16 Dicembre 2016 - Bari, Italia

www.excemed.org

IMPROVING THE PATIENT’S LIFE

THROUGH

MEDICAL EDUCATION

Aspetti di sicurezza a breve e lungo termine

Nuove terapie, nuove strategie

Simona Bonavita

Università della Campania

Luigi Vanvitelli

…una malattia a due fasi

Storia Naturale della SM: Storia Naturale della SM: attività clinica & prognosiattività clinica & prognosi

Predittori (minore) durata Fase 1 ���� raggiungimento EDSS=3.0

• Sesso maschile, maggiore età d’esordio, deficit residuo dopo la prima ricaduta, un

Leray et al., Brain 2010

• Sesso maschile, maggiore età d’esordio, deficit residuo dopo la prima ricaduta, un maggior numero di ricadute durante i primi 2aa di malattia

Predittori durata fase 2 ���� da EDSS 3.0 a 6.0

• La durata della Fase 1 non influenza la durata della Fase 2

• Nessun predittore nella SM progressiva

Liao and Tsai, BioMedicine 2013

DefinitionsDefinitionsDefinitionsDefinitions

• Adverse event

•Adverse reaction•Adverse reaction

–Unexpected adverse reaction

–Serious adverse reaction

•Side effect

5

Medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally

AdverseAdverseAdverseAdverse eventeventeventevent

Medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally related

'A response to a drug which is noxious and unintended,

and which occurs at doses normally used in man for

the prophylaxis, diagnosis, or therapy of disease, or for

AdverseAdverseAdverseAdverse reactionreactionreactionreaction

6

the prophylaxis, diagnosis, or therapy of disease, or for

the modifications of physiological function'

UnexpectedUnexpectedUnexpectedUnexpected adverseadverseadverseadverse reactionreactionreactionreaction

Not consistent with applicable product information or characteristics of drug.

UnexpectedUnexpectedUnexpectedUnexpected adverseadverseadverseadverse reactionreactionreactionreaction

Unintended effect occurring at normal dose related to

the pharmacological properties

Side Side Side Side effecteffecteffecteffect

7

the pharmacological properties

SeriousSeriousSeriousSerious adverse event or reactionadverse event or reactionadverse event or reactionadverse event or reaction

Any untoward medical occurrence that at any dose may

� Results in death

� Threaten life

� Requires inpatient hospitalization or prolongation of existing hospitalization

� Results in persistent significant disability

8

� Results in persistent significant disability

Frequency of adverse drug reactionsFrequency of adverse drug reactionsFrequency of adverse drug reactionsFrequency of adverse drug reactions(CIOMS)(CIOMS)(CIOMS)(CIOMS)

• Very common

• Common (frequent)

• Uncommon (infrequent)

• Rare

• >= 1/10

• > = 1/100 and < 1/10

• >= 1/1000 and < 1/100

• >= 1/10000 and < 1/1000• Rare

• Very rare

• >= 1/10000 and < 1/1000

• < 1/10000

I farmaci IniettiviI farmaci IniettiviI farmaci IniettiviI farmaci Iniettivi

Interferone beta 1-a: un profilo di sicurezza ben caratterizzatoPiù di 15 anni di trial clinici e di esperienza sui pazienti1,2,3,4,5,6,7

4,3% di Grado 3/4 - generalmente lieve e reversibile6Linfopenia

4,3% di Grado 3/4 - generalmente lieve e reversibile

Non segnalati casi di PMLPML

Nessun aumento del rischio di tumori (4,0 vs 6,4 eventi per 1000 pazienti-anno per interferone b-1a vs placebo)7

Neoplasie

Uso

1. PRISMS-2: PRISMS Study Group. Lancet. 1998;352(9139):1498-1504.

2. PRISMS-15: Kappos L, et al. J Neurol Neurosurg Psychiatry. 2015. [Published online first: 15 September 2015.] doi:10.1136/jnnp-2014-310024.

3. PRISMS-7/8: Kappos L, et al. Neurology. 2006;67(6):944-953.

4. PRISMS-4: PRISMS Study Group, University of British Columbia MS/MRI Analysis Group. Neurology. 2001;56(12):1628-1636.

5. Rebif®. RCP Luglio 2015.

6. Rieckmann P, et al. Drug Safety 2004; 27 (10): 745-756.7. Sandberg-Wollheim M, Kornmann G, Bischof D, et al. Mult Scler. 2011;17(4):431-440.

L’interferone beta 1-a può essere utilizzato negli adolescenti e nei bambini sopra i 2 anni di età5

Uso pediatrico

14

• Obiettivo della metanalisi: analizzare gli outcome di studi di fase III di

farmaci di prima e seconda linea indicati nel trattamento della SMRR, per

definire i seguenti indici di beneficio e di rischio:

• NNTB: utilizzato come indice di beneficio, indica il numero di pazienti

trattati che raggiungono un beneficio in un dato tempo. Valori più

bassi di NNTB indicano un’efficacia maggiore.bassi di NNTB indicano un’efficacia maggiore.

• NNTH: utilizzato come indice di rischio, indica il numero di pazienti

trattati che presentano un evento avverso in un dato tempo. Valori

più alti di NNTH sono indicativi di un rischio minore.

• LHH: NNTH/NNTB.

