The Key Business Goal of the company is to create financial value for the shareholders
Slide 1 Navigating the IND: Planning for Success Dr. Barry Rosenblatt, Ph.D. SME Biotech Consulting Target Identification Candidate Selection Candidate Optimization Pre-IND Evaluation and Clinical Trials Time Conc Biotech Process of Creating a Drug t1/2 Target Validation SME Biotech Consulting SME Biotech Consulting Why File an IND A new biologic, drug, or device may not be entered into interstate commerce unless: It is approved by the FDA as safe and effective (biological license application [BLA], new drug application [NDA], pre-market approval [PMA], or other marketing approval) OR … An IND is in effect (exempting the study from the premarketing approval requirements that are otherwise applicable) SME Biotech Consulting SME Biotech Consulting IND Checklist Form FDA 1571 Table of Contents Introductory statement and general investigational plan Investigator’s brochure Protocols Chemistry, manufacturing, and control data Pharmacology and toxicology data Previous human experience Additional information SME Biotech Consulting * SME Biotech Consulting The IND Goal? SME Biotech Consulting SME Biotech Consulting The IND Goal! SME Biotech Consulting SME Biotech Consulting Evaluate safety and explore efficacy and dose ranging Obtain efficacy and safety data for approval Post marketing commitments to monitor safety and efficacy Evaluate safety and side effects IND filing BLA filing Proof of concept, safety, potential toxicity, dosing strategy Phase 1 Phase 2 Phase 3 Preclinical Marketing Phase 4 Getting to Market SME Biotech Consulting * SME Biotech Consulting Drug Development is a Risky Business! Longest R&D cycle of any industry Increased investment has not decreased risk Global development increases complexity Tufts Institute estimates that the average cost to develop a new prescription drug is over $1B Creativity and innovation must be joined by Proficient Planning Clear Thinking Crisp Decision-making Excellent Communication Well-coordinated Teamwork Efficient Execution SME Biotech Consulting SME Biotech Consulting The Duration of Drug Development Keeps Increasing SME Biotech Consulting SME Biotech Consulting Comparability & Getting to Market Specs? Comparability? Comparability? Develop Apply Analyze SME Biotech Consulting SME Biotech Consulting Key Information Prior to First-in-Human Study (Small Molecules) Pharmacologic Efficacy Estimate of potency vs. efficacy, duration of action, and tolerance/ no tachyphylaxis Full dose response relationship established Minimally effective dose in at least one model of efficacy identified Safety Toxicology (usually 28-day study in 2 species) Viable therapeutic index/ exposure multiples, maximum tolerated dose identified SME Biotech Consulting SME Biotech Consulting Key Information Prior to First-in-Human Study (Small Molecules) Pharmacokinetics/ Drug Metabolism Human dose is estimated (via relevant pharmacologic models and allometric scaling) and practical Predicted metabolic stability, bioavailability acceptable In vitro hepatocytes, preclinical PK, toxicokinetic analysis SME Biotech Consulting SME Biotech Consulting Key Information Prior to First-in-Human Study (Small Molecules) Chemistry, Manufacturing & Pharmaceutical Properties Chemistry for large scale synthesis is feasible Acceptable solubility, permeability and stability such that a human formulation supporting a 2-year shelf life can be developed Initial Cost of Goods (COG’s) estimate provided Additional Profiling of compound Negative in Ames assay SME Biotech Consulting SME Biotech Consulting Preclinical Profiling Occurs in Parallel with Chemical Development 10 mg 25-50 mg In vitro screening In vitro profiling 250-500 mg In vivo profiling Acute toxicology studies In vitro metabolism 1-2 kg Chronic animal models 7-day dose ranging toxicology Pre-Formulation Activities GMP 10-15 kg 28-day chronic toxicology Genotox panel, Safety pharm Preclinical PK & metabolism Clinical Supply SME Biotech Consulting SME Biotech Consulting Information Related to Biopharmaceuticals Species Cross-Reactivity Can Be A Major Issue Many studies can only be conducted in non-human primate Anti-drug antibodies can impact PK of protein Safety Toxicology Pharmacology studies have not shown unexpected safety risks Tissue cross-reactivity screen has identified tox species Manufacturing & Pharmaceutical Properties Robust cell line; large scale manufacturing judged feasible Initial formulation developed (lyo