10 Farmaci biologici in reumatologia: the magic bullet? g. valesini

I farmaci biologici in Reumatologia: the magic bullet ?
Guido Valesini,
Reumatologia “La Sapienza”, Roma
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
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
Glossario
…mab = anticorpo monoclonale
…ximab = chimerico
…zumab = umanizzato
…mumab = umano
…cept = molecola di fusione
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
ADALIMUMAB (HUMIRA)
40 mg s.c. ogni 2 settimane
Anticorpo monoclonale umano
Lega TNF impedendone
l’interazione con i propri recettori
GOLIMUMAB (SIMPONI)
50 mg s.c. ogni 4 settimane
Anticorpo monoclonale umano
Lega TNF impedendone
l’interazione con i propri recettori
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.
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.
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
TARGETING THE B CELL
ANTI-B CELLS STIMULATION
Anti-BLys mAb (Belimumab)
Under evaluation
Epratuzumab: anti-CD22
Tecnologia proteine
ricombinanti
MOLECOLE DI FUSIONE
ETANERCEPT (ENBREL)
50 mg s.c. ogni settimana
Proteina di fusione costituita
da 2 recettori p75 del TNF uniti
alla porzione Fc di una IgG1
umana
Lega il TNF solubile
(forma trimerica attiva)
“Old” targets: “old” biologics
Anakinra
(KINERET
)
Canakinumab (Ilaris
)
RA, cryopyrin-associated
periodic syndroms, gouty
arthritis attack
Therapy of autoinflammatory syndromes
Hal M. Hoffman
Journal of Allergy and Clinical Immunology 2009
ABATACEPT (ORENCIA)
Negli adulti: 500 mg (<60 Kg), 750 mg (60-100 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 Fc di una
IgG1 umana
Lega il complesso CD80/86,
interrompendo così l’attivazione del
secondo segnale e, secondariamente,
quella dei linfociti T
• “second-generation” biologic to improve
performance or perhaps decrease
immunogenicity while preserving the
mechanism of action
≠
• “follow on” products (biosimilars)
“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
G. Castellaneda-Hernandez
Biologici in Reumatologia usati prevalentemente per:
- Artriti infiammatorie (AR, SA, AP)
- Connettiviti (LES, SdS, Dermatopolimiositi)
- Vasculiti sistemiche
Bell et al., 2011
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
Early treatment group (n=97)
DMARD + NSAIDs
p=0.001
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
p=0.032
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
What Is the Goal of RA Therapy?
Established RA
Clinical improvement; ideally, full remission
Retard the progression
Maintain functional capacity
Improvement of disability
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
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
Legge 20.40.60
ACR20
60%
ACR50
40%
ACR70
20%
Studio MODERATE
Ceccarelli et al., 2014
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)
Valutazione al basale (T0) e a 3 (T3), 6 (T6) e 12 (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%
Attività di malattia
DAS28 media (±SD) durante il periodo di osservazione
6.0
5.0
4.5
3.7
4.0
3.4
3.2
3.0
2.0
* p<0.0001
* p<0.0001
1.0
* p<0.0001
0.0
Arruolamento
3 mesi
6 mesi
12 mesi
*T-test sulla variazione media dello score a 12 mesi rispetto all’ arruolamento
Risposta secondo i criteri EULAR
(T3 versus T12: P=0,0028;
T6 versus T12: P=0,018)
50,0%
40,0%
30,0%
GOOD
MODERATE
20,0%
NONE
10,0%
0,0%
T3
T6
T12
Età media significativamente più bassa nei soggetti responder rispetto 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
REMISSION
25,0%
20,0%
19,0%
21,0%
15,0%
10,0%
5,0%
0,0%
T6
T12
Non soddisfacente percentuale di pazienti in remissione dopo 12 mesi
Miglioramento nelle strategie terapeutiche anche nei pazienti affetti da AR
moderata?
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
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
Favalli EG et al.
Clinical And Experimental Rheumatology 2011
ELECTIVE SURGERY
In all patients with RA treated with biologic therapy
undergoing elective surgery, the recommendation
is to discontinue the treatment for a period of 2–4 times
the half-life of the biologic agent
according to the type of surgery
Favalli EG et al.
Clinical And Experimental Rheumatology 2011
PERIOPERATIVE CARE
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)
is not recommended
Favalli EG et al.
Clinical And Experimental Rheumatology 2011
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)
years)
Favalli EG et al.
Clinical And Experimental Rheumatology 2011
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
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
Tutti insieme, nel 2013 hanno
guadagnato 76 miliardi di
dollari, circa 55 miliardi di
euro.
No differences in efficacy.
-DAS, ACR, etc
- symptoms
- structural damage
- ESR, CRP
- RF, anti-CCP
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
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.
Biologic treatment of Rheumatic
diseases: Unmet Issues
- Quale scegliere
- Quando smettere
- Quali obiettivi
I RCT SONO UNA RISPOSTA A QUESTI
QUESITI ?
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.
Ioannidis et al., 2013
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, 2059–2067 (2012).
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, 1611–1616 (2012).
Simsek, & Yazici, 2012
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,
313–318 (2003).
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).
Paucity of head-to-head comparisons
Ioannidis et al., 2013
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 followup 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
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
Learn from yesterday, live for today,
hope for tomorrow.
The important thing is not to stop questioning.
Albert Einstein

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