InterferoneInterferoneInterferoneInterferone beta 1beta 1beta 1beta 1----a a a a s.cs.cs.cs.c. . . . risulta il farmaco di prima linea risulta il farmaco di prima linea risulta il farmaco di prima linea risulta il farmaco di prima linea con il rapporto beneficiocon il rapporto beneficiocon il rapporto beneficiocon il rapporto beneficio----rischio più favorevole.rischio più favorevole.rischio più favorevole.rischio più favorevole.1111

Reazioni al sito di iniezione e linfopenia risultano gli unici eventi avversi causati dagli

interferoni che portano ad un LHH≤1.GA=Glatiramer Acetato

1. Mendes D, et al. CNS Drugs 2016; DOI 10.1007/s40263-016-0377-9 -

Hunt et al., N Eng J Med 2014

GALA1

• A phase 3 randomised, multinational, multicentre, parallel-group trial in subjects

with RRMS to assess the efficacy and safety of GA 40 mg/ml injections tiw

THE GALA STUDYTHE GALA STUDYTHE GALA STUDYTHE GALA STUDY

with RRMS to assess the efficacy and safety of GA 40 mg/ml injections tiw

compared with placebo

• 17 countries and 142 sites

• 1404 randomized naive patients

(United States, Israel, Poland, Ukraine, Bulgaria, Russia, Romania, Croatia, Germany, Lithuania, Georgia, Czech Republic, Estonia, Hungary, Italy, United Kingdom, and South

Africa)

1. Khan O et al. Ann Neurol. 2013;73:705-713. 2. Wolinsky JS et al. AAN 2014. Presentation S31.002.

GALA: safety profile of GA 40 consistent with GA 20

Placebo (n=461)Placebo (n=461)Placebo (n=461)Placebo (n=461)GA 40 mg/ml GA 40 mg/ml GA 40 mg/ml GA 40 mg/ml tiwtiwtiwtiw

(n=943)(n=943)(n=943)(n=943)

≥1 AE, n (%) 284 (61.6) 680 (72.1)≥1 AE, n (%) 284 (61.6) 680 (72.1)

≥1 serious AE*, % 4.5 4.5

AEs occurring in ≥5% in either treatment group

Injection-site erythema, n (%) 7 (1.5) 197 (20.9)

Nasopharyngitis, n (%) 39 (8.5) 100 (10.6)

Injection-site pain, n (%) 9 (2.0) 98 (10.4)

Headache, n (%) 55 (11.9) 95 (10.1)

Injection-site pruritus, n (%) 0 (0) 56 (5.9)

Systemic immediate postinjection reactions, n (%) 8 (1.7) 72 (7.6)

*

**

Systemic immediate postinjection reactions, n (%) 8 (1.7) 72 (7.6)

Urinary tract infection, n (%) 23 (5.0) 46 (4.9)

Upper respiratory tract infections, n (%) 25 (5.4) 42 (4.5)

*One patient death (cardiopulmonary failure) was reported in the placebo group.

1. Khan O et al. Ann Neurol. 2013;73:705-713. 2. (glatiramer acetate 20 mg/ml Summary of Product Characteristics. July 2014. 3. glatiramer acetate) 40 mg/ml

Summary of Product Characteristics. XXXXX 2015.

The most common AE were injection site reactions (ISRs: 35.2% of GA 40 mg/ml tiw patients vs. 5% of placebo patients). Most of them (99.9%)

were mild or moderate in severity. No clinically significant changes in laboratory values were seen in either arm

*

GLACIER2

THE GLACIER STUDY

• A phase 3b, open-label, randomised, multicentre, parallel-arm study to assess

safety and tolerability of GA 40 mg/ml tiw vs. 20 mg/ml qd in subjects with RRMS

– Sample size: 209 patients randomised

– National (US) and 31 sites

1. Khan O et al. Ann Neurol. 2013;73:705-713. 2. Wolinsky JS et al. AAN 2014. Presentation S31.002.

GLACIER primary endpoint: Injection-related adverse events (IRAEs)GLACIER primary endpoint: Injection-related adverse events (IRAEs)GLACIER primary endpoint: Injection-related adverse events (IRAEs)GLACIER primary endpoint: Injection-related adverse events (IRAEs)

GA 40 mg TIW reduced annualized IRAE Rate by 50% vs. GA 20 mg QD

EndpointEndpointEndpointEndpoint postpostpostpost----hochochochoc: IRAE moderati/gravi: IRAE moderati/gravi: IRAE moderati/gravi: IRAE moderati/gravi

� Significativa riduzione del 60% nel tasso annualizzato di IRAE moderati/gravi con � Significativa riduzione del 60% nel tasso annualizzato di IRAE moderati/gravi con GA 40 mg/ml TIW vs. GA 20 mg/ml QD (p=0,0021)

2,2

1,0

1,5

2,0

2,5

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de

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/gra

vi

60,0%

RR=0,40*

IC 95%: 0,23-0,72

p=0,0021

RR=0,40*

IC 95%: 0,23-0,72

p=0,0021

1. Wolinsky JS et al. Presented at AAN 2014; Abstract S31.002.

GA 20mg/ml q.d. (n=101)

GA 40mg/ml t.i.w. (n=108)

0,88

0,0

0,5

1,0

Me

dia

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AE

Gli Gli

Anticorpi Monoclonali

NATALIZUMABNATALIZUMABNATALIZUMABNATALIZUMAB

27

28

*

*

29

30

Stime aggiornate del rischio di PML

nei pazienti in terapia con natalizumab.

NOTA INFORMATIVA EMA-AIFA 11 marzo 2016; linee guida versione 16 del luglio 2016

Mult Scler. 2013 Feb;19(2):249-51. doi:

10.1177/1352458512448268. Epub 2012 May 17.

