Download Cystic fibrosis in an era of genomically guided therapy

Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
doi:10.1093/hmg/dds345
Advance Access published on August 21, 2012
R66–R71
Cystic fibrosis in an era of genomically
guided therapy
P.M. Barrett1, A. Alagely1 and E.J. Topol1,2,∗
1
Scripps Translational Science Institute, La Jolla, CA, USA, 2Scripps Health, La Jolla, CA, USA
Received July 31, 2012; Revised July 31, 2012; Accepted August 13, 2012
INTRODUCTION
The discovery of the CFTR gene in 1989 ushered in a new era
of possibilities in the treatment of cystic fibrosis (CF). Several
attempts at manipulating the underlying gene defect have met
with varied levels of success (1 –4). Ivacaftor, a recently
Federal Drug Administration (FDA)-approved CFTR modulating therapy, is the first DNA-guided therapy for a subset of
patients afflicted with CF. Coupling the gene defect with the
therapy most likely to result in clinical benefit is an excellent
demonstration of the strength of a precision therapy. However,
with this level of individualized medicine comes substantial
cost. Medications, which can cost upward of $400 000 per
patient per year, are being approved by the FDA under the auspices of the Orphan Drug Act (5). These therapies, often tailored specifically to the underlying defect of the disease, still
only result in symptomatic benefit rather than a cure. Precision
medicine is certainly needed to target these devastating, often
neglected diseases but if the clinical benefit is primarily
symptom reduction, one has to question to what degree the
extremes in cost offset the remarkable triumphs in molecular
medicine. Moreover, this precedent of a small molecule pill
form of therapy, rather than a biologic, which has a relatively
low cost of goods to manufacture, raise the question as to what
will be considered acceptable norms for DNA-guided therapies in the future.
CYSTIC FIBROSIS
With a frequency of 1 in 2000 – 3000 live births, CF is the
most common fatal autosomal recessive disease among Caucasian populations (6). Worldwide it affects 70 000 people
(7 – 9). Although a multisystem disease, it is the progressive
pulmonary involvement that is responsible for the majority
of the morbidity and mortality associated with the condition.
Currently, there is no cure for CF. The disease results from
mutations in CFTR, a 250 kb gene on the long (q) arm of
chromosome 7 that encodes for the CF transmembrane conductance regulator protein ‘CFTR’ (10– 15). This protein is
an epithelial ion channel that regulates the absorption and secretion of salt and water in a variety of tissues, including the
lung, sweat glands, gastrointestinal tract and pancreas (7,16).
The resultant viscous mucosal obstructions of exocrine
glands with neutrophil dominated debris are among the
∗
To whom correspondence should be addressed at: Scripps Translational Science Institute, 3344 N Torrey Pines Road, Suite 300, La Jolla, CA 92037,
USA. Tel: +1 8585545708; Email: [email protected]
# The Author 2012. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected]
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Although affecting only 4 – 5% of those with cystic fibrosis (CF), the G551D-CFTR mutation is the target of the
recently approved ‘orphan drug’, ivacaftor. The promise of such genomically guided therapies heralds a new
era in the management of CF. A phase 3 trial demonstrated significant improvements in forced expiratory
volume in 1 s (FEV1) from baseline, average weight gain, concentration in sweat chloride and reductions in
pulmonary exacerbations [Ramsey, B.W., et al. A CFTR potentiator in patients with CF and the G551D mutation. N. Engl. J. Med., 2011. 365: 1663 – 1672.)]. Ivacaftor is among a group of recently approved, novel, mutation guided ‘orphan drug’ therapies that have established clinical benefits within their respective disease
categories. They do not, however, offer a cure. Pharmaceutical and biotech companies have leveraged the
incentivized benefits of the Orphan Drug Act to develop more of these drugs for orphan disorders affecting
populations of <200 000 patients. With marked clinical efficacy via DNA sequence guidance, these drugs have
also set a precedent in terms of the substantial annual costs and if this trend continues, such expenditures
may become unsustainable. This paper explores the genomic pathophysiology of CF and how therapies such
as ivacaftor provide benefit to those with the disease but at a considerably elevated price point.
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
Figure 1. Chloride transport structure of CFTR. CFTR (cystic fibrosis transmembrane conductance regulator) is a 1480-amino-acid protein containing
two membrane spanning domains, two nucleotide-binding domains (NBD)
and a regulatory domain. After phosphorylation by protein kinase A at the
regulatory domain, the two membrane spanning domains, each of which is
comprised of six alpha helixes, form a channel for chloride transport.
