The Evolution of Chemotherapeutic Agents in the Treatment of Multiple Sclerosis A Critical, Evidence-Based Review of the Safety and Efficacy of Emerging

The Evolution of The Evolution of Chemotherapeutic Agents in Chemotherapeutic Agents in

the the Treatment of Multiple Treatment of Multiple

SclerosisSclerosis

A Critical, Evidence-Based Review of A Critical, Evidence-Based Review of the Safety and Efficacy of Emerging the Safety and Efficacy of Emerging

TherapiesTherapiesDouglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhD

Associate ProfessorAssociate ProfessorDepartment of NeurologyDepartment of Neurology

Wake Forest University Baptist Medical CenterWake Forest University Baptist Medical CenterWinston-Salem, NCWinston-Salem, NC

New Dimensions and New Dimensions and Landmark Practice AdvancesLandmark Practice Advances

““Chemotherapeutic” Chemotherapeutic”

► Nonspecific cytotoxic agents that kill cells Nonspecific cytotoxic agents that kill cells via a mechanism that involves impairment via a mechanism that involves impairment of cell divisionof cell division

► Usually mediated by an effect on DNA or Usually mediated by an effect on DNA or RNA synthesisRNA synthesis

► Through this mechanism such agents kill T-Through this mechanism such agents kill T-cells, B-cells, and macrophages thus cells, B-cells, and macrophages thus impairing an immune response against a impairing an immune response against a wide variety of stimuliwide variety of stimuli

► Immunosuppressive agents that also Immunosuppressive agents that also increase the risk of infection through the increase the risk of infection through the nonspecific suppression of immune nonspecific suppression of immune functionfunction

The Search for a TreatmentThe Search for a Treatment

► Early on there were no treatments for MSEarly on there were no treatments for MS► Other disciplines (rheumatology) adopted Other disciplines (rheumatology) adopted

the use of chemotherapeutic agents to the use of chemotherapeutic agents to treat autoimmune diseasestreat autoimmune diseases

► MS thought by many to be autoimmune in MS thought by many to be autoimmune in naturenature

► Investigators in the MS field considered Investigators in the MS field considered the use of these agentsthe use of these agents

► Early study designs were flawed and some Early study designs were flawed and some doubted the effectiveness of these agentsdoubted the effectiveness of these agents

Benefits vs. Risk of Benefits vs. Risk of Chemotherapuetuc AgentsChemotherapuetuc Agents

► Chemotherapies are nonspecific Chemotherapies are nonspecific immunosuppressive agentsimmunosuppressive agents

► Many have well known and very serious Many have well known and very serious side effectsside effects● ImmunosuppressionImmunosuppression● InfectionInfection● HepatoxicityHepatoxicity● Secondary malignancySecondary malignancy

► In the absence of other effective In the absence of other effective treatments the benefits outweighed the treatments the benefits outweighed the risks in those with worsening disabilityrisks in those with worsening disability

Agents that have Been Studied in MSAgents that have Been Studied in MS

► AzathioprineAzathioprine► MethotrexateMethotrexate► CyclophosphamideCyclophosphamide► MycophenylateMycophenylate► MitoxantroneMitoxantrone► CladribineCladribine► CyclosporineCyclosporine

AzathioprineAzathioprine

► Earliest studies date back to 1971Earliest studies date back to 1971► Small poorly controlled trials suggested a Small poorly controlled trials suggested a

modest effect on relapsesmodest effect on relapses► Later controlled trials confirmed an effect on Later controlled trials confirmed an effect on

relapse rate but not disability progressionrelapse rate but not disability progression► Cochrane meta analysis suggested an effect Cochrane meta analysis suggested an effect

on relapse rateon relapse rate► Odds ratio of remaining relapse free on Odds ratio of remaining relapse free on

azathioprine was 1.51 at yr 1, 2.04 at yr 2, azathioprine was 1.51 at yr 1, 2.04 at yr 2, and 1.97 at yr 3and 1.97 at yr 3

Yudkin et. al. 1991Yudkin et. al. 1991

AzathioprineAzathioprine

► Used widely in Europe prior to the Used widely in Europe prior to the introduction of IFNintroduction of IFNββss

► Less popular in the modern era of Less popular in the modern era of immunomodulatory therapyimmunomodulatory therapy

► Studied and used widely as a combination Studied and used widely as a combination therapy in those with a suboptimal therapy in those with a suboptimal response to IFNresponse to IFNββs and galtiramer acatete s and galtiramer acatete (GLAT)(GLAT)

► Use as a monotherapy felt to be suboptimal Use as a monotherapy felt to be suboptimal given potential for longterm toxicitygiven potential for longterm toxicity

Azathioprine in Multiple SclerosisAzathioprine in Multiple Sclerosis

► 354 patients randomized to azathioprine vs. 354 patients randomized to azathioprine vs. placeboplacebo

► Double blinded, 3 yr durationDouble blinded, 3 yr duration► At 3 yrs mean EDSS decreased 0.80 in the At 3 yrs mean EDSS decreased 0.80 in the

placebo and 0.62 in the treated groupplacebo and 0.62 in the treated group► At 3yrs the placebo group had an average of At 3yrs the placebo group had an average of

2,5 relapse while the azathioprine group had 2,5 relapse while the azathioprine group had an average of 2.2 relapses (ns)an average of 2.2 relapses (ns)