vs. liquid) Acceptable solubility, permeability and stability for intended use in the clinic SME Biotech Consulting SME Biotech Consulting Section 4: General Investigational Plan The FDA is Interested in: Disease Target Patient Population Phase 1: Healthy Volunteers or Patients? Monotherapy or Combination? The Corporation is Also Interested in: Development Strategy Timeline Year of Launch Return on Investment SME Biotech Consulting SME Biotech Consulting One-third of Development Costs Spent By End of Phase 1 Molecule is safe at single and multiple doses; maximum tolerated dose established; key DDI’s, dose limiting adverse event profile known Success rate still < 10%="" insufficient="" exposure="" lack="" of="" target="" engagement="" unvalidated="" targets="" polypharmacology="" safety="" best="" chance="" to="" manage="" risk="" is="" to="" have="" efficient="" development="" strategy="" to="" demonstrate="" poc="" studies="" should="" be="" designed="" to="" build="" a="" dataset="" that="" address="" key="" items="" needed="" to="" design="" pivotal="" studies="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" four="" fundamental="" questions="" for="" a="" development="" strategy="" does="" the="" product="" profile="" address="" an="" unmet="" medical="" need,="" and="" how="" important="" a="" need?="" does="" the="" plan="" contain="" clear="" decision="" points="" that="" are="" linked="" to="" the="" most="" important="" aspects="" of="" the="" product="" profile?="" has="" the="" drug="" raised="" any="" questions="" during="" preclinical="" development="" that="" should="" be="" addressed="" in="" the="" strategy="" and="" are="" there="" clear="" decision="" points="" linked="" to="" those="" questions?="" is="" the="" speed="" of="" development="" appropriately="" aggressive?="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" drug="" development="" timelines="" &="" decision="" points="" begin="" with="" the="" end="" in="" mind="" key="" elements="" of="" label="" in="" target="" product="" profile="" plan="" clinical="" strategy="" to="" support="" claims="" develop="" clear="" criteria="" to="" enable="" crisp="" decisions="" process="" requires="" prospective="" thinking="" reassess="" performance="" at="" predetermined="" intervals="" have="" data="" changed="" your="" perspective="" has="" competitive="" landscape="" changed="" update="" management="" as="" development="" proceeds="" as="" probability="" of="" success="" increases,="" so="" does="" investment="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" target="" product="" profile="" clinical="" indication="" patient="" population="" projected="" number="" of="" patients="" cmc="" demographics="" juveniles?="" preclinical/tox="" child="" bearing="" age?="" preclinical/tox="" chronic="" vs="" acute="" preclincal/tox="" route="" of="" administration="" preclinical/tox="" dosage="" cmc/preclinical="" con-combinant="" medications?="" cmc/preclinical="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" target="" product="" profile="" formulation="" (dependant="" on="" dose,="" route)="" concentration="" cmc/preclinical="" liquid="" vs="" lyophilyzed="" cmc/preclinical="" vial="" vs="" pre-filled="" syringe="" cmc/preclinical="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" inter-relationship="" between="" cmc="" and="" preclincal/tox="" characterization="" of="" material="" used="" for="" pre-clinical="" studies="" does="" it="" compare="" to="" material="" used="" for="" phase="" i?="" same="" process?="" is="" it="" stable="" during="" the="" study?="" effects="" of="" degradants/contaminants="" on="" interpretation="" of="" study="" (i.e.="" aggregates="" in="" pk/pd)="" virological/microbiological="" profile="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" contents="" of="" the="" cmc="" section="" physical,="" chemical,="" and/or="" biological="" characteristics="" manufacturer(s)="" source="" and="" method="" of="" preparation="" removal="" of="" toxic="" reagents="" quality="" controls="" (e.g.,="" identity,="" assay,="" purity,="" impurities="" profile)="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" contents="" of="" the="" cmc="" section="" description="" of="" testing="" and="" acceptable="" limits="" sterility="" (aseptic="" processing="" or="" sterilization="" process,="" sterility="" and="" endotoxin="" testing,="" etc.)