Channel activity is regulated at the two NBDs. The common CF mutation,
F508del, deletes the amino acid phenylalanine at the surface of NBD1. The
carboxyl terminal (denoted as TRL coding for the amino acids threonine, arginine and leucine) alters CFTR function, conductance, signal transduction
and localization by means of intracellular proteins. Adapted and reprinted
with permission from New England of Medicine (16).
pathological hallmarks of the disease. This mucinous impaction leads to a variety of clinical manifestations including inadequate airway hydration, rendering the airways vulnerable
to chronic infection and inflammation with subsequent irreversible lung damage (17). Chronic fibrosis of the pancreas
due to ductal obstruction causes pancreatic inflammation and
insufficiency. Meconium ileus, a presenting feature in 10%
of newborn CF patients, is almost pathognomonic of the
disease (18,19). Infertility occurs due to glandular obstruction
of the Wolffian ducts in utero in males and secondary amenorrhea as a result of malnutrition in females (16).
CFTR PROTEIN
The CFTR protein contains 1480 amino acids and belongs to
the ATP-Binding Cassette family of proteins that are primarily
concerned with transmembrane transport functions. It has two
intracellular nucleotide-binding domains, two groups of six
membrane-spanning regions and an ‘R domain’ containing
multiple phosphorylation sites. Phosphorylation of the ‘R’
domain by phosphokinase A is required for activation of its
chloride channel (20,21). Channel activity is governed by
two nucleotide-binding domains, which regulate channel
gating and include the carboxyl terminal composed of threonine, arginine and leucine. Six alpha helixes comprise each
membrane-spanning domain (Fig. 1). The role of CFTR may
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Figure 2. Classes of CFTR mutations. CFTR mutations are classified based on
those that result in abnormal CFTR synthesis (class 1), processing (class 2),
chloride channel regulation and gating (class 3), chloride channel conductance
(class 4) and quantity in the cell as a result of stability issues (class 5). Adapted
and reprinted with permission from New England of Medicine (16).
extend beyond chloride permeability and include regulation
of inflammatory response, ion transport and cell signaling
(16). A variety of protein defects result from a host of differing
gene mutations. Efforts to correct such defects have been the
focus of high throughput small molecule screening programs
(Fig. 2).
THE CFTR GENE
More than 1700 CFTR gene mutations have been described to
date with the potential to cause disease (4,22). The
G551D-CFTR mutation encodes for defective protein regulation. The most common mutation is F508del-CFTR, which
is a deletion of three DNA bases coding for the 508th amino
acid residue, phenylalanine. In the USA, 70% of Caucasian
CF patients harbor this mutation. However, only five mutations account for 97% of cases in the Ashkenazi Jewish population (23). CFTR gene mutations can be divided into five
separate classes depending on where the protein function is
affected. Although specific mutations are not used to infer
disease severity, classes 4 and 5 are generally associated
with more severe phenotypic disease expression (6,24,25).
CFTR GENE CLASS MUTATIONS
The G551D-CFTR mutation is the most common class 3 mutation occurring in 4 – 5% of all CF patients (7). Class 3 mutations cause defective protein regulation often by means of
reduced channel activity in response to ATP. Such defects
result in normal CFTR protein production but abnormal
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Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
chloride channel transport. By targeting the abnormal chloride
channel activity, ivacaftor promotes more effective chloride
transfer. Four other classes of mutations exist and each is a
target for future CFTR modulating therapies. Class 1 mutations result in defective protein production. Such mutations
account for 2– 5% of mutations and are usually caused by
frameshift, nonsense or splice site mutations. This results in
premature termination of mRNA and complete absence of
the CFTR protein. Class 2 mutations result in defective
protein processing, which prevents protein transition to its
intended cellular location. Although this defect results in relatively normal chloride channel function, the protein is recognized as misfolded and quickly degraded thereby never
reaching the cell membrane. Importantly, the most common
mutation F508del-CFTR falls into this class. Class 4 mutations
involve defective conductance. As with class 3 mutations,
CTFR is normally produced and localized to the cell surface;
however, the rate of ion flow and duration of channel
opening is reduced. Class 5 mutations result in reduced
number of CFTR transcripts (16,26–29). With several classes
of gene mutations, there are multiple opportunities to target
the disease process, a fact that could be used to great advantage
in those with non-homologous defects.
NOVEL GENOMICALLY GUIDED CFTR
MODULATING THERAPIES
With the discovery of the CFTR gene in 1989, a gene-based
therapy to correct the core abnormalities of the disease
seemed tantalizingly close. Although there were some early
successes with gene therapy, this approach has yet to yield
the promised panacea for CF.
IVACAFTOR
Ivacaftor (VX-770) is a recently FDA-approved therapy for
those with CF designed to act as a ‘potentiator’ of epithelial
CFTR channels thereby prolonging opening and increasing
chloride transport activity. As it does not correct abnormal
protein folding or transcription as is seen in the more
common class 2 F508del-CFTR mutation, studies of ivacaftor
have focused on those with class 3 mutations, primarily
G551D-CFTR (7,25,30).
