Actrims 2016 oratorio lb platform wolinsky_lb1.3 (1)

Efficacy of Ocrelizumab in Patients With PPMS With and Without T1 Gadolinium-Enhancing Lesions at Baseline in a Phase III, Placebo-Controlled Trial

J Wolinsky, DL Arnold, A Bar-Or, J de Seze, G Giovannoni, B Hemmer, K Rammohan, A Sauter, D Masterman, P Fontoura, H Garren, P Chin, X Montalban,

on behalf of the ORATORIO clinical investigators

NCT01194570

Americas Committee for Treatment and Research in Multiple Sclerosis 2016

Platform presentation number LB1.3

DisclosuresJerry Wolinsky has received compensation for service on steering committees or data monitoring boards for Novartis, F. Hoffmann-La Roche Ltd., Genzyme and Teva Pharmaceuticals; consultant fees from AbbVie, Actelion, Alkermes, Athersys, Inc., EMD Serono, Forward Pharma, Genentech, Inc., Genzyme (Sanofi), Novartis, F. Hoffmann-La Roche Ltd., Teva, and XenoPort; research support from Genzyme, Sanofi, the NIH and the NMSS through the University of Texas Health Science Center at Houston (UTHSCH) and royalties for monoclonal antibodies out-licensed to Chemicon International through UTHSCH.

Douglas Arnold reports equity interest in NeuroRx Research, which performed the MRI analysis for the trial, and consultation fees from Acorda Therapeutics, Biogen, Genzyme, F. Hoffmann-La Roche Ltd, Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi Aventis, and Teva.

Amit Bar-Or has received personal compensation for consulting, serving on scientific advisory boards and/or speaking activities from: Bayer, Bayhill Therapeutics, Berlex, Biogen, BioMS, Diogenix, Eli Lilly, Genentech, Inc., GSK, Guthy-Jackson/GGF, Merck Serono, Novartis, Ono Pharmacia, F. Hoffmann-La Roche Ltd, Sanofi-Aventis, Teva Neuroscience and Wyeth.

Jérôme de Seze has received consultancy fees and served as an expert for advisory boards for Alexion, Allergan, Almiral, Bayer, Biogen, Chugai, CSL Behring, Genzyme, LFB, Merck, Novartis, Roche, and Teva.

Gavin Giovannoni has received honoraria from AbbVie, Bayer HealthCare, Biogen, Canbex Therapeutics, Five Prime Therapeutics, Genzyme, GSK, GW Pharma, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, F. Hoffmann-La Roche Ltd., Synthon, Teva Neuroscience, UCB and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz and Novartis; and compensation from Elsevier.

Bernhard Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd., Novartis, Bayer Schering, Merck Serono, Biogen, GSK, Chugai Pharmaceuticals, Micromet, Genentech, Inc. and Genzyme Corporation; serves on the international advisory board of Archives of Neurology , Multiple Sclerosis Journal and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen, Merck Serono, F. Hoffmann-La Roche Ltd., and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis; he has also filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of patients with MS and genetic determinants of neutralizing antibodies to interferon-beta.

Kottil Rammohan has received honoraria for participating in advisory boards and consulting for Acorda, Biogen, EMD Serono, Genentech, Inc/F. Hoffmann-La Roche Ltd, Genzyme, and Teva. He had also received grants from Accera.

Annette Sauter is an employee and shareholder of F. Hoffmann-La Roche Ltd.

Paulo Fontura is an employee and shareholder of F. Hoffmann-La Roche Ltd.

Donna Masterman is an employee and/or shareholder of Genentech, Inc. Group, a member of the Roche Group.

Hideki Garren is an employee and shareholder of F. Hoffmann-La Roche Ltd.

Peter Chin is an employee and/or shareholder of Genentech, Inc., a member of the Roche Group.

Xavier Montalban has received speaking honoraria and travel expense reimbursement for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Receptos, F. Hoffmann-La Roche Ltd., Sanofi, Teva and Trophos.

The study was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this presentation was provided by F. Hoffmann-La Roche Ltd.

B cells are present in the CNS of patients with MS

3

*Normal controls typically exhibit few B cells in the CNS.CNS, central nervous system; PPMS, primary progressive multiple sclerosis; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.Frischer JM, et al. Brain 2009;132(pt 5):1175–89.

