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Piramal | Healthcare
knowledge action care

Antibody Drug Conjugates in Reducing Disease Burden
Immense Promise with Some Challenges
Antibody Drug Conjugates provide a high level of promise, and hence there will be a conscious
effort to expand the application(s) of this technology to disease indications beyond oncology
provide a high level of promise, and hence there will be a conscious effort to expand the
application(s) of this technology to disease Indications beyond oncology.

Vivek Sharma
Chief Executive Officer,
Piramal Pharma Solutions, India.
The global market for oncology drugs has seen a steady growth in recent years with cancer
being the leading area of healthcare spending. Market estimates show that in 2013, the global
spending on oncology drugs reached US$91 billon (including supportive care), growing at a
CAGR of 5.4 percent in the period from 2008-2013. This trend is expected to continue in to 2017
where oncology is expected to drive the global spend on medicines.
Analysis of global pharmaceutical pipeline indicates that close to 30 percent of the overall
pipeline is focused towards the development of anti-cancer drugs.
Targeted therapies dominate the oncology development pipeline with recent approvals of
immunotherapies such as MabThera / Rituxan, Avastin. and Herceptin marking a trend
towards increased use of targeted therapies. The ’selectively acting' therapies have increased
their share of global oncology sales to 46 per cent from 11 per cent over the period 2003-2013.
This has consequently lead to a decline in the share of spend towards cytotoxic and hormonal
Antibody Drug Conjugates (ADCs) provide additional arsenal to the pharmaceutical industry in
its bid to develop targeted therapies for cancers. An ADC consists of amonoclonal antibody, a
biodegradable linker and cytotoxic drug. The antibody binds to the target cancer cell. The whole

ADC is then internalised within the cancer cell, the linker is degraded, and the active drug
released. Due to the targeted mechanism of action, the side effects of potent drug are lower.
The cytotoxic drugs used In ADCs are high-potent APls such as Callcheamycin, Maytansinoids
and Auristatins. While there are other cytotoxic agents that can potentially be used, auristatins
and maytansinoids are the most widely used cytotoxic drug payloads' in ADCs.
History of ADCs
The concept of ADC is not new and can be traced back over a century when the German
physician and scientist Paul Ehrlich proposed the concept of selectively delivering a cytotoxic
drug to a tumor via a targeting agent. Ehrlich even coined the term 'magic bullet’ to describe his
vision. Nearly 50 years later, Ehrlich’s concept of targeted therapy was first exemplified when
methotrexate (MTX) was linked to an antibody for targeting leukemia cell. The earlier versions
of ADCs used murine polyclonal antibodies which were more immunogenic. However, advances
in antibody engineering over time have enabled the production of humanised monoclonal
antibodies that has significantly circumvented the issue of Immunogenicity. The lessons learnt
in the development of technology and clinical evaluation of ADCs ultimately led to the first US
FDA approval of ADC. Mylotarg (gemtuzumab ozogamicin), in the year 2000.
Benefits of ADCs
Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient.
Monoclonal antibodies against antigens on cancer cells offer an alternative tumour-selective
treatment approach. However, most monoclonal antibodies are not sufficiently potent to be
therapeutically active on their own. ADCs use antibodies to deliver a potent cytotoxic compound
selectively to tumor cells, thus reducing exposure of normal tissue to cytotoxic drugs and
improving the therapeutic index of chemotherapeutic agents.

Current Status and Market
Currently, there are two US FDA approved ADCs
available - Adcetris (brentuximab vedotin) and Kadcyla

“The concept of ADC is not new and

(ado-trastuzumab emtansine). As per analyst estimates,

can be traced back over a century

the sales of Adcetris and

Kadcyla are expected to

reach US$1.3 billion and US$1.5 billion by 2020

The overall ADC market is currently

estimated to be US$600 million and is expected to grow
at a CAGR of 48. 1 percent in the period 2013 - 2018

when the German physician and
scientist Paul Ehrlich proposed the
concept of selectively delivering a
cytotoxic drug to a tumor via a
targeting agent. Ehrlich even coined

to reach US$2.8 billion.

the term ‘magic bullet’ to describe
The pharmaceutical industry has noticed the benefits

his vision.”

that ADCs offer, and that has led to an increase in the
number of clinical trials being conducted for ADCs. In the past decade, 2004-2014, there were
a total of 94 clinical trials conducted in the US for ADCs. However, out of this, 79 clinical trials
were initiated in the last five years itself from 2009 to 2014, representing a 618 per cent increase
over the pef1od 2004-2009 during which only 11 trials were conducted. A total of 70 clinical trials
involving ADCs are currently active in the US with 5'0 per cent of these trials being In Phase I.

