Pharmaceutical Commerce - September/October 2017 - 16

Therapy Focus
Drug development in rare diseases
By Sam Falsetti and Usha Iyer, Cambridge BioMarketing

In the United
States, a rare disease is
defined as a condition
that affects fewer
than 200,000 people,
while in the European
Un i o n , a d i s e a s e i s
defined as rare when it
affects fewer than one
in 2,000 people. The
US Orphan Drug Act
was enacted in 1983 to
stimulate investment
into therapeutic
development for rare
diseases through
financial incentives, tax credits, user fee
waivers and marketing exclusivity. Similar
legislation has also been passed in Europe
and Japan, illustrating an increased focus
by regulatory bodies around the world on
providing improved therapeutic options for
these patients.
Although there are more than 7,000
rare diseases identified, only a fraction of
them have approved therapies available.
Advances in DNA sequencing have led to
the identification of the genetic cause of
several rare diseases, which can potentially
lead to better understanding of the disease
and development of targeted therapies.

metabolism and satiation response in
patients with Prader-Willi syndrome, a rare
disease affecting one out of every 15,000
live births, can be hugely beneficial in
developing novel drugs for general obesity.
Finding the drug
As w ith al l dr ug discover y, basic
research into understanding the etiology,
pathophysiology and genetics is the first
step toward identifying viable targets with
a validated role in disease biology. While
drug discovery and development is laden
with intricacies, there are four overall areas
of consideration that must be considered
in the context of rare disease programs: a
validated therapeutic target (or at least an
identified compound through phenotypic
assays), a clinical data set to base clinical
trial development on, a potential regulatory
path forward, and an addressable patient
population both for clinical trials and to
support commercial feasibility.
In r a re m o n o g e n i c d i s e a s e s , t h e
nature of the underlying genetic basis of
disease can provide a clear path to the
development of cellular and animal models
that mimic human biology. However,
e ve n i n m o n o g e n i c d i s o rd e r s w i t h
validated biological models, the path to
development of a clinical therapy is highly

Four factors determine the feasibility of pursuing a rare disease treatment.
Credit: Cambridge Biomktg

In addition to the development of
novel therapies for patients with specific
rare diseases, orphan drug development
programs can also provide a unique
opportunity to understand other disorders
that may be more common. For example,
the study of lipodystrophies, a set of
conditions where patients lack adipose
tissue, has provided tremendous insights
into the role of adipose-derived hormones
such as leptin. Similarly, lessons learned
from studying therapies that can improve

complex. Lysosomal storage disorders
(LSDs) represent an addressable group
of diseases with a validated treatment
paradigm. In these conditions, a lack
of a specific lysosomal enzyme leads to
lysosomal dysfunction and underlies
disease pathology. Replacement of the
deficient enzyme (also known as enzyme
replacement therapy) has been approved
for multiple LSDs. However, many LSDs
remain unaddressed often due to the
relatively small size of specific populations

16 Visit our website at www.PharmaceuticalCommerce.com September | October 2017

or from a lack of clinical data needed to
develop approvable trials.
To address these challenges in the
US, the National Institutes of Health
provides many resources to facilitate the
development of new drugs for rare diseases.
The National Center for Advancing
Translational Sciences' Therapeutics for
Rare and Neglected Diseases program. This
initiative supports preclinical development
of new treatments to advance them to an
Investigational New Drug. Another example
is The Rare Diseases Clinical Research
Network program, which advances medical
research of rare diseases by providing
support for clinical studies and facilitating
collaboration, study enrollment, and data
sharing.
Finding the patient
Due to the nature of rare diseases,
finding a patient is often one of the
biggest challenges in rare disease
programs. Often, only a small fraction
of the estimated population for a given
rare disease is comprised of diagnosed
patients. Many patients go through a long
diagnostic journey before they receive a
correct diagnosis. It takes, on average,
more than seven years for a patient with
a rare disease to get a diagnosis and often
involves four to eight physicians and two
to three misdiagnoses. For many patients,
the end of this diagnostic journey raises
more questions than answers as a formal
diagnosis does not always guarantee that
a therapy is available. A well elucidated
natural history can provide understanding
into disease progression and clinical
management. Shortening this diagnostic
journey and enhancing rates of diagnosis
are critical to both increase the number of
patients able to access a clinical trial and
improve the commercial feasibility of these
programs.
Targeted disease education for physicians
and patients is the first step toward raising
awareness and encouraging identification of
these patients. Mapping the patient journey
can reveal key diagnostic inflection points
for a sponsor to improve awareness and
catalyze diagnosis. Often, hallmark signs
and symptoms can present early in disease
manifestation to suspect-refer audiences
that have low awareness of the condition.
Beyond increasing awareness with these
accessory target audiences at key points in
the patient journey, it is necessary to assist
with providing a clear path of referral to
a center of excellence that can provide an
accurate diagnosis and multidisciplinary
clinical management.
Beyond the patient journey, another
critical step for a sponsor to undertake
is early synergistic engagement with
patient advocacy organizations. In rare
disease, these groups play an essential role
in program development. Often, these
groups are deeply involved in the drug