► Results showed a very small benefit Results showed a very small benefit ► Could not be recommended for most patients Could not be recommended for most patients

with MSwith MSLancet. 1988; 23:179-183Lancet. 1988; 23:179-183

Effect of Azathioprine on MRI Metrics Effect of Azathioprine on MRI Metrics

► 14 patients with at least three gd(+) lesions within 14 patients with at least three gd(+) lesions within 6 months6 months

► Azathioprine dosed up to 3mg/kg daily depending Azathioprine dosed up to 3mg/kg daily depending on lymphocyte countson lymphocyte counts

► Evaluation for six months before treatment and six Evaluation for six months before treatment and six months of treatmentmonths of treatment

► Reduction of greater than 50% observed in 12 of 14 Reduction of greater than 50% observed in 12 of 14 patientspatients

► Reduction of greater than 50% or more in new T2 Reduction of greater than 50% or more in new T2 lesionslesions

► Azathioprine reduced new MS brain lesionsAzathioprine reduced new MS brain lesions

Massacesi, et. al. 2005Massacesi, et. al. 2005

Toxicity of AzathioprineToxicity of Azathioprine

► Bone marrow suppression Bone marrow suppression ● LeukopeniaLeukopenia● LymphopeniaLymphopenia● ThrombocytopeniaThrombocytopenia

► Increased risk of infectionIncreased risk of infection► HepatotoxicityHepatotoxicity► Malignancy risk increased with duration of Malignancy risk increased with duration of

exposureexposure● Solid organ tumors, myelodysplastic Solid organ tumors, myelodysplastic

syndromes, epitheliomas, skin cancersyndromes, epitheliomas, skin cancer

La Mantia 2007, Confravreux 1996La Mantia 2007, Confravreux 1996

CyclophosphamideCyclophosphamide

► Early studies suggested a possible effect in Early studies suggested a possible effect in secondarily progressive MS and rapidly secondarily progressive MS and rapidly progressive MSprogressive MS

► Conflicting results of several trials led to Conflicting results of several trials led to controversy as to whether it was effective controversy as to whether it was effective at allat all

► Some believed it was highly effective and Some believed it was highly effective and others felt it to be ineffective and others felt it to be ineffective and dangerousdangerous

► Both were right. It depended on whether Both were right. It depended on whether the extent of the inflammatory process the extent of the inflammatory process present present

Hauser et. al. Weiner et. al. 1993 Hauser et. al. Weiner et. al. 1993

Northeast Cooperative MS Treatment Northeast Cooperative MS Treatment GroupGroup

► RandomizedRandomized● Standard vs modified inductionStandard vs modified induction● Induction only vs induction + Induction only vs induction +

maintenancemaintenanceIV CTX (700 mg/mIV CTX (700 mg/m22) bimonthly) bimonthly

► InductionInduction● IV CTX (600 mg/mIV CTX (600 mg/m22) days 1, 2, 4, 6, 8) days 1, 2, 4, 6, 8● IV ACTH for 14 daysIV ACTH for 14 days

► MaintenanceMaintenance● IV CTX (700 mg/mIV CTX (700 mg/m22) bimonthly) bimonthly

Weiner et. al. 1993Weiner et. al. 1993

NE NE CooperativeCooperative Study Study

Percentage Stable/Improved on DSSPercentage Stable/Improved on DSS

Months on StudyMonths on Study

66 1212 1818 2424 3030 3636

Induct (20)Induct (20) 75%75% 56%56% 46%46% 24%24% 17%17% 15%15%

Boosters (127)Boosters (127) 71%71% 55%55% 48%48% 38%38% 27%27% 20%20%

P valueP value 0.760.76 0.710.71 0.610.61 0.040.04 0.040.04 0.140.14

NE Cooperative StudyNE Cooperative Study

Months on Study, with MaintenanceMonths on Study, with Maintenance

66 1212 1818 2424 3030 3636

Younger (<41)Younger (<41) 81%81% 62%62% 57%57% 42%42% 40%40% 28%28%

Older (>41)Older (>41) 60%60% 47%47% 40%40% 34%34% 14%14% 21%21%

P valueP value 0.020.02 0.130.13 0.100.10 0.180.18 0.010.01 0.050.05

CytoxanCytoxan

► Factors effecting response to Factors effecting response to therapytherapy● Younger ageYounger age● Rapidly progressive courseRapidly progressive course● Relapses in the year before Relapses in the year before

therapytherapy● <2yrs in the progressive phase<2yrs in the progressive phase● Enhancing lesions on T1+GdEnhancing lesions on T1+Gd

Canadian Cooperative TrialCanadian Cooperative Trial

► CP-MSCP-MS► EDSS 4.0-6.5 and increase EDSS 4.0-6.5 and increase >>1.0 step 1.0 step

prior 1 yearprior 1 year► RandomizedRandomized

● IVCTX + prednisoneIVCTX + prednisone 5555● PlEx + POCTX + prednisonePlEx + POCTX + prednisone 5757● Sham PlEx + placebo po medsSham PlEx + placebo po meds 5656

