L’ esperienza dell’ ASST FF Sacco - · PDF fileExpected patent expiry year...

Piercarlo Sarzi-Puttini

Director Rheumatology Unit

ASST Fatebenefratelli-Sacco

University Hospital Milan-Italy

L’ esperienza dell’ ASST FBF Sacco

Milano 13 gennaio 2017

Farmaci biosimilari: un’alleanza tra farmacisti e reumatologi per la sostenibilità del SSR

biologics: biosimilars or originator?

Biosimilars -background

• Biologics have revolutionized treatment in important

disease areas, such as cancer, diabetes and inflammatory

diseases.

• The downside of the use of biologics is the high cost; in

2002, $46 billion were spent on biologics worldwide and it

is expected that this will increase to $221 billion in 2017

Mielke J et al. Br J Clin Pharmacol (2016) DOI 10.1111/bcp.13076

1990 2000 ‘05

MTX

SSZ

HCQ

CQ

Gold

Cyc-A

AZA

PNC

Biologic

drug

clinical

trials

Biologic EraNonBiologic Era

Etanercept(1998)

Adalimumab

Abatacept

Rituximab

Anakinra

Leflunomide (1998)

Spectrum of RA Treatment

Golimumab

Certolizumab

Tocilizumab

‘06‘03

Year of FDA Approval

‘01 ‘09

Infliximab

Small molecules

Tofacitinib

‘13

• Due to the high prices and the first expiry of patents of biologics over the last few

years, the development of copies of biologics, so-called biosimilars, has recently

gained much attention.

• The European Medicines Agency (EMA) is the leading regulator in this regard,

having approved the first biosimilar in 2006 (Omnitrope, by Sandoz), and since

then, the landscape of authorized biosimilars in Europe has widened considerably.

• Currently, there are 21 products for seven different biologics on the market.

• It is predicted that the use of biosimilars may lead to a $250 billion reduction in

spending on biologics in the US between 2014 and 2024

Biosimilars -background

Mielke J et al. Br J Clin Pharmacol (2016) DOI 10.1111/bcp.13076

Expected patent expiry year

Biologic agent EU USA

Actemra/RoActemra (tocilizumab) 2017 2022

Cimzia (certolizumab pegol) 2021 2024

Enbrel (etanercept) 2015 2028

Humira (adalimumab) 2018 2016

Orencia (abatacept) 2017 2018

Remicade (infliximab) 2015 2018

Rituxan/Mabthera (rituximab) 2013 2016

Simponi (golimumab) 2024 2024

Stelara (ustekinumab) 2024 2023

Reported innovator biologic patent expiration dates

Definizione di biosimilare

• Nel settembre 2012 l’EMA ha diffuso un documento in cui e riportata la seguente definizione: “Per

medicinale biosimilare si intende un medicinale sviluppato in modo da risultare simile a un

medicinale biologico che e gia stato autorizzato (il cosi detto “medicinale di riferimento”).

• I medicinali biosimilari, dunque, differiscono dai farmaci generici che hanno strutture chimiche piu

semplici e che sono considerati identici ai loro medicinali di riferimento.

• Il principio attivo di un biosimilare e quello del suo medicinale di riferimento sono di fatto la stessa

sostanza biologica, tuttavia possano essere presenti differenze minori dovute alla loro natura

complessa e alle tecniche di produzione.

• Come il medicinale di riferimento, il biosimilare presenta un certo grado di variabilita naturale. Un

biosimilare viene approvato quando e stato dimostrato che tale variabilita naturale ed eventuali

differenze rispetto al medicinale di riferimento non influiscono sulla sicurezza o sull’efficacia.”

Agenzia Italiana del Farmaco – Secondo Concept Paper sui Farmaci Biosimilari

Definitions of various biologic therapeuticsTerm (alternative terms) Agency Definition

Biosimilar (follow-on biologic, subsequent entry biologic, similar biotherapeutic product)

FDA [1] A biosimilar product is a biological product that isapproved based on a showing that it is highly similar to an FDA-approved biological product, known as a referenceproduct, and has no clinically meaningful differences in terms of safety and effectiveness from the referenceproduct. Only minor differences in clinically inactivecomponents are allowable in biosimilar products

EMA [2] A similar biological or biosimilar medicine is a biologicalmedicine that is similar to another biological medicine that has already been authorized for use in EU

WHO [3] A similar biotherapeutic product is a biotherapeuticproduct which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeuticproduct

1-U.S. Food and Drug Administration. Biosimilars. http:// www.fda.gov/Drugs/DevelopmentApprovalProcess/How

DrugsareDevelopedandApproved/ApprovalApplications/ TherapeuticBiologicApplications/Biosimilars/default.htm. Accessed13 January 2016.

2- European Medicines Agency. Biosimilar Medicines. http:// www.ema.europa.eu/ema/index.jsp?curl=pages/special_ topics/document_listing/document_listing_000318.jsp. Accessed 13 January 2016.

