Non inferiorità di Azatioprina verso interferone beta nella Sclerosi Multipla: ricadute cliniche ed economiche per il servizio sanitario regionale

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Agostina Lorenzi
7 anni fa
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1 Dipartimento di Neuroscienze, Farmaco e Salute Bambino Neurologia II Centro Riferimento Regionale Sclerosi Multipla National Institute of Neurological Disorders and Stroke Non inferiorità di Azatioprina verso interferone beta nella Sclerosi Multipla: ricadute cliniche ed economiche per il servizio sanitario regionale Luca Massacesi Firenze, SIN Toscana 28 Novembre 2014

2 Costi outline Risultati del 1 RCT italiano in campo neurologico finanziato da fondi per la ricerca indipendente dell AIFA Comune percezione di efficacia e sicurezza azatioprina nella SM Comparazione profili sicurezza

3 Studio finanziato da AIFA tra 2007 e 2012 (bando 2006) 17 Novembre 2014

4 Valore aggiunto di ricerca indipendente Valutazioni per nuove indicazioni di farmaci generici non sviluppati dai privati perché non più coperti da brevetto (di regola post-marketing) Confronto tra farmaci (cosa non richiesta da normativa europea per nuove approvazioni) Efficacia Sicurezza Tollerabilità Maneggevolezza Costi

5 Azathioprine generic medication (patent expired early in the 90s) developed in the 50s (Nobel Prize granted to the authors ) allowed first successful human organ transplantations; still used in kidney transplantation and in autoimmune diseases inhibit cell prolipheration including T cell proliph.; selective immunesuppressive activity recently discovered (AICD through B7 pathway suppression)

6 Multicentric Aza vs IFN Non-inferiority (M.A.I.N.) TRIAL Study design: Non-inferiority Randomized Single blinded pragmatic (drugs were prescribed)

7 efficacia

8 Effect of AZA and of IFNs on annualized Relapse Rate over 2 years 0,7 0,6 0,5 annualized relapse rate 0,4 0,3 0,2 AZA IFN 0,1 6E-16-0,1 I year II year I +II year

9 Non-inferiority of efficacy on relapse rate ratio

10 % pazienti con ricadute in 2 anni aza 1 IFN 1 aza 2 IFN 2 aza ricadute > 0 ricadute IFN 1+2

11 ODDS RATIOS OF BEING RELAPSE FREE AT 2 Y. 2,5 2 Odds Ratio 1,5 1 0,5 0 Cop1 IFNB1a im IFNB1b IFNB1a sc AZA(4)

12 Proportion of relapse free patients Cochrane metanalisis of studies on Aza effect vs placebo in MS (Casetta et al., JNNP 2009)

13 New T2 lesions (FLAIR) volume/2y (AZA n=50; IFNs n=47) mm AZA Trattamento IFN

14 0,6 Differenza EDSS in due anni Disability 0,5 0,4 0,3 0,2 0,1 0-0,1-0,2 aza IFN

15 ODDS RATIOS OF BEING RELAPSE FREE AT 2 Y. Odds Ratio 2,5 2 1,5 1 0,5 0 Cop1 IFNB1a im IFNB1b IFNB1a sc AZA(4)

16 Lesion and lymphocyte number time course 22 Gd+ lesion volume (mm 3 ) Lymphocyte number x * * * * * * * * * baseline induction treatment MONTHS

17 Metodological pitfalls of the AZA vs placebo RCTs Underpowered for the I ary end-point selected (disability); Relapse Rate (base of more recent trials success) II ary end-point ; Population included unfit for evaluating Relapse Rate (no selection of disease form); AZA underdosed Absence of brain MRI evaluation support.

19 compliance

20 Averse events related to Azathioprine Previously reported Bone marrow suppression: WBC Lymphocytes RBC Gastrointestinal problems Abnomal liver function tests General malaise Hair loss Flou like syndrome: Arthralgia/myalgia/fever Infection susceptibility Skin rash Intolerance Thiopurin methiltranferase deficiency Neoplasm risk therapy Observed in our experience (n= 135; FU: 7 aa): Abnomal liver function tests (reversible; 20%) Bone marrow suppression (100%): WBC Lymphocytes RBC Gastrointestinal disturbances (10) Skin rash (sun exposure; 2) Intolerance (2) Infections (1)

21 Titolo asse eventi avversi linfopenia grado 2 nausea flou like syndrome IFN aza pazienti con % pazienti

22 sicurezza

23 Frequenza neoplasie maligne in IBD trattati con Aza o con altro (f.u.: 13.5 aa; Fraser et al., 2002) 100% 80% 60% 40% 20% 0% Aza altro no neo plasi e

24 N e o p l a s i e ma l i g n e n e l l a c o o r t e d i p a z i e n t i S M d i L i o n e d a l a l ( n = ; C o n f a v r e u x e t a l ) 100% 90% 80% 70% 60% 50% % 30% 20% no* cancr o 10% 0% Aza no t r a t t a me nt o

25 Neoplasie maligne in pazienti con LES trattati con Azatioprina per almeno 6 mesi (n= 148) o con altre terapie (n= 210) tra il 1978 ed il 2002 (Nero et al., 2004) 100% 80% 60% 40% 20% 0% Aza altro outcome no neoplasie

26 100% 90% Frequenza trattamenti con Aza fra pazienti SM che hanno sviluppato neoplasie maligne e controlli SM appaiati (Confavreux, 1996) 80% 70% % 50% 40% 30% 20% 10% altro Aza < 1 mese Aza 0% neoplasie no neopl.