ActivityLesions

SlowlyExpanding

Lesions

Normal-Appearing

White Matter

InactiveLesions

Cortex Meninges

CD2

0+B

Cel

ls/m

m2

20

10

0

Acute/RRMS

PPMSSPMSNormal controls*

Targeting CD20+ B cells is a potential approach to treating MS

Image adapted from Krumbholz M, et al. Nat Rev Neurol 2012;8(11):613–23.1. Kappos L, et al. Lancet 2011;378(9805):1779–87.

Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells1

ORATORIO: Phase III study in PPMS Study Design

†The blinded treatment period may be extended until database lock.#2:1 randomization stratified by age (≤45 vs >45 years) and region (US vs ROW).*Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. ‡Continued monitoring occurs if B cells are not repleted.

BL, baseline; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; i.v., intravenous; IgG, immunoglobulin G; MRI, magnetic resonance imaging;PPMS, primary progressive multiple sclerosis; ROW, rest of world; RRMS, relapsing remitting multiple sclerosis;SPMS, secondary progressive multiple sclerosis.1. Polman CH, et al. Ann Neurol 2005;58:840–46.

• Diagnosis of PPMS (2005 revised McDonald criteria)1

• Age 18–55 years• EDSS 3.0–6.5• CSF: elevated IgG

index or >1 oligoclonal bands

• No history of RRMS, SPMS, or PRMS

• No treatment with other MS DMTs at screening

2:1

Rand

omiza

tion#

ORATORIO: MS disease history and baseline characteristics

PlaceboN=244

Ocrelizumab N=488

Age, years, mean (SD) 44.4 (8.3) 44.7 (7.9)Female, n (%) 124 (50.8) 237 (48.6)Time since MS symptom onset, years, mean (SD) 6.1 (3.6) 6.7 (4.0)Time since MS diagnosis, years, mean (SD) 2.8 (3.3) 2.9 (3.2)MS disease-modifying treatment naïve,* n (%) 214 (87.7) 433 (88.7)EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2)MRI

Patients with T1 Gd+ lesions, n (%)Number of T1 Gd+ lesions, mean (SD)Brain T2 hyperintense lesion volume, cm3, mean (SD)Normalized brain volume, cm3, mean (SD)

60 (24.7)0.6 (1.6)

10.9 (13.0)1469.9 (88.7)

133 (27.5)1.2 (5.1)

12.7 (15.1)1462.9 (83.9)

*No disease-modifying treatments in the previous 2 years.EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging; MS, multiple sclerosis;SD, standard deviation.

Evaluation of efficacy in patient subgroups with and without T1 gadolinium-enhancing lesions at baseline is a key area of interest

PPMS study patient populations generally show comparable baseline characteristics

Gd+, gadolinium-enhancing; SD; standard deviation.1. Wolinsky JS, et al. Ann Neurol 2007; 2. Hawker K, et al. Ann Neurol 2009;66:460–71; 3. Lublin FD, et al. Lancet 2016; in press; 61:14–24; 4. Montalban X, et al. ECTRIMS 2015;Abstract 228.

Baseline characteristic

PROMiSe1

N=943OLYMPUS2

N=439INFORMS3

N=970ORATORIO4

N=732

Age, years, mean (±SD) 50.4±8.3 49.9±8.9 48.5±8.4 44.6±8.0

Male, % 48.8 49.7 51.6 50.7

Time since MS symptom onset, years, mean (±SD)

11.0±7.3 9.1±6.6 5.8±2.4 6.48±3.89

EDSS score,mean (±SD) 4.9±1.2 4.8±1.4 4.67±1.03 4.7±1.2

Patients with T1 Gd+ lesions, % 14.1 24.5 13.4 26.4

Time to onset of 12-week confirmed disability progression

*Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age. Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression.CDP, confirmed disability progression; Gd+, gadolinium-enhancing; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.

Overall Study Population(Primary Endpoint)

Total Placebo(N=244)

Ocrelizumab(N=488)

HazardRatio

95% CI

n n Events n Events

Overallpopulation 731 244 96 487 160 0.76 (0.59, 0.98)

T1 Gd+ lesions 193 60 27 133 43 0.65 (0.40, 1.06)

No T1 Gd+ lesions 533 183 68 350 115 0.84 (0.62, 1.13)

24% reduction in risk of CDP

HR (95% CI): 0.76 (0.59, 0.98);p-value (log rank)=0.0321*

(n=488)

Time to onset of 24-week confirmed disability progression

*Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age. Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression.CDP, confirmed disability progression; Gd+, gadolinium-enhancing; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.

Overall Study Population

Total Placebo(N=244)

Ocrelizumab(N=488)

HazardRatio

95% CI

n n Events n Events

Overall population 731 244 87 487 144 0.75 (0.58, 0.98)

T1 Gd+ lesions 193 60 23 133 39 0.67 (0.40, 1.14)

No T1 Gd+ lesions 533 183 63 350 103 0.81 (0.59, 1.10)

(n=488)

25% reduction in risk of CDP

HR (95% CI): 0.75 (0.58, 0.98);p-value (log rank)=0.0365*

0

20

40

60

80

100

120

Placebo n=134 Ocrelizumab n=288

Patients Without T1 Gd+ Lesionsat Baseline

% C

hang

e Fr

om B

asel

ine

Wal

king

Tim

e (M

ean,

95%

CI)

0

20

40

60

80

100

120


Patients With T1 Gd+ Lesionsat Baseline

% C

hang

e Fr

om B

asel

ine

Wal

king

Tim

e (M

ean,

95%

CI)

Change in timed 25-foot walk from baseline to Week 120

*Analysis based on ITT population; p-value based on ranked ANCOVA at 120-week visit adjusted for baseline timed 25-foot walk, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on log-transformed data adjusted for baseline timed 25-foot walk, geographic region and age.CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; LOCF, last observation carried forward; MMRM; mixed-effect model repeated measure.

0

20

40

60

80

100

120



% C

hang

e Fr

om B

asel

ine

Wal

king

Tim

e (M

ean,

95%

CI)

29% relative

Reductionp=0.0404*

-10

-5

0

5

10

15

20Patients Without T1 Gd+ Lesions

at Baseline

% C

hang

e Fr

om B

asel

ine

T2 L

esio

n Vo

lum

e (M

ean,

95%

CI)


-10

-5

0

5

10

15

20Overall Study Population

% C

hang

e Fr

om B

asel

ine

T2 L

esio

n Vo

lum

e (M

ean,

95%

CI)

+7.4% with placebo vs

−3.4% with ocrelizumabp<0.0001*

Change in brain T2 hyperintense lesion volume from baseline to Week 120

*Analysis based on ITT population; p-value based on ranked ANCOVA at 120-week visit adjusted for baseline T2 lesion volume, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on log-transformed data adjusted for baseline T2 lesion volume, geographic region and age.CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; LOCF, last observation carried forward; MMRM; mixed-effect model repeated measure.


-10

-5

0

5

10

15

20Patients With T1 Gd+ Lesions

at Baseline

% C

hang

e Fr

om B

asel

ine

T2 L

esio

n Vo

lum

e (M

ean,

95%

CI)


-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0

Patients Without T1 Gd+ Lesionsat Baseline

% C

hang

e in

Who

le B

rain

Vo

lum

e Fr

om W

eek

24

(Mea

n, 9

5% C

I)-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0

Patients With T1 Gd+ Lesionsat Baseline

% C

hang

e in

Who

le B

rain

Vo

lum

e Fr

om W

eek

24

(Mea

n, 9

5% C

I)

Change of whole brain volume from Week 24 to Week 120

*Analysis based on ITT population with Week 24 and at least one post-Week 24 assessment; p-value based on MMRM at 120-week visit adjusted for Week 24 brain volume, geographic region and age.CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; MMRM; mixed-effect model repeated measure.

-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0


% C

hang

e in

Who

le B

rain

Vo

lum

e Fr

om W

eek

24

(Mea

n, 9

5% C

I)

17.5% relative reduction

p=0.0206*Placebo n=150 Ocrelizumab n=325

Placebo n=31 Ocrelizumab n=83 Placebo n=119 Ocrelizumab n=241

Efficacy of ocrelizumab in patients with/without T1 Gd+ lesions at baseline was consistent with the overall study population

• Ocrelizumab is the first investigational treatment to meet primary and key secondary efficacy endpoints in a Phase III PPMS study

• Consistent with other PPMS study populations, the ORATORIO study population includes a proportion of patients with T1 Gd+ lesions at baseline

• Efficacy of ocrelizumab versus placebo in patients with and without T1 Gd+ lesions at baseline was consistent with that in the overall study population

– However, the ORATORIO study was not powered to demonstrate efficacy differences between these subgroups

PPMS, primary progressive multiple sclerosis; Gd+, gadolinium-enhancing.

