Successfully Navigating the Regulatory Landscape with Multi-specific...

CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 1

Successfully Navigating the Regulatory Landscape

with Multi-specific Therapeutics

CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY

….helping you navigate the drug development process

Presented to the 6th World Bispecific Antibody Summit

Sept 22, 2014

Kaia Agarwal, President, Regulatory Compass, LLC.

[email protected]


Agenda

CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY

• Regulatory Framework for Multi-specific mAbs

– Focus on Preclinical guidelines and considerations

• Discuss options for formal interactions with FDA and EU/EMA

• Practice with a Case Example

2

CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 3CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY

• Regulatory Framework for Multispecific Therapeutics

– Focus on Preclinical guidelines and considerations

• Discuss options for formal interactions with agencies including

FDA and EU

– As early as possible (with some preclinical/maybe prior to GLP)

• Practice what you hear about with a Case Example

3

Guide You To :

Consider and develop plans to address regulations

based on the unique properties of your antibody


First a little background


Antibody Development (1/2)

• High interest in monoclonal antibody development– High specificity for their targets

– New opportunities for treatments• Unprecedented potential for cancer treatment

– Improved technology for production

– Well characterized domains & ability to manipulate for increased affinity, PK or safety

– Approx. 47 mAbs have been approved by the US FDA and EMA for various indications up to May 2015*

* As posted on Webpage for “the Antibody Society”, Aug 18, 2015


Antibody Development (2/2)

• Monoclonal Antibody development is complex for regulators

as well as for sponsors

– Long half life (10-21 days on average)

– Inherent risk to adverse immune-mediated drug reactions

– Often targets have broad tissue distribution (AEs)

– Require specifically designed preclinical studies

– Bispecific antibodies and conjugated antibodies add to complexity


Benefits of Multispecific Antibodies (1/2)

• Advantages when multiple mediators contribute to a disease

• Single antibodies may have limitations on effect regardless of

dose

• Increase specific response to treatment

– Cancer treatments with multi-specific antibodies may improve target

effect


Benefits of Multispecific Antibodies (2/2)

• Potentially Enable:

– simultaneous inhibition of several cell surface

receptors

– simultaneous blocking of several ligands

– crosslinking of two receptors

– recruitment of T cells to proximity of tumor cells.


Schematic of dual- targeting agents

Antibodies 2012, 1, 2-18;

Cross linked mAbs (Ag fork)

chemically coupled

F(ab’)-fragments

2 F(ab’)2 coupled to IgG (HexAb)

tandem bispecific

SC Fragment

variable (bsscFv)

(EI-04): two scFvs

genetically fused to IgG

V region of HC

and LC

of 2 Abs cloned

in frame to an IgG

(CVX-241)

heteromeric

peptide

coupled to IgG

scFvs fused

to Fc-domain

(both termini)2 Ag sites on an

IgG (DVD-IgG)

tandem trispecific sctb

Coupled F(ab’)3-

fragment


Bispecific T cell engager (BiTE) antibody

• Designed to engage two different targets simultaneously,

– One single chain antibody targets a receptor on the malignant cell

– The other specific for CD3 (to the TCR complex of a T cell)

• Juxtaposing the T cells within reach of the targeted cancer cell

– triggering the cell to die (apoptosis) via cytokines.


Blincyto (blinatumomab)

• First CD19-directed CD3 T-cell engager (BiTE) antibody

approved by FDA

– Indicated for Philadelphia-negative (Ph-) relapsed/refractory B-

precursor acute lymphoblastic leukemia (ALL) patients.

– Approved Dec 2014, first single-agent bispecific immunotherapy to be

approved by the FDA

• FDA granted Breakthrough Therapy Designation (July 2014)

• Approved five months ahead of schedule


Regulatory Framework


Regulatory Framework

• Focusing on Early Development:

– Understand the key regulations/guidelines

– Discuss alternate strategies to address specific issues

• One species, carcinogenicity, reproductive tox

– Especially how the science will drive the data required


Regulatory Considerations

• Antibody approaches involve complex science and

manufacturing

• Agencies have an interest in developing new

treatment options

– Specific scientific expertise and insight across programs

– Willingness to meet with sponsors as needed


Regulatory Preclinical Considerations

• Early planning for preclinical work through to FIH

(CTA/IND filing) is critical

– Discuss the science behind any potential issues/hurdles

– Develop plans to address and present data to Agencies

� Avoid regulatory issues later in development


Regulatory Preclinical “First Principles”

Drugs

• MOA and PK/PD

• Toxicology

• Single dose escalation (NOAEL); Repeat dose and Long term (up to 2 yr.)

