Presented at DCAT Week 2014

March 10-14, 2014

New York, NY

Reducing Technical & Regulatory Uncertainty in Biosimilar Development

1

Background

Previous speakers have covered

• Market overview, manufacturing technologies, and recent developments in this area

• The current status of US regulatory pathway for biosimilars and related issues on a state level

In this presentation we will review

• Similarity and differences in the US and EU regulatory framework

• With the objective to understand how to reduce technical and regulatory uncertainty in the US market context

2

Reduce technical and regulatory uncertainty in Biosimilar Development

• Reduce cost and time of biosimilar development and enhance market penetration

Why

• Understanding the basis of approvals of selected products and established and emerging guidelines and open issues

How

• Technical and organizational considerations; analytical characterization, PK/PD studies, and clinical trial designs to address residual uncertainty

What

3

Determinants of success

Cost and time of development

Analytical characterization of reference product

Clone selection and design of upstream

and downstream process

Comparability & similarity; residual

uncertainty

PK/PD, Clinical trial design, human factor

analysis

Market penetration

• Indications & evidence

• Clinical data vs. extrapolation across indications

• Interchangeability (USA)

4

Basis of approvals of selected products

US FDA

• Omnitrope® (Sandoz)

• Tbo-filgrastim® (Teva)

• Generic Enoxaparin (Sandoz-Momenta and Watson-Amphastar)

Products

• Process & Analytical

• Clinical

Evidence

EMA

• Omnitrope® (Sandoz)

• Tbo-filgrastim® (Teva)

• Biosimilar Enoxaparin (none-approved yet)

• Other products

Products

• Process & Analytical

• Clinical

Evidence

5

Established and emerging guidelines

US FDA

• General (e.g., ICH)

• Biosimilar (Emerging)

• Product specific (??)

Guidelines

• Process & Analytical

• Clinical

Review process

EMA

• General (e.g., ICH)

• Biosimilar (Established)

• Product specific (Yes)

Guidelines

• Process & Analytical

• Clinical

Review process

6

TPP & QTPP

• Why add TPP?

What is the specific purpose of TPP & QTPP in biosimilar development?

• How many lots; when to characterize?

How to leverage lot to lot variability in the reference medicinal product?

• Understanding clinical relevance

Which differences are acceptable while ensuring ability to demonstrate similarity?

7

QTTP

• Define the targets for biosimilar development– Prior-knowledge (structure

function, clinical,..) & RLD

• Define ‘similar’ -acceptance criteria– Clinical endpoints &

variability in reference product

• QTPP should identify attributes most relevant – Facilitates development of

meaningful target & acceptance criteria

8

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Expiry Date

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Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology, 29: 310-312, 2011

“This [enoxaparin] approval represents a major development in US regulatory science and policy that will likely affect several other complex drug products...the extensive analytical characterization, as carried out for enoxaparin, will be important in the evaluation of protein products and may help to reduce the scope and extent of animal and clinical studies for biosimilars.”Sau Lee, et. al., Scientific Considerations in the Review and Approval of Generic Enoxaparin in the United States. Nature Biotechnology. Volume 3, 220-226 (2013)

Stepwise approach

Analytic characterization

before in-vivo non-clinical and

then clinical studies

In EU adequacy of analytic

characterization evaluated

during MAA

In US a step wise review

approach has been

established

Companies with internal systems such

as ‘QbD development’

can benefit

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External review should be leveraged but need internal review

Common pitfalls and symptoms

Inadequate focus on TPP, QTPP (analytics) & market research

Functional check-box

Cut-paste approach to clinical trials

Rush to clinical

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Clinical Trials (WHO): Biosimilar

11

96

Clinical Trails (US): Biosimilar

12

28

ClinicalTrail.Gov: Biosimilar

13

‘Biosimilar rituximab development a rocky road’

Roche does not see a threat from biosimilar (rituximab) until 2015

“Samsung and Teva

both suspended their Phase III programs in October

2012 within months of

starting them”

One reason for the delay – clinical considerations; challenge of extrapolation across indications

“Totality of evidence”

Sandoz and Boehringer are both already running Phase III trials, placing them ahead of

Celltrion in the race”

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http://www.ft.com/cms/s/2/dcad130c-a8fb-11e2-a096-00144feabdc0.html#axzz2TqDBcYlB

http://www.biosimilarnews.com/roche-doesnt-see-a-threat-from-biosimilars-till-2015