3- WHO Expert Committee on Biological Standardization. Guidelines on evaluation of similar biotherapeutic products(SBPs), annex 2. World Health Organ Tech Rep Ser 2013;977:53 89.

Definitions of various biologic therapeutics

Term (alternative terms) Agency Definition

Biobetter (next-generation biologic)

Notdefined by any agency

A biologic with the same target or mechanism of action as

a previously approved biological but with structural

changes, bifunctional targeting (with or without a

biosimilar core) or an improved formulation that may

result in an expected improvement in clinical profile

Bioquestionable (biocopy, biomimic, intended copy, non-regulated biologic)

Notdefined by any agency

A copy version of a therapeutic protein that has not been

developed and assessed in line with the scientific

principles of a comparative development programme

against a licensed reference product showing similarity in

quality, safety and efficacy

Goel N, Chance K. Biosimilars in rheumatology: understanding the rigor of

their development. Rheumatology (Oxford). 2016 May 30.

Biosimilar regulations/guidelines in the EU and USA

Niti Goel, and Kamali Chance Rheumatology 2016;rheumatology.kew206

Boxed items represent those timeline items related to the EU, whereas unboxed items reflect the USA.

EMEA: European Medicines Agency; G-CSF: granulocyte colony-stimulating factor; Q&A: questions and answers

Timing of biosimilars approval

• Whereas the EU has led the charge for biosimilar approvals, with 21

approved since the first in 2006, the USA didn’t approve its first biosimilar

via the 351(k) pathway, filgrastim, until 2015 .

• In the EU, among the myriad approved biosimilars, only one biosimilar

mAb and one biosimilar -cept have been approved for the treatment of

indications that include rheumatologic conditions, that is, infliximab

(Celltrion) and etanercept (Samsung).

• Subsequently, Celltrion’s infliximab biosimilar has been approved in >70

countries worldwide, including in the USA in April 2016.

• In July 2012, the Korea Food and Drug Administration (KFDA,currently the Korean Ministry of Food and Drug Safety) approvedCT-P13 (Remsima®, Celltrion), the world’s first follow-onmonoclonal antibody claimed to be biosimilar to infliximab(Remicade®, Janssen Biotech).

• A year later, September 2013, the European Medicines Agency(EMA) also recommended the marketing authorization of CT-P13for treatment of AS and RA.

Biosimilar News. World’s first biosimilar antibody is approved in Korea 7/23/2012.European Medicines Agency. European Medicines Agency recom- mends approval of first two monoclonal-antibody biosimilars.


• It is anticipated that with recent biosimilar application submissions

to the FDA for etanercept (Sandoz) and adalimumab (Amgen), and

to the EMA for adalimumab (Amgen), rituximab (Celltrion) and a

second infliximab biosimilar (Samsung Bioepis), other biosimilar

options for the treatment of rheumatologic diseases may be on the

way.


Come la vede il clinico

• Il razionale per produrre i biosimilari

• Esercizio di comparabilià ed efficacia clinica

• Immunogenicità e sicurezza

• Intercambiabilità, sustituibilità

• Estrapolazione delle indicazioni

• Biosimilari nel mondo reale

• Conclusioni


• Il costo


• L’efficacia clinica



• Estrapolazione deel indicazioni

• Biosimilari ne mondo reale

• Conclusioni

RATIONALE FOR THE DEVELOPMENT OF BIOSIMILARS

• In 2012, worldwide sales of the top three selling TNFα

inhibitors (TNFi) reached US $20 billion, with total annual

sales for rheumatic disorders approaching US$ 30 billion per

year.

• This amounts to a US$ 10.000–30.000 per patient per year

financial burden to patients or third-party payers of

healthcare.

Ann Rheum Dis 2013;72:322–328

RATIONALE FOR THE DEVELOPMENT OF BIOSIMILARS

• In addition, there is a humanistic burden due to

restricted access caused by budget constraints in

many countries around the world.

• Thus, there is significant interest in efficacious,

lower-cost biosimilars.

Ann Rheum Dis 2013;72:322–328

Ann Rheum Dis 2014;73:198–206

Access to biologic disease modifying antirheumatic drugs and gross domestic product per capita, international dollars (n=44). Size of the bubbles is proportional to the population size of the country. AL, Albania; AM, Armenia; AT, Austria; BA, Bosnia and Herzegovina; BE, Belgium;BG, Bulgaria; BY, Belarus; CH, Switzerland; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK,Denmark; EE, Estonia; ES, Spain; FI, Finland;FR, France; GE, Georgia; GR, Greece; HR, Croatia; HU, Hungary; IE, Ireland; IS, Iceland; IT, Italy; KZ, Kazakhstan; LT, Lithuania; LU, Luxemburg; LV, Latvia; MD, Moldova; ME, Montenegro; MK, Macedonia; MT, Malta; NL, Netherlands; NO, Norway; PL, Poland; PT, Portugal; RO, Romania; RS, Serbia; RU, Russia; SE, Sweden; SK, Slovakia; SL,

Slovenia; TR, Turkey; UA, Ukraine; UK, United Kingdom.