► Blinded examining neurologistBlinded examining neurologist

Lancet 337:441, 1991Lancet 337:441, 1991


► Randomized, placebo-controlledRandomized, placebo-controlled

► Clin-def, CP MSClin-def, CP MS

► EDSS 4.0-6.5EDSS 4.0-6.5

► Worsening on EDSS Worsening on EDSS >>1.0 steps prior 1.0 steps prior 12M12M

► Non-blinded monitoring neurologistNon-blinded monitoring neurologist

► Blinded examining neurologistBlinded examining neurologist

Lancet 337:441, 1991Lancet 337:441, 1991


► CTX group (n=55)CTX group (n=55)● IV CTX 1 gm QOD until WBC<4.5 up to 9 IV CTX 1 gm QOD until WBC<4.5 up to 9

gmgm● Prednisone 40 mg qD x 10 then taper over Prednisone 40 mg qD x 10 then taper over

6 d6 d

► PlEx group (n=57)PlEx group (n=57)● PlEx qW for 20 wkPlEx qW for 20 wk● PO CTX 1.5-2.0 mg/kg/d for 22 wkPO CTX 1.5-2.0 mg/kg/d for 22 wk● Prednisone 20 mg QODPrednisone 20 mg QOD

► Placebo group (n=56)Placebo group (n=56)● Sham PlEx, PO CTX placebo, Prednisone Sham PlEx, PO CTX placebo, Prednisone

placeboplaceboLancet 337:441, 1991Lancet 337:441, 1991

Canadian Cooperative TrialCanadian Cooperative TrialResultsResults

No significant differences in:No significant differences in:

► Rate of failure (increase in EDSS Rate of failure (increase in EDSS >>1.0 sustained for 6 months)1.0 sustained for 6 months)

► Proportions improved, stable, worse Proportions improved, stable, worse at each visit up to 36 monthsat each visit up to 36 months

► Mean change in EDSSMean change in EDSS

Lancet 337:441, 1991Lancet 337:441, 1991

► Proportion of treatment failuresProportion of treatment failures● CTXCTX 35%35%● PlExPlEx 32%32%● PlacPlac 29%29%

► Mean time to treatment failure Mean time to treatment failure (months)(months)● CTXCTX 24.8 24.8 ++ 7.6 7.6● PlExPlEx 29.3 29.3 ++ 10.9 10.9● PlacPlac 20.6 20.6 ++ 9.5 9.5


Lancet 337:441, 1991Lancet 337:441, 1991

CTX vs placebo p=0.295CTX vs placebo p=0.295


M12 M12 vs. baselinevs. baseline

ImprovedImproved StableStable WorseWorse

IVCTXIVCTX 3 (6%)3 (6%) 38 (79%)38 (79%) 7 (15%)7 (15%)

PIExPIEx 4 (8%)4 (8%) 39 (81%)39 (81%) 5 (10%)5 (10%)

PlaceboPlacebo 1 (2%)1 (2%) 35 (73%)35 (73%) 12 (25%)12 (25%)

Lancet 337:441, 1991Lancet 337:441, 1991



M24M24 vs. baseline vs. baseline


IVCTXIVCTX 2 (6%)2 (6%) 13 (42%)13 (42%) 16 (52%)16 (52%)

PIExPIEx 1 (3%)1 (3%) 25 (81%)25 (81%) 5 (16%)5 (16%)

PlaceboPlacebo 00 20 (67%)20 (67%) 10 (33%)10 (33%)

Lancet 337:441, 1991Lancet 337:441, 1991



M36M36 vs. baseline vs. baseline


IVCTXIVCTX 2 (4%)2 (4%) 24 (44%)24 (44%) 28 (52%)28 (52%)

PIExPIEx 1 (2%)1 (2%) 34 (59%)34 (59%) 22 (39%)22 (39%)

PlaceboPlacebo 1 (2%)1 (2%) 32 (59%)32 (59%) 21 (39%)21 (39%)

Lancet 337:441, 1991Lancet 337:441, 1991

Kaiser StudyKaiser Study

► CP-MS (EDSS 3.0-8.0)CP-MS (EDSS 3.0-8.0)► Increased EDSS or AI Increased EDSS or AI >>1 step 1 step

prior 1 yearprior 1 year► RandomizedRandomized

● IV CTXIV CTX 2222● PlaceboPlacebo 2020

► Single-blindSingle-blind

Likosky WH et al. JNNP 54:1055, 1991Likosky WH et al. JNNP 54:1055, 1991

Kaiser StudyKaiser StudyResultsResults

* based on EDSS change of * based on EDSS change of >>1.0 step1.0 step

EDSS Stable or Improved*EDSS Stable or Improved*

CTXCTX PlaceboPlacebo

12 Months12 Months 14/22 (64%)14/22 (64%) 14/20 (70%)14/20 (70%)

24 Months24 Months 9/19 (47%)9/19 (47%) 9/17 (53%)9/17 (53%)


Kaiser StudyKaiser StudyResultsResults

Mean Mean EDSSEDSSPlacebo-Placebo-CTX CTX

(95% CI)(95% CI)MonthMonth CTXCTX PlaceboPlacebo

0 to 120 to 12 0.500.50 0.530.53 0.03 (-0.60 to 0.03 (-0.60 to 0.65)0.65)

0 to 180 to 18 0.380.38 0.730.73 0.35 (-0.40 to 0.35 (-0.40 to 1.10)1.10)

0 to 240 to 24 0.580.58 0.970.97 0.39 (-0.45 to 0.39 (-0.45 to 1.23)1.23)


