Download challenges in adc development

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. ALL RIGHTS RESERVED.
AGENDA
CLINICAL
DEVELOPMENT OF
NEXT GENERATION
BIOLOGICS
• Growing Interest in Next Generation
Biologics market
• Key Considerations for Development
• Challenges in ADC development
• Conclusion
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BALANCING COST, RISKS AND REWARD
Innovative biologics
Next Generation Biologics
Biosimilars
New targets
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 & antibodydrug conjugate technology
Already validated target
Validating target mechanism
for disease intervention
Advanced technologies
(recombinant DNA, Mammalian
expression techniques)
Complex manufacturing
facilities
Portfolio Risk
Investment
Reward
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Low risk to pipeline portfolio
Unique manufacturing process
Complex manufacturing
facilities
DUBLIN, IRELAND
GROWING INTEREST IN NEXT
GENERATION BIOLOGICS MARKET
ANTIBODY DRUG CONJUGATES
(ADC)
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DEFINITION OF ANTIBODY DRUG CONJUGATES
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
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
Potential to increase the therapeutic
window of non-selective cytotoxic
agents..
• Warhead (cytotoxic): Potent cell killing
activity, significant toxicity
• Payload = linker + Warhead
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
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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)
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INDUSTRY OVERVIEW OF ADC
59 ADCs in active clinical
development by 24
companies. In 2015, there
are almost
332
unique
80
trials, with a total of
different ADCs (active and
discontinued), with majority
85% targeting solid
of
tumors
Source: Antibody Drug Conjugates Clinical Insights EBook, 2016, Hansonwade
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INDUSTRY OVERVIEW OF ADC
HOW MANY ADCS HAVE BEGAN CLINICAL TRIALS IN 2015?
Source: Antibody Drug Conjugates Clinical Insights E-Book, 2016, Hansonwade
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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
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DUBLIN, IRELAND
KEY CONSIDERATIONS
FOR DEVELOPMENT
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T-DM1 (KADCYLA, ROCHE, GENENTECH) ADO-TRASTUZUMABEMTANSINE
 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
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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)
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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).
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DUBLIN, IRELAND
CHALLENGES IN ADC
DEVELOPMENT
1
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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
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CHALLENGES OF ADC DEVELOPMENT
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 Diamantis and Udai Banerji. British Journal of Cancer (2016) 114,
362–367 | doi: 10.1038/bjc.2015.435
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CHALLENGES OF ADC DEVELOPMENT
1. Antigen related
2. Antibody selection
•
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
•
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
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
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CHALLENGES OF ADC DEVELOPMENT
3. Linkers
4. Conjugation
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•
•
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
•
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
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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
© 2017 PAREXEL INTERNATIONAL CORP. /
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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
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FUTURE PROSPECTS
More stable and effective ADCs due to combination of new linker
technologies and more powerful cytotoxic payloads
More rationally designed ADCs with specific DARs
Use high-affinity molecules as cytotoxic payload carriers
Combination strategies, for example with TKIs
.
Predictive biomarkers
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HAVE WE FINALLY FOUND THE ANSWER TO RATIONAL
TARGETED STRATEGY?
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THANK YOU
© 2017
2016 PAREXEL INTERNATIONAL CORP. /
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CONFIDENTIAL