• In 10 (22%) of the 46 participating countries, none of the eight bDMARDs

were reimbursed,

• 2 countries reimbursed only one bDMARD (rituximab or etanercept),

• two to four bDMARDs were reimbursed in 7 countries,

• 27 countries (59%) had five or more bDMARDs reimbursed (all were EU

member states except for Croatia, Iceland, Norway and Switzerland).

• At least three sDMARDs (always including methotrexate and

sulphasalazine) were available in all 46 countries.

On average, the total time of reimbursement in each country expressed as %

of the total time since EMA approval was 49% (SD 38; median 52).

Ann Rheum Dis 2014;73:198–206

Composite score forrestrictiveness of clinical criteriafor initiation of a firstreimbursed biologic (0–5) in theEuropean Region-

Score is composed of

• minimum required diseaseduration,

• number of sDMARDs thathave to be failed

• the level of DAS28

Ann Rheum Dis 2014;73:2010–2021.



• Esercizio di comparabilità ed efficacia clinica



• Estrapolazione deel indicazioni

• Biosimilari ne mondo reale

• Conclusioni

A. SoldiMateriale di training ad esclusivo uso interno

Vietata la distribuzione a Medici e/o altri operatori sanitari

Il “Comparability Exercise”

Comparability exercise

Biosimilars

Qualitative comparability

Non-clinical comparability

Clinical comparability

To compare the molecular structure and the function of the biosimilar and of the originator.It includes a full analytical analysis, studies of receptors activity and biological tests

Safety and efficacy analysis aimed to show no differences with the originator

European Commission. What you need to know about biosimilar medicinal products. A consensus information document. [Accessed May 2014]. http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf



• La normativa richiede che il programma di ricerca e sviluppo sia volto a dimostrare

la “biosimilarita ” intesa come la comparabilita tra il biosimilare ed il suo prodotto

di riferimento, attraverso “l’esercizio di comparabilita ”, ovvero l’insieme di una

serie di procedure di confronto graduale (stepwise) che inizia con

• gli studi di qualita (comparabilita fisico-chimiche e biologiche),

• la valutazione della comparabilita non-clinica (studi non clinici comparativi)

• La valutazione clinica (studi clinici comparativi) per la valutazione dell’efficacia e

della sicurezza.

Il “Comparability Exercise”

Sample of biosimilar analytical, functional and other non-clinicalassessments reported for biosimilar infliximab

Assessment Test Methods

Physicochemical Primary structure Amino acid analysis, peptide mapping (LC-MS) in combination with MS/MS, peptide mapping(HPLC), N-terminal sequencing, C-terminal sequencing, reduced mass

Higher-order structure Disulphide bonds, free thiol analysis, FTIR, circular dichroism, DSC

Purity/impurity SEC-HPLC, CE-SDS (reduced/non-reduced)

Charged isoforms IEF, IEC-HPLC

Glycosylation Sialic acid analysis, monosaccharide analysis, oligosaccharideprofiling, N-linked glycan analysi

Content Protein concentration (UV280), product specificELISA

Sample of biosimilar analytical, functional and other non-clinicalassessments reported for biosimilar infliximab

Assessment Test Methods

Biological activity Fc receptor related Comparative binding to Fcg receptors using SPR and ex vivo assay using NK cells and neutrophils

F(ab0)2 related Comparative binding to hTNF-a using ELISA and SPR; com-parative tmhTNF-a binding affinity using cell-based ELISA; hTNF-b bindingspecificities; human tissue cross-reactivity using immunohistochemistry; comparative TNF-a binding affinity using SPR; comparative hTNF-a neutralization assay; comparative apoptosis; comparative reverse signalling; effect of blocking sTNF-a in in vitro IBD model by suppression of cyto- kine secretion and apoptosis in epithelial cell line

Fc-F(ab0)2 related Comparative C1q binding affinity using ELISA; comparative CDC; comparative ADCC using tmhTNF-a-Jurkat cells as target cells and hPBMCsas well as NK cells from healthy donors as effector cells; evaluation of regulatory macrophage function by suppression of T cell proliferation by induced regulatory macrophages in MLR assay, quantitation of the induced regulatory macrophages by FACS analysis, and induced regulatorymacrophage-mediated wound healing of colorectal epithelium cells; comparative ADCC activity using transfected Jurkat cells as target cells and either PBMCs or NK cells from CD patients or whole blood from healthydonor or CD patients as effector cells, or using LPS-stimulated monocytesfrom healthy donor or CD patients as target cells and PBMCs as effectorcells

33.European Medicines Agency. Assessment Report- Remsima. 2013. http://www.ema.europa.eu/docs/en_GB/

document_library/EPAR__Public_assessment_report/ human/002576/WC500151486.pdf. Accessed 7 January 2016.

