IFPMA/AIPM Biotherapeutics Workshop, Moscow

Regulatory experience with monoclonal antibody submissions in the EU

15-16th May 2013

Dr Alex Kudrin, Medical Assessor in Biologicals, MHRA, London, UK

Disclaimer

• This presentation is given in personal capacity and represents only the author’s personal views and does not represent policies or recommendations of MHRA, EMA, FDA, any other companies and regulatory bodies mentioned in this presentation.

• No confidential data is disclosed.

• All relevant references and links are from public domain.

Production of biologics

• A total of about 270 antibodies are currently in phase II-III studies (120 are forecasted to be approved based on ~50% attrition rate)

• Products in development for numerous therapeutic indications and not only for conventional oncology and autoimmune disorders

• Total production: 18 tonnes in 2009 – expected to reach 80 tonnes by 2020 (with at least 10% share of biosimilars: 10 tonnes)

• Yield of cell cultures will be improved 5-10-fold times

• Cost of production will be considerably lower in decades to come

Ref: Olav Zulian, 2012

EU assessment of biologics

Mandatory scope for centralised procedure

• Recombinant produced biotechnology products, except for some old biologics

• Biosimilars

• Advanced cell therapy products

• Genetherapy

• Orphan products

• Generics versions of centralised authorised products

• Products for diseases of public importance: oncology and infectious diseases

Background on therapeutic MABs

MAB nomenclature

Source stem

Suffix

o mAb

xi mAb

zu mAb

u mAb

Immunogenicity

Therapeutic indications for EU approved MABs

• Autoimmune diseases (e.g. Humira, Remicade or Mabthera)

• Oncology (Avastin, Erbitux, Herceptin, Perjeta, Adcetris)

• Passive immunotherapy for some infectious diseases, e.g. Synagis for RSV

• Bone disorders: anti-RANKL for PMO (Prolia) and SRE in cancer (Xgeva)

• In development: MABs for cardiovascular diseases, Alzheimer’s disease, neurology indications, muscle wasting etc.

Very potentchemotherapeutic drug

• Tubulin polymerization inhibitors• Maytansines (DM1, DM4)• Auristatins (MMAE, MMAF)

• DNA damaging agents• Calicheamicins• Duocarmycins• Anthracyclines (doxorubicin)

• Humanized monoclonal Ab (IgG1)

• mAb with Fc modifications (modulate ADCC, CDC activity)

• Other mAb fragments

Linker stable in circulation

Antibody-Drug Conjugate (ADC)

Schutten, 2012

>100 of ADC is in development

Quality issues

Q5B Genetic Stability

Numerous Quality Guidelines CoveringBiotech Products

Cell BanksCell Banks ProcessProcess Drug SubstanceDrug Substance Drug ProductDrug Product

Q5D Cell Substrates

Q5A Viral Safety

Q6B Specifications

Q5C Stability

Q5E Comparability

EMEA/CHMP/BWP/157653/2007: Guideline on development, production, characterisation and specifications for monoclonal antibodies and related products

Characterisation is complex

• General characteristics

– Appearance, pH, particulates, protein concentration

• Identity

– Peptide map, IEF, glycosylation, charge profile

• Purity

– SDS PAGE, RP-HPLC, CE-HPLC, SE-HPLC

• Potency

– Bio-assay

• C-terminal sequencing

• Amino acid composition

• Monosaccharide ratios

• Capillary electrophoresis

• Denaturing IEF with Western blot

• Circular dichroism

• Mass spectroscopy

• etc etc

Multiple methodologies used to characterise quality attributes from different angles

Non-clinical issues

Safety

• Conventional approaches may not be appropriatefor biopharmaceuticals (ICH S6)

• Initial concerns = contamination with host cells and host cell DNA

– Realization that safety concerns focused around exaggerated pharmacology

• Two key issues

– Species selection

– Immunogenicity

Typical Toxicology Studies

• Single dose

• Repeat dose

–Generally 1-3 months for biotech products

–Short term use / acute life threatening – 2 wks

–Chronic use – 6 months

• Genotoxicity / Carcinogenicity

–Not required unless cause for concern

• Reproductive toxicity

–Case-by-case basis

Moving into FTIM

Low relevance of NOAEL in determination first dose in humans;

MABEL estimation using desirable receptor occupancy rates of <1-10% using all available animal and in vitro assay data (human primary cell and tissue cultures);

Specific consideration to informed consent procedures and clarification of high-level of risks

TGN1412 victim

Source: Muller and Brennan (2009) Safety Assessment and Dose Selection for

First-in-Human Clinical Trials With Immunomodulatory Monoclonal Antibodies: Clinical pharmacology & Therapeutics 85: 247-258

Clinical issues: efficacy, safety, immunogenicity and RMP

EMA clinical regulatory framework for MAB

• Non-clinical requirements follow ICH guidelines on biotechnology products

• Clinical guidance: no MAB specific guidelines

• Development is guided by guidelines on development of new drugs for rheumatoid arthritis, cancer, multiple sclerosis etc.

• Early pre-phase II-III CHMP SA is encouraged

• General principles for establishing efficacy same as for NCEs

• Case by case, based on therapeutic indication and patient population

• Route of administration is typically parenteral.

