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Manufacturing, Analytical and Regulatory Strategies for Successful Development of ADCs
Nathan Ihle
Seattle Genetics
AAPS Annual Meeting and Exposition
Manufacturing, Analytical and Regulatory Strategies for
Successful Development of ADCs
October 28, 2015, Orlando, Florida
2 Confidential
ADC Technology: Empowering Antibodies
Designed to improve efficacy and
reduce toxicity
Potent cytotoxic agents and stable linkers
with long half-lives
Readily scalable through simple,
reproducible synthesis
SGEN technology empowers more than 20
of the ADCs in clinical development across
the industry, including both proprietary and
collaborator programs
ADCs combine the
targeting ability of
monoclonal antibodies
with the potency of
cytotoxic agents
3
ADC Technology Empowers Antibodies for Cancer
1. Younes A, et al. J Clin Oncol. 2012;30:2183-2189;
2. Forero-Torres, Br J Haematol, 2009;146:171-179.
Relapsed/Refractory Hodgkin Lymphoma
brentuximab vedotin
(anti-CD30 ADC)
SGN-30
(anti-CD30 mAb)
Dose 1.8 mg/kg every 3 weeks1 6 or 12 mg/kg weekly2
No. of Patients 102 35
Response Rate 75% objective responses 0 objective responses*
SGN-30 demonstrated some antitumor activity, including stable
disease in several patients with Hodgkin Lymphoma
*
4
Novel Strategies for ADC Development
• Understand your molecule
o Structure, Process, Analytics, …
• Think about why things are done a certain way
o Are these reasons applicable for the innovative molecule?
• When you diverge from the “normal” way of doing things, do a good
job of explaining why
• Keep the patient in mind
o There is urgency to what we do
5
Innovative Molecules Demand Novel Strategies The normal way of doing things may not be appropriate
6
Company Overview
• Biotechnology company focused on developing and commercializing empowered
antibody-based therapies for the treatment of cancer
o Industry leader in antibody-drug conjugate (ADC) technology
o ADCETRIS® (brentuximab vedotin) is approved in more than 55 countries
o Robust product pipeline designed to address unmet medical needs
• Founded in 1998
• Headquartered in Bothell, WA
• Publicly traded (Nasdaq: SGEN)
• Nearly 700 employees
• Programs in clinical trials o ADCETRIS
o SGN-CD19A
o SGN-CD33A
o SGN-LIV1A
o SGN-CD70A
o ASG-22ME
o ASG-15ME
o SEA-CD40
7
ADC Collaborations with Industry-Leading Companies >$325M generated to date with potential for >$4B in future milestones plus royalties
Collaborator Program Preclinical Phase 1 Phase 2 Pivotal/Phase 3
Glembatumumab vedotin (Anti-GPNMB) Breast cancer
Melanoma
Anti-CD79b (RG7596, DCDS4501A) Non-Hodgkin lymphoma
Anti-NaPi2b (RG7599, DNIB0600A) Ovarian, non-small cell lung cancer
Anti-STEAP1 (RG7450, DSTP3086S) Prostate cancer
Anti-Ly6E (RG7841, DLYE5953A) Breast, non-small cell lung cancer
RG7841 Ovarian, pancreatic cancer
Anti-PSMA ADC Prostate cancer
Anti-GCC ADC Advanced gastrointestinal malignancies
Anti-EGFR ADC Glioblastoma
Undisclosed ADC Cancer
Undisclosed ADC Cancer
Affiliate of Astellas
Anti-ENPP3 ADC Renal cell carcinoma
Anti-CD37 ADC Cancer
Anti-5T4 ADC Solid tumors
Anti-C4.4a ADC Solid tumors
Anti-FGFR2 ADC Cancer
Anti-BCMA ADC Multiple myeloma, hematologic malignancies
Anti-TF ADC Solid tumors (Opt-in at end of phase 1)
Others Several additional collaborator programs
Example # 1 – Don’t Be Afraid of Heterogeneity
9
MMAE Conjugated at Cysteine Residues
• Linker: chemically stable
o Enzymatically cleaved
• Monomethyl auristatin E: synthetic small molecule
o Microtubule disrupter
Drug MMAE cytotoxic agent
Linker
Antibody
Attachment group
Protease- cleavage site
10
Auristatin Conjugation Process
Antibody Reduction
Reaction
Drug-Linker
Formulation
UF/DF
(Purification)
Conjugation
Reaction
Filtration
and Fill
BDS
11
Partial Reduction and Resulting Conjugated Forms
0 2
4
6 8
12
ADC Heterogeneity is Not a Barrier to Development
Nature Biotechnology 22, 1383 - 1391 (2004)
• Sources of heterogeneity: o Biological systems used in production (e.g. CHO cells)
o Physiochemical changes caused during production and subsequent storage
o Conjugation isoforms and variants
• Heterogeneity can be understood and controlled o Process design, understanding, and controls
o Analytical characterization and testing
13
Example # 1 – Don’t Be Afraid of Heterogeneity
• Understand it
• Demonstrate consistency
• Demonstrate safety of the product you have
• Assess the risk-benefit of the product holistically
• Explain yourself
Example # 2 – Evaluate impurities in the context of the significance of their impact
15
• “The amount of free antibody … in the final product should be
determined with limits set …”*
o Concern appears to be related to antibody inhibiting action of ADC
• Is the free antibody a species of special concern?