Natalizumab-associated reversible encephalopathy syndrome

mimicking progressive multifocal leukoencephalopathy.mimicking progressive multifocal leukoencephalopathy.

Décard BF1, Haghikia A, Tönnes C, Thöne J, Lukas C, Chan A, Gold

R.

ALEMTUZUMAB

CARECARECARECARE----MS I e II : Overview MS I e II : Overview MS I e II : Overview MS I e II : Overview deglideglideglidegli AEs AEs AEs AEs osservatiosservatiosservatiosservati a 2 a 2 a 2 a 2 annianniannianni

Adverse Events (AEs)

CARE-MS I1 CARE-MS II2

SC IFNB-1a

44 µg

n=187

n (%)

Alemtuzumab 12

mg

n=376

n (%)

SC IFNB-1a

44 µg

n=202

n (%)

Alemtuzumab 12

mg

n=435

n (%)

Alemtuzumab

24 mg

n=161

n (%)

• Basso numero di interruzioni del trattamento/discontinuazione dallo studio nel gruppo di pazienti con alemtuzumab

Adverse Events (AEs) n (%) n (%) n (%) n (%) n (%)

Patients with AEs 172 (92) 361 (96) 191 (95) 428 (98) 159 (99)

Patients with SAEs 27 (14) 69 (18) 44 (22) 85 (20) 30 (19)

AEs Leading to Treatment

Withdrawal

11 (6) 5 (1) 15 (7) 14 (3) 6 (4)

AEs Leading to Study

Discontinuation

5 (3) 0 6 (3) 1 (<1) 0

Deaths 0 1 (<1) 0 2 (0.5) 0

pazienti con alemtuzumab

• 3 pazienti deceduti nel gruppo in alemtuzumab, nessuna correlazione col farmaco :

• CARE-MS I: incidente stradale

• CARE-MS II: incidente stradale (n=1); ab ingestis in seguito a grave ricaduta (n=1)

AE=adverse event; SAE=serious adverse event

1. Cohen JA et al. Lancet. 2012;380(9856):1819-1828; 2. Coles AJ et al. Lancet. 2012;380(9856):1829-1839.

2-Year Active Controlled

Experience All Available Follow-up

Alemtuzumab 12 mg Alemtuzumab 12 + 24 mg

ReazioniReazioniReazioniReazioni gravigravigravigravi associate associate associate associate all’infusioneall’infusioneall’infusioneall’infusione (≥0.2%) (≥0.2%) (≥0.2%) (≥0.2%)

CAMMS223,

CARE-MS I & II,

Extension

Any Serious IARAlemtuzumab 12 mg

N=919

Alemtuzumab 12 + 24 mg

N=1486

Any serious IAR, n (%) 26 (2.8)* 39 (2.6)**

Hypotension 2 (0.2) 4 (0.3)

Atrial fibrillation 2 (0.2) 3 (0.2)

Headache 1 (0.1) 3 (0.2)

Nausea 2 (0.2) 3 (0.2)

Pyrexia 3 (0.3) 3 (0.2)Pyrexia 3 (0.3) 3 (0.2)

Urticaria 3 (0.3) 3 (0.2)

Chest discomfort 2 (0.2) 2 (0.1)

*Includes events of IAR and incorrect dose administered (both at ≥0.2%).

**Includes 1 event of anaphylactoid reaction.

2222----Year Active Controlled Experience Year Active Controlled Experience Year Active Controlled Experience Year Active Controlled Experience All available follow-up

SC IFNBSC IFNBSC IFNBSC IFNB----1a 1a 1a 1a

44 44 44 44 μμμμgggg

AlemtuzumabAlemtuzumabAlemtuzumabAlemtuzumab

12 mg12 mg12 mg12 mg

Alemtuzumab

12 + 24 mg

IncidenzaIncidenzaIncidenzaIncidenza delledelledelledelle piùpiùpiùpiù comunicomunicomunicomuni infezioniinfezioniinfezioniinfezioni riportateriportateriportateriportate neglineglineglinegli studistudistudistudi

CAMMS223,

CARE-MS I & II,

Extension

Preferred termPreferred termPreferred termPreferred term44 44 44 44 μμμμgggg

N=496N=496N=496N=496

12 mg12 mg12 mg12 mg

N=919N=919N=919N=919

12 + 24 mg

N=1486

Any event, n (%)Any event, n (%)Any event, n (%)Any event, n (%) 264 (53.2)264 (53.2)264 (53.2)264 (53.2) 652 (70.9)652 (70.9)652 (70.9)652 (70.9) 1149 (77.3)1149 (77.3)1149 (77.3)1149 (77.3)

Nasopharyngitis 82 ( 16.5) 216 ( 23.5) 447 ( 30.1)

Urinary tract infection 40 ( 8.1) 162 ( 17.6) 366 ( 24.6)

Upper respiratory tract infection 57 ( 11.5) 141 ( 15.3) 307 ( 20.7)

Sinusitis 34 ( 6.9) 100 ( 10.9) 215 ( 14.5)

Oral herpesOral herpesOral herpesOral herpes 6 ( 1.2) 79 ( 8.6) 134 ( 9.0)

Influenza 25 ( 5.0) 77 ( 8.4) 161 ( 10.8)

Bronchitis 16 ( 3.2) 64 ( 7.0) 156 ( 10.5)

Herpes zosterHerpes zosterHerpes zosterHerpes zoster 4 ( 0.8) 38 ( 4.1) 121 ( 8.1)

Gastroenteritis 5 ( 1.0) 36 ( 3.9) 78 ( 5.2)

Pharyngitis 7 ( 1.4) 36 ( 3.9) 75 ( 5.0)

A Infections with incidence of ≥5.0% in any treatment group shown. bAlthough recommended, patients were not required to receive prophylactic anti-viral therapy with acyclovir.

