clinical development of next generation biologics · (recombinant dna, mammalian expression...

©2017 PAREXEL INTERNATIONAL CORP. ALL RIGHTS RESERVED.

CLINICAL

DEVELOPMENT OF

NEXT GENERATION

BIOLOGICS

Ms. Emily Tan

Corporate Vice President, Portfolio Management,

Asia Pacific, PAREXEL International

February 17th, 2017

PAREXEL India Symposium 2017

© 2017 PAREXEL INTERNATIONAL CORP. / 2

AGENDA

CLINICAL

DEVELOPMENT OF

NEXT GENERATION

BIOLOGICS

• Growing Interest in Next Generation

Biologics market

• Key Considerations for Development

• Challenges in ADC development

• Conclusion


BALANCING COST, RISKS AND REWARD

New targets

Validating target mechanism

for disease intervention

Advanced technologies

(recombinant DNA, Mammalian

expression techniques)

Complex manufacturing

facilities

Innovative biologics Next Generation Biologics Biosimilars

Already validated target

Low risk to pipeline portfolio

Unique manufacturing process

Complex manufacturing

facilities

Portfolio Risk Portfolio Risk

Already established target

Improvement over existing therapy

(safety, efficacy or administration)

Advanced technologies (protein

engineering, novel formulation,

delivery

e.g. affinity maturation, effector

function enhancement, half life

extension, bispecific & antibody-

drug conjugate technology

Investment Investment

Reward Reward


DUBLIN, IRELAND

GROWING INTEREST IN NEXT

GENERATION BIOLOGICS MARKET

ANTIBODY DRUG CONJUGATES

(ADC)


DEFINITION OF ANTIBODY DRUG CONJUGATES

Source: THE CLINICAL LANDSCAPE OF ANTIBODY-DRUG CONJUGATES,

August 1, 2014 | Sohayla Rostami, Ibrahim Qazi, PharmD, Robert Sikorski, doi:

10.14229/jadc.2014.8.1.001

3 main components

• mAb: Specificity bind to cells expressing a

specific target antigen with high affinity and

potentially decrease off-target toxic effects

• Linker: Molecular bridge which conjugates

cytotoxin to mAb

• Warhead (cytotoxic): Potent cell killing

activity, significant toxicity

• Payload = linker + Warhead

A class of therapeutics that combine

the selective targeting properties of

mAbs with potent cell killing activities

of cytotoxic agents

Facilitate delivery of highly potent

cytotoxic molecules directly to tumor

cells expressing unique antigens that

are specific to the mAb

Potential to increase the therapeutic

window of non-selective cytotoxic

agents..


MECHANISM OF ACTION

The ADC complex is engineered to remain stable after administration

until the cellular target is reached

Initial step in the mechanism of action is the binding of the mAb to the

target antigen on the cancer cell.

Once the ADC is localized to the cell surface, the entire complex

(mAb+payload) is internalized through receptor-mediated

endocytosis.

Upon internalization, the ADC is trafficked to intracellular organelles

where the linker is degraded, causing the warhead to be released

inside the cell

Subsequently, the warhead disrupts cell division via a cytotoxin-specific

mechanism, which causes cell cycle arrest and apoptosis.

Two mechanisms of cell cycle arrest are utilized

1) inhibition of tubulin polymerization (eg auristatins and maytansines)

2) based on direct binding to DNA and subsequent inhibition of

replication (eg calicheamicins, duocarmycins, and

pyrrolobenzodiazepines)


INDUSTRY OVERVIEW OF ADC

59 ADCs in active clinical

development by 24 companies. In 2015, there

are almost 332 unique

trials, with a total of 80

different ADCs (active and

discontinued), with majority

of 85% targeting solid

tumors

Source: Antibody Drug Conjugates Clinical Insights E-

Book, 2016, Hansonwade


INDUSTRY OVERVIEW OF ADC

HOW MANY ADCS HAVE BEGAN CLINICAL TRIALS IN 2015?

Source: Antibody Drug Conjugates Clinical Insights E-Book, 2016, Hansonwade


TYPES OF ADC TRIALS

WHAT IS THE RATIO OF SOLID VS LIQUID CANCERS TARGETING

ADCS IN THE CLINIC?