Spectrum of Disease ActivitySpectrum of Disease Activity

► Early inflammatory process with frequent Early inflammatory process with frequent relapse and “apparent” progression may relapse and “apparent” progression may appear “progressive”appear “progressive”

► Usually accompanied by numerous Usually accompanied by numerous enhancing lesions and rapidly increasing enhancing lesions and rapidly increasing T2 lesion burdenT2 lesion burden

► Late stage secondary progression related Late stage secondary progression related to a poorly understood degenerative to a poorly understood degenerative process process

► Infrequent enhancing lesions and little Infrequent enhancing lesions and little evidence of progression on MRI evidence of progression on MRI

► These forms of disease differ in their These forms of disease differ in their response to treatmentresponse to treatment

Relapsing-remittingRelapsing-remitting

Secondary-progressiveSecondary-progressive

PreclinicalPreclinical

TimeTime

Natural History of MSNatural History of MS

Measures of brain volumeMeasures of brain volumeRelapses and impairmentRelapses and impairmentMRI burden of diseaseMRI burden of diseaseMRI activityMRI activity

Reconciliation of Early Studies on the Use of Reconciliation of Early Studies on the Use of Cyclophosphamide and Mitoxantrone in MSCyclophosphamide and Mitoxantrone in MS

► Many early studies probably included patients Many early studies probably included patients with very active inflammation that led to the with very active inflammation that led to the appearance of progressive disease appearance of progressive disease

► The reality was that the dynamics of disease in The reality was that the dynamics of disease in these patients was characterized by active these patients was characterized by active inflammation inflammation

► The Canadian cooperative trial and the Kaiser trial The Canadian cooperative trial and the Kaiser trial probably included a greater proportion of patients probably included a greater proportion of patients with primary progressive MS and true secondary with primary progressive MS and true secondary progressionprogression

► CPM was effective in those with an active CPM was effective in those with an active inflammatory component but not in those with inflammatory component but not in those with slowly progressive degeneration observed in true slowly progressive degeneration observed in true secondary progressionsecondary progression

CyclophosphamideCyclophosphamidePotential Adverse EffectsPotential Adverse Effects

Acute:Acute: Chronic:Chronic:

Nausea / malaiseNausea / malaise InfertilityInfertility

AlopeciaAlopecia Pulmonary Pulmonary fibrosisfibrosis

Hemorrhagic cystitisHemorrhagic cystitis MyocarditisMyocarditis

MyelosuppressionMyelosuppression MalignancyMalignancy

InfectionInfection

MitoxantroneMitoxantrone

► An anthracenedione related to An anthracenedione related to dauxorubicin with potent dauxorubicin with potent immunosuppressive effects immunosuppressive effects

► Intercalates DNA and blocks the Intercalates DNA and blocks the synthesis of RNAsynthesis of RNA

► Inhibits topoisomeraseInhibits topoisomerase

► Potent effects on B-cell and T-cell Potent effects on B-cell and T-cell functionfunction

► Inhibits both passive and active EAEInhibits both passive and active EAE

Clinical Trials of Mitoxantrone in MSClinical Trials of Mitoxantrone in MS

► Early trials produced slightly conflicting Early trials produced slightly conflicting results and employed dose regimens that results and employed dose regimens that differed considerablydiffered considerably

► This may have been due to the patient This may have been due to the patient populations studiedpopulations studied

► What emerged was a marked reduction in What emerged was a marked reduction in relapse rate and a reduction in enhancing relapse rate and a reduction in enhancing lesion frequencylesion frequency

► Suggesting that MITX might be useful in Suggesting that MITX might be useful in rapidly progressive forms of MS rapidly progressive forms of MS characterized by active inflammatory characterized by active inflammatory disease disease

Methylprednisolone and Mitoxantrone in Methylprednisolone and Mitoxantrone in MS (MP+M): Trial DesignMS (MP+M): Trial Design

TriageTriage

M -2M -2 M -1M -1 M 0M 0

M 1M 1 M 2M 2 M 3M 3 M 4M 4 M 5M 5 M 6M 6

M 1M 1 M 2M 2 M 3M 3 M 4M 4 M 5M 5 M 6M 6

Randomized TreatmentRandomized Treatment

Mitoxantrone 20 mg/mo IV +Mitoxantrone 20 mg/mo IV +Methylprednisolone 1 g/mo IVMethylprednisolone 1 g/mo IV

Methylprednisolone 1 g/mo IVMethylprednisolone 1 g/mo IV

Edan et al. 1997.

MP+M: Lower Incidence of MP+M: Lower Incidence of New MRI LesionsNew MRI Lesions

Percentage of Patients Developing New Gd-Enhancing LesionsPercentage of Patients Developing New Gd-Enhancing Lesions

MP (N = 21)

MP+M (N = 21)

0

20

40

60

80

100

Pat

ien

ts (

%)

-1 0 1 2 3 654Months

*

†‡ §

86%Reduction

*P = .009†P = .030‡P = .033§P = .001

MP+M: Slower Progression of MP+M: Slower Progression of Neurologic DisabilityNeurologic Disability

Pat

ient

sP

atie

nts

(%)

(%)

(N = 12)

(N = 8)

(N = 6)

(N = 3)

(N = 1)

(N = 12)

Confirmed EDSS 1-Point Variation* Between Confirmed EDSS 1-Point Variation* Between Patient Inclusion and End of StudyPatient Inclusion and End of Study

*EDSS changes from 6.0-6.5 and from 6.5-7.0 were considered equivalent to 1-point change. The 1-point variation was measured for 2 months running at the end of the study.Edan et al. 1997.