Sandoz Trials: Biosimilar rituximab

• A Randomized, Double-blind, Controlled Study to Evaluate PK, PD, Safety and Efficacy of GP2013 and Rituximab in Patients With Rheumatoid Arthritis Refractory or Intolerant to Standard DMARDs and One or Two Anti-TNF Therapies. (ClinicalTrials.gov Identifier: NCT01274182)

• 164 subjects estimated completion date April 2012

Phase I/II

• A Randomized, Controlled, Double-Blind Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of GP2013 vs. MabThera® in Patients With Previously Untreated, Advanced Stage Follicular Lymphoma (ClinicalTrials.gov Identifier: NCT01419665)

• 618 subjects; estimated completion date March 2014

Phase III

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Boehringer Ingelheim Trials: Biosimilar rituximab

• A Randomized, Double-blind, Parallel-arm, Phase I Study to Evaluate the Pharmacokinetics and Pharmacodynamics of BI 695500 vs. Rituximab (MabThera) Induction Immunotherapy as a First-line Treatment in Patients With Low Tumor Burden Follicular Lymphoma (ClinicalTrials.gov Identifier: NCT01950273)

• 90 subjects; Estimated completion date January 2015

Phase I

• Efficacy, Pharmacokinetics, and Safety of BI 695500 Versus Rituximab in Patients With Moderately to Severely Active Rheumatoid Arthritis: a Randomized, Double-blind, Parallel Arm, Multiple Dose, Active Comparator Trial (ClinicalTrials.gov Identifier: NCT01682512)

• 360 subjects; Estimated completion date January 2016

• Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis: an Open-label Extension Trial (ClinicalTrials.gov Identifier: NCT01955733)

• 250 subjects; Estimated completion date December 2016

Phase III

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Celltrion Trials: Biosimilar rituximab

• A Phase 1, Multicenter, Open-Label, Single-Arm Study to Evaluate the Initial Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of CT-P10 Given in Combination With Dexamethasone, Cytosine Arabinoside, and Cisplatin (DHAP) in Patients With Diffuse Large B-Cell Lymphoma as Second-Line Chemotherapy (ClinicalTrials.gov Identifier: NCT01534949)

• 10 Subjects; currently recruiting

• Phase 1, Randomized, Controlled, Multicenter, 2-Arm, Parallel-Group, Double-Blind Study to Demonstrate the Equivalence of CT-P10 to MabThera With Respect to the Pharmacokinetic Profile in Patients With Rheumatoid Arthritis

• 147 subjects; Estimated primary completion date August 2013

• An Open-Label, Single-Arm, Maintenance Study to Demonstrate Long-Term Efficacy and Safety of CT-P10 in Patients With Rheumatoid Arthritis Who Were Treated With Rituximab (MabThera or CT-P10) in Study CT-P10 1.1 (ClinicalTrials.gov Identifier: NCT01873443)

• 102 subjects; Estimated primary completion date September 2014

Phase I

• A Phase 3, Randomized, Parallel-Group, Active-Controlled, Double-Blind Study to Compare the Efficacy and Safety of CT-P10 With MabThera, Each Administered in Combination With Cyclophosphamide, Vinc... (EudraCT Number: 2011-002813-12)

• Study terminated

Phase III

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The totality of evidence

Proven comparability in the most sensitive indication are the key to secure (extrapolation of)

indications (achieve TPP)

A greater degree of analytical comparability & RLD variability

informing on remining uncertinty

Design of manufacturing process and controls to deliver a product

conforming to QTTP

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Key areas for consideration

Overcoming the ‘blind spots’

• Sampling and statistical criteria (starting with RLD samples)

Analysis of knowledge

• Pertaining to analytical characterization and comparability acceptance criteria

Evidence logic & communication

• Argumentation is a central means by which the community assesses the promise of conjectures and the validity of claims

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Multiple disciplines & stakeholders

Organizing for success

Early investment in analytics and understanding variability in RLD

TPP & QTPP in the context of residual uncertainty

Review/challenge/integration system that does not impede development

Design of clinical trials to address scientific and clinical (market) uncertainty

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Thank You!

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Ajaz@ajazhussain.com

Ajaz S. Hussain, Ph.D.