Source: Antibody Drug Conjugates Clinical Insights E-Book, 2016, Hansonwade


DUBLIN, IRELAND

KEY CONSIDERATIONS

FOR DEVELOPMENT


T-DM1 (KADCYLA, ROCHE, GENENTECH) ADO-TRASTUZUMAB-

EMTANSINE

The only ADC licensed in non-haematological malignancies

Trastuzumab: humanised IgG1 anti-HER-2 Ab linked with a stable non-cleavable linker to Maytansinoid DM1

Approved in 2nd line setting by FDA in 2013 for HER-2 positive patients who had previously received treatment with trastuzumab and taxane chemotherapy.

Also being investigated as a single agent compared to docetaxel in previously treated gastric cancer with results

Overall tolerable toxicity profile with most common adverse events being fatigue, transaminitis, nausea, thrombocytopenia and rash.

In USA, T-DM1 carries black box warnings for hepatotoxicity, embryo-fetal and cardiac toxicity


BRENTUXIMAB VEDOTIN (BV, ADCETRIS, SEATTLE GENETICS)

Anti-CD30 mAb connected with a cleavable peptide to the highly

potent tubulin inhibitor MMAE

Gained accelerated approval for treatment of patients with

relapsed or refractory CD30þ HL following autologous stem cell

transplant (ASCT) or patients not legible for ASCT who have failed

at least two other chemotherapy treatments. Also approved for

patients with anaplastic large cell lymphoma (ALCL) as a second

line

– Approval for Hodgkin’s lymphoma was based on a single-arm

phase II clinical trial (73% response rate, 32% complete remission,

median duration 20.5 months) (Younes et al, 2012).

– Indication for ALCL established based on results of the phase II

study (86% overall response rate, 54% complete responses) (Pro

et al, 2012).

Most common adverse reactions were peripheral sensory

neuropathy, neutropenia, fatigue, nausea and thrombocytopenia.

In USA, Carries a black box warning for progressive multifocal

leukoencephalopathy (Younes et al, 2012)


GEMTUZUMAB OZOOGAMICIN (GO, MYLOTARG, PFIZER)

First ADC to be approved by FDA in 2000

– positive results were from the first single-agent phase II studies achieving 30% remissions (Tsimberidou et al, 2006).

Consisted of a humanised IgG4 mAb directed against CD33 (a surface antigen present in 85–90% of AML) linked to a calicheamicin cytotoxin

Licensed as a monotherapy in patients over 60 years old with acute myelogenous leukemia (AML) who were not candidates for cytotoxic chemotherapy

In 2010, results of a post-approval phase III study showed no clinical benefit. In fact, patients in the GO arm had a higher risk of fatal AEs

– This trial led to the retraction of its FDA licence approval (Petersdorf et al, 2013).

– The failures were attributed to an unstable linker allowing premature release of the cytotoxic payload and to the notso-selective antibody target (ten Cate et al, 2009).

– More recent trials such as the ALFA-0701 using intermittent dosing regimens have showed good results, improving event-free survival and overall survival in patients with AML, reigniting discussions about the future of GO (Castaigne et al, 2012).


DUBLIN, IRELAND

CHALLENGES IN ADC

DEVELOPMENT

1

4


TARGET ANTIGENS FOR ADC IN SOLID TUMOR

Source: Antibody-drug conjugates—an emerging class of cancer treatment. Nikolaos Diamantis1 and Udai Banerji*. British Journal of Cancer (2016) 114,

362–367 | doi: 10.1038/bjc.2015.435


CHALLENGES OF ADC DEVELOPMENT

Source: Antibody-drug conjugates—an emerging class of cancer treatment. Nikolaos Diamantis and Udai Banerji. British Journal of Cancer (2016) 114,

362–367 | doi: 10.1038/bjc.2015.435

Bystander effect

• Helps with problem of non-homogeneous expression of the

target antigen in solid tumors from the linker

• However, can increase off-target systemic toxicity

Rate of internalization (receptor mediated endocytosis) of the

ADC in the cancer cell poorly understood

Delivery efficiency

Drug Antibody Ratio

• Optimal DAR is undetermined and highly dependent on

other ADC variables; More commonly the ADCs aim to

attain a DAR close to 4



Source: Antibody-drug conjugates—an emerging class of cancer treatment. Nikolaos Diamantis1 and Udai Banerji*. British Journal of Cancer

