11 - venditti 12 nov 2012 · 2020. 7. 9. · bio9pharmaceu

Adriano Vendi+ Ematologia

Fondazione Policlinico Tor Vergata Roma

Fa#ori di crescita granulocitari: il punto di vista dell’ematologo

Development of drug generic version

Drug X

Patent Expiry

Generic X

Identical compounds

Identical compounds

Synthesis

Bio-‐Pharmaceu<cals: New genera<on of chemotherapeu<cal agents

•  Copies of human endogenous proteins -  Complex three-dimension structure -  High molecular weight

•  Made either by hybridoma or DNA recombinant technology

•  Manufactured by living cells


•  Generating an exact copy of a biologic agent is technically impossible (microheterogeneity)

•  The manufacturing process is a proprietary knowledge

•  Developing process not identical in different manufacturing settings

•  “Biosimilars” or “follow-on proteins” -  Unique biologic agents similar but not identical to

the “innovator” or “originator”


‘due to the complexity of biological and biotechnology-derived products the generic approach is scientifically not appropriate for these products’

European Medicines Agency

•  New and alternative regulatory pathway -  “Comparability Exercise”

•  Comparability between the “originator” and the “biosimilar” should be demonstrated in terms of quality, efficacy and safety

Focus of biosimilar development

•  Not to establish pa<ent benefit per se –  It has been already done for the originator

•  To demonstrate high similarity with RBP –  Repe<<on of the en<re development program is scien<fically unnecessary

–  Study design, pa<ent popula<on and/or endpoints may be different from those used for RBP

–  Surrogate endpoints accepted •  Acceptable microheterogeneity pa#ern

–  Even between different batches of the same product (rigorous controls on batch-‐to-‐batch consistency)

G-‐CSF biosimilars licensed in Europe


INN* Brand Name RBP rHu-‐metGCSF Filgras<m Neupogen®

SBP XM02 Filgras<m Tevagras<m® EP2006 Filgras<m Zarzio®

Filgras<m Hexal® Biogras<m®

Filgras<m Ra<opharm® PLD108 Filgras<m Nives<m®

RBP = Reference Biotherapeutic Product SBP = Similar Biotherapeutic Product *International no-property name

European Public Assessment Report SBP vs Neupogen® – Clinical Data

XM02 (approved 09/08)

EP2006 (approved 02/09)

PLD108 (approved 06/10)

Phase I studies

2 PK/PD studies in healthy volunteers



Phase III Studies

3 RCT in pa<ents with BC, LC, NHL

1 N-‐CS in pa<ents with BC

1 RCT in pa<ents with BC

Efficacy* Similar to Neupogen®

Similar to Neupogen®


Safety Similar to Neupogen®



*Based on: mean ANC nadir and <me to recovery; CD34+ cell count


EORTC 2010 recommendations

Recommendation Grade

1 Patient-related risk factors should be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy

B

2 Consideration should be given to the elevated risk of FN when using certain chemotherapy regimens

A/B

3 In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF should be used as a supportive treatment

A

4 The risk of complications related to FN should be assessed individually for each patient at the beginning of each cycle

A

5 Treatment with G-CSF for patients with solid tumours and malignant lymphoma and ongoing FN is indicated only in patients who are not responding to appropriate antibiotic management and who are developing life-threatening infectious complications

B

6 Filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents, according to current administration guidelines, to prevent FN and FN-related complications, where indicated. Filgrastim biosimilars are now also a treatment option in Europe.

A

Summary of biosimilar G-‐CSF •  Manufactured in facili<es with “state-‐of-‐the-‐art”

technologies •  Fulfillment of regulatory requirements for approval •  In March 2010, the US Congress passed legisla<on crea<ng

a legal pathway for biosimilar (Under Pa<ent Protec<on and Affordable Care Act)

•  In April 2010, the WHO Expert Commi#ee on Biological Standardiza<on published the final guidelines on “Evalua<on of SBPs”

•  FDA-‐EMEA established a “biosimilar cluster” to promote scien<fic discussion and global development of biosimilars

Patient Protection and Affordable Care Act, as amended by the 111° Congress, H.R.3590 U.S. Food and Drug Administration. Draft guidance on biosimilar product development.