P<.01

Mitoxantrone and IVMP in RPMS Mitoxantrone and IVMP in RPMS Relapse AssessmentRelapse Assessment

Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62:112-118.

IVMPIVMP

(n=21)(n=21)

Mito + Mito + IVMPIVMP

(n=21)(n=21)P-valueP-value

Baseline annualized Baseline annualized relapse raterelapse rate 2.92.9 3.13.1 NSNS

On study annualized On study annualized relapse raterelapse rate 3.03.0 0.70.7 0.0030.003

Patients free of relapses Patients free of relapses on studyon study 7 (33%)7 (33%) 14 (67%)14 (67%) 0.0310.031

MP+M: ConclusionsMP+M: Conclusions

► Addition of mitoxantrone to Addition of mitoxantrone to methylprednisolone significantlymethylprednisolone significantly

● Reduced new MRI lesionsReduced new MRI lesions● Slowed the progression of neurologic disabilitySlowed the progression of neurologic disability● Reduced relapse rateReduced relapse rate

Edan et al. 1997.

Mitoxantrone in Multiple Sclerosis Mitoxantrone in Multiple Sclerosis (MIMS): Study Design(MIMS): Study Design

► 2-year, double-blind, multicenter, placebo 2-year, double-blind, multicenter, placebo controlledcontrolled

► 194 patients, 18-55 years, EDSS 3-6 194 patients, 18-55 years, EDSS 3-6

► Treatment armsTreatment arms● Mitoxantrone 5 mg/mMitoxantrone 5 mg/m22, IV, q3mo, IV, q3mo● Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22, IV, q3mo, IV, q3mo● PlaceboPlacebo

MIMS DesignMIMS Design

Rx every 3 months x 24 monthsFollow up at Month 36

PlaceboPlacebo

Mitoxantrone 5 mg/mMitoxantrone 5 mg/m22

Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22

RRAANNDDOOMMIIZZEE

Hartung, H.P. et al. The Lancet 2002. v360 2018-2025

MIMS StudyMIMS StudyInclusion and Exclusion CriteriaInclusion and Exclusion Criteria

► Age 18 to 55Age 18 to 55► Definite MS (Poser’s Definite MS (Poser’s

criteria)criteria)► Secondary progressive Secondary progressive

or remitting progressive or remitting progressive MSMS(worsening RRMS)(worsening RRMS)

► EDSS progression EDSS progression 1 point in preceding 1 point in preceding 18 months18 months

► Baseline EDSS from Baseline EDSS from 3.0-6.03.0-6.0

► Benign or primary Benign or primary progressive MSprogressive MS

► Relapse or treatment Relapse or treatment with corticosteroids in with corticosteroids in precedingpreceding8 weeks8 weeks

► Prior treatment with Prior treatment with NOVANTRONENOVANTRONE®®

► Immunosuppressive Immunosuppressive therapytherapyin preceding 9 monthsin preceding 9 months

► Cardiac risk factorsCardiac risk factors► Major medical illnessMajor medical illness

Inclusion CriteriaInclusion Criteria Exclusion CriteriaExclusion Criteria

Hartung, H.P. et al. The Lancet 2002. v360 2018-2025

MIMS Baseline Demographics* (1)MIMS Baseline Demographics* (1)

* No significant differences between the 3 * No significant differences between the 3 groupsgroups

Hartung, H.P. et al. The Lancet 2002. v360 2018-2025Hartung, H.P. et al. The Lancet 2002. v360 2018-2025

PlaceboPlacebo(n=64)(n=64)

Mitox 5Mitox 5(n=64)(n=64)

Mitox 12Mitox 12(n=60)(n=60)

Male/Female (%)Male/Female (%) 52/4852/48 39/6139/61 53/4753/47

Mean age (years)Mean age (years) 4040 4040 4040

Type of MSType of MS

Remittent progressive (%)Remittent progressive (%) 4545 5858 4747

Secondary progressive (%)Secondary progressive (%) 5555 4242 5353

Mitoxantrone Efficacy at 2 Years: Mitoxantrone Efficacy at 2 Years: Primary Efficacy VariablesPrimary Efficacy Variables

NR=not reached within 24 months.NR=not reached within 24 months.

Placebo Placebo (n=64)(n=64)

Mitoxantrone Mitoxantrone 12 mg/m12 mg/m22

(n=60)(n=60)

P-value P-value Mitoxantrone Mitoxantrone 12 mg/m12 mg/m22 vs. vs.

