I biosimilari in oncologia

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I BIOSIMILARI ONCOLOGIA IN

Maria Grazia Rodriquenz Rionero in Vulture (PZ)

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From… To…

PRIDE AND

PREJUDICE SCIENCE

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Agenda

• Why biosimilars in Oncology?

• What oncologists know about biosimilars

• Metodology of pivotal trials on biosimilars

• Biosimilars in Oncology (Trastuzumab, Bevacizumab)

• Potential barriers to biosimilars uptake in the marketplace

• Conclusions

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Outline

• Why biosimilars in Oncology?

• Conclusions

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-Increase ACCESS to biologic therapies in EU and worldwide -Lower COSTS

-Contribute to the SUSTAINABILITY of healthcare systems

- Expenditure for medicinal products will be up to 1.3 trillion EUR by 2020 - In the EU, biosimilars are approved by a stringent regulatory process - When properly developed and prescribed biosimilars represent an

OPPORTUNITY to

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In the base case scenario, introduction of biosimilars could result in almost €2 billion of savings in 2021

Aitken M, et al. ESMO 2017

La presa di coscienza in tema di sostenibilità

In the base case scenario, introduction of biosimilars could result in almost €2 billion of savings in 2021

Aitken M, et al. ESMO 2017

La presa di coscienza in tema di sostenibilità

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Outline

• What oncologists know about biosimilars

• Conclusions

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ESMO Survey on Biosimilarsin Oncology

Existing challenges for uptake of oncology biosimilars

• Understanding of the concept

• Feeling at ease with prescriptoin

• Address potential concerns

• Understanding the process of data generation

• Definition of biosimilar

• Being comfortable with the

prescription of EMA approved biosimilars

BACKGROUND Q1-5

Biosimilar development and evidence

Q6-12

Extrapolation Q14-16 Interchangea

bility and switching

Q17-19 ESMO

COLLOQUIUM – Are biosimilars the key to access, in practice?

ESMO congress, 21 October 2018

393 responders

(Europe=321, Asia-Pacific=

84, America=55)

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CONCLUSION

Education & data are key for the successful uptake of biosimilars

Education

There is an encouraging level of prescriber use and general knowledge of biosimilars – but huge

need for education among all healthcare professionals- physician, nurses, patient and

payers too.

Immunogenicity & switching:

There is a need for data on the effects of switching patients from the reference biologic to

a biosimilar, biosimilar to a biosimilar and biosimilar to the reference biologic

Extrapolation:

More efforts are needed to improve knowledge about extrapolation of indications

Education & data are the key for the successful uptake of

biosimilars

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77 responders

(52 physicians, 16 pharmacists, 9 advanced practive providers)

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Oncology is the therapy area most targeted by biosimilar developers

Drug product Biosimilar propietary names

Trastuzumab Ontruzant, Herzuma, Kanjinti, Ogivri, Trazimera Bevacizumab Mvasi, Zirabev

Rituzimab Truxima, Blitzima, Ritemvia, Rixathon, Riximyo, Rituzema

Filgrastim Accofil, Zarzio, Nivestim, Tevagrastim, Gastrofil, Filgrastim exal Pegfilgrastim Pelgraz, Udenyca

Epoetina alfa Binocrit, Epoetin alfa Hexal, Abseamed Epoetina zeta Retacrit, Silapo

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Outline

• Metodology of pivotal trials on biosimilars

• Conclusions

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Biosimilar development – “Comparability exercise”

PROCESSO DI SVILUPPO DEI BIOSIMILARI:

ESERCIZIO DI COMPARABILITA’

Lääkealan turvallisuus- ja kehittämiskeskus

Comp. Clinical studies

Comparative in vitro biological characterisation (+in vivo tox if needed)

Manufacture, characterisation, control, stability

Biosimilar

How to demonstrate biosimilarity?

Analytical comparability

Similarity is demonstrated in a

comprehensive physicochemical and biological comparability

exercise

Similarity is confirmed in comparative clinical

studies.

8 Feb 2017 niklas.ekman@fimea.fi 7

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A new paradigm for drug development

Phase III trial→

better performance -More efficacy

-Less toxicity/

better tolerability -Both

A brand new paradigmfor drug development

New language + new methodology Learning curve

vs

Pharmaceutical quality studies Pharmaceutical quality studies

Comparative analytical functional tests

RMP

Comparative Non clinical tests

Com para v e Clinical studies

Safety/Efficacy PK/PD, Immunogenicity

RMP

BIOSIMILAR Reference DRUG

NON clinical tests/

PharmacologyToxicology

Clinical studies Safety/Efficacy

PK/PD, Immunogenicity

Pivotal trial S&E COMPARABILITYEx

And along comes a “new” paradigm for drug development

Phase III trial Better performace Comparability

Biosimilar Reference

DRUG

More efficacy

Less toxicity/ Better tollerability Both

VS

New language + new metodology =learning curve

L’importanza della formazione sugli aspetti metodologici

Giuliani R, et al. ESMO Open 2017; 1:e000142

Objectives, endopoints and trial designs are completely different from those used to prove efficacy of one new treatment

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AIM:

to compare efficacy and safety of biosimilar to the originator

NOT

to determine patient benefit per se

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Studi clinici per biosimilari:

potenziali popolazioni di studio

Studi clinici per biosimilare di trastuzumab:

potenziali popolazioni di studio

Popolazione più omogenea Nessuno o limitati

trattamenti precedenti Maggiore possibilità che le differenze eventualmente osservate tra i gruppi siano attribuibili al farmaco

Tumore della mammella HER2+ in stadio precoce

Tumore della mammella HER2+

metastatico

Tumore dello stomaco HER2+

metastatico Popolazione più eterogenea

Possibile diversità di trattamenti precedenti sia farmacologici, sia chirurgici, sia

radioterapici.

