N E W S & A N A LY S I S
FROM THE ANALYST’S COUCH
Autism spectrum disorders
Sarah Nightingale
Autism spectrum disorders (ASDs) are
developmental disorders typically defined
by four core symptoms: communication
deficits, irritability, repetitive behaviours and
restricted interests. Although the aetiology
remains largely unknown, recent studies
have determined that genetics, sex and
environmental exposures are significant risk
factors. Interestingly, the prevalence of ASDs
has dramatically increased over the past few
decades. This is considered to be a result of
the changes in diagnostic criteria and greater
overall awareness of the disorder. However,
a true increase in prevalence cannot be ruled
out. In 2011 it was estimated that there were
6.6 million cases of ASDs across the seven
major markets (the United States, Japan,
France, Germany, Italy, Spain and the United
Kingdom)1 (FIG.1), representing 1% of the
population.
Current therapeutic options
Currently, there are just two pharmacotherapies
approved for the management of the disorder:
risperidone (Risperdal; Johnson & Johnson)
and aripiprazole (Abilify; Bristol-Myers
Squibb/Otsuka Pharmaceuticals). Both of
these products are atypical antipsychotics
indicated for the management of irritability
symptoms associated with ASDs in children
and adolescents (aged 5–17 years) in the
United States. There are currently no
treatments approved in Japan or the five
major European markets.
Risperdal has historically been the market
leader. It was approved by the US Food
and Drug Administration (FDA) in 2006 and
faced little competition from branded agents
until Abilify’s approval in 2009. Abilify rapidly
superseded Risperdal owing to its favourable
side-effect profile. In addition, the launch
of generic risperidone in 2005 (Europe)
and 2008 (United States) negatively affected
sales of Risperdal. Despite offering superior
efficacy over Abilify, weight gain associated
with Risperdal remains a key concern.
Patents for alternative formulations of
Risperdal will expire from 2015 onwards.
Abilify’s key strength lies in its partial
agonism of dopamine receptors: a unique
mechanism of action that produces a superior
side-effect profile compared to Risperdal.
In addition, Abilify remains under patent
Courtesy of Squint, www.squintlimited.com
protection until 2014 in the European Union
(EU) and until 2015 in the United States.
Expiration of Abilify’s US and EU patents will
exert a substantial impact on the ASD market
as the prescription of generics and off-label
products will dominate the market.
A key obstacle to the use of pharmaco­therapy in the management of ASDs includes
the deeply entrenched position of behavioural
interventions in treatment guidelines
and the negative perceptions surrounding
the use of antipsychotics. As there are no
disease-modifying drugs for ASDs, treatment
guidelines state that pharmacological
approaches should only be initiated for the
management of disruptive symptoms to aid
compliance and outcomes of the behavioural
interventions.
Developing efficacious treatments for the
core symptoms of ASDs, such as the social and
communication impairments and behavioural
symptoms, is considered to be the primary
unmet need. For this to occur, basic research
is required to help elucidate the aetiology
of ASDs. Moreover, there are currently no
treatments approved for the management of
ASDs in adults. In 2011 there were estimated to
be 5.3 million adults (aged 20 years and above)
diagnosed with ASDs compared to 1.3 million
children and adolescents (aged 3–19 years)1.
R&D trends
The research and development (R&D) pipeline
for ASDs has more than doubled since
April 2011, reaching a total of nine candidates
(TABLE 1). Although the ASD pipeline is small
in relation to other mental health conditions,
the increasing number of candidates in the
pipeline is a reflection of the increased interest
in ASDs. In March 2012, an unprecedented
multicentre collaboration between industry
and academia was formed with the sole aim of
identifying and developing novel and targeted
treatments for autism. The collaboration,
spearheaded by Roche and titled ‘European
Autism Interventions — A Multicentre Study
for Developing New Medications’ (EU-AIMS),
has secured a grant of US$38.7 million and is
one of the largest investments ever seen in the
mental health sector.