PlaceboPlacebo

Multivariate primary efficacy Multivariate primary efficacy criterioncriterion <0.0001<0.0001

EDSS change (mean)EDSS change (mean) 0.230.23 -0.13-0.13 0.01940.0194

Mean no. of treated relapsesMean no. of treated relapses 1.201.20 0.400.40 0.00020.0002

Time to first treated relapse Time to first treated relapse (median months)(median months) 14.214.2 NRNR 0.00040.0004

SNS change (mean)SNS change (mean) 0.770.77 -1.07-1.07 0.02690.0269


Mean Change in EDSSMean Change in EDSSC

ha

nge

s in

ED

SS

Ch

ang

es

in E

DS

S(m

24 -

Ba

selin

e)

(m24

- B

ase

line

)

† Placebo vs. Mitoxantrone 12 mg/m2

p = 0.0194 †


EDSS >1.0 Point Deterioration EDSS >1.0 Point Deterioration from Baselinefrom Baseline

% o

f p

ati

en

ts

† Placebo vs. Mitoxantrone 12 mg/m2

p = 0.036 †

(N=5)

(N=16)


Time to First Treated RelapseTime to First Treated Relapse

Placebo Mitox 12

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24

p=0.0004†

MonthsMonths† Placebo vs. Mitoxantrone 12 mg/m2

Placebo =14.19 m.

Mitox 12mg not reached


MIMS: Patients WithMIMS: Patients WithNew Gd-Enhancing Lesions New Gd-Enhancing Lesions (N = 110)(N = 110)

P = .02 at Month 24

Pat

ient

s (%

)P

atie

nts

(%)

PlaceboMitoxantrone 12 mg/m2

MonthMonth

12%12%(N = 4)(N = 4)

19%19%(N = 7)(N = 7)

0%

16% 16% (N = 5)(N = 5)

(N = 0)

Significantly Reduced the Change in the Significantly Reduced the Change in the Number of T2-Weighted Lesions vs Number of T2-Weighted Lesions vs

PlaceboPlacebo

Mean Change inMean Change inNumber ofNumber of

T2-Weighted T2-Weighted Lesions at 24 Lesions at 24

MonthsMonths

PlaceboPlacebo(n=32)(n=32)

MitoxantroneMitoxantrone12 mg/m12 mg/m22

(n=28)(n=28)

85%reduction

Potential Adverse Effects of Potential Adverse Effects of MitoxantroneMitoxantrone

► AcuteAcute● AlopeciaAlopecia● MyelosupressionMyelosupression● InfectionInfection● Nausea/vomitingNausea/vomiting● MalaiseMalaise● Discoloration of Discoloration of

sclera sclera ● ArrhythmiaArrhythmia

► ChronicChronic● Cardiac toxicityCardiac toxicity● MalignancyMalignancy● AmenorrheaAmenorrhea● InfertilityInfertility● Fetal malformationFetal malformation

MitoxantroneMitoxantrone

► Approved by the FDA for worsening Approved by the FDA for worsening RR MS, SP MS with relapse, and PR RR MS, SP MS with relapse, and PR MSMS

► Recognized as a rescue therapyRecognized as a rescue therapy

► More dangerous than A,B,C,RMore dangerous than A,B,C,R

► Useful in those failing conventional Useful in those failing conventional therapy or with aggressive disease therapy or with aggressive disease from the outsetfrom the outset

The “Evolution”The “Evolution”

► Much has changed since the advent of Much has changed since the advent of mitoxantronemitoxantrone

► Our understanding of the disease process Our understanding of the disease process and the importance of the inflammatory and the importance of the inflammatory process has grown substantiallyprocess has grown substantially

► Not much has changed regarding the Not much has changed regarding the profiles of the chemotherapeutic agents profiles of the chemotherapeutic agents used and being developedused and being developed

► Cladribine is a perfect example Cladribine is a perfect example

CladrbineCladrbine

Synthetic purine analogue product (adenosine analogue)

Deoxycytidine kinase (phosphorylation)

Affect cellular metabolism, induce DNA damage and apoptosis in dividing and non dividing cells

Reduction of CD4 and CD8 T cells, B cells but also other immune cells such as neutrophils and monocytes

BackgroundBackground

► Approved by FDA for:Approved by FDA for:● Hairy cells leukemiaHairy cells leukemia● Malignant lymphomaMalignant lymphoma

► A few phase 1 and 2 studies have A few phase 1 and 2 studies have been conducted in MS with been conducted in MS with cladribine iv or s/c.cladribine iv or s/c.

► Pregnancy category DPregnancy category D

The FDA has a categorization of drug risks to the fetus that runs from: "Category A" (safest) to "Category X" (known danger--do not use!)

Category A

Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.

Category B

Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).

Category C

Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Category D

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Category X

Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

CLARITY - Treatment RegimenCLARITY - Treatment Regimen

ScreeningScreening1326 1326

randomizedrandomized(1:1:1)(1:1:1)

► Annual short-course treatmentAnnual short-course treatment● Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive

days per monthdays per month● Courses given for 2 or 4 consecutive months in Year 1 and Courses given for 2 or 4 consecutive months in Year 1 and

for 2 consecutive months in Year 2for 2 consecutive months in Year 2

First 48 weeks Second 48 weeksX X X X

X X

X X

••Placebo

Cladribine tables: 4 courses, total dose 3.5 mg/kg

Cladribine tables: 6 courses, total dose 5.25 mg/kg

••

••••••

X

•

Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. April 30, 2009.