Possibile diversità di patologie

concomitanti, sedi di malattia, sintomi, etc.

Minore possibilità che le differenze

eventualmente osservate tra i gruppi siano attribuibili al farmaco

Le principali caratteristiche degli studi registrativi dei biosimilari

La fiducia nell’estrapolazione può essere limitata

HER2+ EBC HER2+ MBC

HER2+ MGC Le principali caratteristiche degli studi registrativi dei biosimilari

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Per la dimostrazione di biosimilarità, sono necessari studi di equivalenza

Studio di equivalenza (basato su un margine

pre-specificato)

Usato per la registrazione dei farmaci biosimilari Dimostra che il farmaco

ha un effetto simile al comparator

Studio di non inferiorità

Studio di superiorità

Disegni usati per il confronto tra un nuovo farmaco e il trattamento standard

Dimostra che il farmaco è superiore al

trattamento di controllo Dimostra che il farmaco

non è meno efficace del trattamento di controllo

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…agli studi di equivalenza

Risk ratio e intervallo di confidenza, per es. 90% o 95%.

X rappresenta il margine di NON rilevanza clinica, predefinito.

Per la dimostrazione di biosimilarità, sono necessari studi

di equivalenza

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Studi clinici per biosimilari:

Selezione di endpoint sensibili

1. Response

• pCR in early disease

• ORR in metastatic disease

2. Safety

3. Immunogenicity 4. Pharmacokinetics

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Equivalence margins: how similar is similar enough?

‘Minimally Clinically Important Difference’ (MCID)

Confidence interval for the absolute difference in primary endpoint between biosimilar and reference product

Confidence interval for the ratio of primary endpoint for biosimilar versus reference product

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Outline

• Biosimilars in Oncology (Trastuzumab, Bevacizumab)

• Conclusions

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Limited access to Trastuzumab even in Europe

Cherny N et al Ann Onc 2016

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Trastuzumab - Biosimilars

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Each RCT found similar rate of pCR & safety

of the biosimilar and Trastuzumab

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Early disease

Demographics & Baseline Characteristics

Pivot X, et al. J Clin Oncol 2018; 36:968-974

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Early disease

Efficacy Result

Primary endpoint SB3 (n=402) Trastuzumab (n=398)

bpCR 51.7% 42%

Risk difference, (95% Cl) Ratio (95% CI)

10.7% (4.13, 17.26) 1.259(1.112 – 1.426)

0 +13

-13 Favours Trastuzumab Favours SB3

Difference in bpCR (%)

10.7

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Results of safety

Summary of safety during overall study period

Results of safety

Safety Result

TEAEs withincidenceof→ 10% during neoadjuvant period

n, number of subjects with TEAEs; TEAE, Treatment Emergent Adverse Event Pivot X, et al. J Clin Oncol 2018; 36:968-974

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Results of safety

Mean ± SD LVEF change during overall study

Mean ± SD LVEF

Baseline Cycle 5 Pre-surgery Cycle 14 End of Study

SB TR

Pivot X, et al. J Clin Oncol 2018; 36:968-974 Results of safety

Safety Result

TEAEs withincidenceof→ 10% during neoadjuvant period

n, number of subjects with TEAEs; TEAE, Treatment Emergent Adverse Event Pivot X, et al. J Clin Oncol 2018; 36:968-974

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Primary endpoint: week 24 ORR

Secondary endpoints: TTP, PFS, week 48 OS, AEs

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Treatment Adverse Event and Serious adverse event

Cardiac function (LVEF) in the safety population

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Pivot&Petit

My answer: NO, at scientific/data level

(providedthat biosimilarity is assessedby EMA)

Phase III clinical trials are not really the most important piece of evidence biosimilarsdevelopment

Clear regulatoryrequirements:

if fulfilled, I’mhappy with that

-Strength of the statistical demonstration of equivalenceis a key parameter in the

quality of this comparability exercise.

-Population studiedand the endpoint used to claim equivalence

-Next step: assessment of the impact in terms of cost savings resulting from the implementation

of these biosimilars

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Bevacizumab - Biosimilars

ABP 215 MVASI

PF-06439535 ZIRABEV

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PF-06439535 ZIRABEV

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Primary endpoint: ORR by week 19

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Safety

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PK Immunogenicity

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Because of the high similarity, there is no reason to believe that the body’s immune system would react differently to the biosimilar compared with the original biological upon a switch

Immunogenicity is always investigated pre-approval using validated state-of-the-art methods to measure anti-drug antibodies (ADAs)

Harmful immunogenicity is not expected to be triggered by a switch unless the new version of the reference product, after a manufacturing change is of inferior quality, (not truly

comparable)

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Outline

• Potential barriers to biosimilars uptake in the marketplace

• Conclusions

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Barriers to biosimilar uptake in U.S.

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NURSES

EU COMMISSION

EMA

WHO

ESMO

CLINICIANS

PATIENTS

PHARMACISTS

MS/NCA

Other Societies/

Acaademic bodies

End users + data generators

Capture Data Systems (registries, PhVig, et cet…

INDUSTRY

)

SCIENCE GUIDANCE INTERACTION/

COLLABORATION DATA COLLECTION DATA ANALYSIS

HOW TO BUILD → HOW TO CONSOLIDATE CONFIDENCE

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Available at https://www.esmo.org/Policy and on ESMO booth.

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Conclusions

• Biosimilar represents an important area of drug development where more evidence- based data are being collected

• A methodological rigour is bejond the “equiparability exercise”

• Introducing biosimilars into the standard of care will be a dynamic process involving multiple stakeholders, but could potentially help the susteintability of cancer care.

• Education for physicians about these complex issues will be imperative

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