group rather than a true increase in relapses in the Antegren
`group. Disability scales did not show consistent or marked dif-
`ferences for patients receiving natalizumab versus placebo.
`However, this is not surprising, as improvement in disability
`has generally not been observed in trials of DMAs after such a
`short treatment period [9-11].
`Another
`randomized, double-blind, placebo-controlled
`Phase II(b) study was conducted in 26clinical centers in the
`USA, Canada and the UK [16]. Inclusion criteria included
`EDSSscores of 2.0 to 6.5, inclusive, two or more relapses
`within the past 2 years and three or more T2 lesions on
`MRI. Patients were excluded if they had used immunomod-
`ulating drugs within the past 3 months or had an MS
`relapse, or used corticosteroids within 30 days of study
`
`entry. A total of 213 patients with relapsing—remitting or
`secondary progressive MS were randomized to monthly
`intravenous infusions of natalizumab 3 mg/kg (n = 68),
`natalizumab 6 mg/kg (n = 74), or placebo (n= 71)
`for
`6 months. Patients were monitored for adverse events
`throughout the study and for 6 months after cessation of
`study therapy. There were nosignificant differences in base-
`line patient demographics or MRI parameters among the
`three treatment groups.
`The mean number of new Gd+ lesions (the primary out-
`come measure) was 9.6, 0.7 and 1.1 in the placebo and
`natalizumab 3 and 6 mg/kg groups, respectively, over the
`6 months of treatment
`(p < 0.001 for both natalizumab
`doses vs. placebo) [16]. This represented reductions in new
`lesions of 93% with natalizumab 3 mg/kg and 88% with
`natalizumab 6 mg/kg compared with placebo. The differ-
`ence between natalizumab groups was notstatistically sig-
`nificant. The decrease in new Gd+ lesions was evident both
`in patients with relapsing-remitting MS and in those with
`secondary progressive MS. Natalizumab also produceda sig-
`nificant reduction in the numberof newactive lesions (0.8
`and 1.1 for natalizumab 3 and 6 mg/kg, respectively, vs. 9.7
`for placebo; p < 0.001 for both natalizumab doses vs. pla-
`cebo). In addition, both dose levels of natalizumab pro-
`duced substantial reductions in total volume of enhancing
`lesions
`and
`in
`the
`percentage
`of
`scans
`showing
`inflammatoryactivity compared with placebo.
`Although the study was not powered to detectstatistically
`significant differences in clinical parameters, natalizumab
`demonstrated improvements in clinical outcomes.
`In the
`natalizumab groups, there was a reduction of approximately
`50% in the numberofpatients experiencing a relapse com-
`pared with placebo (relapse experienced by 38% ofpatients in
`the placebo group and 19% in each treatmentgroup, p = 0.02
`for both natalizumab doses vs. placebo) [16]. Natalizumab 3
`and 6 mg/kg also significantly improved patients’ sense of
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`

`Rudick & Sandrock
`
`well-being (as measured by a visual analog scale) compared
`with placebo (p = 0.04 and 0.03, respectively). In addition,
`more patients receiving placebo (81%) required intravenous
`methylprednisolone for the treatment of relapse than those
`receiving natalizumab 3 mg/kg (38%; p < 0.001) or 6 mg/kg
`(50%; p = 0.002).
`Additional analyses of these data [16] showed that natalizu-
`mabsignificantly suppresses the evolution of new Gd¢+lesions
`to T1-hypointense lesions [23]. Specifically, compared with
`placebo, natalizumab (3 or 6 mg/kg) significantly decreased
`the proportion of patients with new Gd+ lesions that evolved
`to T1-hypointense lesions (p = 0.01), the proportion of new
`Gd+ lesions that became T1 hypointense (p = 0.045) and the
`odds ratio of converting from Gd+ into T1-hypointense
`lesions (p = 0.031).