27 Sopravvivenza al 2002 di pazienti SM trattati con Aza (2.5 mg/kg/die; n= 149) o placebo (n= 151) per tre anni dal (Taylor et al., 2004) 100% 90% 80% 70% 60% 50% 40% % 20% 10% 0% Aza altro Aza altro trattamento no neopl. neopl. mal. viventi deceduti

28 Costi annuali SM Complessivi / anno/paziente EDSS < 5 Prev. 100/ : x = / anno paziente EDSS > 5 Prev. 70/ : x = Tot. Italia : / anno Farmaci per forme RR 300 M, Ia linea Circa 9.500/paz./ anno Interferoni beta Copaxone 140 M: IIa linea circa 20500/paz./ anno fingolimod natalizumab azatioprina 600/anno/ paziente

29 Number needed to treat to have 1 patient relapse free for 2 y Euros needed to pay in order to have 1 patient relapse free for 2 y NNT Keuro Cop1 IFNB1a IFNB1b IFNB1a sc AZA 0 Cop1 IFNB1a IFNB1b IFNB1a sc AZA

30 Grazie!

31 Indicazione ex 648: malattie autommuni a carattere neurologico ex lege 648 Ex lege 648, lista uso consolidato Consenso scritto Registro Report AIFA periodico Consenso scritto registro

34 Activity on brain Gd+ lesions number 3,5 of new treatments and AZA mean Gd+ lesion number 3 2,5 2 1,5 1 0,5 58% (10) 84% (14) 58% (33) 49% (35) 63% (8) 64% (14) 0 COP1 IFNB1b IFNB1a 22x3 sc IFNB1a 11x3 sc IFNB1a im AZA pretreatment pretreat. (new les.) treatment treatment (new les.)

35 MAIN trial End point Primary Non-inferiority of the Aza efficacy on Relapse Rate vs IFNs Secondary New brain lesion number EDSS Intervention Aza 3 mg/kg/day (target dose) IFN: Avonex 38%; Betaferon 6%; Rebif22 45%; Rebif44 11% Follow up 30 italian centers Centralized randomization 2 years FU Clinical evaluation: every 3 months and at relapses treating and blinded evaluating neurologist MRI 25 centers baseline, month 12, month 24

36 Power and sample size n 2 q q= 0.8 = 0.84 k= α 0.05 = k sd 2 Sample size is direct function of variability (sd), of predefined significance α (k) and of power (q), whereas is inverse function of

37 Method: noninferiority Treatment S is noninferior when lower CI (one tail) of its effect vs control treatment T, falls within a predefined margin μ named noninferiority margin M value: arbitrary clinically meaning ful predefined

38 Non -inferiority: established metodology Availability of data related to a number od RCT against placebo, consitent among them, allowing to reliably establish μ value

39 M estimate Dati da RCT storici numero eventi Placebo Farmaco T effetto T-P

40 IFN efficacy vs. placebo in reference studies TRIAL treatment Betaferon (ΒIFN 1b, 1993) PRISMS (ΒIFN 1a 44, 1997) PRISMS (ΒIFN 1 a 22, 1997) n relapse n./2y n relapse n./2y n relapse n./2y Β IFN , Placebo ,56 2,55 delta 0,86 0,83 0, ratio 1,51 1,48 1,40 1,46 ARR IFN/Placebo= 1.46

41 Statistics Non-inferiority 1.46, relapse rate ratio detected in 2 pivotal historical trials (PRISMS; Betaferon) between the Placebo and the IFNbeta groups AZA will be considered non-inferior to IFNs if the 95% C.I (one tail) of the ratio between relapse rates in the AZA group and in the IFN group will be < 1.23 non inferiority margin M established a priori as 50% of the excess to 1.0 (= 1.23)

42 Eligibility Criteria Inclusion criteria Exclusion criteria RR MS Y < 10 y disease duration EDSS betweeen > 2 relapses in the last 2 y relapse or steroides in the 30 days previous to recruitment AZA or other DMT in the previous 6 months Pregnancy/ breastfeeding Cognitive decline preventing informed consent

43 Baseline characteristics of the population included

44 Relapse rate

45 Time to first relapse

46 New T2 lesions (FLAIR)/2Y (AZA n=50; IFNs n=47) Lesion number 2,2 2 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 Aza IFN

47 Non-inferiority of efficacy on new T2 lesion rate ratio

48 Gd+ lesion number at baseline and at month 24 (ITT analysis; Aza n= 50, IFN n= 47) 3,8 3,6 3,4 3,2 3 2,8 2,6 2,4 2,2 p< p< lesion number 2 1,8 1,6 1,4 1,2-83% baseline month24 1 0,8-88% 0,6 0,4 0,2 0 Aza Treatment IFN

50 The mean number of relapses during one year the AZA group than in the IFNβ products group (0.28 vs 0.64, P<0.05). 20 relapses (42.6 %) in the IFNβ products group and 11 (23.4 %) in the AZA group. 63/ 94 patients (67 %) remained relapse-free during one year of follow-up; 27 (57.4 %) in the IFNβ products group and 36 (76.6 %) in the AZA group (P<0.05). Odds ratio 2.42 (95 % CI, 1.0, 5.9; P=0.048), indicating a relative increase of 142 % in the odds of remaining relapse free during the first year of therapy for patients receiving AZA compared with those receiving IFNβ products.

51 Conclusions Aza effect on Relapse Rate is at least as intensive as that of IFNs Aza effect on Relapse Rate and Disability raise the hypothesis of supertiority vs IFNs Aza effect in suppressing brain new lesions is similar to that of IFNs Short term safety profile is different from IFNs but overall well tolerated

52 Trials on Aza efficacy in MS carried out in the 80s

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