Other Infections that may Occur with Other Infections that may Occur with Other Infections that may Occur with Other Infections that may Occur with AlemtuzumabAlemtuzumabAlemtuzumabAlemtuzumab

• HPV infection occurred in 2% of alemtuzumab-treated patientsHuman Papilloma Virus

(HPV)Human Papilloma Virus

(HPV)

• Active and latent tuberculosis cases occurred in 0.3% of alemtuzumab-treated patients, most often in endemic regions

TuberculosisTuberculosis

• Fungal infections, especially oral and vaginal candidiasis, occurred more commonly in alemtuzumab-treated patients (12%) than in patients treated with interferon beta-1a (3%) in controlled clinical trials in MS

Fungal infectionsFungal infections

• Listeria meningitis has been reported in alemtuzumab-treated patients. Cases of listeria meningitis occurred within 1 month of alemtuzumab dosing. The duration of increased risk for listeria meningitis is unclear

Listeria meningitisListeria meningitis

Conta linfocitaria e incidenza infezioni Conta linfocitaria e incidenza infezioni Conta linfocitaria e incidenza infezioni Conta linfocitaria e incidenza infezioni

CARE-MS II

Nessuna correlazionea Data are shown for alemtruzumab pooled

Havrdova E et al. ENS 2013, P528.

• Among 1486 patients treated with alemtuzumab (8266 patient-years of follow-up), the incidence of any malignancy was 2.4%a

No Increased Risk of Malignancies in No Increased Risk of Malignancies in No Increased Risk of Malignancies in No Increased Risk of Malignancies in AlemtuzumabAlemtuzumabAlemtuzumabAlemtuzumab----Treated PatientsTreated PatientsTreated PatientsTreated Patients

Thyroid Malignancy

• Most frequently occurring was thyroid malignancy

• Trial evidence suggests no increased risk; ascertainment bias may have been a factor, due to additional screening for alemtuzumab patients with thyroid AEs

• Risk not significantly different vs retrospective cohort of 32,348 MS patientsc

Thyroid Malignancy

Alemtuzumab 12 mg

(N=1217)

Alemtuzumab Pooled (N=1486)

Incidence of thyroid malignancy (%) 0.4 0.4

Rate of thyroid malignancyb 0.076 0.073

• Risk not significantly different vs retrospective cohort of 32,348 MS patients

• All cases of thyroid malignancy were stage 1 and of a papillary type; 3 patients had microcarcinomas (<10 mm)

39

Cut-off date: May 1, 2015.a 0.496 events per 100 patient years; b events per 100 patient-years; c Standardised incidence ratio (SIR): 0.98, 95% CI: 0.44–2.19.Expected number of events was 6.10/1000 patient-years.

Lecumberri B et al. ECTRIMS 2015, P117.

Continued assessment of malignancies in long-term follow-up studies and

post-marketing experience

DACLIZUMABDACLIZUMABDACLIZUMABDACLIZUMAB

OverviewOverviewOverviewOverview safetysafetysafetysafetyStudi verso placeboStudi verso placeboStudi verso placeboStudi verso placebo

SELECT

Placebo

(n=204)

Daclizumab

150 mg

(n=208)

Daclizumab

300 mg

(n=209)

SELECTION: AEs e SAEs pazienti trattati continuativamente per 2 anni erano simili a quelli dello studio SELECT e a quelli dei pazienti che

SELECT (n=208) (n=209)

Any AE, % 79 73 76

Any serious AE, % 26 15 17

Any serious AE excluding MS relapse, % 6 7 9

Death, n 0 1* 0

Discontinuation of treatment due to AE, % <1 3 4

Withdrawal from trial due to AE, % <1 2 1

SELECTION: AEs e SAEs pazienti trattati continuativamente per 2 anni erano simili a quelli dello studio SELECT e a quelli dei pazienti chehanno iniziato daclizumab nel SELECTION.

*Paziente deceduto in seguito a complicanze di un ascesso allo psoas. Nello studio SELECTION un paziente passato a Daclizumab300 mg è deceduto per epatite autoimmune.

Gold R, et al; SELECT study investigators. Lancet. 2013; Giovannoni G, et al; SELECTION Study Investigators. Lancet Neurol. 2014

Daclizumab Daclizumab

AEsAEsAEsAEs più comuni* più comuni* più comuni* più comuni* Studi verso placeboStudi verso placeboStudi verso placeboStudi verso placebo

SELECT, AE, %Placebo

(n=204)

150 mg

(n=208)

300 mg

(n=209)

MS relapse 38 23 20

Nasopharyngitis 15 14 14

Upper respiratory tract infection 7 9 11

Headache 10 10 10

Pharyngitis 4 6 6

Oral herpes 5 5 6

Rash 3 6 5

Risultati simili sono stati osservati nel SELECTION

* AE osservati in più del 5% dei pazienti

In grassetto= valori con una differenza >2% rispetto al placebo

Gold R, et al; SELECT study investigators. Lancet. 2013; Giovannoni G, et al; SELECTION Study Investigators. Lancet Neurol. 2014

STUDIO DECIDEIFN beta-1a

30 mcg

(n=922)

