La minimizzazione del rischio di eventi avversi nelle nuove terapie per la Sclerosi Multipla Anna Maria Repice

Disclosures Dr. Anna Maria Repice has recived honoraria for public speaking, advisory board and travel grants by Novartis, Merck Serono, Biogen, Sanofi Genzyme, Teva, Roche

LA SCELTA TERAPEUTICA Terapia di escalation vs Terapia induttiva Tintorè M et al. LA SCELTA TERAPEUTICA Terapia di escalation vs Terapia induttiva ( criteri AIFA) l’efficacia La tollerabilità La sicurezza Modalità di somministrazione Caratteristiche del paziente

Farmaci di seconda linea Sicurezza Reazioni di infusione Infezioni Tumori Parametri ematologici Gravidanza I nuovi farmaci - Alemtuzumab - Cladribina - Ocrelizumab

Minimizzazione del rischio Fase di screening Esami di laboratorio Esami strumentali vaccinazioni Fase di monitoraggio

Farmaci di seconda linea Sicurezza Reazioni di infusione Infezioni Tumori Parametri ematologici Gravidanza I nuovi farmaci - Alemtuzumab - Cladribina - Ocrelizumab

Alemtuzumab AE studi registrativi e real life

Norme Igienico Alimentari  sicurezza dei cibi (Guidelines on the application of general principles of food hygiene to the control of Listeria monocytogenes in ready-to-eat foods)  Istruire tutti coloro che preparano il cibi alle norme igieniche suppletive  Attenzione alla preparazione Lavarsi le mani prima di maneggiare il cibo. Usare utensili e piani di lavoro per la preparazione puliti Separare i cibi crudi dai cibi cotti Lavare accuratamente le verdure fresche prima del consumo Dividere gli avanzi di cibo in contenitori poco profondi per un raffreddamento veloce Conservazione accurata dei cibi refrigerati Cuocere il cibo scongelato entro le due ore Finire di cuocere gli alimenti semicotti prima di servirli Consumo dei cibi reperibili entro la data di scadenza Portare ad ebollizione le minestre e le salse prima di servirli  

Profilassi Antibiotica ABN Guidelines Evitare i seguenti prodotti   Prodotti di latteria non pastorizzati ( creme, yogurt, burro) Formaggi non pastorizzati o che contengono muffe ( preferire prodotti caseari pastorizzati) Pollame crudo o poco cotto , carni, pesce e frutti di mare crudi o poco cotti Salumi a breve Pesce fresco affumicato pronto per il consumo 6. Evitare prodotti freschi di pasticceria ed il gelato artigianale (preferire il prodotto industriale) 7. Evitare cibi cotti da troppo tempo 8. Evitare centrifugati di verdura fresca 9. Preparazioni gastronomiche da consumarsi fredde (per es. patè di carni fresche) 10. Attenzione all’acqua da bere Per coloro che praticano giardinaggio e/o hanno animali domestici la raccomandazione di lavarsi sempre accuratamente le mani dopo ogni contatto. Profilassi Antibiotica ABN Guidelines per i pazienti non osservanti la dieta: cotrimossazolo 960mg 3 volte a settimana per tutto il mese successivo alla somministrazione per pazienti osservanti la dieta: amoxicilina da 1 gr cpr tre volte al giorno nei 7 gg precedenti e dieta nel mese successivo o in alternativa cotrimossazolo 960 mg due volte al giorno nei 4 giorni precedenti la 1 infusione e 8 giorni dopo e dieta nel mese successivo

Farmaci di seconda linea Sicurezza Reazioni di infusione Infezioni Tumori Parametri ematologici Gravidanza I nuovi farmaci - Alemtuzumab - Cladribina - Ocrelizumab

Scheda tecnica Mavenclad

Farmaci di seconda linea Sicurezza Reazioni di infusione Infezioni Tumori Parametri ematologici Gravidanza I nuovi farmaci - Alemtuzumab - Cladribina - Ocrelizumab

Ocrelizumab IRR sintomi (≥5%) OPERA I & OPERA II1 ORATORIO2 Patients, n (%) IFN β-1a 44 µg (n=826) Ocrelizumab 600 mg (n=825) Placebo (n=239) Ocrelizumab 600 mg (n=486) Total number of patients with IRRs 80 (9.7) 283 (34.3) 61 (25.5) 194 (39.9) Pruritus 6 (7.5) 85 (30.0) 2 (3.3) 56 (28.9) Flushing 9 (11.3) 45 (15.9) 10 (16.4) 46 (23.7) Rash 2 (2.5) 1 (1.6) 40 (20.6) Headache 14 (17.5) 27 (9.5) 21 (34.4) 31 (16.0) Pyrexia 11 (13.8) 12 (4.2) 4 (6.6) 26 (13.4) Throat irritation 1 (1.3) 67 (23.7) Nausea 13 (16.3) 10 (3.5) 16 (8.2) Oropharyngeal pain 24 (8.5) 15 (7.7) Dizziness 5 (6.3) 6 (2.1) 7 (11.5) 13 (6.7) Tachycardia 13 (4.6) 3 (4.9) 12 (6.2) Urticaria 25 (8.8) 10 (5.2) Hypotension 9 (3.2) 6 (9.8) 7 (3.6) More patients in the ocrelizumab group (34.3%) than in the IFN β-1a group (9.7%) had at least one IRR The most frequent IRR symptoms (occurring in ≥5% patients ) over 96 weeks in the ocrelizumab group were pruritus, rash, throat irritation and flushing In contrast, the most frequent IRR symptoms in the IFN β-1a group were headache, tachycardia, nausea and pyrexia Infusion-related reaction (IRR): any sign or symptom experienced by patients during the infusion of a pharmacological agent, or any event occurring on the first day of drug administration Percentages of total number of patients with IRRs are based on N. Percentages of number of patients with symptoms are based on total number of patients who had IRRs. IFN, interferon; IRR, infusion-related reaction. 1. Selmaj K, et al. Presented at EAN 2016 (Poster P11195); 2. Montalban X, et al. Presented at EAN 2016 (Poster P21133).

OPERA (pooled) controlled Infezioni e SAE Event OPERA (pooled) controlled treatment period* ORATORIO controlled Ph II/Ph III and OLEs population† OCR all-exposure population‡  IFN β-1a rate per 100 PY (95% CI)§  OCR rate per Placebo rate per 100 PY (95% CI)§ Feb 2018 rate per 100 PY (95% CI)§,‖ Infections and infestationsf Urinary tract infection Nasopharyngitis Upper respiratory tract infection Bronchitis Influenza 67.8 (63.5–72.2) 9.7 (8.1–11.4) 8.3 (6.9–9.9) 9.4 (7.8–11.1) 2.2 (1.5–3.1) 3.3 (2.4–4.4) 84.5 (79.9–89.4) 11.6 (9.9–13.5) 13.0 (11.2–15.0) 13.3 (11.5–15.3) 3.5 (2.6–4.6) 3.1 (2.3–4.2) 72.5 (66.5–79.0) 17.8 (14.9–21.2) 17.7 (14.8–21.0) 2.9 (1.8–4.4) 3.4 (2.2–5.1) 70.8 (66.8–75.0) 15.1 (13.2–17.1) 12.8 (11.1–14.6) 5.2 (4.2–6.5) 2.6 (1.9–3.5) 4.6 (3.6–5.7) 71.5 (69.8–73.2) 13.0 (12.3–13.7) 11.2 (10.5–11.9) 9.6 (9.0–10.3) 3.2 (2.9–3.6) 3.1 (2.7–3.4) 74.5 (72.9–76.1) 12.6 (12.0–13.3) 12.7 (12.0–13.4) 9.8 (9.2–10.4) 3.1 (2.8–3.5) 3.4 (3.0–3.7) Serious adverse events¶ Serious infections‡‡ Number of confirmed serious OIs§§ 6.29 (5.05–7.75) 1.79 (1.16–2.64) 5.39 (4.26–6.72) 0.83 (0.43–1.45) 12.07 (9.68–14.87) 3.02 (1.89–4.57) 10.15 (8.65–11.83) 2.74 (1.99–3.68) 7.65 (7.10–8.23) 2.14 (1.85–2.45) 2 7.23 (6.73–7.75) 2.00 (1.74–2.28) Slide provided by client Overall Adverse Events As of February 2018, the rate of AEs was 242 (95% CI 239–245) per 100 PY in the OCR all-exposure population, consistent with the rate observed at the primary analysis cut-off date The most common AEs included IRRs, UTIs and upper respiratory tract infections Of those patients who received OCR, serious AEs were reported at a rate of 7.23 (95% CI 6.73–7.75) events per 100 PY in the OCR all-exposure population The most common events were classified as infections As of February 2018, the rate of AEs leading to treatment withdrawals was 1.06 (95% CI 0.88–1.27) per 100 PY in the OCR all-exposure population The rate of AEs leading to treatment withdrawals remained stable with additional patient exposure *Hauser SL, et al. Presented at ECTRIMS 2018 (Poster number P1229).