• Phases of development often blurred due to patient populations targeted e.g oncology

• Use of biomarkers is encouraged with co-development and validation of diagnostic companion test

– Potential for highly targeted therapies e.g. HER2 (Herceptin); KRAS (Vectibix and Erbitux)

Evaluation of the efficacy data

• The magnitude of the clinical effect (e.g. OS increase)

• The longevity of the effect

• Type of clinical benefits: disease modifying vs symptomatic effects (e.g. radiographic data with anti-RA MABs)

• Effect on quality of life

• Effect on outcomes, e.g. effect on survival or CV-composite endpoints

• Effect in different sub-populations and age groups

• Effect in subgroups stratified by biomarker

General principles in immunogenicity evaluation

• The assay should be in place from Phase I study

• Risk-driven evaluation of immunogenicity data

• Assay validated for sensitivity and specificity

• Screening, confirmation and neutralisation assays

• Justification of periodicity and timing of sampling

• Sensitive patient population and subgroup analyses (exposure related, immunosuppression status related, across indications, AE-related, loss of efficacy, PK/PD modelling)

• Monitoring of immunogenicity up to 12 month

• Commonly descriptive evaluation of immunogenicity

Examples of MAB-associated immunogenicity

MAB Indication Type Patients with immune response %

Infliximab RA, CD Chimeric 10-60%

Adalimumab RA, CD Human 12-25%

Natalizumab CD, MS Humanized Up to 30%

Trastuzumab Breast, gastric cancer

Humanized 4%

Rituximab RA, lymphoma Chimeric 1.1-12.7%

Immunogenicity: assessment

–Deficiencies: assays are crude and not sufficiently sensitive with false-negative results

–Lack of interpretation of the data, e.g. failure to correlate Ab presence with any detrimental clinical effect in individual patients (trough levels of MAB, and ACR20)

–Clinical implementation of immunogenicity testing during postmarketing period (has been done with Remicade)

Safety

• Some serious and poorly understood risks:

• Infusion reactions with rituximab

• Opportunistic and serious infections

• PML with rituximab, natalizumab, efalizumab, etc.

• Tumorigenicity (lymphoma with adalimumab and infliximab);

• Osteonecrosis of the jaw and atypical fractures with denosumab

Risk management plan is mandatory for any new

biotechnology products

Safety of biologics

• Singh et al. (2011) included 160 RCTs with 48,676 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs.

• Biologics as a group were associated with a statistically significant higher rate of total AEs (OR) 1.28, 95% CI 1.09 to 1.50;

• Number needed to treat to harm (NNTH) = 22, 95% CI 14-60,

• Serious infections (OR, 1.37, 95% CI 1.04 to 1.82, NNTH = 108 95% CI, 50 to 989)

• TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706).

• Infliximab was associated with a statistically significantly higher risk of total AEs OR 1.55, 95% CI 1.01 to 2.35; NNTH = 13, 95% CI 8 to 505) and withdrawals due to AEs compared with control (OR 2.34, 95% CI 1.40 to 4.14; NNTH = 10, 95% CI 5 to 30) – put in context of NNT (1.5).

Singh et al., 2011 Adverse effects of biologics: a network meta-analysis andCochrane overview (Review)

RMP examples: Infliximab and adalimumab

• Routine PV activities will be sufficient for a majority of signals

• Education of prescribers and patients (including alert cards)

• If necessary, registries can be set-up if required on the basis of existing registries with Remicade, Humira and Cimzia in EU and US

• Pregnancy registries or PASS study

Case example: Natalizumab

• Natalizumab is approved for adult patients with relapsing forms of MS (EU)

• Currently around 150 PML cases reported with nearly 80,000 patients receiving Tysabri worldwide, and >40,000 in the US

• PML is seriously disabling and potentially fatal ADR (>20%)

• Restricted prescribing and enhanced monitoring allows to reduce risk of PML (based on TOUCH and Tygris data)

• JC serology assay recently introduced into US and EU labels allows guidance on risk stratification (the highest in JC-positive patients who were treated with Tysabri for >24 months and who also receive other immunosuppressant therapy)

REMS / RMP: Natalizumab

• US: A restrictive prototype of TOUCH-MS or TOUCH-CD REMS program are instituted

• EU Enhanced research monitoring TYGRIS registry (5000 patients in EU and US)

• JC serology assay companion diagnostic assay as per Tysabri SmPC

• Pregnancy register

• Industry led PML consortium (Roche, Pfizer, Biogen)

New EU pharmacovigilance directive 2010/84/EU) Some medicinal products are authorised subject to additional

monitoring. This includes all medicinal products with a new active substance and biological medicinal products, including biosimilars, which are priorities for pharmacovigilance.

Member states shall ensure, through the methods for collecting information and where necessary through the follow-up of suspected adverse reaction reports, that all appropriate measures are taken to identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory which is the subject of a suspected adverse reaction report, with due regard to the name of the medicinal product, and the batch number.

Typical clinical issues arising during EMA evaluation of MABs

• The efficacy is insufficiently demonstrated (e.g. minor increase in overall survival with oncology MABs or lack of consistency between PFS/OS or lack of OS data)

• Narrow net benefit

• Risk confined to the drug and the type of ADRs: e.g. serious infections, malignancies and MACE AEs with briakinumab (anti-IL12) and not compatible with the proposed clinical use (outpatient treatment of psoriasis)

• Important identified risks that are difficult to predict, control or minimise (e.g. Raptiva withdrawal from EU in 2009 due to PML issue (4 cases reported with incidence of 1:500 in psoriasis vs 1:800-1000 with Tysabri in MS)

CONCLUSIONS

• EU regulations on novel MABs is focused around Quality issues

• Non-clinical guidance is drawn from ICH

• Clinical guidance is product group specific and shared with NCE

• Safety requirements vary but safety databases are usually extensive

• RMP and enhanced postmarketing surveillance are mandatory with MABs

Questions and thanks for your participation