`
`PhaseIll studies
`
`SENTINELis a double-blind, placebo-controlled, parallel-
`group, multicenter global study designed to determine theeffi-
`cacy and safety of natalizumab when added to a standard regi-
`men of intramuscular IFN-B-1a in a relapsing—remitting MS
`patient population that experienced breakthrough disease
`(defined as >1 relapse within 12 months of study enrollment)
`while on intramuscular
`IFN-B-la therapy for at
`least
`12 months [26]. A total of 1196 patients were randomized 1:1
`to natalizumab 300 mgor placebo intravenous infusions every
`4 weeks in addition to their current IFN-B-1a regimen (30 pg
`intramuscular weekly) for up to 116 weeks. Inclusion criteria
`included 18 to 55 years of age, an MS diagnosis (McDonald
`criteria,
`types 1-4)
`[25],
`a baseline EDSS score 0.0-5.0
`(inclusive),
`treatment with intramuscular
`IFN-B-la
`for
`12 months or longer prior to randomization and MRIlesions
`consistent with MS. Patients with primary progressive, second-
`ary progressive or progressive relapsing MS, those with relapse
`within 50 days of randomization or unstable from prior relapse
`and those receiving treatment with any IFN product aside from
`intramuscular IFN-B-1a within 12 months of randomization or
`treatment with oral glatiramer acetate within 3 months of
`randomization were excluded (26, BIOGEN IDEC, DATA ONFILE].
`Theprimary efficacy outcomes of SENTINELaretherate of
`clinical relapse at year 1 and sustained disability progression as
`assessed with the EDSSat year 2. Secondary measuresat year 1
`are the numberof new or enlarging T2 hyperintense lesions,
`the number of Gd+ lesions and the proportion of relapse-free
`subjects. Secondary measures at year 2 are therate ofrelapse,
`the volume of T2 hyperintense lesions, the number of T1
`hypointense lesions and the progression of disability assessed
`with the MSFC scale [BIOGEN IDEC, DATA ON FILE]. Additional
`end points include the assessment of quality of life, cognitive
`changes and brain parenchymal fraction. Safety assessments
`include laboratory testing, physical examinations and adverse
`event monitoring.
`
`There are two ongoing PhaseIII clinical trials - AFFIRM and
`SENTINEL — designed to confirm the safety and efficacy of
`natalizumab alone (AFFIRM) or in combination with intra-
`muscular IFN-B-la (SENTINEL)
`in patients with relaps-
`ing-remitting MS. These 2-year trials are scheduled to be
`completed in late 2004 and early 2005,respectively.
`AFFIRM is a double-blind, placebo-controlled, parallel-
`group, global study designed to evaluate the efficacy and
`safety profile of natalizumab over 2 years in patients with
`relapsing—remitting MS [24]. Patients 18 to 50 years of age
`with a diagnosis of MS (McDonaldcriteria, 1-4) [25], a base-
`line EDSS score 0.0-5.0 (inclusive), one or more relapse
`within the past 12 months and MRIlesions consistent with
`MSwereeligible for inclusion. Exclusion criteria included
`primary progressive, secondary progressive or progressive
`relapsing MS, relapse within 50 days of randomization or
`unstable from prior relapse; treatment with IFN-8 orglati-
`ramer acetate for 6 months or more, treatment with IFN-f,
`glatiramer acetate, cyclosporin, azathioprine, methotrexate,
`Postmarketing surveillance, safety & tolerability
`or immunoglobulin within the past 6 months; and treat-
`Natalizumab is not currently approved by any regulatory
`ment with cyclophosphamide or mitoxantrone within the
`last year. A total of 942 patients were randomized (2:1) to
`agency for human use. Therefore,it’s use is restricted to clinical
`natalizumab 300 mg or placebo intravenous infusion every
`trials and no postmarketing data are available.
`Currently, natalizumab has been administered to over
`4 weeks for up to 116 weeks[24].