(2016) 114, 362–367 | doi: 10.1038/bjc.2015.435

1. Antigen related

• Tumor Antigen density

• Target antigens expressed in normal cells

• Heterogeneity of target antigen expression in the

tumor

• Antigen shedding in circulation

• Down-regulation after treatment with ADC

2. Antibody selection • Humanized & fully human e.g. human IgG isotypes

• Early generation ADCs used murine Ab causing

significant immunogenicity and reducing efficacy

• Multi mode of action: receptor inhibitors/ signal

modulators, activate immune functions or

complement-dependent cytotoxicity. can lead to

increased toxicity, reduced tumor localization and

internalization of the ADC



3. Linkers

• Influence the ADC’s PK, therapeutic index and efficacy

• The ideal linker should be:

• Stable so that the ADC does not release the cytotoxic

drug before reaching its target, causing off-target toxicity.

• Able to release the drug efficiently once internalized

• Non-cleavable and cleavable:

• Noncleavable: following lysosomal degradation the

cytotoxic payload remains active while still being

attached to the linker and an amino acid residue.

- Cleavable: acid/ lysosomal protease/ gluthathione

sensitive linkers, release of cytotoxic drug, increasing

the possibility of bystander effect

4. Conjugation • Nonspecific conjugation to lysine residues – undesirable

heterogeneous mixture of ADCs, with high DAR.

• Ongoing efforts for more homogeneous ADCs with

increased number of drug molecules stably linked to the Ab.

• Site-specific conjugation has enabled the production of

homogeneous ADCs with the desired and prespecified

DAR


DRUG RESISTANCE ISSUES

Mechanism of resistance is complex and variable: confronts

different components

• The cytotoxic drug - subject to the same multidrug resistance

mechanisms

• The monoclonal antibody

• By activating survival signaling pathways

• Mechanisms that will limit the intracellular concentration of

the ADC.

• e.g. -DM1 - down regulation of the target antigen,

reduced internalization of ADC, diminished lysosomal

degradation or increased ADC recycling to the cell

surface and masking of the antigen epitope.

Potential combinations with small molecule inhibitor to overcome

resistance

• Evidence that activation of PI3K/AKT, MEK/ERK and

JAK/STAT pathways leads to increased ADC resistance


Source: Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates MABS 2016, VOL. 8, NO. 4, 659–671


DRUG TOXICITY ISSUES

• The payload often drives the toxic effects. However, the target and linker may determine the

organ specificity of the toxicity

• Different toxicities in different disease types with the same drug

• During the dose escalation of polatuzumab vedotin, DLTs were observed in patients with CLL at much lower doses than NHL. Analysis of the PK

profile revealed lower exposure and faster clearance in patients with CLL compared to NHL, consistent with target-mediated clearance due to

higher numbers of circulating B cells in CLL.4

• Ocular toxicities

• Commonly reported: Blurred vision, keratitis, dry eye and microcystic epithelial damage

• Payload association, with ocular toxicity typically induced by ADCs that include DM4 and MMAF. Both tend to utilize a stable linker:

• Unclear why the eye is particularly sensitive to toxicities with these payloads, but, for MMAF-conjugated ADC, the toxicity may be related to

accumulation of the drug within cells

• Therapeutic window of ADCs can be increased by dose modifications to optimize the plasma

concentration.

• Good monitoring of PK profiles in patients beyond Phase 1

Source: Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates MABS 2016, VOL. 8, NO. 4, 659–671


FUTURE PROSPECTS

More stable and effective ADCs due to combination of new linker

technologies and more powerful cytotoxic payloads

More stable and effective ADCs due to combination of new linker

technologies and more powerful cytotoxic payloads

Predictive biomarkers Predictive biomarkers

Use high-affinity molecules as cytotoxic payload carriers Use high-affinity molecules as cytotoxic payload carriers

Combination strategies, for example with TKIs

.

Combination strategies, for example with TKIs

.

More rationally designed ADCs with specific DARs

More rationally designed ADCs with specific DARs


HAVE WE FINALLY FOUND THE ANSWER TO RATIONAL

TARGETED STRATEGY?

© 2017 PAREXEL INTERNATIONAL CORP. / 24 © 2016 PAREXEL INTERNATIONAL CORP. /

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