Daclizumab

150 mg

(n=919)

Overview safetyStudio verso IFNβ

(n=922) (n=919)

Any AE, n (%) 842 (91) 838 (91)

AEs by severity, n (%)

Mild

Moderate

Severe

241 (26)

493 (53)

108 (12)

229 (25)

482 (52)

127 (14)

SAE (excluding MS relapse), n (%) 88 (10) 141 (15)

Treatment discontinuation due to AE (excluding MS relapse), n (%) 81 (9) 130 (14)

Death*,n 4 1

*All deaths were considered unrelated to treatment. Deaths in the IFN beta-1a group were acute myocardial infarction, peritonitis, suicide, and metastatic cancer of the pancreas. The death in the Daclizumabgroup was due

to aspiration pneumonia in a patient who had a MS relapse involving the brain stem after withdrawing from the study.

Elaborato da Kappos L, et al. N Engl J Med. 2015;373:1418–28.

STUDIO DECIDE

IFN beta-1a

30 mcg

(n=922)

Daclizumab

150 mg

(n=919)

Infezioni, eventi cutanei e tossicità epaticaStudio verso IFNβ

(n=922) (n=919)

Infections, n (%)

Any AE

SAEs

523 (57)

15 (2)

595 (65)

40 (4)

Cutaneous events, n (%)

Any AE

SAEs

177 (19)

1 (<1)

342 (37)

14 (2)

Hepatic laboratory abnormalities, n (%)

ALT or AST >5x ULN

ALT or AST >3x ULN and Total Bilirubin >2x ULN

31 (3)

1 (<1)

59 (6)

7 (<1)

*

*ALT or AST >3x ULN and Total Bilirubin >2x ULN

Hy’s Law Cases*

1 (<1)

1

7 (<1)

1

*Clinical assessment of causality based on structured approach (Rockey et al. 2010. Hepatology 51:2117). One case in each group with causality score of “probable” or higher.

Elaborato da Kappos L, et al. N Engl J Med. 2015;373:1418–28.

*

Lancet 2011; 378: 1779–87Lancet 2011; 378: 1779–87

Efficacy and safety of ocrelizumab in relapsing multiple sclerosis

- results of the interferon-beta-1a-controlled, double-blind,

Phase III OPERA I and II studiesPhase III OPERA I and II studies

S.L. Hauser

, G.C. Comi

, H.-P. Hartung

, K. Selmaj

, A. Traboulsee

, A. Bar-Or

, D.L. Arnold

, G. Klingelschmitt

,A. Kakarieka

Overall, the proportion of patients in the ocrelizumab

group with adverse events was similar to interferon beta-1a

in a pooled analysis of both studies (83.3 percent in each

treatment group); the most common adverse event

associated with ocrelizumab was infusion-related

reactions (34.3 percent of patients who received

ocrelizumab experienced at least one infusion-related ,A. Kakarieka

, F. Lublin

, H. Garren

, L. Kappos

, on behalf of the OPERA I and II

clinical investigators

ocrelizumab experienced at least one infusion-related

reaction vs. 9.7 percent for interferon beta-1a). The

proportion of patients in the ocrelizumab group with

serious adverse events, including serious infections, was

also similar to interferon beta-1a (6.9 percent vs. 8.7

percent, respectively).

Ectrims, 2015

Efficacy and Safety of Ocrelizumab in Primary Progressive

Multiple Sclerosis: Results of the Phase III Double-Blind, Placebo-

Controlled ORATORIO Study

Overall, adverse events and serious adverse events were Overall, adverse events and serious adverse events were

similar in both groups.Xavier Montalban11,

Bernhard Hemmer4,7,

Kottil Rammohan9,

Gavin Giovannoni6,

Jerome De Seze8,

Amit Bar-Or3,

Douglas Arnold5,3,

Annette Sauter1,

Donna Masterman2,Donna Masterman2,

Paulo Fontoura1,

Hideki Garren1,

Peter Chin2 and

Jerry Wolinsky10

AAN, 2016

I farmaci oraliI farmaci oraliI farmaci oraliI farmaci orali

*

*

*

*

*

*

*

*

*

53

56

Overview safety Overview safety Overview safety Overview safety studistudistudistudi DEFINE+CONFIRMDEFINE+CONFIRMDEFINE+CONFIRMDEFINE+CONFIRM

*

*

B confermati a 6 anni (ENDORSE)

*Incidence represents cumulative incidence throughout the observation period; †No death was assessed by the investigator as related to study drug. Deaths included a

cardiorespiratory arrest following respiratory failure due to aspiration pneumonia and an MS relapse/cardiorespiratory arrest in the bid/bid group and a suicide (liver failure

due to paracetamol overdose) in tid/tid group. Percentages based on ITT population.

Pozzilli C et al. ECTRIMS 2015

EventiEventiEventiEventi avversiavversiavversiavversi comunicomunicomunicomuni (≥10%) (≥10%) (≥10%) (≥10%) neglineglineglinegli studistudistudistudi fasefasefasefase

Be nell’estensione a 6 anni (ENDORSE)

Pozzilli et al ECTRIMS 2015

EventiEventiEventiEventi avversiavversiavversiavversi seriseriseriseri neglineglineglinegli studistudistudistudi fasefasefasefase

Phillips T. AAN 2013

Bconfermati nell’estensione a 6 anni (ENDORSE)

Pozzilli et al ECTRIMS 2015

IncidenzaIncidenzaIncidenzaIncidenza tumoritumoritumoritumori neglineglineglinegli studistudistudistudi fasefasefasefase

Phillips AAN 2013

… confermata… confermatanell’estensione a 5

anni (ENDORSE)

Pozzilli et al AAN 2015

RegistroRegistroRegistroRegistro gravidanzegravidanzegravidanzegravidanze ((((TECgistryTECgistryTECgistryTECgistry))))

Everage et al. ECTRIMS 2016

GravidanzaGravidanzaGravidanzaGravidanza

• Sulla base dei dati ad oggi disponibili, l’esposizione* al DMF nonè associata con un aumento di rischio di anomalie fetali o dioutcomes sfavorevoli.outcomes sfavorevoli.

• L’incidenza di aborti spontanei non differisce tra i gruppi ditrattamento ed è consistente con quella della popolazionegenerale.

*I dati ad oggi disponibili si riferiscono all’esposizione al DMF nel 1° trimestre di gravidanza.

Everage et al. ECTRIMS 2016, Li et al ECTRIMS 2015

67

AEs Occurring in ≥10% of Patients in the AEs Occurring in ≥10% of Patients in the AEs Occurring in ≥10% of Patients in the AEs Occurring in ≥10% of Patients in the TeriflunomideTeriflunomideTeriflunomideTeriflunomide 14 mg Arm14 mg Arm14 mg Arm14 mg Arm

AEs in Teriflunomide Core Studies

(Phase II, TEMSO, TOWER, and TOPIC)

Adverse Event,a n (%)

Placebo

(n=997)Teriflunomide 14 mg (n=1002)

Any class 853 (85.6) 885 (88.3)

Headache 150 (15.0) 157 (15.7)

ALT increase 98 (8.9) 150 (15.0)

Diarrhea 75 (7.5) 136 (13.6)

Hair thinning 50 (5.0) 135 (13.5)

*

*

*

aEvents with a crude incidence rate of ≥10% in the teriflunomide group (patients randomized to teriflunomide 14mg or 7mg), and ≥ 2% greater than placebo.

Comi et al. Mult Scler Relat Disord. 2016;5:97.

Hair thinning 50 (5.0) 135 (13.5)

Nausea 72 (7.2) 107 (10.7)

*

*

Long-Term Safety of Teriflunomide: AEs of Special Interest

Parameter Extension Data

• During the extension studies, most hepatic disorder-related AEs were ALT elevations that were

transient and reversible1-4

• ALT increase was the most frequent reason for treatment discontinuation in the extension studies

and Pool 21-3,5a

Hepatic events1-5 and Pool 21-3,5a

– This was driven by protocol requirements for treatment discontinuation upon ALT elevations of

>3x ULN

• Overall, data from Pool 2 did not suggest an increased risk of clinically relevant hepatic events with

longer term teriflunomide exposure5

Infections3,6

• Infection types similar between core and extension studies6

– Most common: nasopharyngitis, influenza, upper respiratory tract infection, urinary tract

infection, sinusitis, bronchitis, and gastroenteritis

• Serious infections infrequent and at a similar rate across treatment groups in both core and

extension studies for phase 2 and TEMSO, and at a lower rate for TOWER extension vs core

studies3,6

aPool 2 includes the placebo-controlled core studies and the Phase 2 and TEMSO extensions, represent >6800 patients years of treatment.

1. Kremenchutzky et al. Poster P7.223, AAN 2015. 2. O’Connor et al. Neurology. 2016;86:920. 3. Freedman et al. Poster EP1460, ECTRIMS 2015. 4. Comi et al. Poster P439, ECTRIMS 2011. 5. Comi et al. Mult Scler Relat Disord. 2016;5:97. 6. Leist et al. Poster P7.268, AAN 2015.

Malignancies5,6

• Does not appear to be an increased risk of malignancy with teriflunomide in the clinical trial

program to date5,6

• Reported tumors had no unusual pattern of occurrence5,6

• No hematological malignancies (ie, leukemia or lymphomas) were reported5,6

*

Infection TEAEsInfection TEAEsInfection TEAEsInfection TEAEs

Infection TEAE, n (%) Placebo

(n=806)

Teriflunomide 7 mg (n=838)

Teriflunomide 14 mg (n=786)

Any Infection TEAE 439 (54.5) 454 (54.2) 420 (53.4)

Serious TEAE 20 (2.5) 20 (2.4) 20 (2.5)

Two serious opportunistic infections in the teriflunomide 14 mg group• One patient experienced gastrointestinal tuberculosis, leading to permanent discontinuation of

treatment• One patient developed hepatitis with cytomegalovirus infection, and discontinued treatment

• Two patients died as a result of infections• 1 placebo patient / respiratory tract infection

Serious TEAE 20 (2.5) 20 (2.4) 20 (2.5)

Opportunistic infection* 56 (6.9) 68 (8.1) 72 (9.2)

Serious opportunistic infection 2 (0.2) 0 2 (0.2)

• 1 placebo patient / respiratory tract infection• 1 teriflunomide 14 mg patient / Gram-negative bacterial sepsis

TEAE, treatment-emergent adverse event

*A search for opportunistic infections was performed based on the available guideline recommendations from the Centers for Disease Control and Prevention (CDC), the

National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America

72

PostPostPostPost----marketing Case Reportmarketing Case Reportmarketing Case Reportmarketing Case ReportFatal Toxic Epidermal NecrolysisFatal Toxic Epidermal NecrolysisFatal Toxic Epidermal NecrolysisFatal Toxic Epidermal Necrolysis

Post-marketing Case Report1

• A woman with RMS was admitted to hospital with symptoms of dyspnea, fever, catarrh (excessive build-up of thick

phlegm), vulvar pruritus (vaginal itching), odynophagia (painful swallowing) and an erythematous macular eruption

(rash).(rash).