By using a high throughput-screening library containing
nearly 228 000 candidate compounds, Vertex Pharmaceuticals
identified VX-770 (Ivacaftor) as a possible ‘potentiator’ of the
CFTR function (30,31). Subsequent in vitro assays demonstrated that human bronchial epithelia expressing
G551D-CFTR showed the greatest increase in chloride
channel potentiation after stimulation of the cAMP/PKAsignaling pathway when compared with those cells expressing
the F508del-CFTR or wild-type mutation. Further preclinical
testing using open circuit recordings of nasal potential differences revealed similarly positive results, again in those with
the G551D-CFTR mutation. These encouraging results
prompted fast-track clinical trials beginning in 2006 directed
at CF patients harboring at least one G551D-CFTR mutation
(30,32,33).
Figure 3. Improvements in FEV1 and weight gain with ivacaftor. In the phase
3 clinical trial, G551D-CFTR patients showed a 10.6% increase in FEV1, a
secondary endpoint for lung function (A) and a mean 3 kg increase in
weight (B) after 48 weeks of treatment with ivacaftor. Reprinted with permission from New England of Medicine (7).
A recent phase 3, randomized, double-blind, placebocontrolled study demonstrated that ivacaftor significantly
improved predicted forced expiratory volume in 1 s (FEV1)
by 10.6 percentage points (P , 0.001) over a 48-week
period (7). Subjects also were 55% less likely to have a pulmonary exacerbation (P , 0.001) and gained more weight
(P , 0.001) than those receiving placebo alone (Fig. 3). Importantly, there was no difference in adverse events between
the two groups. Although each subject had at least one
G551D-CFTR mutation thereby limiting the potential
broader applicability of the study, it is indeed a leap forward
in treatment of CF. For the first time, a therapy that targets
the protein defect itself may become part of the armamentarium of the treating physician. A separate compound also discovered by Vertex Pharmaceuticals, VX-809 would appear
more suitable for the treatment of those harboring the more
frequent F508del-CFTR mutation. Although it has proven
safe in phase 2a trials assessing its use in isolation and in combination with ivacaftor, its effect on pulmonary function have
been mixed (17,34,35).
FUTURE DIRECTIONS
Ivacaftor has demonstrated the considerable benefits achievable with the development of precision therapies that target
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
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Table 1. Orphan drug therapies, costs and prevalence
Drug
Small molecules
KalydecoTM (ivacaftor)
Zavescaw (miglustat)
Remodulinw (treprostinil)
Flolanw (epoprostenol)
Biologics
Solirisw (eculizumab)
Elaprasew (idrsulfase)
Naglazymew (galsulfase)
Cinryzew
[C1 esterase inhibitor (human)]
Estimated
annual cost, $
Disease
Estimated prevalence
in the USA
294 000a
128 000c
120 000e
100 000e
Cystic fibrosis, G551D-CFTR
Gaucher disease type I
Pulmonary arterial hypertension
Pulmonary arterial hypertension
1200b
4000d
175 000f
175 000f
409 500g
375 000g
365 000g
350 000g
Paroxysmal nocturnal hemoglobinuria
Hunter syndrome
Maroteaux –Lamy syndrome (Mucopolysaccharidosis VI)
Hereditary angioedema
8000g
500g
50–300g
6200h
a
(44); b(44); c(45); d(45); e(46); f(47); g(5); h(48).
the very defect underlying the disease itself. Although this is a
major step forward in the treatment for one molecular form of
CF, it must be remembered that it remains a symptomatic
therapy rather than a cure. For the applicable 4 – 5% of the
CF population with the G551D-CFTR mutation, this clinical
benefit will come with a large price tag. The yearly cost per
patient receiving ivacaftor is approximately $294 000 (36).
A combination pill including VX-809, which could be prescribed to a much broader population of CF patients would
likely be similarly priced. With patients likely to receive
such therapies for 30 years or more, the cumulative lifetime
cost for a symptomatic therapy would be substantial. The
possibility of such treatments being initiated at even earlier
time points in the course of the disease could see this figure
continue to grow.
Ivacaftor and other such novel, high cost therapeutics have
appeared mainly because many pharmaceutical companies
have shied away from development of drugs targeting
common conditions due to increasing development costs and
decreasing likelihood of approval. Instead, many pharmaceutical companies have focused their efforts on orphan drug
development, targeting diseases affecting ,200 000 patients.
Although rare, an estimated 25 million Americans suffer
from any one of the 6000-plus rare diseases, a figure rising
to 30 m in Europe (37).
The Orphan Drug Act of 1983 was introduced to incentivize
the development of therapies for conditions that were classically ignored by pharmaceutical or biotech companies, as often
the relatively small sales revenues generated in comparison to
the development costs would be prohibitive. The benefits of
developing such ