I farmaci biologici in Reumatologia: the magic bullet? Guido Valesini, Reumatologia La Sapienza, Roma

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1 I farmaci biologici in Reumatologia: the magic bullet? Guido Valesini, Reumatologia La Sapienza, Roma

2 I farmaci biologici in Reumatologia: the magic bullet? 1. Quali sono i biologici usati in Reumatologia? 2. Quando si usano i biologici in Reumatologia? 3. Sono efficaci? 4. Sono sicuri? 5. Unmet needs

4 Glossario mab = anticorpo monoclonale ximab = chimerico zumab = umanizzato mumab = umano cept = molecola di fusione

5 INFLIXIMAB (REMICADE ) 3-5 mg/kg e.v. alle settimane 0, 2, 4; poi ogni 6-8 settimane Anticorpo monoclonale chimerico Regione murina variabile e regione umana costante IgG1 Lega TNF con alta affinità e specificità il TNF solubile e di membrana

6 ADALIMUMAB (HUMIRA ) 40 mg s.c. ogni 2 settimane Anticorpo monoclonale umano Lega TNF impedendone l interazione con i propri recettori

7 GOLIMUMAB (SIMPONI ) 50 mg s.c. ogni 4 settimane Anticorpo monoclonale umano Lega TNF impedendone l interazione con i propri recettori

8 CERTOLIZUMAB PEGOL (CIMZIA ) 400 mg s.c. alle settimane 0, 2 e 4; poi 200 mg ogni 2 settimane Frammento Fab umanizzato coniugato con polietilenglicole (PEG) Lega TNF solubile e di membrana Non contiene il frammento cristallizzabile (Fc), normalmente presente in un anticorpo completo, e quindi non fissa il complemento né causa citotossicità cellulo-mediata anticorpo-dipendente in vitro. Non induce apoptosi in vitro in monociti o linfociti derivanti dal sangue periferico umano, o degranulazione dei neutrofili.

9 TOCILIZUMAB (ROACTEMRA ) 8 mg/kg (ma non più di 800 mg) e.v. ogni 4 settimane Anticorpo monoclonale umanizzato Lega il recettore di membrana e quello solubile di IL-6.

10 RITUXIMAB 1000 mg e.v. a distanza di 14 giorni ogni 6 mesi Anticorpo monoclonale chimerico La regione di derivazione murina lega il CD20 presente sulla superficie delle cellule B; quella di derivazione umana avvia la deplezione delle cellule B con meccanismi di: citotossicità cellulo-mediata citotossicità complemento-mediata apoptosi

11 TARGETING THE B CELL ANTI-B CELLS STIMULATION Anti-BLys mab (Belimumab)

12 Under evaluation Epratuzumab: anti-cd22

13 Tecnologia proteine ricombinanti MOLECOLE DI FUSIONE

14 ETANERCEPT (ENBREL ) 50 mg s.c. ogni settimana Proteina di fusionecostituita da 2 recettori p75 del TNF uniti alla porzione Fcdi una IgG1 umana Lega il TNF solubile (forma trimerica attiva)

15 Anakinra (KINERET ) Old targets: old biologics Canakinumab (Ilaris ) RA, cryopyrin-associated periodic syndroms, gouty arthritis attack Therapy of autoinflammatory syndromes Hal M. Hoffman Journal of Allergy and Clinical Immunology 2009

16 ABATACEPT (ORENCIA ) Negli adulti: 500 mg (<60 Kg), 750 mg ( Kg), 1000 mg (>100 Kg) e.v.alle settimane 0, 2, 4; poi ogni 4 settimane Nei bambini: 10 mg/kg (<75 Kg); come per gli adulti ( 75 Kg, ma mai > 1000 mg) Proteina di fusione costituita dal dominio extra-cellulare della molecola CTLA4 unito alla porzione Fcdi una IgG1 umana Lega il complesso CD80/86, interrompendo così l attivazione del secondo segnale e, secondariamente, quella dei linfociti T

17 second-generation biologic to improve performance or perhaps decrease immunogenicitywhilepreservingthe mechanism of action follow on products(biosimilars)