• Reproductive, Embryofetal Development, and Carcinogenicity

mAbs

• Species selection - in vitro/ex vivo assessments of binding

• Lack of animal model; consider a surrogate antibody for animal work

• PK/PD with tissue cross reactivity

Multi-Specific

• For combination drugs with two or more MOAs:

• Expect safety and efficacy data for each component individually AND impact of combination

• For multispecific mAbs individual binding sites need to be studied and combination justified


And it always starts with mice……

Licensed from S. Harris via Cartoonstock.com for presentation


Preclinical Safety Evaluation

• Prior to Clinical Testing:

– Optimal characterization of preclinical PK-PD relationships

in relevant species

• How much drug is needed

– Feasible dose and route, frequency

• If it works and how will we know?

– Potential Safety liability

• For FIH and future trials


Key Relevant Preclinical Guidelines for mAbs (1/3)

Guideline Title Agency Year

Adopted

Preclinical Safety and Immunogenicity Testing:

ICH guideline M3 (R2): Nonclinical Safety Studies for the conduct of clinical

trials with pharmaceuticals (Step 4)

EMA/FDA/Japan 2010

ICH Guideline S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived

Pharmaceuticals

EMA/FDA/Japan 2012

Points to Consider in the Manufacture and Testing of Monoclonal Antibody

Products for Human Use

FDA 1997

ICH Guideline S8: Immunotoxicity Studies For Human Pharmaceuticals EMA/FDA/Japan 2006

ICH Guideline S9: Nonclinical Evaluation for Anticancer Pharmaceuticals EMA/FDA/Japan 2010

Guideline on Immunogenicity Assessment of Biotechnology-Derived

Therapeutic proteins

EMA 2007



Adopted

First in Man Human dosing and Minimum Anticipated Biological Effect Level

(MABEL):

Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for

Therapeutics in Adult Healthy Volunteers

FDA/CDER 2005

Guideline on Strategies to identify and Mitigate risks for First in Human

Clinical Trials with Investigational Medicine products

EMA/CHMP 2007

Developmental and Reproductive Toxicity Studies:

Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to

Male Fertility

FDA/EMA/Japan 2000

Carcinogenicity Studies:

ICH Guideline S1A: Guideline on the Need for Carcinogenicity Studies of

Pharmaceuticals

FDA/EMA/Japan 1995




Adopted

Immunotoxicity Testing:

Immunotoxicology Evaluation of Investigational New drugs FDA 2002

Draft Guidance for Immunotoxicity Testing Japan 2001



Minimum Prior to a FIH Study

• Single dose studies (dose ranging) [ICH S6]

• Repeat dose studies [ICH S6]

– related to the duration of the FIH trial and onwards

• at least n+1 of FIH trial ; 3 to 6 months expected for longer trials/use

– Include safety pharmacology aspects

• Absorption and distribution studies [ICH S6]

• Immunogenicity studies [ICH 7A]

• Local Tolerance Studies [ICH S6]


Lets Take a break!

BREAK


Preclinical Expectations

for Multispecific mAbs


General Expectations

• Assessment of Exposure

– Pharmacokinetics/Toxicokinetics

• Evaluate exposure, absorption, disposition and clearance

– Clinical Assay development for mAb (best same for animals and

humans)

• Safety Pharmacology

– Assess undesirable functional effects on physiological systems

– Incorporate into the toxicity and later in clinical studies


• Two species (1 rodent and 1 non rodent)

– Ensures assessment of potential variability, esp. if relevant

species is not identified

– Single Dose Toxicity

– Repeat Dose Toxicity

• Duration appropriate to use of the product

– Studies of 6 months has generally been appropriate; shorter

durations can be scientifically justified

General Toxicology Studies


• Binding vs Functional Activity (downstream effects)