o Does it impact safety or efficacy of the product?
FDA Guidance on Purity of Immunoconjugates
*Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, FDA, 1997
16
• 5x higher dose of unconjugated antibody only partially blocks ADC
activity
Unconjugated mAb Typically a Poor Competitor
0 1 0 2 0 3 0
0
5 0 0
1 0 0 0
1 5 0 0
K a r p a s -1 0 3
D a y s p o s t d o s e
Me
an
Tu
mo
r V
olu
me
(m
m3
)SGN-35 cAC10
- -
- 2
2 -
2 2
2 10
Dose (mg/kg)Dose (mg/kg)
ADC mAb
- -
- 2
2 -
2 2
2 10
Fu Li
Data on file
17
• “The amount of free antibody … in the final product should be
determined with limits set …”*
• Free antibody may not inhibit ADC activity
o No direct effect on safety or efficacy
o Not a critical quality attribute
o Treat as product variant or innocent bystander
FDA Guidance on Purity of Immunoconjugates
*Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, FDA, 1997
Example # 3 – Principles from small molecule development can be helpful
19
• “The amount of … free components in the final product should be
determined with limits set …”*
o Small molecule impurities
“Free Drug” and/or “Free Linker”
• The free components are of special concern
o Free drug generally toxic
FDA Guidance on Purity of Immunoconjugates
*Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, FDA, 1997
20
What Free Drugs To Monitor?
Precursors
Degradants
Theoretical Actual
By-products
21
• “…selection of impurities in a new drug substance specification
should be based on the impurities found in batches …”*
o If you don’t observe an impurity, it does not need to be specified, or
reported
ICH Q3A&B Applied to Drug-Related Impurities
*ICH Q3A(R2) – Impurities in New Drug Substances
22
Drug-Related Impurities With Auristatins?
MMAE vcMMAE
NAC-vcMMAE
Degradants
23
• “The amount of … free components in the final product should be
determined with limits set …”*
What Are Appropriate Limits on Free Drug?
*Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, FDA, 1997
24
ICH Q3A&B Applied to Drug-Related Impurities
• ICH guidances* provide framework for establishing limits:
*ICH Q3A(R2) – Impurities in New Drug Substances; ICH Q3B (R2) – Impurities in New Drug Products
Daily Dose Reporting
Threshold
Identification
Threshold
Qualification
Threshold
Drug Substance
Impurities (≤ 2 g/day) 0.05% 0.10% or 1.0 mg TDI 0.15% or 1.0 mg TDI
Degradation Products
(10-100 mg/day)
0.1% 0.2% or 2 mg TDI 0.5% or 200 µg TDI
25
Are ICH Q3A Limits Safe?