For safety results in the overall study population, please refer to ACTRIMS 2016 poster #023, “A randomized, double-blind, parallel-group, placebo-controlled

phase III trial to evaluate efficacy and safety of ocrelizumab in PPMS”

AUTRALIASt Vincent's Hospital MelbourneRoyal Hobart Hospital

AUSTRIAWagner-Jauregg-KrankenhausMedizinische Universität WienUniversitätsklinikum InnsbruckAllgemeines Krankenhaus LinzChristian-Doppler-Klinik Salzburg

BELGIUMCHU TivoliAZ Alma-Sijsele

BRAZILUnião Brasileira de Educação e Assistência - Hospital São Lucas da

PUCRSHospital das Clinicas da Universidade Federal de GoiasSanta Casa De Belo HorizonteUniversidade Federal do Rio de Janeiro - Hospital Universitário

Clementino Fraga Filho

BULGARIAMultiprofile Hospital for Active Treatment “National Cardiology Hospital”Multiprofile Hospital for Active Treatment of Neurology and Psychiatry

"Sv. Naum“

CANADAMontreal Neurological Institute/Clinical Research UnitOttawa HospitalRecherche Sepmus, Inc.Health Sciences CentreSt. Michael's HospitalUniversity Of British Columbia HospitalFoothills Medical Centre

CZECH REPUBLICFakultni nemocnice BrnoVseobecna fakultni nemocnice v PrazeKrajska zdravotni, a.s. - Nemocnice Teplice, o.z.

FINLANDTurun yliopistollinen keskussairaalaTampereen yliopistoHelsingin yliopistollinen keskussairaala / Meilahti

FRANCEGroupe Hospitalier PellegrinHôpital Gui de ChauliacGroupe hospitalo-universitaire CaremeauHopital PurpanHopital Gabriel MontpiedHôpital de HautepierreCHRU NancyHôpital Côte de NacreFondation RothschildHôpital de PoissyHôpital Guillaume et René LaënnecHôpital PasteurGroupe Hospitalier Pitié- SalpétrièreCHU de la Timone - Hôpital d'AdultesHôpital Maison BlancheHôpital Roger SalengroHôpital Pierre Wertheimer - Hôpital Neurologique

Acknowledgements: Investigators and patients involved in the ORATORIO study

GERMANYMedizinische Einrichtungen des Bezirks Oberpfalz GmbHJustus-Liebig-University of GiessenUniversitätsklinikum FrankfurtHeinrich Heine Universität DüsseldorfC/O Jüdisches KrankenhausCharité - Universitätsmedizin BerlinKlinikum rechts der Isar der Technische Universität MünchenRuhr-Universität BochumMarianne-Strauß-KlinikDeutsche Klinik für Diagnostik GmbHKliniken der Stadt Köln gGmbHUniversitätsklinikum MünsterKlinikum Bayreuth GmbHUniversität HeidelbergUniversitätsklinikum LeipzigUniversitätsklinikum UlmUniversitätsklinikum TübingenUniversitätsklinikum Carl Gustav Carus an der TU Dresden

GREECE401 Military Hospital of Athens"AHEPA" University General Hospital of Thessaloniki"Georgios Papanikolaou" General Hospital of Thessaloniki

HUNGARYUzsoki Utcai KórházPécsi TudományegyetemJahn Ferenc Dél-Pesti Kórház és RendelöintézetVaszary Kolos KórházClinexpert Egészségügyi Szolgáltató és Kereskedelmi Kft.Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ

ISRAELThe Chaim Sheba Medical CenterRabin Medical CenterTel Aviv Sourasky Medical CenterHadassah University Hospital Ein KeremBarzilai Medical CenterMedical Center 'Ziv' Safed

ITALYAzienda Sanitaria Ospedaliera S. Luigi GonzagaOspedale San Raffaele S.r.l.Ospedale BinaghiIRCCS Azienda Ospedaliera Universitaria San Martino - Istituto

Nazionale per la Ricerca sul Cancro

LITHUANIAKlaipeda University HospitalHospital of Lithuanian University of Health Sciences Kaunas ClinicsRepublican Siauliai Hospital

MEXICOGrupo Médico CaminoCentro de Estudios Clinicos y Especialidades Medicas SCInstituto Nacional de Neurologia y NeurocirugiaInstituto Biomédico de Investigación A.C.