="" linkage="" of="" pharmacological="" and/or="" toxicity="" batches="" to="" clinical="" trial="" batches="" stability="" information="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" contents="" of="" the="" cmc="" section="" source="" of="" material="" initial="" construct="" banking="" system="" master="" cell="" bank="" (mcb)="" working="" cell="" bank="" (wcb)="" genetic="" stability="" (eop,="" cal)="" description="" of="" production="" process="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" contents="" of="" the="" cmc="" section="" description="" of="" purification="" process="" analytic="" characterization="" lot="" release="" stability="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" effects="" of="" the="" tpp="" on="" the="" ind="" choice="" of="" expression="" system:="" type="" of="" product="" (small="" protein="" vs="" large="" glycoprotein)="" level="" of="" expression="" needed="" choice="" of="" production="" system="" scale="" batch="" vs="" fed="" batch="" vs="" perfusion="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" effects="" of="" the="" tpp="" on="" the="" ind="" down="" stream="" process="" scale="" contaminant="" profile="" i.e.="" high="" multidose="" requires="" better="" contaminant="" profile="" than="" low="" single="" dose="" formulation="" excipient="" safety="" profile="" stability="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" exercise="" your="" company:="" muwbiotech="" has="" a="" new="" product="" in="" development:="" a="" recombinant="" humanized="" monoclonal="" targeting="" a="" receptor="" in="" the="" eye="" that="" is="" key="" in="" macular="" degradation.="" the="" drug="" must="" be="" injected="" inter-occularly="" to="" be="" effective.="" the="" patient="" population="" may="" include="" juveniles.="" what="" other="" critical="" attributes="" may="" affect="" the="" tpp?="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" exercise:="" tpp="" worksheet="" sme="" biotech="" consulting="" sheet1="" target="" product="" profile="" worksheet="" clinical="" indication="" drug="" type="" protein="" nucleic="" acid="" cellular="" peptide="" virus="" vector="" mab="" dna="" stem="" cell="" allegeneic="" intact="" virus="" strain="" cytokine="" rna="" adult="" vlp="" other="" hesc="" vaccine="" modified="" yes/no="" type="" of="" modification="" conjugated="" differentiated="" in="" vitro?="" genetically="" modified?="" transient="" expression="" dosage="" range="" weight="" adjusted?="" dosage="" frequency="" chronic="" multiple="" single="" daily="" weekly="" biweekly="" monthly="" semiannual="" annual="" prn="" route="" of="" administation="" i.v.="" i.p.="" s.c.="" p.o.="" i.n="" i.m="" push="" bolus="" infusion="" formulation="" liquid="" lyophilized="" target="" concentration="" sheet2="" sheet3="" sme="" biotech="" consulting="" case="" study="" use="" of="" pk="" studies="" to="" support="" target="" product="" profile:="" the="" pk="" studies="" were="" conducted="" in="" two="" animal="" species="" and="" used="" the="" final="" pegylated="" version="" of="" rbche="" (human="" butyrylcholinesterase)="" for="" the="" first="" time.="" in="" general,="" the="" conjugation="" of="" proteins="" with="" polyethylene="" glycol="" (peg)="" has="" been="" shown="" to="" decrease="" immunogenicity,="" increase="" circulating="" serum="" half-life="" and="" increase="" stability="" of="" recombinant="" proteins.="" the="" data="" from="" these="" studies="" confirm="" that="" the="" specific="" peg="" chosen="" for="" conjugation="" to="" rbche="" will="" significantly="" improve="" the="" half="" life="" of="" the="" protein="" in="" vivo.="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" case="" study="" the="" pk="" studies="" demonstrated="" that="" protexia®="" had="" a="" half="" life="" of="" approximately="" four="" days="" in="" primates="" and="" three="" days="" in="" rodents="" when="" administered="" by="" intramuscular="" injection.="" these="" data="" compare="" favorably="" with="" what="" was="" predicted="" for="" the="" drug's="" pk="" profile="" in="" these="" animal="" species="" "these="" results="" are="" very="" meaningful="" in="" that="" they="" show="" that="" protexia®="" meets="" or="" exceeds="" our="" target="" product="" profile="" for="" use="" as="" a="" chemical="" nerve="" agent="" prophylaxis.="" the="" impressive="" half="" life="" data="" also="" confirm="" that="" the="" pegylation="" of="" rbche="" as="" part="" of="" our="" manufacturing="" process="" achieved="" the="" goal="" of="" extending="" the="" half-life="" of="" the="" protein="" to="" one="" which="" makes="" it="" a="" feasible="" product="" for="" use="" in="" humans."