Rate of serious infections for 100 patient-years during the phase III studies and OLE 2 1 3 4 6 5 7 8 9 Rate Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 PPMS exposure (PY): RMS exposure (PY): 633 OCR; 235 PBO 1,422 OCR; 793 IFN β-1a 601 OCR; 217 PBO 1,360 OCR; 606 IFN β-1a 422 OCR; 186 PBO 1,254 OCR 403 OCR; 85 PBO 882 OCR 368 OCR 609 OCR 206 OCR 198 OCR RMS OCR RMS IFN β-1a PPMS OCR PPMS PBO Slide provided by client Rate per 100 patient years of serious infections during the Phase III studies and OLE periods Infections As of February 2018, the rate of infections was 74.5 (95% CI 72.9–76.1) per 100 PY in the OCR all-exposure population (Table 2), consistent with the rate observed at the primary analysis cut-off date The most common serious infections were UTIs and pneumonia In the OCR all-exposure population, the rate per 100 PY of serious infections as of February 2018 (2.00 [95% CI 1.74–2.28]) was similar to the rate observed at the primary analysis cut-off date In the pooled RMS population, the rate per 100 PY of serious infections increases until Year 3 (1.75 [95% CI 1.10–2.66]), with no further sustained increase (Figure 2) Among patients with PPMS, the rate per 100 PY of serious infections increases from Year 3 to Year 5 (Figure 2) There was no change in the type or pattern of serious infections observed over time Serious opportunistic infections (post-marketing and in clinical trials outside of the controlled treatment period) To date, there have been no fatal cases of serious opportunistic infections reported Despite extensive attempts to follow up, not all post-marketing cases are well documented For cases where information is available, patients recovered with treatment by standard therapies Outside of the controlled treatment period, there have been reported cases of serious opportunistic Herpes infections There have been other individual cases of serious opportunistic infections, with no pattern in type of infection As of September 2018, no unconfounded cases of PML with OCR have been reported Six confirmed cases of carry-over PML from a previous DMT were reported outside of the OCR clinical trials (none fatal). The cases have been reported by the treating physicians and submitted to the regulators as related to the previous treatment with either natalizumab (five cases) or fingolimod (one case) Hauser SL, et al. Presented at ECTRIMS 2018 (Poster number P1229).

Pooled OPERA I and OPERA II (RMS)1 Herpes infection incidence OPERA I , OPERA II and ORATORIO (as of 20 January 2016) Pooled OPERA I and OPERA II (RMS)1 ORATORIO (PPMS)2 Slide provided by client In the active-controlled (RMS) clinical trials and in the placebo controlled (PPMS) clinical trial, herpes infections were reported more frequently in ocrelizumab treated patients than in the control groups Herpes infections were predominantly mild to moderate in severity; all herpes infections were mild-to-moderate in ORATORIO and all but one were in OPERA (one patient was hospitalised with a severe case of genital herpes simplex infection, which resolved with treatment) IFN β-1a 44 μg (n=826) Ocrelizumab 600 mg (n=825) Placebo (n=239) Ocrelizumab 600 mg (n=486) 1. Hauser S et al. N Engl J Med 2017;376:221–34; 2. Montalban X et al. N Engl J Med 2017;376:209–20.