Park W, et al. Ann Rheum Dis 2013;72:1605–1612

250 AS patients randomised to receive 5 mg/kg of CT-P13 (n=125) or INX

(n=125) at weeks 0, 2, 6 and then q8 weeks up to week 30

Primary endpoint:

PK equivalence at steady state (AUC and Cmax,ss) between wks 22 and 30

Secondary endpoints:

Additional PK, efficacy endpoints (ASAS20 and ASAS40) at week 14 and 30,

safety.

Results:

- No significant differences in AUC and Cmax,ss

- No significant differences in ASAS 20 and 40 achievement

- No significant differences in safety profile

Phase I

The primary aim was to evaluate the efficacy of infliximab and CT-P13 incombination with methotrexate (MTX) in 606 patients unresponsive to MTX whowere randomised 1:1.

The primary endpoint was the achievement of ACR20 after 30 weeks, and thesecondary endpoints were the CDAI and SDAI scores.

Yoo DH, et al. Ann Rheum Dis 2013;72:1613–1620.

The “intention-to-treat” analysisshowed that ACR20 was achieved by60.9% of the patients treated with CT-P13 and 58.6% of those treated withinfliximab, and 73.4% and 69.7% inpatients per protocol (PP) population(n=499, 95% CI −4% to 12%) for CT-P13 and INX, respectively (figure 2A).

Equivalent results were also shown forACR responses in the PP population atweeks 14 and 30 (figure 2B,C) .

Efficacy


Mean improvements from baseline for additional secondary efficacy endpoints includingCDAI, SDAI, EULAR response, DAS28-CRP, etc at week 14 and 30 were similar.

The results of the PLANETRA study were also compared with those of the registration studiesof infliximab in RA: the ACR 20 results were better than those observed in the ATTRACT trialand similar to those observed in the START trial.


Safety

Adverse events were observed inrespectively 60.1% (CT-P13) and 60.8%(IXN) of the patients.

The majority of TEAEs were mild-to-moderate in intensity.

The safety results were similar to those ofthe ATTRACT and ASPIRE studies


Ann Rheum Dis 2015;0:1–7.

A phase III, randomised, double-blind, parallel-group, multicentre study with a24-week primary endpoint.

Patients with moderate to severe RA despite MTX treatment were randomisedto receive weekly dose of 50 mg of subcutaneous SB4 or ETN.

The primary endpoint was ACR20 response at week 24. Other efficacy endpoints as well as safety, immunogenicity and

pharmacokinetic parameters were also measured.

34

596 patients were randomised to either SB4(N=299) or ETN (N=297).

Ann Rheum Dis 2015;0:1–7.

35

The incidence of treatment-emergentadverse events was comparable (55.2%vs 58.2%), and the incidence of antidrugantibody development up to week 24was lower in SB4 compared with ETN(0.7% vs 13.1%).

To explain this difference:

The immunogenicity system wasmore sensitive

The immunogenicity was measuredmore frequently;

The antibodies detected in this studywere generally transient and non-neutralising,

Conclusions:

SB4 was shown to be equivalent with ETN in terms of efficacy at week 24. SB4 was welltolerated with a lower immunogenicity profile. The safety profile of SB4 was comparablewith that of ETN

.Ann Rheum Dis 2015;0:1–7.

• To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab

(RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or

intolerances to antitumour necrosis factor agents.

• In this randomised phase I trial, patients with active RA were randomly assigned

(2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued

methotrexate therapy).

• Primary endpoints were area under the serum concentration–time curve from

time zero to last quantifiable concentration (AUC0–last) and maximum serum

concentration after second infusion (Cmax).


PK endpoints (PK population)

The PK of CT-P10 and RTX

were equivalent since 90%

CIs for the ratio of geometric

means (CT-P10/RTX) for both

AUC0–last and Cmax were within

the bioequivalence range.

All secondary PK endpoints

were also highly similar

between groups


(A) Proportion of patients with

an ACR20, ACR50 and

ACR70 response.

(B) Proportion of patients

achieving a good or

moderate EULAR

response.


• Adverse events occurred in 52 (51.0%) and 38 (74.5%) patients in

the CT-P10 and RTX groups, respectively, and serious adverse

events in 5 (4.9%) and 3 (5.9%).

• Infusion-related reactions occurred in 17 (16.7%) patients in the CT-

P10 group and 10 (19.6%) in the RTX group.

• Infections occurred in 24 (23.5%) and 13 (25.5%) patients in the CT-

P10 and RTX groups, respectively.

• There were no life-threatening (grade 4) adverse events or deaths.

Adverse events


Immunogenicity

Immunogenicity can be influenced by several factors (for example, adifferent pattern of glycosylation can expose or hide antigenic epitopes,alter solubility or affect protein degradation).

Immunogenicity is related to the appearance of anti-drug antibodies whichare associated with the development of adverse events and/or loss ofefficacy and can be evaluated by means of comparability testing.