="" sme="" biotech="" consulting="" *="" used="" for="" treatment="" of="" nerve="" gas="" (organophosphate)="" victims.="" sme="" biotech="" consulting="" case="" study="" in="" this="" case,="" the="" tpp="" defined="" the="" need="" for="" development="" of="" a="" form="" of="" the="" drug="" that="" had="" an="" extended="" half-life.="" this="" decision="" drove="" the="" cmc="" process="" to="" develop="" and="" characterize="" a="" pegylated="" form="" of="" the="" drug="" the="" pk="" data="" and="" the="" cmc="" data="" together="" allowed="" for="" continuation="" into="" the="" next="" phase.="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" biomarkers:="" new="" tools="" for="" drug="" development="" provide="" data="" on="" pharmacological="" effect="" in="" human="" objective="" measurement="" enables="" decision-making,="" early="" termination="" of="" inferior="" compounds="" reduce="" risk="" in="" drug="" safety="" and="" efficacy="" identification/="" evaluation/="" validation="" should="" begin="" in="" discovery="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" biomarkers:="" new="" tools="" for="" drug="" development="" categories:="" target:="" does="" compound="" reach="" intended="" tissue?="" mechanism:="" does="" compound="" elicit="" biochemical="" change?="" clinical:="" does="" relevant="" aspect="" of="" disease="" state="" change?="" holy="" grail:="" surrogate="" (clinically="" relevant)="" endpoint="" requires="" extensive="" correlation="" with="" clinical="" endpoint="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" proof="" of="" concept="" demonstrate="" effect="" on="" short="" term="" clinical="" outcome="" ideally,="" enroll="" 200="" or="" fewer="" patients="" for="">< 4 weeks longer studies require more extensive preclinical safety support not necessarily based on clinical efficacy biomarker panels, surrogate markers can be used may relate to demonstration of safety advantage sme biotech consulting sme biotech consulting proof of concept criteria should be well-defined in the development strategy in order to make clear go/no go decisions evaluate emerging versus target product profile(s); reassess risks do the data support the early commercial projections? sme biotech consulting sme biotech consulting additional considerations development in asia considered, development plans consistent with local needs target product profile is viable for global markets global commercial assessment is available early clinical plan content and timing prepared invention data package filed, legal risk assessment provided sme biotech consulting sme biotech consulting emerging versus target product profile(s) refine strategy, define the positioning and the phase 3 program key claims, key studies planned decision on comparators for pivotal trials manufacturing strategy product positioning and pricing (global) 4="" weeks="" longer="" studies="" require="" more="" extensive="" preclinical="" safety="" support="" not="" necessarily="" based="" on="" clinical="" efficacy="" biomarker="" panels,="" surrogate="" markers="" can="" be="" used="" may="" relate="" to="" demonstration="" of="" safety="" advantage="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" proof="" of="" concept="" criteria="" should="" be="" well-defined="" in="" the="" development="" strategy="" in="" order="" to="" make="" clear="" go/no="" go="" decisions="" evaluate="" emerging="" versus="" target="" product="" profile(s);="" reassess="" risks="" do="" the="" data="" support="" the="" early="" commercial="" projections?="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" additional="" considerations="" development="" in="" asia="" considered,="" development="" plans="" consistent="" with="" local="" needs="" target="" product="" profile="" is="" viable="" for="" global="" markets="" global="" commercial="" assessment="" is="" available="" early="" clinical="" plan="" content="" and="" timing="" prepared="" invention="" data="" package="" filed,="" legal="" risk="" assessment="" provided="" sme="" biotech="" consulting="" sme="" biotech="" consulting="" emerging="" versus="" target="" product="" profile(s)="" refine="" strategy,="" define="" the="" positioning="" and="" the="" phase="" 3="" program="" key="" claims,="" key="" studies="" planned="" decision="" on="" comparators="" for="" pivotal="" trials="" manufacturing="" strategy="" product="" positioning="" and="" pricing="">