`2800 patients, including healthy volunteers, patients with MS
`The primary efficacy outcomes of AFFIRM are therate of
`clinical relapse at year 1 and sustained disability progression
`and those with inflammatory bowel disease [BIOGEN IDEC, DATA
`as assessed with the EDSSat year 2 [24]. Secondary measures
`ON FILE]. In PhaseI trials evaluating single intravenous doses of
`at year 1 are the number of Gd+ lesions, the number of new
`natalizumab, treatment was well-tolerated. There were noclini-
`or enlarging T2 hyperintense lesions and the proportion of
`cally apparent changes in vital signs, laboratory values, or elec-
`relapse-free subjects. Secondary measuresat year 2 are the rate
`trocardiograph measurements. Most of the adverse events were
`of relapse, the number of T1 hypointense lesions, the volume
`mild in severity with headache and fatigue being the mostfre-
`quently reported events. Only one serious adverse event was
`of T2 hyperintense lesions and the progression of disability
`reported in PhaseI trials (i.e., MS exacerbation and depression
`assessed with the Multiple Sclerosis Functional Composite
`requiring hospitalization), although this event was considered
`(MSFC) scale [BIOGEN IDEC, DATA ON FILE]. Additional end
`unrelated to natalizumab. In PhaseItrials with a placebo com-
`points include the assessment of quality of life, cognitive
`changes and brain parenchymal fraction. Safety assessments
`parator, no differences were noted between placebo andnatali-
`include laboratory testing, physical examinations and adverse
`zumabin the proportion of patients with an adverse event or a
`laboratory abnormality [19, BIOGEN IDEC, DATA ONFILE].
`event monitoring.
`
`576
`
`Expert Rev. Neurotherapeutics 4(4), (2004)
`
`

`

`
`
`Table 3. Adverse events reported among patients with
`relapsing-remitting or relapsing secondary progressive
`multiple sclerosis receiving natalizumab 3, 6 mg/kg or
`placebo every 28 days for 6 months[16].
`
`Adverse event
`
`Placebo Natalizumab Natalizumab
`(n = 71)
`3 mg/kg
`6 mg/kg
`
`(n = 68)
`(n = 74)
`40
`27
`
`Headache
`
`38
`
`Infection
`
`Urinary tract infection
`
`Accidental injury
`
`Pharyngitis
`
`Myasthenia
`Paresthesia
`
`Rash
`
`Pruritis
`
`Back pain
`
`Diarrhea
`
`Sinusitis
`
`15
`
`15
`
`7
`
`11
`
`15
`13
`
`8
`
`10
`
`8
`
`6
`
`4
`
`22
`
`22
`
`16
`
`15
`
`18
`13
`
`10
`
`12
`
`4
`
`10
`
`10
`
`19
`
`18
`
`18
`
`22
`
`9
`16
`
`11
`
`5
`
`12
`
`3
`
`4
`
`Similar results were reported in Phase II trials; natalizu-
`mab was well-tolerated, with no overall difference in the
`number of adverse events occurring in the placebo and
`natalizumab groups [16,17, BIOGEN IDEC, DATA ONFILE]. In one
`study involving patients receiving once-monthly infusions of
`natalizumab 3 mg/kg (n = 68), 6 mg/kg (n = 74), or placebo
`(n = 71)
`for a period of 6 months,
`the most frequently
`reported events were headache,
`infection, urinary tract
`infection, accidental
`injury, pharyngitis, myasthenia and
`paresthesia (TABLE3) [16]. There were 20 serious adverse events
`among 15 participants in the study,
`including 11 events
`among seven patients in the placebo group,
`five events
`amongfive patients in the natalizumab 3 mg/kg group and
`four events amongthree patients in the natalizumab 6 mg/kg
`group. There were four immune-mediated events considered to
`be related to study medication but these events occurred in
`less than one out of 250 infusions. In the second published
`Phase II trial, there was no significant difference between
`patients receiving natalizumab or placebo with