Owing to the heterogeneity of the
symptomatology and unknown aetiology of
ASDs, various therapeutic approaches are
NATURE REVIEWS | DRUG DISCOVERY
under investigation in the clinical pipeline.
Each candidate targets a different mechanism
of action, with three-quarters of the candidates
targeting core symptoms. However, given the
array of symptom presentation and severity
in patients suffering from ASDs, along
with the unknown aetiology, developing a
single treatment for the core symptoms is
an ambitious objective. Nevertheless, using
broad end points in the early-stage clinical
trials could help to identify symptoms that
could be targeted more successfully with
drug candidates in future trials.
Publicly available clinical trial data for
current pipeline candidates are sparse.
The most promising candidate, CM-AT
(Curemark), completed a Phase III trial
in December 2011 and benefits from the
FDA-designated ‘Fast Track’ status. Although
the active ingredient of CM-AT has not
yet been revealed, it is thought to target
enzyme deficiencies in autistic children to aid
protein digestion and the production of vital
amino acids. It is one of the first treatments
endeavouring to address the underlying
physiology of autism; if successful, this
would revolutionize the pharmacological
management of the disorder. The active
▶
501,000
370,000
486,000
2,613,000
697,000
511,000
1,411,000
United States
Japan
France
Germany
Italy
Spain
United Kingdom
Figure 1 | Prevalence of autism spectrum
dis­orders in 2011. Data presented are for the
Nature(United
ReviewsStates,
| Drug Japan,
Discovery
seven major markets
France, Germany, Italy, Spain and the United
Kingdom).
VOLUME 11 | O CTOBER 2012 | 745
© 2012 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S
FROM THE ANALYST’S COUCH
▶ ingredient has been clinically available for
over 40 years, which has been a developmental
advantage for the product; the FDA rendered
toxicology studies unnecessary, propelling
CM-AT rapidly into Phase III studies.
However, competition from generic versions
represents a considerable commercial
disadvantage for CM-AT.
AT001 (fluoxetine; Autism Therapeutics),
a selective serotonin reuptake inhibitor,
is also in Phase III development for ASDs and
benefits from FDA ‘Fast Track’ and ‘Orphan
Drug’ status. Although its development
has been marred by negative Phase II trial
results, Autism Therapeutics is investigating
a novel strategy aiming to identify and target
likely responders. STX-209 (arbaclofen;
Seaside Therapeutics), a selective GABAB
(γ-aminobutyric acid type B) receptor
agonist, is currently under Phase IIb clinical
investigation for the treatment of irritability
associated with ASDs. Overactivity of
glutamate has been associated with abnormal
neurodevelopment, particularly affecting
children from the age of 2, when glutamate
levels are naturally highest. This coincides
with the typical age at which symptoms of
ASDs are often observed. Excessive glutamate
transmission in ASDs is thought to result
from suppression of the GABAergic system
and overactivation of NMDA (N-methyl-Daspartate) receptors. STX-209 is attempting
to correct this imbalance by supporting
the GABAergic functions. By contrast,
memantine hydrochloride (Merz/Forest
Laboratories) targets this mechanism through
NMDA receptor antagonism. It is in Phase II
development and is the only pipeline candidate
under clinical investigation for the treatment of
both children and adults with ASDs. Although
this will offer key product differentiation,
the product will need to reach the autism
market ahead of the 2015 patent expiry in
order to maximize return on the investment.
The remaining Phase II pipeline candidate
is a stem cell therapy under development
in China by Beike Biotech. Although this
represents one of the first treatments to
attempt to cure ASDs, the use of stem cells
remains a highly contentious issue that is
marred by developmental challenges and safety
concerns. The efficacy of such a treatment
will need to be particularly high in order to
outweigh the potential safety risks.
