Nonclinical Safety Assessment of Biotherapeutics

Transcription

1 Nnclinical Safety Assessment f Bitherapeutics BIO-Latin America Regulatry Sessin 10 September 2014 Ri de Janeir Andreas Baumann, Bayer Rafael Pnce, Amgen Paul Andrews, Eisai Frank Brennan, UCB Tim McLachlan, Nvartis BIOTECHNOLOGY INDUSTRY ORGANIZATION 1

2 BiSafe Organizatin and Annual Meetings BiSafe Leadership Cmmittee BiSafe General Membership Special Bilgics Wrk Grup Pharmackinetics / Pharmacdynamics (PK/PD) Wrk Grup Mechanism f Actin / Mechanism f Txicity Wrk Grup BiSafe General Membership Meeting (Spring) BiChina, Bi Latin America BiSafe Eurpe (Fall) BIO Internatinal Cnference BiSafe - FDA Liaisn Meetings (Yearly) BiSafe Liaisn Meetings with ther HA s (EMA, PMDA, CFDA) BIOTECHNOLOGY INDUSTRY ORGANIZATION 2

3 We share a cmmn missin T serve as a resurce fr BIO members and BIO staff by identifying and respnding t key scientific and regulatry issues related t the preclinical safety evaluatin f bipharmaceutical prducts. We are representatives frm pharmaclgy, pharmackinetic, txiclgy and regulatry departments f large and small bipharmaceutical cmpanies. BIOTECHNOLOGY INDUSTRY ORGANIZATION 3

4 Nnclinical Safety Assessment f New Therapeutics View frm BIOSafe Gal: The evaluatin and identificatin f ptential human safety issues thrugh evaluatins in predictive mdel systems Identificatin f target rgans f txicity and characterizatin f thse txicities Nature f effect, reversibility, translatability (animals-t-humans) Infrm patient mnitring Establish the relatinship between safety bservatins and drug expsure (C max and/r AUC) Gal f nnclinical safety testing is the identificatin f: Safety margins r therapeutic windws Safe starting dses, dse escalatin ratinale BIOTECHNOLOGY INDUSTRY ORGANIZATION 4

5 Nnclinical Safety Assessment f Bitherapeutics Regulatry Backgrund These principles are utlined in: ICH S6(R1) [Preclinical safety evaluatin f bitechnlgyderived pharmaceuticals] ICH S9 [Nnclinical evaluatin fr anticancer pharmaceuticals] ICH M3(R2) [Guidance n nnclinical safety studies fr the cnduct f human clinical trials and marketing authrizatin fr pharmaceuticals] WHO Guideline n rdna Prducts Generally, d HA s in Latin America accept nnclinical submissins cnducted in accrdance with these guidances? Are there rutine areas f cncern r additinal expectatins in Latin America? BIOTECHNOLOGY INDUSTRY ORGANIZATION 5

6 General safety cncerns fr bilgics are distinct frm small mlecules Gal: The evaluatin and identificatin f ptential human safety issues thrugh evaluatins in predictive mdel systems Catablized t building blcks (amin acids), nt metablized t ther active r reactive mlecules. Generally, d nt crss bilgical membranes t interact with DNA r ther intracellular mlecules. Highly specific binding prperties with few ff target effects. Because f size d nt interact with in channels. Only rarely affect metablizing enzymes. Mdality (cnstructin) assciated with unique bilgical characteristics. The pharmaclgy f the bilgic determines the txicity prfile and the required safety assessment design. Leads t a case-by-case design f the nn-clinical prgram BIOTECHNOLOGY INDUSTRY ORGANIZATION 6

7 Nn-Clinical Develpment f Bilgics: Defining the Case by Case Apprach Baumann. A. (2009) Nnclinical develpment f bipharmaceuticals. Drug Discvery Tday (2009) 14, BIOTECHNOLOGY INDUSTRY ORGANIZATION 7

