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
Bio-‐Pharmaceu<cals: New genera<on of chemotherapeu<cal agents
• 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”
Bio-‐Pharmaceu<cals: New genera<on of chemotherapeu<cal agents
‘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
European Medicines Agency
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
4 PK/PD studies in healthy volunteers
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®
Similar to Neupogen®
Safety Similar to Neupogen®
Similar to Neupogen®
Similar to Neupogen®
*Based on: mean ANC nadir and <me to recovery; CD34+ cell count
European Medicines Agency
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