The early-stage (Phase I) pipeline includes a
transnasal formulation of the oxytocin receptor
antagonist carbetocin (Kyalin Biosciences)
and a dopamine antagonist, lurasidone
Table 1 | Products in clinical development for ASDs (September 2012)
Drug
Mode of
action
CM-AT
Protease
stimulant
Fluoxetine
Selective
(AT001;
serotonin
previously
reuptake
NPL-2008)
inhibitor
Arbaclofen
GABAB
(STX-209)
receptor
agonist
hUCB-MNC
Stem cell
therapy
Memantine
NMDA
hydrochloride receptor
antagonist
Carbetocin
Oxytocin
receptor
agonist
RO-5028442
Unknown
Formulation
ASD
indication
Core
symptoms
Core
symptoms
Companies
(licensee)
Curemark
Oral capsule
Irritability
Seaside
Therapeutics
IIb (United
States)
Injectable
Core
symptoms
Beike Biotech
IIa (China)
Oral capsule
Core
symptoms
Forest Laboratories
and Merz Pharma
II (United
States)
Inhaled
transnasal
Core
symptoms
Kyalin Biosciences
(previously Cypress
Bioscience)
I (United
States)
Unspecified
Core
symptoms
Roche
I (United
States)
RG-7314
Vasopressin
antagonist
Unspecified
Social
deficits
Roche
I (United
States)
Lurasidone
hydrochloride
Dopamine
antagonist
Oral tablet
Core
symptoms
Sunovion
Pharmaceuticals
I (United
States)
Oral powder
Oral rapidly
disintegrating
tablet
Autism
Therapeutics
(previously
Neuropharm)
Phase
(country)
III (United
States)
III (United
States)
ASD, autism spectrum disorder; GABAB, γ-aminobutyric acid type B; hUCB-MNC, human umbilical cord
blood mononuclear stem cell; NMDA, N-methyl-D-aspartate.
hydrochloride (Sunovion Pharmaceuticals).
Roche is leading the development of two
pipeline candidates: RG-7314, a vasopressin
antagonist, and RO-5028442, which has an
as-yet unknown mode of action. Both oxytocin
and vasopressin are peptides involved in
social functioning, and children with autism
have significantly lower levels of oxytocin
compared to controls. As such, it has been
hypothesized that increasing levels of oxytocin
can protect against the development of ASDs.
In addition, increased levels of vasopressin
have been associated with repetitive and
aggressive behaviours, supporting the rationale
for investigating vasopressin antagonists for
the treatment of autism. However, it will be
important to demonstrate a cardiovascularrelated safety profile as vasopressin receptors
have been associated with cardiovascular
functions.
Future epidemiology
The current prevalence of ASDs in the
seven major markets is expected to remain
constant over the next 10 years, given the
current state of disease awareness and
refined diagnostic criteria. Using recent
population-based studies and underlying
risk factors, Datamonitor expects the
746 | O CTOBER 2012 | VOLUME 11
number of prevalent cases of ASDs in the
seven major markets to increase slightly by
3.4%, from 6.6 million in 2011 to 6.8 million by
2021 (REF. 1). The United States will continue
to have the largest number of cases across the
forecast period, followed by Japan; variations
will be largely driven by population numbers.
By 2021, adults with ASDs will represent 81%
of the total number of ASD cases across the
seven major markets. As such, tapping into this
large and as yet underserved market offers a
substantial growth opportunity for companies
that are successful in demonstrating efficacious
treatments for adults with ASDs.
Sarah Nightingale is an analyst at Datamonitor,
119 Farringdon Road, London EC1R 3DA, UK.
e-mail: snightingale@datamonitor.com
doi:10.1038/nrd3771
Published online 24 September 2012
1. Datamonitor. Epidemiology: autism spectrum disorders
— increasing recognition drives growth of treatable
population. Code: HC00106‑001 (February 2011).
Competing interests statement
The author declares no competing financial interests.
FURTHER READING
Autism Speaks website — 19 March 2012 press release:
http://www.autismspeaks.org/about-us/press-releases/
research-academic-industry-drug-discovery
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