• Species specificity vs. Surrogate antibodies

– Lack of relevant animal models; Need for surrogates to

homologous animal proteins

– Single species rationale needed

• ICHS6 allows for a case by case assessment for

biopharmaceuticals

Challenges of mAbs


Immunogenicity

• “Immunogenicity” = anti-antibody responses

– Most Mabs are now humanized to avoid this issue

• But could be changes in structure during production, frequency of dosing or due to the patient disease

– Result in:

• potentially serious side effects,

• alterations in PK parameters (mostly increased clearance)

• loss of efficacy


• Pharmacologically relevant animal model – mAb binds to the target in that species

– mAb elicits same pharmacological effect as that expected in humans

• For Humanized Mabs this is usually nonhuman primates

– May need different models for the different targets of the Bispecific antibody

Species Selection (1/2)


Species Selection (2/2)

• in vitro and ex vivo assays to justify and validate the species selection

– Binding study for cross reactivity (tissue) with potency and affinity

– Does species exhibit the disease, receptors etc..

• Receptor occupancy via in vitro testing for dose selection

• Consider long term exposure studies (Carc, Repro)

• Single Species Justification (but don’t decide out of hand)


Alternate Preclinical Strategies (1/2)

• Consider Alternate Models– Antigen presents differently/not available in usual rodent models

– No relevant animal model, aside from non human primate

• Consider a surrogate antibody i.e. Mouse mAb

– Does not represent the behavior of the clinical candidate mAb

– May be needed for full toxicology profile

• Especially if one of more of the domains of a bispecific have not been

licensed


Alternate Preclinical Strategies (2/2)

• Can consider transgenic animal models

– When there is no animal model of disease

– Allows use of the clinical candidate in animals

– Inherent Issues:• potential alterations in biology/stability of the molecule

• added resources and time

• limited value to predict what will be observed in humans


• Adverse immune-mediated drug reactions in humans

• infusion reactions, cytokine storms, immunosuppression and

autoimmunity

• Determine activity in animal species for cell depletion,

suppression, activation, cytokine production, effects on global

immune regulators

• Unexpected antibody dependent cell-mediated cytotoxicity

(ADCC) or complement dependent cytotoxicity (CDC)

Immunotoxicity (1/2)


Immunotoxicity (2/2)

• Historical Example:

– mAb TGN142 (TeGenero) anti-CD28 humanized mAb

• Severe life threatening systemic inflammatory response in a FIH in 2006

• Wake-up call to industry, clinical trial community, and WW regulatory

agencies

• Reports issued on the causes of the adverse events

– animal testing did not detect the problems; MABEL was not helpful

– Avoid future issues in first-in-human (FIH) studies agencies require

standard in vitro assays run in a biologically relevant manner (per

taskforce recommendations 2007)


Dose Selection (1/2)

• Preclinical data determines dose selection for FIH study

– No observed adverse effect level (NOAEL) vs.

minimum anticipated biological effect level (MABEL)

• Relates to the pharmacologically active dose

– Should evaluate with both approaches; use the one the data and risk concerns dictate

– Build this into the nonclinical development

• Ensure the maximally feasible dose (MFD) is tested


Dose Selection (2/2)

• Per FDA guidances:

– Determine NOAEL and MABEL

– Convert to a Human Equivalent Dose (HED) from most

appropriate species

– Apply a safety factor – at least 10 fold to give the

Maximum recommended Starting Dose (MRSD)

– Adjust if needed for the pharmacologically active dose via

MABEL


Long Term Studies Expected for Phase 2/3

Depending on Indication:

• General repeat dose tox study (usually in dogs 9 mos)

• Development/Reproductive Toxicity (DART)

– 3 segments:

• Seg I - Fertility and early embryonic (effects before mating)

• Seg II - Prenatal and postnatal development (teratogenicity)

• Seg III - Embryofetal development (parturition to weaning)

• Carcinogenicity

– Depends on MOA and justification


Combination Drug Philosophy

• Guidance applied to the combination or concomitant use of a

drug/biologic/device (defined under 21 CFR 3.2(e))

• Rationale required for each active component

– Agencies understand that the bi-specific domains are not

separate entities

– They expect understanding contributions of each binding

domain• efficacy and safety from both domains

• can be in vitro and/or published data


Conclusion - Preclinical Approach is a “build”

• Can use standard testing as a means to get general “off target”

toxicology

• Additionally need to run alternates studies to obtain more

specific on target information

OFF TARGET ON TARGET

OVERALL PRECLINICAL PROFILE

gap


Studies in Mice …

Not the Whole Story!