Placebocourse

Cladribinecourse

0

0.1

0.2

0.3

0.457.6% reduction

(P < 0.001)

PlaceboPlacebo(n = 437)(n = 437)

CladribineCladribine3.5 mg/kg3.5 mg/kg(n = 433)(n = 433)


Ann

ualiz

ed r

elap

se r

ate

Ann

ualiz

ed r

elap

se r

ate

0.140.14 0.150.15

0.330.33

ITT = intent-to-treat population; error bars indicate upper limit of 95% confidence interval.Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

54.5% reduction (P < 0.001)

Primary Outcome Primary Outcome Reduction in Relapse Rates (ITT)Reduction in Relapse Rates (ITT)

Secondary Outcome Secondary Outcome Reduction in Disability Progression (ITT)Reduction in Disability Progression (ITT)

Time to sustained change for 3 months in EDSS of 1 point (or 1.5 point if baseline EDSS was 0, or 0.5 point if baseline EDSS was 5); CI = confidence interval; *Cox proportional hazards model. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

Pro

port

ion

with

3-m

onth

Pro

port

ion

with

3-m

onth

conf

irmed

ED

SS

pro

gres

sion

(%

)co

nfirm

ed E

DS

S p

rogr

essi

on (

%)

33%33% 31%31%

RelativeRelativereductionreduction

Number of patients at risk:Placebo3.5 mg/kg5.25 mg/kg

437433456

424424447

399407425

373389404

355379388

333364375

315355363

304347350

304347350

Placebo

Cladribine 3.5 mg/kg 0.67 (0.48, 0.93); P = 0.018

Cladribine 5.25 mg/kg 0.69 (0.49, 0.96); P = 0.026

Hazard ratio vs placebo (95% CI)*

–73.4%*–86.8%*

–87.9%*

–74.6%*

–76.9%* –77.9%*

Secondary Outcome Secondary Outcome Improvement in MRI Parameters (ITT)Improvement in MRI Parameters (ITT)

SE = standard error. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

2.00

1.50

1.00

0.50

0

Mea

n ±

SE

lesi

on

s/p

atie

nt/

scan

T1 Gd+ lesions

Active T2lesions

Combined unique lesions

Placebo Cladribine 3.5 mg/kg Cladribine 5.25 mg/kg

*P < 0.001 *P < 0.001 *P < 0.001

0.91

1.43

1.72

0.120.38 0.43

0.11 0.33 0.38

Patients with AE (%)Patients with AE (%)PlaceboPlacebo(n = 435)(n = 435)

CladribineCladribine3.5 mg/kg3.5 mg/kg

(n = 430)(n = 430)

CladribineCladribine5.25 mg/kg5.25 mg/kg

(n = 454)(n = 454)

CladribineCladribineoveralloverall

(n = 884(n = 884))

Any treatment-emergent AEAny treatment-emergent AE

AEs leading to discontinuationAEs leading to discontinuation

AEs leading to withdrawalAEs leading to withdrawal

Serious AEsSerious AEs

Deaths*Deaths*

73.373.3

2.12.1

1.11.1

6.46.4

0.50.5(n = 2)(n = 2)

80.780.7

3.53.5

1.21.2

8.48.4

0.50.5(n = 2)(n = 2)

83.983.9

7.97.9

2.02.0

9.09.0

0.4 0.4 (n = 2)(n = 2)

82.482.4

5.85.8

1.61.6

8.78.7

0.40.4(n = 2)(n = 2)

*Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial *Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardiorespiratory arrest. cardiorespiratory arrest.

AEs = adverse eventsAEs = adverse events

Secondary Outcome Secondary Outcome Safety OverviewSafety Overview

Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Seattle, USA; April 30, 2009.

CD4+ (helper T cells)

CD8+ (cytotoxic T cells)

CD19+ (B cells)

CD19+/CD56+ (natural killer cells)

CladribineCladribine

Guarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55].Guarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55].

Placebo Cladribine 0.7 mg/kg Cladribine 2.1 mg/kg

Depletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS Depletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS and PPMSand PPMS

Cladribine: Effect after 3-5 years on Naïve Cladribine: Effect after 3-5 years on Naïve (CD45RA+) and Memory (CD45RO+) - CD4+ (CD45RA+) and Memory (CD45RO+) - CD4+

Tcells Tcells

Raspadori D, et al. Raspadori D, et al. LeukemiaLeukemia. 1999;13:1254-1257.. 1999;13:1254-1257.

Hairy Cell Leukemia patients were treated with Cladribine (1 mg/kg c.i. for 7 days)

At 3-5 years post dose, there was a decrease in CD4+/CD45RA+ cells while CD4+CD45RO+ cells slightly increased

These findings may suggest that CD4+/CD45RA+ cells are more sensitive than CD4+/CD45RO+ to the toxic effect of cladribine

Laboratory Laboratory testtest StatisticsStatistics

Cladribine 5.25 Cladribine 5.25 mg/kg (n=454)mg/kg (n=454)

n (%)n (%)

Cladribine 3.5 Cladribine 3.5 mg/kg (n=430)mg/kg (n=430)

n (%)n (%)

Placebo Placebo (n=435)(n=435)n (%)n (%)

HaemoglobinHaemoglobin Mean duration (SD) (weeks)Mean duration (SD) (weeks)

Median duration (weeks)Median duration (weeks)

Min;Max duration (weeks)Min;Max duration (weeks)

0 0 (1 total)(1 total) 3 3 (5 total)(5 total)17.5 (6.8)17.5 (6.8)

18.118.1

10.4;24.010.4;24.0

2 2 (3 total)(3 total)13.0 (8.3)13.0 (8.3)

13.013.0

7.1;18.97.1;18.9

WBCWBC Mean duration (SD) (weeks)Mean duration (SD) (weeks)



