1. 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

2. Introduction Biologics a major modern advancement in medicine

3. 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),

4. 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

5. 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:

6. Challenges in Clinical Development of Biologics Immunogenicity Dose selection Comparability

7. 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

8. Challenges in Clinical Development
Immunogenecity

9. 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

10. 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

11. 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): doi: /

12. 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

13. Challenges in Clinical Development
Dose Considerations in Biologics

14. 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

15. 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:
(2) Lu JF et al., Cancer Chemother Pharmacol (2008) 62:779–786
(3)
Patnaik A et al. Clin Cancer Res 2015; 21:

16. Challenges in Clinical Development
Comparability

17. 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”.

18. Multistep hierarchical process
Challenges in Clinical Development
Multistep hierarchical process

19. 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

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

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

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

23. 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

24. 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