discovery and development process, as
well as disease education for patients and
physicians. For example, the Cystic Fibrosis
Foundation's novel venture philosophy
model-based partnership between the
foundation and a for-profit pharmaceutical
company, Aurora Biosciences (now Vertex
Pharmaceuticals), led to development
and approval for Kalydeco, the first drug
to treat the underlying cause of cystic
fibrosis. Developing a patient advocacy
engagement plan prior to first-in-human
trials is essential as these groups can both
provide greatly needed visibility into the
clinical development program and inform
the potential commercial feasibility of a
program.
Patient meets drug
Nowhere is the importance of advocacy
group engagement more pronounced than
in considerations regarding enrollment and
completion of clinical trials. This can be
a daunting task in any disease area due to
the many logistical challenges of finding
and recruiting patients, as well as ensuring
patient adherence to dosing and other
restrictions, such as diet or medications.
The complexities of finding the patients are
even more pronounced when the disease
for which the treatment is being tested
affects a limited number of patients or a
significant proportion of pediatric patients,
or if many of the patients go undiagnosed
for a long period of time. Unfortunately,
many of these circumstances occur in the
rare community.
Trials can place large burdens on patients
in terms of travel to the site, time missed
from work or school, and physical effects
of the treatment itself. Patient-centric trial
design is becoming more popular and is
especially important for rare disease
trials. Pharmaceutical companies often
partner with patients and patient advocacy
groups to gather input to strike a balance
of minimally burdensome design while
ensuring the generation of meaningful data.
Endpoint selection in rare-disease clinical
trials can be particularly challenging since
often there is a large gap in understanding
of the disease pathophysiology and clinical
manifestations over time. These elements,
combined with lack of treatments or clinical
trial precedents, can create a puzzle. During
this process, it is important to identify
biomarkers that correlate with clinical
endpoints and can be linked to longterm benefits for the patient. Choosing an
endpoint that demonstrates the clinical
benefit of the drug is vital to ensure postABOUT THE AUTHORS
Sam Falsetti is head of medical strategy
and product innovation and Usha Iyer
is senior medical director at Cambridge
BioMarketing, a Cambridge, MA full-service
advertising and communications agency
serving pharmaceutical and biotech clients.


http://www.PharmaceuticalCommerce.com

Table of Contents for the Digital Edition of Pharmaceutical Commerce - September/October 2017

