Emerging therapies in multiple
`sclerosis
`
`Martin Duddy
`Royal Victoria Infirmary
`Newcastle upon Tyne
`
`Biogen Exhibit 2124
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 36
`
`
`sclerosis
`
`Martin Duddy
`Royal Victoria Infirmary
`Newcastle upon Tyne
`
`Biogen Exhibit 2124
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 36
`
`
`
`Outline
`
`• what have we got?
`• what would we like?
`• what are we getting?
`
`Page 2 of 36
`
`Page 2 of 36
`
`
`
`Disease modifying therapy
`First line
`
`• Five licensed therapies
`– Interferon-β
`• Avonex
`• Betaferon
`• Extavia
`• Rebif
`– Copaxone
`• Prescribed under ABN
`guidelines
`
`Page 3 of 36
`
`Page 3 of 36
`
`
`
`First line DMTs
`
`Summary of results from pivotal phase 3 trials
`
`Agent
`
`Dosage
`
`Reduction in
`relapses, % †
`
`Relapse-free
`patients, % †
`
`34
`
`32
`
`29
`
`32
`
`29
`
`31
`
`38
`
`27
`
`32
`
`34
`
`Reduction in
`disease
`progression, % †‡
`29
`
`37
`
`23
`
`31
`
`12
`
`Interferon beta-1b
`(Betaferon)
`
`8 mIU (250 µg)
`SC every other
`day
`
`Interferon beta-1a
`(Avonex)
`
`30 µg
`IM once weekly
`
`Interferon beta-1a
`(Rebif)
`
`22 µg
`SC 3 times
`weekly
`
`44 µg
`SC 3 times
`weekly
`
`20 mg
`SC once daily
`
`Glatiramer acetate
`(Copaxone)
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`
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`
`
`
`Adapted from Galetta S, et al. Arch Int Med 2002; 162; 2161-2169
`
`Page 4 of 36
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`Page 4 of 36
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`
`
`Who’s best?
`
`• Betaferon vs Avonex (INCOMIN)
`• Rebif vs Avonex (EVIDENCE)
`• Betaferon vs Copaxone (BEYOND)
`• Rebif vs Copaxone (REGARD)
`• Rebif 44 vs Rebif 22 (PRISMS)
`• Betaferon 500 vs Betaferon 250 (BEYOND)
`• Avonex 60 vs Avonex 30
`• Extavia = Betaferon
`• retrospective audits: QUANTMS
`
`Page 5 of 36
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`Page 6 0f 36
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`Page 6 of 36
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`Page 6 of 36
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`
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`Good things
`about first line
`DMTs
`• they work better than
`placebo
`• 20 years safety data
`• some excellent responders
`
`Not so good
`things about first
`line DMTs
`• →75% relapse within 2 years
`• → 27% worsen by ≥1 point on
`EDSS within 2 years
`• inefficacy in progressive disease
`• route and frequency of
`administration
`• tolerability
`• poor adherence
`• neutralising antibodies
`• cost
`• cost effectiveness
`
`Page 7 of 36
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`Page 7 of 36
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`
`
`Second line DMTs
`
`• mitoxantrone
`
`• natalizumab (Tysabri)
`
`Page 8 of 36
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`Page 8 of 36
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`
`
`Mitoxantrone (MX)
`
`rapidly progressive
`disease with or without
`relapses
`
`Hartung HP et al. Lancet 2002; 360: 2018–25
`
`Page 9 of 36
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`Page 9 of 36
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`
`
`Good things
`about mitox
`
`• relapses ↓62%
`• cheap
`• 1/3 relapse free @ 5 yr
`• ? role in progressive
`disease
`• ? role in induction
`therapy
`
`Not so good
`things about
`mitox
`• trial data questionable
`• benefit for pure progressive
`disease?
`• benefit beyond relapse
`prevention?
`• toxicity
`– cardiomyopathy
`– secondary infertility
`– leukaemia (0.5-2%)
`– cumulative dose limit
`
`Hartung HP et al. Lancet 2002; 360: 2018–25
`
`Page 10 of 36
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`Page 10 of 36
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`
`
`Natalizumab: good things
`
`Patients With ≥2 Relapses in Prior Year and ≥1 Gd+ Lesion At Baseline
`
`81%
`64%
`
`reduction in annualised relapse rate
`vs. placebo over 2 years (p< 0.001)
`
`reduction in the risk of disability
`progression, sustained for 24 weeks, as
`assessed over 2 years (p=0.008)
`
`AFFIRM Highly Active* 1 (n= 148 for TYSABRI, 61 for PBO)
`
`Page 11 of 36
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`Page 11 of 36
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`
`
`Natalizumab: good things
`
`disease freedom: highly active group
`
`
`
`ctivity(9’0)
`
`
`
`
`
`Patientswithoutdiseasea
`
`70
`
`ON 0
`
`50
`
`40
`
`30
`
`20
`
`10
`
`89/ 137
`
`El Plambo
`- Natalizumab
`
`
`
`no combined
`
`2%
`
`27%
`
`25.7%
`
`[17.7-33.7]
`
`Page 12 0f36
`
`1.
