Clinical Development of Biologics Unique Challenges in Clinical Development of Biologics Hyun Jung Helen Lee, M.D. U.S.A. Chief Strategy Officer Samyang Biopharmaceuticals

Introduction Biologics a major modern advancement in medicine

Unique Features of Biologics Recombinant human proteins, monoclonal antibodies, Nucleic acid therapeutics, gene therapy Large highly complex molecules derived from living systems Very high target affinity and species specificity hence limit toxicity Difficult to deliver : sub-cutaneous or intravenous Expensive to manufacture Process is Product First biomolecular drug launched in 1982: Humulin (human insulin),

Biologics in the Market “Biologic agents will continue to outpace overall pharma spending growth and are expected to represent 19-20% of the total market value by 2017”. Ref: The Global Use of Medicines Outlook through2017, Report by the IMS Institute for Health care

Top 10 Biologic Blockbusters Biologics in the Market Top 10 Biologic Blockbusters Product INN Company Sales (Bn) Humira Adalimumab AbbVie/Esai 14.01 Rituxan Rituximab Roche 7.3 Lantus Insulin glargine Sanofi 7.09 Avastin Bevacizumab 6.95 Herceptiin Trastuzumab 6.80 Remicade Infliximab Janssen 6.56 Prevnar Prenummococal conjuagte vaccine Pfizer 6.24 Enbrel Etanercept Amgen 5.36 Neulasta Pegfigrastin 4.72 Novorapid Insulin aspart Novonordisk 3.98 Source: http://labiotech.eu/top-10-best-selling-biologicals-blockbusters-2015/

Challenges in Clinical Development of Biologics Immunogenicity Dose selection Comparability

Clinical Preclinical CMC Post Approval Model Selection Immunogenicity Mechanism of action Toxicology studies Comparability Process is Product Process change Assay validation Dose considerations Unique PK profiles Pharmacovigilance Boxed warnings Change in process -comparability

Challenges in Clinical Development Immunogenecity

Challenges in Clinical Development Potential to elicit anti-drug antibodies (ADAs) through non-neutralizing antibodies (NNab) or neutralizing antibodies (Nab) Immunogenicity testing is a key component in the demonstration of clinical safety& efficacy and required by the FDA Areas of concern for Nab: efficacy Neutralize biological effects and compromise further therapy Cross react with endogenous protein to induce adverse affects: safety Effect bioavailability, alter PK/PD (increased or decreased rate of clearance) Product-specific antibody sampling considerations

Challenges in Clinical Development Usually ADRs are « on-target » and thus often affect the immune system. Possible safety concerns based on immunogenicity Anaphylaxis - rare Serum sickness – rare Immune complex disease - rare Changes in immune function status - rare Immune response generated to the biologic - more common, include infections, reactivation of viruses and bacteria, malignancies

Challenges in Clinical Development Case Study : TGN 1412 (TeGenero) Lack of Preclinical Toxicity Finding cannot necessarily predict the fate of human interaction. Phase I trial for CD28 superagonist antibody was conducted in 6 human volunteers All six volunteers faced life-threatening conditions including multi organ failure, Initial signs appeared 50–90 min after dosing Results were a consequence of ‘Cytokine Release Storm’ Attarwala H. TGN1412: From Discovery to Disaster. Journal of Young Pharmacists : JYP. 2010;2(3):332-336. doi:10.4103/0975-1483.66810.

Challenges in Clinical Development Immune Related Safety Warnings of Top Biologics Biologic Type Indications Immune Related Safety Warning Adalimumab Human mAb RA, CD, AS Serious infections, malignancies, HSTCL, immunogenicity Etanercept Fusion protein RA, AS,psoriasis Serious infections (TB,fungal), malignancy PML, neutropenia, infections Infliximab Chimeric mAb RA, CD, AS, UC Serious infections,malignancy, PML, HSTCL,immunogenicity CRS/SIRS, immunogenicity Rituximab NHL, CLL, RA, Wegener’s granulomatosis Acute infusion reactions,CRS, TLS, severe mucocutaneous reactions, PML Nivolumab Met Melanoma, Met NSCLC, Adv RCC, Relapsed Hodgkin lymphoma Immune mediated pneumonitis, colitis, hepatitis, endocrinophathies, encephalitis, rash, nephritis and renal dysfunction

Challenges in Clinical Development Dose Considerations in Biologics

Challenges in Clinical Development Non Linearity Biologically Active Dose determination Panitumumab shows non-linear pharmacokinetics Young et al. Clinical Pharmacokinetics, November 2010, Volume 49 pp 729–740

Challenges in Clinical Development Various Dose Considerations in Biologics - Examples Cetuximab: Dose escalation was determined on the basis of target saturation Target engagement, instead of MTD, was used to support dose selection (1) Bevacizumab: The concentration data analyzed were obtained from eight bevacizumab clinical studies (2) Pembrolizumab: phase II dose selected using pharmacodynamics and tumor size marker (3) (1) Baselga J et al., J. Clin. Oncology 2000;18: 904-14 (2) Lu JF et al., Cancer Chemother Pharmacol (2008) 62:779–786 (3) Patnaik A et al. Clin Cancer Res 2015; 21: 4286-93

Challenges in Clinical Development Comparability

Challenges in Clinical Development Comparable means “highly similar” not necessarily “identical” • ICH Q5E – “The demonstration of comparability does not necessarily mean the quality attributes of the pre-change and post-change products are identical; but that they are highly similar and existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety and efficacy of drug product”.

Multistep hierarchical process Challenges in Clinical Development Multistep hierarchical process

Challenges in Clinical Development Comparability issues due to process change during Clinical Study Process is Product Process change can cause delays during development of a biologic Manufacturing unable to cope with demand for drug - serious breach of GCP Comparability studies completion if process change is necessary Circumvent possibility of non-bioequivalent product Detailed planning of clinical study requirements is important

Challenges in Clinical Development Comparability Case Study Ref: Soulières et al. BMC Cancer (2016) 16:19

Challenges in Clinical Development Comparability Case Study (cont.) Soulières et al. BMC Cancer (2016) 16:19 Page 2 of 10

Challenges in Clinical Development Comparability Case Study (cont.) Ref: Soulières et al. BMC Cancer (2016) 16:19

Challenges in Clinical Development Important considerations while designing clinical studies for Biologics Avoid process change in the middle of the study Biologically effective dose may be more relevant criteria as compared to MTD Incorporate immunogenicity assessments in design Product specific antibody sampling schedule for immunogenicity testing

Conclusions Process is product Preclinical and Clinical Study design careful & meticulous planning and execution Immunogenicity considerations Well defined biologically active dose Cross functional collaboration key to the success of biologics Development Plan