Incidence rates per 100 patient years of all malignancies over time: crude compared with the Danish MS registry 0.48 (0.35–0.64) 0.45 (0.32–0.63) (0.31–0.64) 0.40 (0.26–0.59) 0.44 (0.29–0.65) 0.43 (0.26–0.66) (0.33–0.60) Ph II/Ph III and OLEs population OCR all-exposure population Slide provided by client Danish MS registry: 0.67 (0.63–0.71) PBO+IFN β-1a 0.20 (0.05–0.50) Over time, the crude incidence rate of malignancy per 100 PY in the OCR all-exposure population fluctuated and remained within epidemiological range for patients with MS (Figure 3A) Primary analysis cut-off datea January 2016a June 2016a September 2016a February 2017a September 2017b February 2018b The incidence rate of first malignancy (number of first malignancy events per 100 PY) was calculated. Crude incidence rate (95% CI): Hauser SL, et al. Presented at ECTRIMS 2018 (Poster number P1229).

Incidence rates per 100 patient years of female breast cancer over time: crude compared with two MS registries (Swedish and Canadian) 0.21 (0.11–0.37) 0.19 (0.09–0.37) 0.22 (0.10–0.41) 0.23 (0.11–0.44) (0.10–0.46) 0.26 (0.11–0.54) 0.20 (0.10–0.34) Ph II/Ph III and OLEs population OCR all-exposure population Slide provided by client (0–0.29) Swedish: 0.20 (0.30–0.31) The crude incidence rate of female breast cancer in the OCR all-exposure population remained stable over time (Figure 4A) Canadian: 0.14 (0.11–0.16) PBO+IFN β-1a Primary analysis cut-off datea January 2016a June 2016a September 2016a February 2017a September 2017b February 2018b The incidence rate of first malignancy (number of first malignancy events per 100 PY) was calculated. Crude incidence rate (95% CI): Canadian British Columbia MS registry: 0.14 (0.11–0.16); Swedish MS registry: 0.20 (0.18–0.22). aIncludes patients who received any dose of OCR during the controlled treatment and associated OLE periods of the Phase II and Phase III studies; bIncludes patients who received any dose of OCR during the controlled treatment and associated OLE periods of the Phase II and Phase III studies, plus VELOCE, CHORDS, CASTING and OBOE. CI, confidence interval; IFN, interferon; MS, multiple sclerosis; OCR, ocrelizumab; OLE, open-label extension; PBO, placebo; Ph, Phase; PY, patient years; SEER, Surveillance, Epidemiology, and End Results Hauser SL, et al. Presented at ECTRIMS 2018 (Poster number P1229).

Ph II/Ph III and OLEs population OCR all-exposure population Incidence rates per 100 patient years of female breast cancer over time: age-standardized compared with the Danish MS registry and SEER database Ph II/Ph III and OLEs population OCR all-exposure population 0.20 (0.10–0.40) 0.19 (0.08–0.42) 0.21 (0.09–0.47) 0.23 (0.10–0.50) 0.24 (0.10–0.54) 0.28 (0.10–0.67) (0.10–0.36) Danish MS registry: 0.17 (0.14–0.21) DATO STANDARDIZZATO PER ETà SEERc: 0.14 (0.14–0.14) Primary analysis cut-off datea January 2016a June 2016a September 2016a February 2017a September 2017b February 2018b Hauser et al. ECTRIMS 2018. P#1229