18 Old targets: biosimilars What Are Biosimilars? a biosimilar is a biological product that is "highly similar" to a U.S.-licensed biological product, without regard to minor differences in clinically inactive components. There must also be no clinically significant difference, in terms of safety, purity, and potency When is a copy good enough to be treated as the real thing? bioequivalence and interchangeability

19 G. Castellaneda-Hernandez

20 Biologici in Reumatologia usati prevalentemente per: - Artriti infiammatorie (AR, SA, AP) - Connettiviti (LES, SdS, Dermatopolimiositi) - Vasculitisistemiche

21 Bell et al., 2011

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25 Early treatment group (n=97) DMARD + NSAIDs p=0.001 p=0.032 Delayed treatment group (n=109) Initial treatment with NSAIDs (DMARD after ~ 5 months) The beneficial effect of early DMARD treatment on the radiological progression of joint damage is still present at 4 years

26 There is a Window of Opportunity in early disease during which the rate of radiologic progression can be reset Early DMARD intervention slows the progression of structural joint damage, improves long term outcome and patient quality of life O Dell JR. Arthritis Rheum 2002

27 What Is the Goal of RA Therapy? Established RA Clinical improvement; ideally, full remission Retard the progression Maintain functional capacity Improvement of disability

28 What Is the Goal of RA Therapy? Established RA Clinical improvement; ideally, full remission Retard the progression Maintain functional capacity Improvement of disability Early RA Full clinical remission Window of opportunity Prevention of joint destruction Prevention of disability

30 Legge ACR20 60% ACR50 40% ACR70 20%

31 Studio MODERATE Ceccarelli et al., 2014

32 Valutazione della risposta al trattamento con anti-tnf in pazienti naïve affetti da AR moderata: studio MODERATE Studio osservazionale, longitudinale, multicentrico, non interventistico, di coorte Selezionati pazienti affetti da AR con malattia moderatamente attiva (DAS28>3,2 e 5,1) Valutazionealbasale(T0)ea3(T3),6(T6)e12(T12)mesi 157 pazienti(87,3% sesso femminile, età media±ds = 55±13 anni, età media all'esordio = 48±13 anni) 134 pazienti(85,3%) completavano lo studio. Terapia anti-tnf: etanercept 59,2% adalimumab 21,7% certolizumab 16,6% golimumab 6,4% infliximab 1,3%

33 Attività di malattia DAS28 media (±SD) durante il periodo di osservazione * p< * p< * p< Arruolamento 3 mesi 6 mesi 12 mesi *T-test sulla variazione media dello score a 12 mesi rispetto all arruolamento

34 Risposta secondo i criteri EULAR 50,0% 40,0% (T3 versust12: P=0,0028; T6 versus T12: P=0,018) 30,0% 20,0% GOOD MODERATE NONE 10,0% 0,0% T3 T6 T12 Età media significativamente più bassa nei soggetti responderrispetto ai non responder(53,09±12,67 vs 58,96±12,41 anni; P=0,0387) Percentuali di risposta alla terapia con anti-tnf in pazienti con AR moderata sovrapponibili a quelle riportate in letteratura

35 REMISSION 25,0% 20,0% 15,0% 10,0% 5,0% 0,0% 19,0% T6 21,0% T12 Non soddisfacente percentuale di pazienti in remissione dopo 12 mesi Miglioramento nelle strategie terapeutiche anche nei pazienti affetti da AR moderata?

37 TUBERCULOSIS LTBI screening (TST, chest x-ray and exposure history) is mandatory before starting a treatment with anti-tnf agents RA patients with a positive screening for LTBI must be treated with antitubercular drugs (e.g. isoniazid 300 mg/day for 9 months) for one month before starting biological treatment FavalliEG etal. Clinical And Experimental Rheumatology 2011

38 ELECTIVE SURGERY In all patients with RA treated with biologic therapy undergoing elective surgery, the recommendation is to discontinue the treatmentfor a period of 2 4 times the half-life of the biologic agent according to the type of surgery FavalliEG etal. Clinical And Experimental Rheumatology 2011

39 PERIOPERATIVE CARE

40 VACCINATIONS Influenza and pneumococcal vaccination, can be safely recommended for patients treated with anti-tnf, RTX or ABAT The use of live attenuated vaccines (e.g. BCG, yellow fever, herpes zoster) isnot recommended FavalliEG etal. Clinical And Experimental Rheumatology 2011