8 8 (10 total)(10 total)11.8 (10.3)11.8 (10.3)

9.09.0

1.4;29.11.4;29.1

6 6 (6 total)(6 total)3.7 (1.9)3.7 (1.9)

3.43.4

1.6;6.01.6;6.0

2 2 (2 total)(2 total)2.8 (0.9)2.8 (0.9)

2.82.8

2.1;3.42.1;3.4

NeutrophilsNeutrophils Mean duration (SD) (weeks)Mean duration (SD) (weeks)



17 17 (17 total)(17 total)8.1 (9.6)8.1 (9.6)

5.95.9

1.1;42.11.1;42.1

12 12 (12 total)(12 total)5.2 (3.8)5.2 (3.8)

4.94.9

1.0;12.11.0;12.1

17 17 (18 total)(18 total)4.8 (3.1)4.8 (3.1)

4.34.3

1.1;12.11.1;12.1

LymphocyteLymphocyte Mean duration (SD) (weeks)Mean duration (SD) (weeks)



108 108 (203 total)(203 total)29.4 (20.8)29.4 (20.8)

24.124.1

2.9;88.02.9;88.0

52 52 (110 total)(110 total)25.4 (19.8)25.4 (19.8)

23.423.4

0.9;92.70.9;92.7

2 2 (2 total)(2 total)4.6 (0.6)4.6 (0.6)

4.64.6

4.1;5.04.1;5.0

Subject with Resolved Grade 3 and 4 ToxicitySubject with Resolved Grade 3 and 4 ToxicityHematology (resolved = returning to Grade 1 or Hematology (resolved = returning to Grade 1 or

0)0)► App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~ App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~

24 wks24 wks► Almost all other Grade 3 and 4 toxicities resolved on studyAlmost all other Grade 3 and 4 toxicities resolved on study

PS. Sorenson, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 10, 2009; Poster 472.

Adverse Events of Special InterestAdverse Events of Special InterestHerpes ZosterHerpes Zoster

► Herpes zoster was reported more frequently with cladribine Herpes zoster was reported more frequently with cladribine tablets than placebotablets than placebo

● 20 patients had 21 zoster events in the cladribine tablets groups20 patients had 21 zoster events in the cladribine tablets groups

● All 21 cases were self-limiting and dermatomalAll 21 cases were self-limiting and dermatomal

Preferred term, Preferred term, n (%) patients n (%) patients

PlaceboPlacebo (n=435)(n=435)

Cladribine Cladribine 3.5 mg/kg3.5 mg/kg (n=430)(n=430)

Cladribine Cladribine 5.25 mg/kg5.25 mg/kg

(n=454)(n=454)


(n=884)(n=884)

Herpes zoster Herpes zoster 0 0 8 (1.9) 8 (1.9) 11 (2.4) 11 (2.4) 19 (2.1)19 (2.1)

Herpes zoster oticus Herpes zoster oticus 00 00 1 (0.2) 1 (0.2) 1 (0.1)1 (0.1)

Varicella Varicella 1 (0.2)1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.2)2 (0.2)

S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009. S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009.

Adverse Events of Special Interest Adverse Events of Special Interest MalignanciesMalignancies

Preferred term, % (n)Preferred term, % (n) PlaceboPlacebo(n = 435)(n = 435)




(n = 884)(n = 884)

During studyDuring study

Cervix carcinoma Stage 0Cervix carcinoma Stage 0

Malignant melanomaMalignant melanoma

Ovarian cancerOvarian cancer

Pancreatic cancer, Pancreatic cancer, metastaticmetastatic

During post-study surveillance During post-study surveillance

ChoriocarcinomaChoriocarcinoma

00

00

00

00

00

00

0.2 (1)0.2 (1)

0.2 (1)0.2 (1)

0.2 (1)0.2 (1)

00

0.2 (1)0.2 (1)

00

00

00

0.2 (1)0.2 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

CladribineCladribine

Cladribine SummaryCladribine Summary

► Efficacy is comparable to high dose IFNEfficacy is comparable to high dose IFN► Toxicity is considerableToxicity is considerable

● Risk of malignancyRisk of malignancy● Long-term immunosuppressionLong-term immunosuppression● Increased risk of herpes infectionsIncreased risk of herpes infections● InfertilityInfertility● Fetal malformationFetal malformation● Graft vs. hostGraft vs. host

► How long can it be used with CD-4 counts How long can it be used with CD-4 counts markedly reducedmarkedly reduced

► What do you do if patients are worsening?What do you do if patients are worsening?

Evolution?Evolution?

► There has been no evolution!There has been no evolution!► Chemotherapeutic agents remain Chemotherapeutic agents remain

nonselective, broad spectrum cytotoxic nonselective, broad spectrum cytotoxic agents that suppress the immune system in agents that suppress the immune system in a nonspecific fashiona nonspecific fashion

► They all have considerable risk of adverse They all have considerable risk of adverse events that include secondary malignancy, events that include secondary malignancy, infection, infertility, fetal malformation, and infection, infertility, fetal malformation, and other end organ toxicityother end organ toxicity

► Newer monoclonal antibodies and other Newer monoclonal antibodies and other innovative therapies appear equally or more innovative therapies appear equally or more effective and have manageable risk effective and have manageable risk

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