Table of Contents
Pharmaceutical Commerce - September/October 2017 - Cover1
Pharmaceutical Commerce - September/October 2017 - Cover2
Pharmaceutical Commerce - September/October 2017 - Table of Contents
Pharmaceutical Commerce - September/October 2017 - 4
Pharmaceutical Commerce - September/October 2017 - 5
Pharmaceutical Commerce - September/October 2017 - 6
Pharmaceutical Commerce - September/October 2017 - 7
Pharmaceutical Commerce - September/October 2017 - 8
Pharmaceutical Commerce - September/October 2017 - 9
Pharmaceutical Commerce - September/October 2017 - 10
Pharmaceutical Commerce - September/October 2017 - 11
Pharmaceutical Commerce - September/October 2017 - 12
Pharmaceutical Commerce - September/October 2017 - 13
Pharmaceutical Commerce - September/October 2017 - 14
Pharmaceutical Commerce - September/October 2017 - 15
Pharmaceutical Commerce - September/October 2017 - 16
Pharmaceutical Commerce - September/October 2017 - 17
Pharmaceutical Commerce - September/October 2017 - 18
Pharmaceutical Commerce - September/October 2017 - 19
Pharmaceutical Commerce - September/October 2017 - 20
Pharmaceutical Commerce - September/October 2017 - 21
Pharmaceutical Commerce - September/October 2017 - 22
Pharmaceutical Commerce - September/October 2017 - 23
Pharmaceutical Commerce - September/October 2017 - 24
Pharmaceutical Commerce - September/October 2017 - 25
Pharmaceutical Commerce - September/October 2017 - 26
Pharmaceutical Commerce - September/October 2017 - 27
Pharmaceutical Commerce - September/October 2017 - 28
Pharmaceutical Commerce - September/October 2017 - 29
Pharmaceutical Commerce - September/October 2017 - 30
Pharmaceutical Commerce - September/October 2017 - 31
Pharmaceutical Commerce - September/October 2017 - 32
Pharmaceutical Commerce - September/October 2017 - 33
Pharmaceutical Commerce - September/October 2017 - 34
Pharmaceutical Commerce - September/October 2017 - Cover3
Pharmaceutical Commerce - September/October 2017 - Cover4
https://www.nxtbook.com/nxtbooks/pharmcomm/202006
https://www.nxtbook.com/nxtbooks/pharmcomm/202003
https://www.nxtbook.com/nxtbooks/pharmcomm/201911
https://www.nxtbook.com/nxtbooks/pharmcomm/201909
https://www.nxtbook.com/nxtbooks/pharmcomm/201906
https://www.nxtbook.com/nxtbooks/pharmcomm/201903
https://www.nxtbook.com/nxtbooks/pharmcomm/201811
https://www.nxtbook.com/nxtbooks/pharmcomm/201809
https://www.nxtbook.com/nxtbooks/pharmcomm/201806
https://www.nxtbook.com/nxtbooks/pharmcomm/20180304
https://www.nxtbook.com/nxtbooks/pharmcomm/20171112
https://www.nxtbook.com/nxtbooks/pharmcomm/20170910
https://www.nxtbook.com/nxtbooks/pharmcomm/20170708
https://www.nxtbook.com/nxtbooks/pharmcomm/20170506
https://www.nxtbook.com/nxtbooks/pharmcomm/20170304
https://www.nxtbook.com/nxtbooks/pharmcomm/20170102
https://www.nxtbook.com/nxtbooks/pharmcomm/20161112
https://www.nxtbook.com/nxtbooks/pharmcomm/20160910
https://www.nxtbook.com/nxtbooks/pharmcomm/20160708
https://www.nxtbook.com/nxtbooks/pharmcomm/20160506
https://www.nxtbook.com/nxtbooks/pharmcomm/20160304
https://www.nxtbook.com/nxtbooks/pharmcomm/20160102
https://www.nxtbook.com/nxtbooks/pharmcomm/20151112
https://www.nxtbook.com/nxtbooks/pharmcomm/20150910
https://www.nxtbook.com/nxtbooks/pharmcomm/20150708
https://www.nxtbook.com/nxtbooks/pharmcomm/20150506
https://www.nxtbook.com/nxtbooks/pharmcomm/20150304
https://www.nxtbook.com/nxtbooks/pharmcomm/20150102
https://www.nxtbook.com/nxtbooks/pharmcomm/20141112
https://www.nxtbook.com/nxtbooks/pharmcomm/coldchaindirectory2014
https://www.nxtbook.com/nxtbooks/pharmcomm/20140910
https://www.nxtbook.com/nxtbooks/pharmcomm/20140708
https://www.nxtbook.com/nxtbooks/pharmcomm/20140506
https://www.nxtbook.com/nxtbooks/pharmcomm/20140304
https://www.nxtbook.com/nxtbooks/pharmcomm/20140102
https://www.nxtbook.com/nxtbooks/pharmcomm/dataservicedirectory
https://www.nxtbook.com/nxtbooks/pharmcomm/20131112
https://www.nxtbook.com/nxtbooks/pharmcomm/20130910_hubreport
https://www.nxtbook.com/nxtbooks/pharmcomm/20130910
https://www.nxtbook.com/nxtbooks/pharmcomm/20130708
https://www.nxtbook.com/nxtbooks/pharmcomm/20130506
https://www.nxtbook.com/nxtbooks/pharmcomm/coldchain2013
https://www.nxtbook.com/nxtbooks/pharmcomm/20130304
https://www.nxtbook.com/nxtbooks/pharmcomm/20130102
https://www.nxtbook.com/nxtbooks/pharmcomm/20121112
https://www.nxtbook.com/nxtbooks/pharmcomm/20120910
https://www.nxtbook.com/nxtbooks/pharmcomm/20120708
https://www.nxtbook.com/nxtbooks/pharmcomm/20120506
https://www.nxtbook.com/nxtbooks/pharmcomm/20120506_coldchain
https://www.nxtbook.com/nxtbooks/pharmcomm/20120304
https://www.nxtbook.com/nxtbooks/pharmcomm/20120102
https://www.nxtbook.com/nxtbooks/pharmcomm/20111112
https://www.nxtbook.com/nxtbooks/pharmcomm/20110910
https://www.nxtbook.com/nxtbooks/pharmcomm/20110708
https://www.nxtbook.com/nxtbooks/pharmcomm/20110506
https://www.nxtbook.com/nxtbooks/pharmcomm/20110304
https://www.nxtbook.com/nxtbooks/pharmcomm/20110102
https://www.nxtbook.com/nxtbooks/pharmcomm/20101112
https://www.nxtbook.com/nxtbooks/pharmcomm/20100910
https://www.nxtbook.com/nxtbooks/pharmcomm/20100708
https://www.nxtbook.com/nxtbooks/pharmcomm/20100506
https://www.nxtbook.com/nxtbooks/pharmcomm/201004
https://www.nxtbook.com/nxtbooks/pharmcomm/201003
https://www.nxtbook.com/nxtbooks/pharmcomm/20100102
https://www.nxtbook.com/nxtbooks/pharmcomm/20091112
https://www.nxtbookmedia.com