`
`Havrdova et al. Lancet Neurol 2009; 8:254
`
`no disease
`
`19%
`
`67%
`
`48.5%
`
`activity
`[relapse/ TEDSS]
`
`[36.0—61.0]
`
`no radiology
`
`4%
`
`38%
`
`34.7%
`
`[Gd/ NET2]
`
`[25.4-44.0]
`
`
`
`
`
`Natalizumab: not so good things
`
`• hypersensitivity
`• NAbs
`• PML (13/25000 >12m)
`• cost
`• restricted license
`• difficulty with
`combinations,
`including staggered
`combination
`
`Page 13 of 36
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`Page 13 of 36
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`
`
`What do we want?
`
`Disease
`improvement
`
`
`Freedom from
`disease activity
`
`
`Relapse rate
`reduction
`
`
`
`Disability
`progression
`reduction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`Page 14 of 36
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`
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`Page 15 0f 36
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`Page 15 of 36
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`Page 15 of 36
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`
`
`Oral medication
`
`• candidates (phase II or beyond)
`– cladribine
`– fingolimod
`– teriflunomide
`– BG00012
`– laquinimod
`
`Page 16 of 36
`
`Page 16 of 36
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`
`
`Cladribine: good things
`
`• 3.5mg/kg 4 courses: 5.25mg/kg 6 courses
`• 70% Rx naive
`(0.33 → 0.14)
`• 55-58% ↓ ARR
`• 80% relapse free (v 61% pbo)
`• 31-33% reduction in sustained disability
`(EDSS @ 3m)
`• 44% disease free (vs 16% pbo)
`
`CLARITY study n=1300
`
`Page 17 of 36
`
`Page 17 of 36
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`
`
`Not so good things about cladribine
`
`• ↑ herpes zoster and varicella
`• ? ↑ malignancy
`– melanoma
`– ovarian
`– pancreatic
`– choriocarcinoma
`• TB death
`• teratogenic and embryotoxic
`– (3 live healthy births in study)
`• no long term safety data in humans
`• cytotoxic
`
`Page 18 of 36
`
`Page 18 of 36
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`
`
`Way forward for cladribine?
`
`• ONWARD:
`– cladribine + Rebif
`– safety in combination
`• CIS trial
`• extension trial
`– repeated dosing
`– 2 cycles + follow up
`
`Page 19 of 36
`
`Page 19 of 36
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`
`
`Fingolimod: good things
`
`0 phase III vs placebo in
`progress ( results autumn)
`- novel mechanism of
`
`acflon
`
`
`
`- vs Avonex
`
`— TRANSFORMS
`
`— 52% reduction in ARR
`
`— + MRI data
`
`— reduced brain atrophy
`
`° PPMS trial
`
`
`
`
`
`FTYO.5
`
`FTYl.25 Avonex
`
`Page 20 0:36
`
`TRANSFORMS trial: ECTRlMS 2009
`
`
`
`Not so good things about
`fingolimod
`• completely new class of drug
`• bradycardia
`• localized skin cancers
`• extensive monitoring in trial
`• 2 deaths on monotherapy
`– HSV encephalitis
`– Varicella
`– no long term safety data
`
`Page 21 of 36
`
`Page 21 of 36
`
`
`
`Teriflunomide
`
`• phase 2 only
`• +ve for MRI (activity ↓61%)and EDSS @36wk
`• trend for relapse (↓32%)
`• daily dosing
`• monitoring
`• extensive trial programme
`– CIS, combination GA/IFN
`
`Page 22 of 36
`
`Page 22 of 36
`
`
`
`BG 12
`
`• fumarate
`• not an immunosuppressant
`• phase II
`• relapses ↓32% (NS) 24 week trial
`• phase III: DEFINE, CONFIRM (vs GA)
`
`Page 23 of 36
`
`Page 23 of 36
`
`
`
`Laquinimod
`
`• MRI result in phase 2
`• ARR ↓ 33%
`• good safety in open label extension
`
`Page 24 of 36
`
`Page 24 of 36
`
`
`
`Good things about alemtuzumab
`
`• ?unrivalled efficacy
`• cheap (at the minute)
`• long term follow up on small numbers
`• good numbers in trial (n=330)
`• annual treatment regimen
`
`Page 25 of 36
`
`Page 25 of 36
`
`
`
`CAMSZZB results 3yr (2008)
`
`- Rebif44 Alemtuzumab
`
`
`
`sustained accumulation
`of disability
`
`-7 1%
`
`MRI T2
`
`43.3% 46.4%
`
`Page 26 of36
`
`
`
`Campath-1: effect on disability
`
`SPMS
`
`RRMS
`
`Coles et al. J Neurol 2006;253:98-108
`
`Page 27 of 36
`
`Page 27 of 36
`
`
`
`CAMMS trial of alemtuzumab treatment of multiple sclerosis:
`
`much reduced chance of becoming disabled compared to interferon treatment
`
`25
`
`
`
`
`
`High—Dose IFNB—1a
`Alemtuzumah Low-Dose
`Alemtuzumah High—Dose
`
`Risk
`
`Reducfion
`
`[35% 88%
`
`“In of
`
`patients
`acquiring
`permanent
`disabilityr
`
`20
`
`15
`
`10
`
`5
`
`D
`
`o
`
`I
`3
`
`s
`
`s
`
`12
`
`15
`
`1s
`
`21
`
`24
`
`P =0.0098
`
`33%;: 333
`
`311
`
`29?