41 LYMPHOMAS AND SOLID TUMOURS Considering the timing of oncologic remission of 5 years, TNF inhibitors should be avoided in patients with a recent history of malignancy (<5 years) FavalliEG etal. Clinical And Experimental Rheumatology 2011

43 Stanford Prevention Research Centre, Department of Health Research and Policy, Stanford University School of Medicine, 1265 Welch Road, Stanford, CA 94305, NATURE REVIEWS RHEUMATOLOGY 2013, 9, 665

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45 Tutti insieme, nel 2013 hanno guadagnato 76 miliardi di dollari, circa 55 miliardi di euro.

46 No differences in efficacy. -DAS, ACR, etc - symptoms - structural damage - ESR, CRP - RF, anti-ccp

47 No evidence that any one TNF blocking agent should be used before another one can be tried, just as there is no evidence that any TNF blockers is more effective than any other in RA

48 There is evidence that loss of response to a TNF blocking agent can occur and studies suggest that failure to respond to one TNF blocking agent does not preclude response to another.

49 Biologic treatment of Rheumatic diseases: Unmet Issues - Quale scegliere - Quando smettere - Quali obiettivi I RCT SONO UNA RISPOSTA A QUESTI QUESITI?

50 su 212 RCT anti-tnf in malattie autoimmuni reumatologiche registrati in ClinicalTrials.gov database ad oggi sono pubblicati i risultati di soli 82 ( 38,7%). 56 dei trials registrati rimangono non pubblicati ad un anno dalla conclusione.

51 Ioannidis et al., 2013

52 The available data revealed a trend for higher rates of non-publication for pharmaceutical-industry-funded RCTs compared with non-pharmaceuticalindustry-funded clinical trials in RA Khan, N. A., Lombeida, J. I., Singh, M., Spencer, H. J. & Torralba, K. D. Association of industry funding with the outcome and quality of randomized controlled trials of drug therapy for rheumatoid arthritis. Arthritis Rheum. 64, (2012).

53 Patient populations Nella revisione sistematica di 66 RCT solo il 20% riportava in modo completo tutte le fasi ( es. screening failure) Simsek, I. & Yazici, Y. Incomplete reporting of recruitment information in clinical trials of biologic agents for the treatment of rheumatoid arthritis: a review. Arthritis Care Res. (Hoboken) 64, (2012).

54 Simsek, & Yazici, 2012

55 Patient populations most patients who are seen in routine care - academic rheumatology clinics or those who were under the care of private practice rheumatologists - do not meet the inclusion criteria for RCTs conducted in RA. Sokka, T. & Pincus, T. Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor α agents in rheumatoid arthritis. Arthritis Rheum. 28, (2003).

56 Patient populations Empirical evidence from studies using diverse medical interventions suggests that trials conducted in less-developed countries often report more favourable results than trials of the same intervention performed in moredeveloped countries. Panagiotou, O. A., Contopoulos-Ioannidis, D. G. & Ioannidis, J. P. Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment. BMJ 346, F707(2013).

57 Paucity of head-to-head comparisons Ioannidis et al., 2013

58 1. The clinical trial evidence relating to biologic agents used to treat rheumatic diseases has several shortcomings that prevent optimal implementation of these agents in clinical practice and complicate regulatory decision making 2. A paucity of head-to-head comparisons, limited follow- up times, variations in outcome definitions and nomenclature, and non-publication of trials and outcomes limit our understanding of biologic agents 3. Most trials are pharmaceutical-industry-sponsored, and have short follow-up periods and small sample sizes, which restrict our interpretation of the clinical relevance of the findings with regard to long-term disease outcomes Ioannidis et al., 2013

59 4. The lack of long-term randomized trials of biologic agents has limited our understanding of the association of these drugs with adverse events, particularly the risk of malignancies and serious infections 5. Larger study populations, longer follow-up times, better reporting and head-to-head comparisons of biologic agents would increase knowledge of the benefits and risks associated with the different treatments available Ioannidis et al., 2013

60 Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning. Albert Einstein