STRAND V, KIMBERLY R, ISAACS JD.. Nat Rev Drug Discov. 2007; 6: 75-92. PASCUAL-SALCEDO D, PLASENCIA C, RAMIRO S, et al. Rheumatology 2011; 50: 1445-52. W. Reinisch, J. Smolen / Seminars in Arthritis and Rheumatism 44 (2015) S9–S15

• The PLANETRA and PLANETAS studies evaluated the immunogenicity of

CT-P13 after 30 weeks, the results were good, but a published data

suggest that longer observation periods are necessary . For example, anti-

drug antibodies generally appear in RA patients after the fourth infusion,

and sometimes even after one year .

Immunogenecity

41

• In the clinical trial of SB4, ADAs were observed in only 0.7% of subjects receiving the

biosimilar compared with 13.1% of subjects who received the bio-originator.

• The additional ADAs detected to bio-originator etanercept were transient, of low titre and

detected mostly at early time points between weeks 4 and 8.

• There was no difference between biosimilar and bio-originator in either safety or efficacy

among ADA-positive and ADA-negative patients, suggesting that ADAs did not interfere

with clinical activity.

Emery P, et al. Ann Rheum Dis 2015;0:1–7.

Highly sensitive electrocheminulinescence

bridging assay to detect ADAs

• An ELISA was used to study immunogenicity in the HD203 study, wherein eight

patients receiving the biosimilar developed ADAs (three of which had

neutralising ADAs) and three patients receiving bio-originator etanercept

developed ADAs (one of which had neutralising ADAs).

• These numbers are too low to identify any potential clinical consequences of

ADAs.

Bae S-C, et al. Ann Rheum Dis 2016;0:1–7.

294 patients enrolled

• 103 patients were assigned to CT-P10 and 51 to RTX.

• Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles.


• 250 consecutive patients with rheumatic diseases under Remicade and 77 controls were retrospectively

selected for the study.

• Anti-IFX antibodies at drug through levels were measured in parallel with three different bridging ELISA

assays: Promonitor-ANTI- IFX kit, which uses Remicade to detect antibodies, and two more assays that use

either Inflectra or Remsima with the same format.

• In all comparisons positive and negative percentage agreements were 100%, and correlation coefficients were

≥0.995.

• Findings imply that ATI-positive patients treated with RMC should not be considered for switching to a

biosimilar treatment, since pre-existing ATI will interact with the new drug, enhance clearance and

potentially lead to loss of response and infusion-related reactions.

Ruiz-Arguello MB, et al. Ann Rheum Dis 2016;0:1–

4.

• in the SB2 study, in which 55.1% of patients treated with SB2 and

49.7% of patients treated with bio-originator infliximab developed

ADAs,

• ADA-positive patients were more likely to experience infusion or

hypersensitivity reactions and less likely to achieve the primary

outcome of an ACR20 response.

• Nonetheless, SB2 and bio-originator infliximab remained equivalent

in analyses stratified for the presence or absence of ADAs.

Choe J-Y, et al. Ann Rheum Dis 2015;0:1–7.

Denominazione e identificazione dei farmaci biologici, compresi i farmaci biosimilari

• Come richiesto dalla normativa europea, tutti i farmaci autorizzati alla commercializzazione

devono presentare una denominazione commerciale che puo essere rappresentata da un nome di

fantasia (brand) oppure dalla denominazione del principio attivo seguita da un marchio o dal nome

dell'azienda titolare di AIC.

• ogni farmaco biologico, inclusi i biosimilari, e chiaramente identificabile attraverso una

denominazione univoca formalmente approvata dalle Autorita regolatorie competenti come parte

del processo di autorizzazione.

• La denominazione commerciale approvata, insieme al numero di lotto, e importante per una

chiara identificazione del farmaco ai fini del monitoraggio delle reazioni avverse e per raccogliere le

informazioni sul farmaco e, quindi, garantirne la tracciabilita .

Agenzia Italiana del Farmaco – Secondo Concept Paper sui Farmaci Biosimilari- giugno 2016








• Conclusioni

Extrapolations for indications

• A biosimilar may obtain extrapolation to other indications for

which the reference product is approved without specific studies of

those indications, provided that proper scientific rationale is

provided for each indication for which extrapolation is requested .

• The rationale for the EU and the USA should address each

indication and patient population for which licensure of the

biosimilar is sought:

• The rationale may not always be sufficient

depending on the regulatory authority and their

interpretation of the results; for example, the

infliximab biosimilar, while approved for all

innovator indications in the EU and the USA, did

not gain approval in IBD indications in Canada.

Extrapolations for indications

58.Health Canada. Summary basis of decision (SBD): Inflectra. 2014. http://www.hc-sc.gc.ca/dhp-

mps/prod pharma/sbd-smd/drug-med/sbd_smd_2014_inflectra_ 159493-eng.php. Accessed 13 January 2016.

Biosimilar’s licensure application

• At the time of the biosimilar’s licensure application, if a clinical

programme has been conducted, usually fewer patient-years of exposure

are required for a biosimilar in contrast to typical large innovator safety

databases, for example, current innovator safety databases in an initial

indication of RA often exceed 2500 patients.