Indica<ons for Neupogen®

•  Reduc<on of the dura<on of neutropenia and incidence of FN in pts treated with CHT or receiving SCT –  with the excep<on of MDS and CML

•  Mobiliza<on of PBSC •  In pts with severe congenital cyclic neutropenia or idiopathic neutropenia when ANC < 0,5x109/L

•  In pts with advanced HIV infec<on and persistent neutropenia

Indica<ons for XM02 – EP2006 – PLD108

•  Reduc<on of the dura<on of neutropenia and incidence of FN in pts treated with CHT or receiving SCT –  with the excep<on of MDS and CML

•  Mobiliza<on of PBSC •  In pts with severe congenital cyclic neutropenia or idiopathic neutropenia when ANC < 0,5x109/L

•  In pts with advanced HIV infec<on and persistent neutropenia

“Approval achieved in all the indica<ons of the RBP through a process of extrapola<on from healthy adults and CIN

studies”

Concerns about the extrapolated use of SBP G-‐CSF

•  Mobiliza<on of PBSC –  unknown whether efficacy in CIN can be fully extrapolated to PBSC mobiliza<on

•  Poten<al risk for healthy donors –  the EBMT group and the WMDA have advised against the use of SBP in unrelated donors

•  Special pa<ents popula<on –  Children –  AML –  Renal insufficiency –  Hepa<c insufficiency

Safety Issues

•  Limited safety data •  Lack of long-‐term safety data •  Immunogenicity •  Side-‐effects

–  a higher incidence of bone pains and myalgia reported for PLD108

•  Subs<tu<on –  Common prac<ce with generic drugs, not appropriate with biopharmaceu<cs

FilgrasMm

Benzinger R et al. MICROBIOLOGICAL Reviews, 1978; 42; 194-‐236 Herbert P. Schweizer et al. BioTechniques, 2008; 44: 633-‐641

RCP Granulokine

Tecnologia DNA ricombinante:

Differenze chimiche e struQurali tra i G-‐CSF

Cellula batterica

E.Coli

Transfezione

Cellula di mammifero

CHO

LenograsMm

CHO: cellule ovariche di Hamster cinese

RCP Myelos<m Hoglund M et al. Med Oncol, 2008; 15:229-‐233.

Depositato presso AIFA in data 11/04/2012

• Lenogras<m induce la mobilizzazione di un numero assoluto maggiore di cellule CD34+

rispe#o a filgras<m (15,34 ±3.1 x106vs 11.04 ±2.41 x106 p<0,01)

Ria et al. Bone Marrow TransplantaMon 2010 45(2):277-‐81.

• La percentuale di pazien< che raggiunge il target di raccolta (3x106 CD34+/Kg) già alla seconda aferesi è del:

75% con Lenogras<m vs. il 48% con filgras<m (p<0,001)

Differenze nella mobilizzazione

n° c

ellu

le x

106 /K

g

75% 48%

P<0,001

lenograsMm filgrasMm Elaborazione grafica da da< testuali

% di pazienM a target già alla 2a aferesi

2010

Depositato presso AIFA in data 11/04/2012

Considera<ons

•  SBP poses new challenges and possibili<es •  Number of SBP is likely to grow fast •  SBP have become a reality in EU and will be soon available in US

•  The regula<on of SBP is a constantly evolving process •  Rigorous programs of pharmaco-‐surveillance

–  long-‐term evalua<on of SBP

•  Randomized clinical trials –  SCT sevng –  Special popula<ons of pa<ents

11 - venditti 12 nov 2012 · 2020. 7. 9. · bio9pharmaceu

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