The Promise of ADCs
Adcetris was granted approval for treatment of patients with Hodgkin Lymphoma (HL) and




(ALCL). It is commercially available for
these indications in more than 40




expansion planned. Adcetris is the first
new FDA approved treatment for HL
since 1977 and the first one to be

specifically indicated to treat ALCL. Clinical trial results show highly impressive response rates
observed with Adcetris in patients with HL and ALCL (73 percent and 86 percent respectively).
Similarly, significant clinical benefit was observed with Kadcyla which is approved as a single
agent indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast
cancer. Approval of Kadcyla was based on the phase III EMILIA trial which compared Kadcyla
to lapatinib and capecitabine therapy. The trial showed a strong benefit in overall survival against
the current best therapy showing an Improvement in overall survival of nearly six months.
With the success of Kadcyla against solid tumours comes the real promise of ADCs in tackling
the most aggressive and resistant tumours with the worst clinical outcomes. Current targets
include cancers with high unmet need for treatment such as triple negative breast cancer, gastric
tumours, small cell lung cancer, melanoma and pancreatic cancer. The technology behind ADCs
is continuing to develop and mature at a rapid rate. ADC programs are increasingly progressing
from the lab to the clinic with more ADC projects entering the clinic each year. An increasing
amount of later phase clinical data on ADC is becoming available and the knowledge and
confidence in the technology is growing. Excellent clinical data combined with a low overall
failure rate is driving the ADC revolution.
Roche/Genentech is one of the most active companies in the ADC market. Banking on the
success of Kadcyla and a strong pipeline of ADCs, the company plans to invest more than
US$200 million for setting up ADC manufacturing plant in Basel. Switzerland.3There is now a
huge interest in ADCs w1th other Industry majors such as Sanofi, Bayer, GSK, Amgen, BMC,
Abbvie. Eli Lily, Astellas. Takeda / Millennium and Novartis also running ADC programs.
The technology used in ADCs is relatively undeveloped and despite such wide involvement, the
ADC technology space is dominated by a handful of players. This means there are a limited
number of payloads available. The maytansine platform from lmmunogen and the auristatin
platform from Seattle Genetics both have the same mechanism of action which may not be
suitable for all cancers. Groups are investigating other payloads, but to date few have managed
to make a significant impact.

In clinical trials. ADC associated toxicities have also been observed,
due to early release of the payload. These side-effects point to the
importance of linker chemistry in ensuring therapeutic safety of ADCs.
There is an effort from the industry towards improving antibody
technology, site specific conjugation and linking chemistries to tackle the common toxicities

observed across drug platforms. It is likely that the next generation of ADCs will show fewer side
effects than the current generation of late phase and approved projects.
The manufacturing of ADCs poses several challenges due to nature of the molecules. Some of
these are identified as:

Antibody binding activity after conjugation
Biological activity of cytotoxic drug after conjugation
Production of components requiring both cell culture and synthetic chemistry capabilities
Cytotoxic nature of the drug requires high containment faculties
Conjugation of antibody to drug-linker requires cGMP containment room/suites

Global ADC Market Size (8Mn, 2013-2018}
As a result, majority of ADC manufacturing (70 per cent to 80 per
cent) is outsourced to contract manufacturers. However, only few
players provide the complete suite of services for ADC
manufacturing. Further, there are several small biotechnology
companies which are entering into the ADC market. The resulting
growing pipeline has underlined the need for integrated service
providers with the capability to handle high-potent drugs and
provide complete suite of ADC manufacturing servlces.3

Piramal is one of the global leaders in providing customer-centric
ADC manufacturing Solutions. With world-class facilities in UK
and US and backed by highly experienced team, it offers
Integrated services from development through clinical and

commercial ADC GMP batch manufacturing and ADC fill/finish. The focus on quality and on time
delivery has led to several recognitions, including recent ones such as the ‘World ADC Award’
in 2014 for conjugation services, and the ‘2015, CMO Leadership Award’ for quality,
reliability and regulatory excellence.
ADCs provide a high level of promise, and hence there will be a conscious effort to expand the
application(s) of this technology to disease indications beyond oncology. The lower overall
failure rate for ADCs shows promise from a patient perspective, and the hope is that the next
generation of this technology will lead to further Improvements. In the near future, one can expect
CMOs involved in the ADC space to expand, potentially consolidate, and focus on providing
end-to-end solutions from development through fill/finish.
”Antibody--drug conjugates: Current Status and Future Directions”, Heidi L. Perez et.at.
Elsevier, December 2013
Thomson Reuters Cortellis. Sales Forecasts
“ADC Contract Manufacturing Market, 2014 --2024", Roots Analysis
Vivek Sharma is Chief Executive Officer, Piramal Pharma Solutions. Prior to this, he was
Managing Director at THL Partners, a Boston based PE firm where he was responsible for
working with THL's Portfolio companies to identify value creation opportunities and partner with
the company's leadership team for execution of growth/restructuring and cost optimization
initiatives. Vivek has over 20 years of Global Management experience and is a Chartered
Accountant from India a qualified CPA and also has a Masters in international Business from

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