biosimilar guidance_dr thomas schreitmueller hoffmann rochet

5/25/2018 Biosimilar Guidance_Dr Thomas Schreitmueller Hoffmann Rochet

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Biosimilar Guidance Luxury or Necessity?

Dr. Thomas Schreitmueller, Regulatory Policy and Strategy Biologics

F. Hoffmann La Roche Ltd., Basel, Switzerland


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Table of content

Biosimilars Regulations

Raptiva

Myozyme

Alpheon

Pegaferon

Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed

Conclusions


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Global Regulatory Requirements Reflect the

Complexity of Biological Products

The Pharmaceutical industry is the second most regulated industry in the world

following aviation.

Manufacturers of biological products must comply with an extensive set of regulationsand guidance documents to insure quality and safety of biological products.

Regulations and Guidance for Development and Manufacture of Biological Products

US FDA

(9) Regulations/Proposed Rules;

(6) Points to Consider Documents; (22) Guidance Documents

EMA

(18) Guidelines

ICH

(10) Guidance Documents

Safety and Efficacy

ICH S6 Preclinical safety Evaluation of Biotechnology-Derived Pharmaceuticals

EMA: Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins, ClinicalInvestigation of Recombinant Factor VIII and IX Products, Immunogenicity Assessmentof Biotechnology-derived Therapeutic Proteins, Comparability of Biotechnology-DerivedMedicinal Products after a change in the Manufacturing Process - Non-Clinical andClinical Issues


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Biological product complexity:Examples of modi f ications: inherent or due to the

manufactur ing process

Adapted from: Steven Kozlowski; FDA

K

pyro-E

G

D

O

D

G

O

D

pyro-E Pyroglutamyl peptides

K

C-terminal Lysine

D

D

D Deamidation

O

O Methionine oxidation

G

G

Glycation

High mannose, G0, G1, G1, G

Sialylation

Modifications may result in approximately 108 potential variants


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Protein Microheterogeneity

Small MoleculeDrug

ProteinDrug


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Biotech products are very complex, sensitive,heterogenious mixtures of protein molecules.

Each molecular entity of that mixture is characterized

by specific physical, chemical and biologicalproperties.

Any change in the composition of that mixture is

potentially going to affect patients safety and chance

of cure.

Biotech products


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Biosimilars:Different process, di f ferent pro duc t

Biosimilar that is different from the

originator

Even if a biosimilar uses the same human gene as its innovator, It willdiffer in other parts of the manufacturing process

Same gene as

innovator

FermentationCloning into

DNA vector

Transfer into

host cell

Bacterial ormammalian cell

produces protein

Human

gene

Formulation

DNA

vector

Differences in the process


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EU biosimilar guidelines & products

GuidelineGuideline on Similar Biological Medicinal Products

Guideline on Quality Issues

Guideline on

Non-clinical/Clinical Issues

GHInsulin G-CSF Epoetin

HX 575 (Binocrit,

Epoetin-alfa Hexal,

Abseamed)

Alpheon

rejected

(IFN-alfa)

Product-Class Specific Guidelines on Nonclinical/Clinical:

SB309 (Silapo, Retacrit)

Biograstim

Ratiograstim

Filgrastim

Ratiopharm

Tevagrastim

Proof of Similarity with

a reference product as

the basis for approval

Full dossier plus head-to-

head comparison to

reference product

Reduced dossier, head-to

head comparison toreference product

Filgrastim Hexal

Zarzio

LMWH

IFN-alfa

Nivestim


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Biosimilars in EUThe Problem of Interchangeability/Substitution


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Biosimilars in EUInterchangeability/Substitution: The English Way


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Biosimilars Global Regulations


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Key points from the WHO biosimilar guideline

Global high standard guidance based on scientific rationale due to

complexity of biologicals Based on demonstration of similarity at quality, safety and efficacy

Comparative quality, non-clinical and clinical studies to the samereference requested

Equivalence design in clinical studies preferred option, however,

non-inferiority designs may be considered if appropriately justified Extrapolation across indications possible if certain conditions are

fulfilled

National implementation of the WHO guideline supported

The guideline principles should be adopted as a whole

Pharmacovigilance is appropriately addressed but countries should haveappropriate PhV frameworks relevant for biologicals

The guidance does not address interchangeability/substitution


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Table of content


Raptiva

Myozyme

Alpheon

Pegaferon


Conclusions


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The Raptiva (Efalizumab) Experience (1/2)

Raptiva (efalizumab) was originally manufactured by XOMA and used in the

Phase I/II trials and up to Phase III. Manufacturing was transferred to Genentech

(with full information).

