Manufacturing, Analytical and Regulatory Strategies for ... · Manufacturing, Analytical and Regulatory Strategies for Successful Development of ADCs Nathan Ihle Seattle Genetics

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