8 Despite diverse mdalities and targets, characteristic cncerns exist Are we aligned? Nnclinical species selectin Justificatin Number f species Dse extraplatin t humans - PKPD Duratin f lngest general txicity studies Develpmental and reprductive txicity assessment Carcingenicity assessment Gentxicity assessment Cardivascular safety assessment Dse selectin fr txicity studies Tissue crss-reactivity Immuntxicity testing Immungenicity BIOTECHNOLOGY INDUSTRY ORGANIZATION 8

9 Nnclinical species selectin What data supprt animal species selectin fr bitherapeutic txicity studies? Pharmaclgical relevance used t justify a species Similarity t humans in pharmaclgic respnse (e.g., signaling pathway, target binding, pharmacdynamic activity) Species chice will depend n the relevant pharmaclgy and the assessment tls available What is similar enugh? Bussiere JL (2008) Species selectin cnsideratins fr preclinical txiclgy studies fr bitherapeutics. Expert Opin Drug Metab Txicl 4(7):871-7 BIOTECHNOLOGY INDUSTRY ORGANIZATION 9

10 Number f species t be studied As with small mlecules, ne each f rdent and nnrdent species, if pssible Many bitherapeutics are nly pharmaclgically active in nnhuman primates A single nnhuman primate species is sufficient, usually cynmlgus macaque Studies in chimpanzee n lnger cnducted due t ethical and practical issues Special case: N suitable species (e.g., target is nly expressed with disease, n crss-reactive species) Optins: Use engineered mdels, ex viv tls, paper-based argument t create weight-f-evidence argument fr patient dsing decisins Bussiere et al (2009) Alternative strategies fr txicity testing f species-specific bipharmaceuticals. Int J Txicl. 28(3): BIOTECHNOLOGY INDUSTRY ORGANIZATION 10

11 PK Supprt f First in Human Dsing and Beynd Predict key PK parameters in man (CL, V ss, biavailability) Input parameters fr expsure estimates Estimate expsure (AUC, C max ) at the starting dse Needed fr calculatin f safety margins Estimate therapeutic expsure (based n PK/PD) Need t estimate efficacius dse range Hints fr nn-linearity / higher variability (Target mediated dispsitin) Ptential impact n dse steps in SD escalatin study Give hints fr special risks based n bilgics mdality (e.g. Metablism, Drug-Drug Interactins, Distributin) Planning f clinical mnitring BIOTECHNOLOGY INDUSTRY ORGANIZATION 11

12 Carcingenicity assessment Des the therapeutic prmte tumr frmatin by nn-txic genetic r epigenetic mechanisms? Small mlecules Tw year rat carcingenicity study + six mnth (transgenic mice) r tw year muse carcingenicity study Bitherapeutics Carcingenicity weight-f-evidence assessment : literature review, in vitr and/r in viv studies Tw year rdent studies are generally nt apprpriate Special cncerns: Grwth factrs and immunmdulatrs Vahle JL et al. (2010) Carcingenicity assessments f bitechnlgy-derived pharmaceuticals: a review f apprved mlecules and best practice recmmendatins. Txicl Pathl. 38(4): Bugelski PJ et al. (2010) Critical review f preclinical appraches t evaluate the ptential f immunsuppressive drugs t influence human neplasia. Int J Txicl. 29(5): BIOTECHNOLOGY INDUSTRY ORGANIZATION 12

13 New Challenges in Nn-clinical safety testing f Bilgics Appraches t refine use f nn-human primates in nn-clinical safety testing f bilgics and current experience n the use f minipigs as alternative nn-rdent species. Tissue distributin studies as a useful tl t supprt pharmackinetic/pharmacdynamic (PKPD) assessment f bilgics, in that they prvide valuable mechanistic insights at drug levels at the site f actin. Mechanisms f nnspecific txicity f antibdy drug cnjugates (ADC) and ways t increase the safety margins. Althugh bilgics txicity typically manifests as exaggerated pharmaclgy there are sme reprted case studies n unexpected txicity. Specifics f nn-clinical develpment appraches f nncannical mnclnal antibdies (mabs),l ike bispecifics and nanbdies. Baumann A et al (2014) New Challenges in Nn-clinical safety testing f Bilgics. Regulatry Txicl. & Pharmacl. 69, BIOTECHNOLOGY INDUSTRY ORGANIZATION 13