FDA Review of Blincyto®

• Binds to CD19+ B cells and cytotoxic T cells expressing CD3 T-

cell for ALL (acute lymphoblastic leukemia)

• Comprehensive Preclinical

- High Unmet Medical Need

• MOA Safety in Animal findings � Human Trial

- Black Box Warning

- Risk Evaluation and Mitigation Strategy (REMS)


Blinatumomab Core Preclinical

� 2 Repeat dose studies

� IV dosing every day / 4

weeks

� SC dosing BID for 13 weeks

� 2 CNS safety pharmacology

studies

� Preliminary Embryo-fetal study

� No Repro/Dev (known MOA)

� Repeat IV dose

once weekly for 5

weeks

� Cellular Binding

� Cellular activtation

� cytotoxicity

� MOA

� Tissue X reactivity

In Vitro / Ex Vivo Mouse Surrogate Monkey

Expected Efficacy Dose SelectionSurrogate Safety

Specific Safety


Lets Take a break!


Regulatory Interactions


Regulatory Agency Interaction

• Start interaction with Agencies earlier than

IND/CTA

– Meet key agencies – FDA, EU Nationals , EMA SAWP

– Address the molecule specific science with the agencies

and prepare for their requests such as:

• Preclinical development - Both on-target and off-target tox

programs

• Transgenic Mice and Surrogate antibody generation


Benefits of Early Interactions

• Ensures that you have early agreement for development

– Assures you are on the same page

– Creates an atmosphere of shared development

• Establishes an iterative process to discuss new data

– both internally and externally


Key Regulatory Filings to Consider

• Orphan Drug Designation (US, EU)

• Fast Track (US)

• Trials with surrogate endpoint - oncology (US and EU)

– “accelerated approval” in US

• Breakthrough Designation (US)

• Priority Review


FDA Accelerated Development

Nature of Program Fast Track Breakthrough

Qualifying criteria - A drug is intended to treat a serious

condition AND non clinical or clinical

data demonstrate the potential to

address an unmet medical need, OR

- A drug designated as a qualified

infectious disease product

- A drug that teats a serious

condition AND preliminary clinical

evidence indicates that the drug

may demonstrate substantial

improvement on a clinically

significant endpoint(s) over

available therapies

When to submit request - With IND or after

- Ideally no later than pre-BLA

meeting

- With IND or after

- Ideally no later than end of phase 2

Timelines for FDA response Within 60 calendar days of receipt of

request

Within 60 calendar days of receipt of

request


Meetings with Regulators

• Most regions encourage meetings

– FDA allows meeting with each FDA Division

– EMA has meetings with a Scientific Advice Working Party

– EU Nationals allow non binding scientific advice meetings

– Many agencies encourage meetings (S. Korea, Japan)

• All have set processes


Briefing Package

• For Any Agency:

– Briefing Document for scientific/medical discussion

– Start with a list of objectives: in what key areas do you need feedback?

– Each Question should be drafted with your position in mind (for FDA there is a small preamble included)

– Background Information needs to be written with the answer in mind to each questions

• It is not a “data dump”

• Each section should have a purpose to make your points clear

• (ie. IB is not suitable substitute)


What Is Important To A Regulator

• Discuss the general guidance for preclinical work and the

issues with the mAb in development

– Develop rational approaches to each topic

– proposed work around that might work to meet regulatory concerns

• Approach agencies prior to conducting your preclinical

program

– gain scientific input on issues and proposals

• Agencies have insight across platforms and products


Case Study – Try Being the Regulatory Lead!


Exercise

• Review the brief summary on the fictitious bispecific product

provided

• Work individually to consider how what we have discussed

today can affect the preclinical program (15’)

• Then work as a table to discuss your collective thoughts and

outline them on the flip chart (20’)

• We will share general thoughts and one key item from each

table (20’)


Questions to Consider

• What areas would you consider might be of concern for this

type of compound?

• Does this compound meet all expectations

– If not, in what ways will it be a challenge?

– How might those challenges be explained with data?

• What will you suggest/highlight to the team?