`
`286
`
`282
`
`2713
`
`27“
`
`25?
`
`254
`
`Months From First Treatment
`
`Page 28 of 36
`
`Presented at the MN, May 2007
`
`Page 28 of 36
`
`Page 28 of 36
`
`
`
`Not so good things about
`alemtuzimab
`
`• thrombocytopenic purpura
`– 6/216
`
`• thyroid 16.2% @ 2yr (1.6% Rebif)
`–23% @ 3 yr
`• neutralising antibodies?
`• miles off
`
`Page 29 of 36
`
`Page 29 of 36
`
`
`
`Where will they all fit?
`
`riSk
`
`<> mitoxantrone
`
`<> Tysabri
`. fingolimod
`. cladribine
`
`. teriflunamid
`
`efficacy
`
`<> Campath
`
`Avonex <>Rebif
`<><><>
`
`Co axone
`p
`
`Betaferon Extavia
`/
`
`BG 12
`
`.
`.
`.
`.
`disc/a/men to no sCIent/fic scale
`
`and based on pure guesswork
`
`Page 30 of 36
`
`
`
`Where will they all fit?
`
`riSk
`
`<> mitoxantrone
`
`<> Tysabri
`. fingolimod
`. cladribine
`
`. teriflunamid
`
`efficacy
`
`<> Campath
`
`Rebifa BG 12
`
`Avonex
`
`<><>
`
`Co axone
`p
`
`Page 31 of 36
`
`Betaferon Extavia
`/
`
`.
`.
`.
`.
`disc/a/men to no sCIent/fic scale
`
`and based on pure guesswork
`
`
`
`Where will they all fit?
`
`riSk
`
`<> mitoxantrone
`
`<> Tysabri
`. fingolimod
`. cladribine
`
`. teriflunamid
`
`efficacy
`
`<> Campath
`
`Avonex <>Rebif
`<><><>
`
`Co axone
`p
`
`Betaferon Extavia
`/
`
`BG 12
`
`.
`.
`.
`.
`disc/a/men to no sCIent/fic scale
`
`and based on pure guesswork
`
`Page 32 of 36
`
`
`
`Where will they all fit?
`
`riSk
`
`<> mitoxantrone
`
`<> Tysabri
`. fingolimod
`. cladribine
`
`”teriflunamidQfi-‘iCacy
`
`Copaxone
`
`<> Campath
`
`Avonex <>Rebif
`<><>
`
`BG 12
`
`Betaferon Extavia
`/
`
`Page 33 of 36
`
`.
`.
`.
`.
`disc/a/men to no sCIent/fic scale
`
`and based on pure guesswork
`
`
`
`Where will they all fit?
`
`riSk
`
`<> mitoxantrone
`
`<> Tysabri
`. fingolimod
`. cladribine
`
`. teriflunamid
`
`efficacy
`
`<> Campath
`
`Avonex <>Rebif
`<><><>
`
`Co axone
`p
`
`Betaferon Extavia
`/
`
`BG 12
`
`.
`.
`.
`.
`disc/a/men to no sCIent/fic scale
`
`and based on pure guesswork
`
`Page 34 of 36
`
`
`
`Conclusion
`
`• what do we have?
`• what would we like?
`• what are we getting?
`
`Page 35 of 36
`
`Page 35 of 36
`
`
`
`Questions
`Questions
`
`Page 36 0f 36
`
`Page 36 of 36
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`Page 36 of 36
`
`
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