• This patient was previously treated with teriflunomide for 28 days. On day 19 post treatment initiation, she had

transitory flu-like symptoms with resolution after self-medication with paracetamol.

• On day 28 post treatment initiation, she reported fever and asthenia (weakness and loss of energy), and teriflunomide

was discontinued. The patient was hospitalized on day 30.

• This patient developed acute respiratory failure during hospitalization, with a toxic epidermal necrolysis (TEN) specific

severity-of-illness score of 5 (predictive mortality of 83%), and clinical symptoms including detached diffuse erythema,

confluent flaccid blisters with positive Nikolsky’s sign, and detachment of the skin and mucosae.

• Diagnosis of TEN was confirmed shortly thereafter. The patient was treated with cyclosporin and cholestyramine, to

accelerate the clearance of teriflunomide. The patient’s clinical condition worsened with no cutaneous healing and

multiple organ failure, leading to death 9 days after hospitalization, 39 days after initiation of teriflunomide treatment.

• Teriflunomide was reported as the only causative drug in this case. This opinion was based on usage of the ALDEN (algorithm of drug causality for EN) algorithm used to evaluate drug causality for both Stevens-Johnson syndrome and TEN1,2

The patient had previously received IFN-β1a and dimethyl fumarate, which were discontinued due to poor tolerance (flu-like symptoms and rash, respectively)1

1. Gerschenfeld et al. Mult Scl J. 2015;21:1476. 2. Sassolas et al. Clin Pharmacol Ther. 2010:88:60.

multiple organ failure, leading to death 9 days after hospitalization, 39 days after initiation of teriflunomide treatment.

Preclinical Studies: Risk of Preclinical Studies: Risk of Preclinical Studies: Risk of Preclinical Studies: Risk of TeratogenicityTeratogenicityTeratogenicityTeratogenicity

• In animal studies, teriflunomide had embryotoxic and teratogenic effects1

• Genetic and teratogenic effects were likely due to the pharmacologic1

mechanism of action of teriflunomide (DHODH inhibition)

To date, no human signal for teratogenicity has been observed in the

teriflunomide clinical development program2

CLARITY: study design and endpoints

76

Primary endpointARR at Year 2

Secondary and tertiary endpoints at Year 2 • Proportion of relapse-free patients• Time to 3-month sustained disability progression• Mean number of combined unique MRI lesions• Mean number of active T1 Gd+ and active T2

lesions.

ARR, annualized relapse rate; Gd+, gadolinium enhancing; RRMS, relapsing–remitting MS.

Giovannoni G et al. N Engl J Med 2010;362:416–26.

CLARITY: safety overview

Placebo Cladribine tablets

Patients, n (%)(n=435)

3.5 mg/kg

(n=430)

5.25 mg/kg

(n=454)

All cladribine

(n=884)

Any AE 319 (73.3) 347 (80.7) 381 (83.9) 728 (82.4)

Most common AEsa

Headache 75 (17.2) 104 (24.2) 94 (20.7) 198 (22.4)

Lymphopenia 8 (1.8) 93 (21.6) 143 (31.5) 236 (26.7)

Nasopharyngitis 56 (12.9) 62 (14.4) 58 (12.8) 120 (13.6)

URTI 42 (9.7) 54 (12.6) 52 (11.5) 106 (12.0)

Nausea 39 (9.0) 43 (10.0) 50 (11.0) 93 (10.5)

AEs leading to treatment discontinuation 9 (2.1) 15 (3.5) 36 (7.9) 51 (5.8)

AEs leading to study withdrawal 5 (1.1) 5 (1.2) 10 (2.2) 15 (1.7)

In CLARITY, AEs were

generally similar

between groups

77

AEs leading to study withdrawal 5 (1.1) 5 (1.2) 10 (2.2) 15 (1.7)

Serious AEs 28 (6.4) 36 (8.4) 41 (9.0) 77 (8.7)

Deathsb 2 (0.5) 2 (0.5) 2 (0.4) 4 (0.4)

Events, n

Any AE 1958 2514 2712 5226

AE, adverse event; URTI, upper respiratory tract infection. Cook S et al. Mult Scler 2011;17:578–93. See notes pages for footnotes.

CLARITY: most cases of lymphopenia in patients treated with cladribine tablets are mild or moderate in severity (Grade 0–2)

In CLARITY, most patients treated with

cladribine tablets had lymphocyte

counts between Grades 0 and 2

over 2 years

78

. aGraded according to the Common Terminology Criteria for Adverse Events: 1, <lower limit of normal–800/mm3; 2, <800–500/mm3; 3, <500–200/mm3; 4, <200/mm3. Giovannoni G et al. N Engl J Med

2010;362:416–26 (supplementary materials).