Share Thoughts


Summary

• Monoclonal Antibodies present unique issues

• There is a mutual desire to be cautious for FIH and beyond

• Focus on Early Development:

– We discussed a general framework of the key guidelines

• Alternate strategies offered by regulators to address specific issues with the type of antibody or disease state

– Especially how the science will drive the data required


Summary

– Use this framework to provide a perspective for the role of regulatory affairs in your work

• To work with you to resolve issues and opportunities to discuss them with regulators


Role of Regulatory Affairs

• Whether in your company or as externals:

– Use this framework to provide a perspective for the role of regulatory affairs in your work

– To work with you to resolve issues and opportunities to discuss them with regulators


Thank you for your attention!


Back Ups


Meeting with Regulators – US FDA (cont’d)

• Formal Meetings with Sponsors and Applicants for PDUFA (Prescription Drug User Fee Act) Products (2015)

– Outlines types of meetings available, Type A, B or C

– Timelines for arranging the meeting and submission of a supporting briefing document differ

– To use this guidance one needs to have an IND opened in the US

– Steps include formal meeting request letter, briefing document, meeting and submission of post meeting minutes

– Pre-IND meetings are always T/C; others can be in-person or in writing only


Types of FDA Meetings

Type A B C

Confirmation of

scheduling

14 days 21 days 21 days

Held no later than 30 days 60 days 75 days

Briefing package due With meeting request 1 month 1 month

Description, Comments Dispute resolution,

Clinical holds,

Special Protocol

Assessment

Post action meeting (+3

months after)

preIND, EOP1, EOP2,

preNDA/BLA,

REMs* or PMRs**

Any other than A or B

Written Response

(WRO) only is an option

now

EOP = end of phase; * Risk Evaluation and Mitigation Strategy

**Post Marketing Requirements


Meeting with Regulators – EU

• Sponsors may request Scientific Advice from the

European Medicines Agency (EMA)

– All member states are represented at a Scientific Advice

Working Party (SAWP)

– Possible at any time during development or post-

authorisation

– Development or Protocol Advice


• SAWP publishes a year calendar for all steps for SA

– Option to have a pre-submission meeting to review meeting content before the meeting (add 30 days)

• If no questions from SAWP Panel close of procedure at + 40 days

• If questions arise during review SAWP adds a step taken

– Request or clarifications in writing and/or verbally at SAWP meeting Day +60

– Finalisation of procedure and adoption by CHMP Day +75

• Overall takes approx. 4 months from start to finish

Meeting with Regulators – EU (cont’d)


Timing for SA Meetings Step TimelineSponsor submits Letter of Intent (no presubmission meeting) ~ D - 30Submit draft SA request (or PA request) ~ D -15Validation questions arrive ~ D -10Submission ~ D - 5Final document submitted by sponsor ~ D - 5SAWP review by coordinators of the SA ~ D +20SAWP 2 Discussion of the reports ~ D +30Review Ends OR Questions of clarification sent to the sponsor ~ D + 40 If Questions then SAWP 3 Discussion meeting with sponsor and preliminary conclusion by coordinators; issues a joint report to the Agency Secretariat ~ D +63CHMP adopts the final advice letter ~ D + 70


Sample Schedule for SAWP


Removab (catumaxomab)

• First approved triomab for cancer treatment by the EU in April 2009

• The antibody possesses 2 different antigen binding sites

– one targets the human epithelial cell adhesion molecule (EpCAM)

– The other the human CD3 expressed on T-lymphocytes

• The Fc region binds to the Fcγ-receptor-type I (CD64), -type IIa and type III

(CD16), which are expressed on positive accessory cells

• Indication: “intraperitoneal treatment of malignant ascites in patients with

EpCAM positive carcinomas where standard therapy is not available or no

longer feasible”


Review of Blinocyte FDA Review (cont’d)

– Several in vitro cytotox studies

– No single dose tox study

– Repeat dose study in mice with surrogate mAb• 2 CNS safety pharmacology studies

• IV dosing every day / 4 weeks

• SC dosing BID for 13 weeks – MTD identified

• Embryo-fetal study in mice but no repro and dev tox due to known MOA – Preg cat C – only if Benefits outweigh the risks

– Repeat dose in chimps with blinatumomab• 5 weeks once weekly IV

• Increase in cytokines and infection -- similar to clinical patients

– Studied cross reactivity to normal tissues – negative

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