Ocrelizumab scheda tecnica

OCRE and vaccines: results from VELOCE study 68 pts OCRE and 34 pts INF underwent to tetanus vaccine, PPV-23 e PCV-13, and seasonal influenza vaccine after 1 cycle with different timing 12 wks TT, 16 wks 23 PPV-23 and 20 wks PCV-13 Anti-tetanus titer Positive response to number of S. pneumoniae serotypes 4 weeks after 23-PPV administration OCR (all) Control (IFN β or no DMT) OCR (all) Control (IFN β or no DMT) Slide provided by client Total IgG, IgA, and IgM levels were evaluated in 15 patients with NMOSDs treated with RTX (median follow-up 70 months). Anti-aquaporin 4 (AQP4)-IgG titration was performed on samples from 9 positive patients. Anti-tetanus (TET), anti-varicella-zoster virus (VZV), and anti-Epstein–Barr virus nuclear antigen (EBNA) IgGs were also tested in patients with NMOSDs and in 6 healthy controls (HCs). Results RTX reduced total IgG by 0.42 g/L per year, IgA by 0.08 g/L per year, and IgM by 0.07 g/L per year. Hypogammaglobulinemia (hypo-IgG) (IgG < 7 g/L) developed in 11/15 patients. Severe hypo-IgG (IgG < 4 g/L) was found in 3/15 patients, of whom 2 patients developed serious infectious complications. In group analysis, anti-AQP4 IgG titers were reduced by RTX over time, and a significant correlation between anti-AQP4 IgG titers and total IgG levels was found. The effects of RTX were observed on pathogen-specific IgGs as well. In particular, the levels of anti-TET IgG in patients were significantly lower than those in HCs. The half-life of anti-TET IgG was reduced by about 50% in patients compared with the general population. Conclusions Long-term RTX treatment is associated with the risk of hypo-Ig and reduction of anti-TET protection in patients with NMOSDs. Results obtained in this study suggest the importance of monitoring total and specific Ig levels before and during treatment with anti-CD20 drugs to prevent hypo-Ig–related complications and to optimize clinical management. Protective titer level Effect of vaccines is attenuated but still protective as for anti-tetanus D Stokmaier et al. VELOCE, Platform presentation number S36.002 AAN 2018

OCREVUS: criteri AIFA Pazienti SM-RR con malattia attiva in base a caratteristiche cliniche o radiologiche secondo criterio A (subresponder) o criterio B (highly active, spt naive) Pazienti SM-PP in fase precoce (durata e disabilità), con caratteristiche radiologiche di attività di malattia Controindicazioni: infezioni attive in corso  screening infettivologico Neoplasie maligne attive note  assicurarsi che il/la pz abbia effettuato gli esami di screening neoplastico consigliati per sesso ed età stato severamente immunocompromesso Wash-out: IFN/GA/BG12: nessuno (emocromo) TER: eliminazione accelerata (emocromo) FTY: 4-6 settimane (emocromo) natalizumab: 6 settimane + escludere PML con RM alemtuzumab: 9-12 mesi dopo ultima infusione Slide provided by client

Vaccine identity card Recommended vaccines: Timing of administration: Seasonal influenza every year Tetanus/diphtheria/pertussis acellular if never received or if tetanus more than 5-10 years Haemophilus influenzae type b Hepatitis B (3 doses) if HBcAb negative and HBsAb negative Hepatitis A (2 doses) if hepatitis A virus IgG negative and pts with risk factors or travelers Pneumococcal conjugate (PCV13) (1 dose) then by PPV23 (1 dose) after >2 months Meningococcal vaccines: MCV4 (1 dose) and MenB (2 doses) HPV for those <45 years (3 doses 0, 2 and 6 months) Varicella for those VZV IgG negative (2 doses 0 and at least 1 month) Measles/Rubella/Mumps in those with IgG negative Inactivated Herpes Zoster (only in VZV IgG positive, NOT YET available) Timing of administration: Inactivated vaccines: at least 2 weeks before the first administration of IS or after a variable period of interruption of tretment. Live attenuated vaccines: at least 4-6 weeks before the first administration of IS; they should not administrated during IS treatment or only after a variable period of interruption of DMD In case of therapy with high-dose steroids: Inactivated vaccines 4 weeks after the last dose of steroids Live attenuated vaccines 3 months after the last dose of steroids Slide provided by client

Take Home Messages Screening di base e monitoraggio nel tempo Considerare sempre il percorso terapeutico Necessità di adattare il programma di screening e di monitoraggio al farmaco e al profilo di rischio del singolo paziente Se possibile vaccinare alla diagnosi

Grazie per l’attenzione Gruppo Sclerosi Multipla Responsabile Prof Luca Massacesi Dott.ssa Anna Maria Repice Dott.ssa Claudia Mechi Dott.ssa Benedetta Forci Dott.ssa Alice Mariottini Dott. Matteo Pasca Dott. Stefano Filippini Dott.ssa Maria Di Cristinzi