UTILIZATION OF CLINICAL PHARMACOLOGY DATA TO SUPPORT A DEMONSTRATION OF BIOSIMILARITY

Date: Feb 24, 2014

Partha Roy, Ph.D.

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OUTLINE

Regulatory Framework and Guidance

Role and scope of comparative Clinical Pharmacology data

Filgrastim’s Clinical PK and PD Story

Future applications - acceptability of PK/PD

Conclusions

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UNDERLYING REGULATORY FRAMEWORK AND EXPECTATIONS

• Data requirements for a BIOSIMILAR application will be less than a full complement of product-specific preclinical and clinical data required for an original BLA application

• FDA may waive any of these data requirements if it finds the data are “unnecessary”

• FDA has a “longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources…and avoiding ethical concerns associated with unnecessary duplication of human or animal testing.”

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FDA’S DRAFT CLINICAL PHARMACOLOGY GUIDANCE FOR BIOSIMILARS

• Draft Guidance published on May, 2014

• Clinical pharmacology roadmap in the context of assessing clinically meaningful differences and supporting a demonstration of biosimilarity

• Categories of analytical characterization Not similar – 351K path not appropriate

Similar – significant differences noted and therefore additional analytical and/or PK/PD data needed to resolve differences

Highly Similar – just meeting the statutory standard for similarity and candidate for a targeted and selective program to resolve residual uncertainty

Highly Similar with Fingerprint-like similarity – highest level of similarity and comfortably meeting the statutory standard for similarity and candidate for a even more targeted and selective program

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HIGHLY SIMILAR ANALYTICAL AND PK/PD DATA = LOWER RISK OF CLINICAL DIFFERENCES

• Risk-Based, Stepwise, Totality of

Evidence

• Analytical Characterization is the

foundation

• PK/PD is a key component of initial

clinical assessment

• Comparative Immunogenicity

assessment expected

PK/PD

Nonclinical

Analytical

Clinical

Sim

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Ref

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Red

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• Additional Clinical studies, if

needed

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QUALITY ATTRIBUTES THAT IMPACT PHARMACOKINETICS AND PHARMACODYNAMICS

Attributes Impact on PK, PD

Primary amino acid sequence, Fc receptors

Ligand binding impacts distribution and elimination

FcRn binding Alters elimination rate

Folding, disulfide bridges Misfolding is associated with faster clearance

Oxidation Can impact FcRn binding

Glycosylation Impacts immunogenicity and has the potential to impact PK

Degradation Degraded products have faster clearance

Adopted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014

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PK AND/OR PD STUDY DESIGN CONSIDERATIONS

Cross-over vs. Parallel

Healthy subjects vs. patients

Dose(s) and routes of administration

Availability of validated assays

Sensitive and clinically relevant PD markers

Impact of PK on PD response

Alternate data analysis strategy to deal with PK and PD variability

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UTILITY OF PHARMACOMETRIC APPROACHES TOWARDS BIOSIMILARITY EVALUATION

Population PK alone is not adequate to demonstrate PK similarity; it is additional supportive data towards an overall demonstration of biosimilarity

M&S tools can be useful when designing a PK and/or PD study Selection of an optimally informative dose (s) for evaluating PD similarity Evaluating an Exposure (or Dose) – Response relationship Developing acceptable limits for PD similarity based on PD-clinical endpoint relationship

Modeling exercise to compare relevant PK parameters, such as clearance and volume of distribution following multiple routes of administration following single and multiple-dose administration

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PK, PD, PK/PD ARE KEYS TO EXTRAPOLATION TO OTHER INDICATIONS NOT STUDIED IN THE PROGRAM

Indication 3Indication 2

Robust CMC Data

Keys to Extrapolation

Fewer IndicationsAll Indications

Pivotal PK/PD/Phase 3 in Core Indication

Agency Negotiation

MOA/PK/PD/BiodistributionToxicity

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PK SIMILARITY DEMONSTRATED BETWEEN NEUPOGEN AND SANDOZ FILGRASTIM BIOSIMILAR

• Single-dose conc-time curves

superimposable between 5 mg/kg

IV Neupogen and Sandoz

Biosimilar – PK similarity met

• Met the predefined similarity limits

for PK (90% CI within 80‐125%)

following 10 mcg/kg dose

IV route

Adapted from McCamish M and Woollett G (2012) Clinical Pharmacology & Therapeutics

Adapted from Sandoz Briefing Book from ODAC Advisory Committee Meeting, Jan 7, 2015

SC route

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PD (ANC AND CD34+) SIMILARITY DEMONSTRATED FOLLOWING SINGLE DOSE ADMINISTRATION