Analytical and formulation differences expected to be inconsequential were

observed (changes in charge heterogeneity, increase in C-terminal processing,

higher levels of acidic forms, higher galactosylation)

In a bioequivalence study, some differences in PK parameters were observed:

However, because of the unpredictable nature of these PK changes an

additional Phase III study was performed to determine the safety and efficacy of the

Genentech material.

Xoma GNE Ratio (G:X)

AUCinf 27.9 36.9 1.324

AUCt 26.9 35.6 1.324

Cmax 3.59 4.22 1.175

Source: W.F. Bennett, Genentech


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The Raptiva (Efalizumab) Experience (2/2)

Source: W.F. Bennett, Genentech

26,6%

38.9%

2.4%0%5%

10%

15%

20%

25%

30%

35%40%

45%

Placebo

(n=170)

1.0

mg/kg/wk

XOMA

material

(n=162)

1.0

mg/kg/wk

GNE

material

(n=369)

Percentage

ofSubjects

improved75%

Trend for lower PASI* Response to Raptiva Efalizumab) despitehigher peripheral Drug Concentrations

Changes that were believed not to affect the properties of the protein resultedin clear differences in pharmacokinetics. Given the complexity of

therapeutic proteins, the impact of changes in pharmacokinetics (and probably

pharmacodynamics) on safety and efficacy cannot be reliably predicted.

Improved > 75%

*PASI = Psoriasis Area and

Severity Index


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Table of content


Raptiva

Myozyme

Alpheon

Pegaferon


Conclusions


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Case Study:Comp lexi ty of B io logical Produc t Manufacture

Myozyme: FDA rejects Genzymes own scaled-up version

Mack G. Nature Biotechnology 2008; 26:592.

FDA reject Genzymes

application to scale up

production of Myozyme fromthe 160-litre facility to the

2,000-litre facility

The FDA was concerned about differences in the carbohydrate structure of the

products manufactured at each facility and therefore stipulated that the 2,000-litre

product required a new biologic license


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Case Study:Comp lexi ty of B io logical Produc t Manufacture

Myozyme: FDA rejects Genzymes own scaled-up version

Mack G. Nature Biotechnology 2008; 26:592.

30% bioavailability

2881% hepatic uptake2065% muscle uptake

Myozyme produced in the 2,000-litre-scale facility has lower bioavailability,

higher hepatic uptake and lower muscle (site of action) uptake compared with

Myozyme produced in the approved 160-litre-scale facility


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Table of content


Raptiva

Myozyme

Alpheon

Pegaferon


Reditux

Biosimilars in the EU (Alpheon BioPartners)


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Biosimilars in the EU (Alpheon, BioPartners)


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Table of content


Raptiva

Myozyme

Alpheon

Pegaferon


Conclusions


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Pegaferon

Name : Pegaferon

Batch: 07-B

MFD: 06 / 2007

Exp. Date 06 / 2009

SDS PAGE Sil St i d d


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The following clipping sites were characterized by ESI-MS and MALDI-MS/MS