• Consider at the time of innovator infliximab approval for its initial indi-

cations of Crohn’s disease and RA, in 1998 and 1999, respectively, the

sizes of the safety databases for the patients exposed to the biologic in

each indication were relatively small (n = 177 and n = 342, respectively)

• While the safety database of 439 patients

exposed to biosimilar infliximab in AS and RA was

therefore quite numerically comparable, in

contrast the biosimilar achieved approval in all

eight indications in the EU based on the

scientific justifications provided rather than the

innovator’s two indications

Biosimilar’s licensure application

Post-marketing safety analysis

• Currently for both innovators and biosimilars, the EMA does require a risk

management plan and the FDA may require a risk evaluation mitigation

strategy if instituted for the reference product.

• The EMA and FDA both also tend to require post-marketing safety

evaluations if late-occurring safety events are of concern.

• Post- marketing evaluation of Celltrion’s infliximab as per EMA’s public

assessment report is to include participation in various established EU

registries

33.European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology- derived

proteins as active substance: non-clinical and clinical issues. 2014. http://www.ema.europa.eu/docs/en_ GB/document_library/Scientific_guideline/2015/01/ WC500180219.pdf. Accessed 7 January 2016.

34.U.S. Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a

reference product. 2015. http://www.fda.gov/down loads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM291128.pdf. Accessed 2 February 2015

• Post-marketing evaluation of biosimilars may or may not be impacted by naming

conventions for their proper identification.

• For many years in the EU, biosimilars have been licensed with the same

international non-proprietary (generic) name (INN) as the innovator along with a

proprietary brand name.

• In the USA, the recent non-proprietary Naming of Biological Products draft guid-

ance proposes that the biosimilar and its reference innovator biologic should have

the same INN with a unique four-letter suffix appended to the INN to distinguish

them along with different proprietary names

• The recently approved biosimilar infliximab has the 4-letter suffix of dyyb while

there has been no modification of the reference product’s INN.

Post-marketing safety analysis

L’ utilizzo dei farmaci biologici off-label

• Poiche anche i prodotti biologici possono essere

utilizzati per l’uso off-label, nel caso di un medicinale

biosimilare il cui corrispondente medicinale biologico

di riferimento sia gia stato autorizzato per l’utilizzo off-

label e sia, quindi, presente nel richiamato elenco

l’inserimento del biosimilare non e automatico, ma

verra verificato caso per caso dalla CTS.









• Conclusioni

Intercambiabilità

• Riguardo al concetto di intercambiabilita riferita alla pratica medica si riportano le

seguenti definizioni:

• Secondo la definizione dell'OMS e prodotto farmaceutico intercambiabile: “un

prodotto che si prevede abbia lo stesso effetto clinico di un prodotto

comparatore e possa essere sostituito ad esso nella pratica clinica” (Ref: WHO

Technical Report Series, No. 937, 2006).

• L’intercambiabilita si riferisce alla pratica medica di sostituire un farmaco con un

altro, che si prevede produca il medesimo effetto clinico in un determinato

contesto clinico in qualsiasi paziente, su iniziativa o con l'accordo del medico

prescrittore (definizione Biosimilars Consensus Information Paper).


Interchangeability: different position of EMA and FDA

• If a proposed biosimilar is designated interchangeable in the USA at

the federal level, products may be substituted for the reference

product without the intervention of the prescribing health care

provider. The FDA does have the authority to approve

interchangeable biologic products,

• The EMA does not have the authority to approve interchangeble

biologic products; the decision is left to the regulatory authorities

in each EU country.

Sostituibilità

• La sostituibilita fa, invece, riferimento alla pratica di sostituire un farmaco con un

altro farmaco, spesso piu economico per il Servizio Sanitario o per il paziente che

abbia la stessa composizione qualitativa e quantitativa di sostanze attive, la stessa

forma farmaceutica e via di somministrazione e sia bioequivalente con il medicinale di

riferimento sulla base di appropriati studi di biodisponibilita .

• La sostituibilita automatica (degli equivalenti) da parte dei farmacisti si riferisce alla

pratica per cui il farmacista ha la facolta, oppure e tenuto, conformemente a norme

nazionali o locali, a dispensare, al posto del medicinale prescritto, un farmaco

equivalente e intercambiabile, senza consultare il medico prescrittore.