NETHERLANDSErasmus MCOrbis Medisch Centrum

NEW ZEALANDWaikato HospitalWellington Hospital

NORWAYOslo universitetssykehus HF, Ullevål

PERUClinica Anglo AmericanaHospital Dos de MayoHospital IV Alberto Sabogal Sologuren

POLANDAkson Clinical Research Maciejowski-Bielecki Sp. j.Zespol Opieki Zdrowotnej w KonskichNiepubliczny Zaklad Opieki Zdrowotnej KENDRONM.A. - LEK A.M. Maciejowscy SC. Centrum Terapii SMSPZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego

Uniwersytetu Medycznego w LodziSamodzielny Publiczny Szpital Kliniczny nr 4Niepubliczny Zaklad Opieki Zdrowotnej NEURO-MEDIC

PORTUGALCentro Hospitalar e Universitário de Coimbra, EPEHospital Garcia de OrtaCentro Hospitalar Lisboa Norte, E.P.E.Hospital Fernando FonsecaCentro Hospitalar do Porto – Hospital de Santo António

ROMANIATargu Mures Emergency County Clinical HospitalSC Clubul Sanatatii SRL"Elias" Emergency University HospitalTimisoara Emergency County Clinical Hospital

RUSSIAResearch Medical Complex "Vashe Zdorovie“

SPAINHospital Universitario Ramón y CajalHospital Clinico San CarlosHospital de la Santa Creu i Sant PauHospital General de MalagaHospital Universitario Vírgen MacarenaHospital del MarHospital Universitario de La PrincesaHospital Universitario Vall d'HebronHospital DonostiaHospital General Universitario de AlicanteHospital Clinico Universitario de SantiagoHospital Universitari de Girona Dr. Josep TruetaOrganización Sanitaria Integrada Bilbao BasurtoHospital Clinic de Barcelona

SWITZERLANDOspedale Regionale Lugano CivicoUniversitätsspital Basel

UKRAINEMunicipal Institution of Kyiv Regional Council "Kyiv Regional Clinical

Hospital"Municipal Institution “Odesa Regional Clinical Hospital"State Treatment and Prevention Institution “Central Clinical Hospital of

Ukrzaliznytsya”SI "Ukrainian State Research Institute of Medical and Social Problems of

Disability" MOH of UkraineVinnytsya National Medical University n.a. M.I. PyrohovLviv Regional Clinical HospitalBukovinian Medical State UniversityMunicipal Institution “Dnipropetrovsk Regional Clinical Hospital

n.a. I.I. Mechnykov”Volyn Regional Clinical HospitalKyiv City Clinical Hospital #4"State Institution ""Institute of Neurology, Psychiatry and

Narcology of NAMS of Ukraine“

UNITED KINGDOMKing's College HospitalQueen's Medical CentreRoyal Victoria InfirmaryBarts and the London NHS TrustThe Walton Centre For Neurology And Neurosurgery

USAUniversity of California, DavisLegacy Health SystemNewport Beach Clinical Research Associates, Inc.Wayne State UniversitySwedish Medical CenterUniversity of MinnesotaMayo Clinic- ScottsdaleHenry Ford Health SystemMS Center, Carolinas Medical CenterSutter East Bay Medical FoundationWashington UniversityMS Specialty Clinic University of New MexicoCentral Texas NeurologyRaleigh Neurology Associates, PAUniversity of Texas SouthwesternHope Research Institute, LLCWinthrop University HospitalComprehensive Multiple Sclerosis Care Center at South Shore

Neurologic Associates, P.C.Phoenix Neurological AssociatesMaxine Mesinger MS Clinic/Baylor College of MedicineNeurology Associates Of Stony BrookUniversity of Kansas Medical CenterTrustees of the University of PennsylvaniaIndiana University Medical CenterMount Sinai School of MedicineUniversity of ColoradoBarrow Neurology ClinicWeill Medical College of Cornell UniversityOklahoma Medical Research FoundationHoly Name HospitalOhio State University Medical CenterThe Neurology Foundation, Inc.Michigan Institute For Neurological DisordersMidAmerica Neuroscience InstituteNeurological Associates, Inc.MS Center of Vero BeachUniversity Of MiamiNeurology Clinic, P.C.University of California San Francisco

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Actrims 2016 oratorio lb platform wolinsky_lb1.3 (1)