CLARITY: serious adverse events

Placebo Cladribine tablets

(n=435)3.5 mg/kg 5.25 mg/kg

Cladribine

overall

There was no distinct pattern of

malignancy types in patients

Patients, n (%)

(n=435)3.5 mg/kg

(n=430)

5.25 mg/kg

(n=454)overall

(n=884)

Any SAE 28 (6.4) 36 (8.4) 41 (9.0) 77 (8.7)

Most commona SAEs that show treatment

differencesb by system organ class

Neoplasms – benign, malignant and

unspecified

0 6 (1.4) 4 (0.9) 10 (1.1)

Gastrointestinal disorders 2 (0.5) 4 (0.9) 5 (1.1) 9 (1.0)

Injury, poisoning and procedural complications 2 (0.5) 9 (2.1) 0 9 (1.0)

Most commonc SAEs that show treatment

differencesb by system organ class

malignancy types in patients

treated with cladribine tablets in

CLARITY and no evidence of a

dose-dependent effect on

malignancy

In CLARITY, the SIR for malignancies compared

with the expected rate in a population matched for country, gender and age

79

differencesb by system organ class

Uterine leiomyoma 0 3 (0.7) 2 (0.4) 5 (0.6)

Lymphopenia 0 3 (0.7) 1 (0.1) 4 (0.5)

. aReported in >1% of patients in any treatment group. bThe percentage of patients in one active treatment group is ≥2 x the percentage of patients in the placebo group, or the percentage of patients in the

placebo group is ≥2 x the percentage of patients in the active treatment group. cReported in >0.5% of patients in any treatment group.

SAE, serious adverse event; SIR, standardized incidence ratio. Cook S et al. Mult Scler 2011;17:578–93.

country, gender and age was 0.99 (95% CI:

0.25, 2.70)

Independent evidence of no increased risk of malignancy with cladribine tablets in 2Independent evidence of no increased risk of malignancy with cladribine tablets in 2Independent evidence of no increased risk of malignancy with cladribine tablets in 2Independent evidence of no increased risk of malignancy with cladribine tablets in 2----year year year year pivotal studiespivotal studiespivotal studiespivotal studies

Proportion of patients with malignancy in treatment groups of all trials The authors concluded that cladribine at the doses

used in CLARITY does not increase the risk of cancer in patients with RMS over 2 years. The

SENTINEL – natalizumab (+continued IFN β-1a use)

TENERE – IFN β-1a

TENEERE – teriflunomide

CARE-MS II – IFN β-1a

CARE-MS II – alemtuzumab

CARE-MS I – IFN β-1a

CARE-MS I – alemtuzumab

TRANSFORMS – IFN β-1a

TRANSFORMS – fingolimod

AFFIRM – natalizumab

TEMSO – teriflunomide

SENTINEL

AFFIRM

TEMSO

Phase III trials Proportion of patients with malignancy in

placebogroups of Phase III trials

Phase III trials

cancer in patients with RMS over 2 years. The supposed increase in risk may have been driven by an unusually low cancer rate in the placebo group

of CLARITY

FREEDOMS – fingolimod

CONFIRM – glatiramer acetate

CONFIRM – dimethyl fumarate

DEFINE – dimethyl fumarate

CLARITY – cladribine

IFN, interferon; RMS, relapsing MS. Pakpoor J et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158.

TEMSO

FREEDOMS

CONFIRM

DEFINE

CLARITY

81

0 1 2 3 4 50 1 2 3 4 5

Phase III trials

Proportion of patients with malignancy (%)Proportion of patients with malignancy (%)

Paziente a basso R, progetto di gravidanza a brevePaziente a basso R, progetto di gravidanza a brevePaziente a basso R, progetto di gravidanza a brevePaziente a basso R, progetto di gravidanza a breve

Comorbidità SIComorbidità

• Tiroidea

• Epatica

• Autoimmune

• Renale

• Tratto trombofilico

SI

Glatiramer acetato

NO

GA, Interferone -beta

Paziente a basso R, no progetto di gravidanza a brevePaziente a basso R, no progetto di gravidanza a brevePaziente a basso R, no progetto di gravidanza a brevePaziente a basso R, no progetto di gravidanza a breveComorbidità

• Tiroidea

• Epatica

• Autoimmune

SI

Glatiramer acetato

NO

• Renale

• Tratto trombofilico

GA, Interferone –beta, Teri, BG-12

Se comorbidità

• Epatica

• Ipertensione arteriosa

• Infettiva (TBC)

• Neuropatia

Evitare

Teri

Se comorbiditàSe comorbidità

• Gastrointestinale

• Infettiva

• Renale

Evitare

BG-12

Se paziente a R oncologico (Pap- test, mammella, storia clinica)

Evitare

Teri, BG-12

Paziente a medio R (attività media, midollo +) Paziente a medio R (attività media, midollo +) Paziente a medio R (attività media, midollo +) Paziente a medio R (attività media, midollo +)

Fingolimod

Paziente ad alto R (alta attività )Paziente ad alto R (alta attività )Paziente ad alto R (alta attività )Paziente ad alto R (alta attività )

JCV- JCV+

Natalizumab Alemtuzumab

Eterogeneità e disomogeneità geografica degli studi disponibili

Comorbidità con maggiore incidenza: Comorbidità con maggiore incidenza:

ipertensione, stroke e tumori

Comorbidità con maggiore prevalenza:

depressione, ansia, ipertensione, iperlipidemia, malattie respiratorie croniche

Comorbidità = riduzione di tollerabilità, aderenza e sicurezza

Raccomandazioni consensuali:

Promuovere studi su incidenza comorbidità (malattie

autoimmuni, diabete, tumori, ipertensione, emicrania)

Muoversi verso trials più pragmatici, che includano soggetti con

comorbidità salvo controindicazioni specifiche

Effettuare analisi di sottogruppo per comorbiditàEffettuare analisi di sottogruppo per comorbidità

Promuovere ed ottimizzare studi di fase IV (farmacovigilanza)

Marrie et al., Neurology 2016