M ECHA NI SM I N A UTOI M M UNI TY

Safety, efficacy and immunogenicity of switchingfrom innovator to biosimilar infliximab in patientswith spondyloar thr itis: a 6-month real-lifeobservational study

Maur izio Benucci1 • Francesca Li Gobbi1 • Francesca Bandinelli1 •

Ar ianna Damiani1 • Mar ia Infantino2• Valentina Grossi2 • Mar iangela Manfredi2 •

Simone Par isi3 • Enr ico Fusaro3• Alber to Batticciotto4

• Piercar lo Sarzi-Puttini4 •

Fabiola Atzeni4 • Francesca Meacci2

Ó Springer Science+Business Media New York 2016

Abstract Biosimilar infliximab (INX) was recently approved by the European Medicine Agency for the treatment of

rheumatoid arthritis, ankylosing spondylitis (AS), Crohn’s disease, ulcerative colitis, psoriatic arthritis (PsA), and psoriasis

on the grounds that its pharmacokinetics, safety, and efficacy were comparable to those of innovator INX. The aim of this

study was to investigate the real-li feefficacy, safety, and immunogenicity of switching from innovator to biosimilar INX in

patients with spondyloarthritis (SpA). Forty-one patients attending three Italian rheumatology centres with a previous

diagnosis of SpA and clinically inactive or moderate disease activity (ASDAS-CRP\ 2.1; 22 with AS, five with

enteropathic arthritis, 10 with PsA, and four with undifferentiated SpA), who had been treated for more than 6 monthswith

innovator INX in accordance with the ASAS/EULAR guidelines, were switched to biosimilar INX for pharmaco-economic

reasons (Tuscany Law No. 450 of 7 April 2015) and followed up for 6 months. A record was kept of their BASDAI,

BASFI, ASDAS-CRP, DAS28-CRP (in the presence of peripheral disease), MASES, VAS pain scores, the duration of

morning stiffness, and adverse events (AEs). At the time of the switch, the patients had a median age of 50.9 years (range

23–80), a median disease duration of 124.5 months (range 14–372), and a median duration of treatment with innovator

INX of 73.7 months (range6–144). After 6 months of biosimilar INX therapy, there were no statistical differences in their

median BASDAI (2.73 ± 1.5 vs. 2.6 ± 1.3, p = .27), BASFI (2.34 ± 1.3 vs. 2.17 ± 1.2, p = 0.051), ASDAS-CRP

(1.35 ± 0.3 vs. 1.28 ± 0.2, p = 0.24), DAS28-CRP (2.66 ± 0.67 vs. 2.67 ± 0.35, p = 0.92), MASES (0.35 ± 0.7 vs.

0.17 ± 0.4, p = 0.08), or VAS pain scores (18 ± 14.7 vs. 16.7 ± 11.3, p = 0.55), whereas the median duration of

morning stiffness had significantly decreased (7.2 ± 6.9 vs. 5.8 ± 6, p = 0.02). Furthermore, there was no change in

circulating INX (4.22 ± 2.89 vs 4.84 ± 2.86 l g/mL, p = 0.80) or anti-INX antibody levels (27.76 ± 17.13 vs

27.27 ± 17.28 ng/mL, p = 0.98). The switch from innovator to biosimilar INX in this Italian multicentre SpA cohort was

not associated with any statistically significance differences in efficacy, adverse events or anti-drug antibody level.

Keywor ds Biosimilar CT-P13 Switching Spondyloarthritis

Fabiola Atzeni and Francesca Meacci contributed equally to this

article.

& Maurizio Benucci

[email protected];

[email protected]

1 Rheumatology Unit, Azienda Sanitaria di Firenze, S.

Giovanni di Dio Hospital, Via Torregalli 3, 50143 Florence,

Italy

2 Allergology and Immunology Laboratory, S.Giovanni di Dio

Hospital, Florence, Italy

3 Rheumatology Unit, Citta della Salute e della Scienza di

Torino University Hospital, Turin, Italy

4 Rheumatology Unit, L. Sacco University Hospital, Milan,

Italy

Maur izio Benucci

123

Immunol Res

DOI 10.1007/s12026-016-8843-5

Author's personal copy

The study involved 41 SpA patients (22 with AS, five with enteropathic

arthritis, 10 with PsA and four with undifferentiated SpA) attending three

Italian rheumatology centres, who had been treated for more than 6 months

with iINX in accordance with the ASAS/EULAR guidelines and showed

clinically inactive or moderate disease activity (ASDAS-CRP \ 2.1), and

were switched to bINX for pharmaco-economic reasons (Tuscany Law

No. 450, of 7 April 2015).

Immunol Res. 2016 Jul 23. [Epub ahead of print]

61

After 6 months of bINX therapy, there were no statistical differences in the median BASDAI BASFI, ASDAS-CRP, DAS28-CRP, MASES (, or VAS pain scores , but the median duration of morning stiffness was significantly shorter (7.2 ± 6.9 vs. 5.8 ± 6 p = 0.02).

There was no change in circulating INX or anti-INX antibody levels.

Very few patients experienced an AE, and therewas no significance difference from the AEs

between the two cohorts.