PD parameter(ANC) Ratio (95% CI)

AUEC0-120h 103 (100 – 106)

Emax 100 (96 – 105)

Adapted from Sandoz Briefing Book from ODAC meeting, Jan 7, 2015

PD parameter(CD34+) Ratio (95% CI)

AUEC0-120h 102 (94 – 112)

Emax 105 (92 – 120)

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PD (ANC AND CD34+) SIMILARITY DEMONSTRATED FOLLOWING MULTIPLE DOSE ADMINISTRATION

Adapted from Sandoz Briefing Book from ODAC meeting, Jan 7, 2015

ANC

CD34+

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PD ATTRIBUTES FOR BIOSIMILARITY DEMONSTRATION

• Prior knowledge from drug and disease

• Mechanistic basis for drug action (both ANC and CD34+)

• Relevant to disease process related to effectiveness and safety (ANC is correlated with Duration of Severe Neutropenia)

• Sensitivity to detect clinically meaningful differences between the two products (CD34+ cell counts correlated with CFU-GM cell level)

• Can be assessed after a sufficient period of time after dosing, and with appropriate precision (Day 1 and Day 7)

• Multiple PD parameters generate relevant fingerprinting and reduce residual uncertainty

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ANALYTICAL PK PD SIMILARITY ABBREVIATED CLINICAL PROGRAM

• Demonstration of highly similar physicochemical and functional characteristics between the potential biosimilar and the reference biologic is the foundation on which biosimilarity stands

• Following analytical similarity, step-wise demonstration of PK and PD similarity based on the 80-125% equivalence margin was sufficient (w.r.t. efficacy) for gaining ODAC’s recommendation for approval

• The sponsor undertook a supportive clinical study designed as an active-controlled, double-bind, parallel, safety, tolerability and immunogenicity study in breast cancer patients treated with myelosuppressive chemotherapy

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TYPICAL GLOBAL CLINICAL PROGRAM :CAN WE DO BETTER THAN THIS?

Products Phase 1(3-way PK)

Phase 3(Equivalence trial)

Estimated Costs

Trastuzumab(Herceptin)

~100 HVs 600 - 800 pts $40 million

Bevacizumab(Avastin)

~100 HVs 800 – 1200 pts $60 million

Etanercept(Enbrel)

~80 HVs 500 – 600 pts $40 million

Rituximab(Rituxan)

~300 patients 500 – 1000 pts $50 million

Adapted from Nick C. DIA Biosimilars Meeting, Washington DC, 2014

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LOOKING FOR A SENSITIVE PD/SURROGATE

Clinical Endpoint PD Marker /Clinical Surrogate

Clinical endpoint with which the reference product was approved is often not sensitive enough to identify clinically meaningful

differences

Human PK and PD data may be able to substitute a large Phase 3 study in order to support a demonstration of biosimilarity in select cases

Adapted from Nick Holford

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TRADITIONAL CLINICAL ENDPOINTS ARE BLUNT INSTRUMENTS TO DETECT ANALYTICAL DIFFERENCES

Adapted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014

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EXPLORATORY PK/PD EVALUATION THAT MAY ABBREVIATE CLINICAL PROGRAMS

Biologics PK/PD metrics Outcome

Omalizumab(Anti-IgE)

PK – free & total IgE – asthma exacerbation

Support for the approved BW and IgE-based dosing table (ref: Xolair USPI 2014)

Tocilizumab(Anti-IL-6) PK – DAS28 response model

Dosing regimen justified(ref: Clinical Pharmacology review of BLA125472, 1/29/2013)

Adalimumab(Anti-TNF)

PK – remission and time to response in the induction treatment phase in moderate to severe UC

Support for optimal dosing(ref: FDA Gastrointestinal AdCom meeting for Adalimumab, FDA Clinical Pharmacology slide presentation, 08/28/2012)

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CONCLUSIONS

• Based on the draft FDA Guidance, comparative clinical safety and effectiveness data will be necessary if there are residual uncertainties about the biosimilarity of the two products.

• Clinical Pharmacology data is a critical part of the totality of evidence to support a demonstration of biosimilarity to a Reference product

• PK and PD data has been utilized as pivotal clinical data to support clinical similarity between the biosimilar product and the reference product for Filgrastim

• Exposure-Response evaluation has the potential to substantially abbreviate a biosimilar clinical development

• PK/PD can eventually replace a Phase 3 therapeutic equivalence study for biosimilars, at least for some biological products

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CONTACT INFORMATION

Partha Roy, Ph.D.Director

PAREXEL ConsultingPartha.Roy@PAREXEL.com

www.PAREXEL.com