• 5 mg/kg dose for 70 kg patient
o 350 mg/dose
o 17 mg/day
• 0.10% impurity (i.d. level)
o 0.35 mg/dose
o 17 µg/day
• Questions to ask:
o Is 0.10% impurity expected to be pharmacologically active?
o What is the tolerability of this dose, relative to the ADC itself?
o Is impurity dose significant in relation to the level of drug exposure due
to in vivo processing of the ADC?
mAb
Bound Drug (3.5%)
Impurity (0.10%)
26
Justification of Free Drug-Related Impurity Specifications
• Understand your product and your process
o What are the actual, relevant free drug-related impurities
• Understand safety of your small molecule and the ADC
o What are the relevant ICH safety thresholds
o What is the relative toxicity of the drug and the ADC
• Account for uncertainty
o If identity and/or safety of an impurity are not known, assume equivalent
to the relevant “toxic” drug
27
Recommended Test, Limits, & Justification
Test Analyte Acceptance
Criteria
Justification
HPLC
Specified (observed) Impurities
A, B, C …
≤ 0.15 % or
Qualified Level
Complies with ICH
Q3A(R2)
Unspecified Impurities Each impurity
≤ 0.10%
Complies with ICH
Q3A(R2)
Total Reportable Impurities ≤ X% Limit based on
process experience
At Licensure
• Don’t specify or report any impurities that are < 0.05%
o Don’t specify free drug unless it is observed ≥ 0.05%!
• Higher limits may be acceptable during clinical development, or following ICH
Q3A(R2) decision trees
• With sufficient manufacturing experience, removal of test from specification can be
justified
• Removal of test from DP can be justified, if no degradation observed
28
Manufacture of ADCs
29
Current ADC Manufacture
• Four stages manufactured by four different CMOs
• Full release of intermediates, BDS and drug product
mAb
Drug-Linker
Bulk Drug
Substance Drug Product
30
Manufacture of Drug and Linker for ADCs
• Drug-Linker manufactured in chemical manufacturing facilities
o Intermediate, not an API
o Manufactured with API-like controls
o Smaller scale than typical API (typically < 100 mg/patient)
31
Manufacture of Drug and Linker for ADCs
• Drug is a typically a high potency cytotoxic compound
o Requires specialized facilities and procedures
Assure worker safety
Focus on preventing cross-contamination
32
Advances in Antibody Process Capability and Impact of Targeted Therapy Drives Process Volumes Down
• Increased antibody titers results in smaller volume requirements
• ADC typically requires less protein per patient than traditional antibodies
M. Croughan, R. D. Kiss
33
Manufacture of ADC Bulk Drug Substance
• BDS manufacture requires specialized (hybrid) facility o Process hygiene
Closed systems and/or SIP
Classified air handling Pressure cascades to exclude contaminants
Microbial control Low bioburden and endotoxin
o Aqueous process streams WFI
Sterile buffers
o Bioprocessing unit operations UF/DF
Sterilizing filters
Tight process controls impacting proteins (temperature, pH, shear, etc.)
o Organic co-solvents Compatible materials of construction
o High potency cytotoxic handling Containment
Pressure cascades to contain material
Use of isolators
Personal Protective Equipment (PPE)
Increased emphasis on cross-contamination risks and cleaning validation
May require dedicated facility
34
Manufacture of ADC Drug Product
• Drug product is manufactured in multiproduct cytotoxics manufacturing facilities with lyophilization capability
o Aseptic processing
o Aqueous process streams
o Bioprocessing unit operations
o High potency cytotoxic handling
o Rigorous and complex product changeover/cleaning validation
• Ideal facility utilizes isolators/RABS with highly automated filling line
o Maintains aseptic environment
o Provides containment to protect operators
o Minimizes manual operations/interventions
• Experience with biologics in a high potency, cytotoxic facility
o Typically small molecule operations
o Tighter process controls impacting proteins (temperature, pH, shear, etc.)
35
Successful Strategies for ADC Development
• Published guidances provide useful framework for unique ADC
attributes, but application can be open to interpretation
• Points to consider in setting ADC specifications
o Product heterogeneity – don’t be afraid, but understand and control
o Unconjugated antibody may not impact efficacy or safety – specification
should be set accordingly
o ICH Q3A guides selection and limits of free drug-related impurities in the
specifications
• Consistent application of these strategies throughout the industry will
help deliver important new drugs to patients in need, while assuring
patient safety
36
Novel Strategies for ADC Development
• Understand your molecule
o Structure, Process, Analytics, …
• Think about why things are done a certain way
o Are these reasons applicable for the innovative molecule?
• When you diverge from the “normal” way of doing things, do a good
job of explaining why
• Keep the patient in mind
o There is urgency to what we do
37 Confidential
THANKYOU
Audience
Colleagues
Patients