Immunol Res. 2016 Jul 23. [Epub ahead of print]

M ECHA NI SM I N A UTOI M M UNI TY

Safety, efficacy and immunogenicity of switchingfrom innovator to biosimilar infliximab in patientswith spondyloar thr itis: a 6-month real-lifeobservational study

Maur izio Benucci1 • Francesca Li Gobbi1 • Francesca Bandinelli1 •

Ar ianna Damiani1 • Mar ia Infantino2• Valentina Grossi2 • Mar iangela Manfredi2 •

Simone Par isi3 • Enr ico Fusaro3• Alber to Batticciotto4

• Piercar lo Sarzi-Puttini4 •

Fabiola Atzeni4 • Francesca Meacci2

Ó Springer Science+Business Media New York 2016

Abstract Biosimilar infliximab (INX) was recently approved by the European Medicine Agency for the treatment of

rheumatoid arthritis, ankylosing spondylitis (AS), Crohn’s disease, ulcerative colitis, psoriatic arthritis (PsA), and psoriasis

on the grounds that its pharmacokinetics, safety, and efficacy were comparable to those of innovator INX. The aim of this

study was to investigate the real-li feefficacy, safety, and immunogenicity of switching from innovator to biosimilar INX in

patients with spondyloarthritis (SpA). Forty-one patients attending three Italian rheumatology centres with a previous

diagnosis of SpA and clinically inactive or moderate disease activity (ASDAS-CRP\ 2.1; 22 with AS, five with

enteropathic arthritis, 10 with PsA, and four with undifferentiated SpA), who had been treated for more than 6 monthswith

innovator INX in accordance with the ASAS/EULAR guidelines, were switched to biosimilar INX for pharmaco-economic

reasons (Tuscany Law No. 450 of 7 April 2015) and followed up for 6 months. A record was kept of their BASDAI,

BASFI, ASDAS-CRP, DAS28-CRP (in the presence of peripheral disease), MASES, VAS pain scores, the duration of

morning stiffness, and adverse events (AEs). At the time of the switch, the patients had a median age of 50.9 years (range

23–80), a median disease duration of 124.5 months (range 14–372), and a median duration of treatment with innovator

INX of 73.7 months (range6–144). After 6 months of biosimilar INX therapy, there were no statistical differences in their

median BASDAI (2.73 ± 1.5 vs. 2.6 ± 1.3, p = .27), BASFI (2.34 ± 1.3 vs. 2.17 ± 1.2, p = 0.051), ASDAS-CRP

(1.35 ± 0.3 vs. 1.28 ± 0.2, p = 0.24), DAS28-CRP (2.66 ± 0.67 vs. 2.67 ± 0.35, p = 0.92), MASES (0.35 ± 0.7 vs.

0.17 ± 0.4, p = 0.08), or VAS pain scores (18 ± 14.7 vs. 16.7 ± 11.3, p = 0.55), whereas the median duration of

morning stiffness had significantly decreased (7.2 ± 6.9 vs. 5.8 ± 6, p = 0.02). Furthermore, there was no change in

circulating INX (4.22 ± 2.89 vs 4.84 ± 2.86 l g/mL, p = 0.80) or anti-INX antibody levels (27.76 ± 17.13 vs

27.27 ± 17.28 ng/mL, p = 0.98). The switch from innovator to biosimilar INX in this Italian multicentre SpA cohort was

not associated with any statistically significance differences in efficacy, adverse events or anti-drug antibody level.

Keywor ds Biosimilar CT-P13 Switching Spondyloarthritis

Fabiola Atzeni and Francesca Meacci contributed equally to this

article.

& Maurizio Benucci

[email protected];

[email protected]

1 Rheumatology Unit, Azienda Sanitaria di Firenze, S.

Giovanni di Dio Hospital, Via Torregalli 3, 50143 Florence,

Italy

2 Allergology and Immunology Laboratory, S.Giovanni di Dio

Hospital, Florence, Italy

3 Rheumatology Unit, Citta della Salute e della Scienza di

Torino University Hospital, Turin, Italy

4 Rheumatology Unit, L. Sacco University Hospital, Milan,

Italy

Maur izio Benucci

123

Immunol Res

DOI 10.1007/s12026-016-8843-5

Author's personal copy

Quando utilizzare i farmaci biosimilari?

• Nei pazienti naive

• Nei pazienti non responder (per inefficacia o tollerabilità) a un differente biologico

• Nello switch di paziente con patologia stabilizzata da tempo

Switching?










• Conclusioni

Conclusions

• The availability of biosimilars will allow the treatment of more

patients with severe diseases and at the same time will offer

greater economic sustainability to the NHS, particularly in the case

of naive patients.

• It could also lead to savings useful for the sustainability of national

healthcare systems, although a careful assessment of the adverse

events and immunogenicity of the switch is still necessary.

Conclusions

• To bring a biosimilar to market still requires a significant investment of

money, resources and time, although currently less than that required for

an innovator product.

• To be successful in biosimilar development requires comprehensive, in-

depth planning of the entire programme, with a global outlook and the

ability to adapt to an ever-changing regulatory landscape.

• Ultimately, the goal of biosimilar development is to provide more

opportunities for patients to have access to these potentially life-changing

drugs.

Goel N, Chance K. Biosimilars in rheumatology: understanding the rigor of

their development. Rheumatology (Oxford). 2016 May 30

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