90

QQLNDLEACVIQGVGVTETPLMK112

12.4 kDCDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFG

FPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA

WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMK

EDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSF

SLSTNLQESLRSKE

Reduced Gel

7.1 kDCDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFG

FPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA

WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMK

EDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMR

SFSLSTNLQESLRSKE

6.0

14.4

3.5

21.5

55.466.3

SDS-PAGE Silver Stain reduced

Extended Characterization


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EK

SR

LS

EQ

LN

TS

LS

F RS

A

M

IE

V

R

W

EV

PC

A

Y

S

Q RI

TL

Y

L

E

RVA

C

Y F

ET

P L

M E D S I L

CV

I

Q

G

V

G

V

T

D

FY

TL

N

D

LE

A

QQ Y

L E

D

L

PQ

T

HS

L G S R R T L M L L A

F

Q

L

S

I

R

M

D

E

T

L

L C

S

F

S

T

D

S

S

AAW

M

I

Q

Q

I

F

NL

E H

L

V

P

I

T

E

A

Q

F

Q

N

E

E

F

G

G

FPQ

H

D

F

LD

R

K

K

KK

K K

K

K

K

KNH

2

164

131

133

134

112

31

49

83

70

23

121

111

59

Pegylated IFN alfa-2a

IE-HPLC (Routine Analysis Drug Substance)


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IE-HPLC (Routine Analysis Drug Substance)

Separation of different PEG-IFN isomers in Pegaferon

1

2

3

4

5

6 7

89

1011

The qualitative and quantitative positional isomer composition inPegaferon is completely different as compared to Pegasys

Two additional positional isomers are present in Pegaferon not

being present in Pegasys

Isomer Profile of Pegaferon


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PEG-IFN pre-clinical safety results

PEG-INFas are currently used for the treatment of hepatitis C, but are

associated with lung toxicity. Here we show that INFa as well as

PEGINFas activate human lung cells to release IP10, ET-1 and eotaxin,

each of which are specifically associated with lung inflammation. Of the

INFs tested PEGINFa2a was the weakest as an inducer of inflammatory

mediators. Using human lung microvascular endothelial cells as a screen, we

found that by comparing responses of PEGINFa2a with selected isoforms, we

could separate the efficacy for anti-viral effects (Foser, Weyer et al. 2003)from those associated with induction of inflammatory mediators. This

study provides data relevant to INFa induced lung toxicity and describes a

screen by which safer isoforms of PEG-INFa may be identified.

INTERFERON (IFN) ALPHA PREPARATIONS ACTIVATE HUMAN LUNG

MICROVASCULAR ENDOTHELIAL CELLS TO RELEASE THE CHEMOKINE IP10

(AASLD)1Jane A Mitchell, 1Rekha Badiger 2Andreas Tietz, 1Catherin Aitkin,1Hime Gashaw, 2Heather J Hinton, 3Trevor T Hansel, 2Thomas Singer and 2Tobias Manigold1Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, UK;

2Roche, Basel, Switzerland; 3Imperial Clinical Respiratory Research Unit (ICRRU),

St. Mary's Hospital, Paddington, London, UK


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Table of content


Raptiva

Myozyme

Alpheon

Pegaferon


Conclusions


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Products approved according to the EU guidelines:

What does s imi lar mean? Simi lar enoug h?


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Biosimilars in EU


A one year safety study involving 300 patients suffering from chronic kidneydisease about to embark on dialysis, comparing EPO Hexal vs. Johnson &

Johnsons Erypo, has been suspended; this study was designed to assess the

safety of sub-cutaneous, rather than intravenous, EPO alfa administration

On 5 Aug 2009, Germanys BfArM (Bundesinstitut fr Arzneimittel und

Medizinprodukte) confirmed that the trial was suspended due to safetyconcerns, specifically a case of pure red cell aplasia (PRCA) in a patient

enrolled in a study in Germany, and a case of EPO neutralizing antibodies in a

patient enrolled in a study in Russia

In the statement, BfArM commented that after termination of this study,

BfArM explicitly states that Epo Alfa Hexal, Binocrit and Abseamed should onlybe administered via the intravenous route when prescribed for renal anemia

More investigations are taking place


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Table of content


Raptiva

Myozyme

Alpheon

Pegaferon


Conclusions

Conclusions


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Conclusions

Biologics are large and complex molecules

The manufacturing process confers unique properties on abiologic product

Biosimilars are not identical to the original molecule

Immunogenic reactions can occur to biologics and areunpredictable

Pharmacovigilance is required

Regulations

All biosimilars must undergo stepwise and head-to-head comparisonswith the originators

Countries adopting EMA and/or WHO guidance will have a robust

biosimilar approval pathway

Thank You !


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Thank You !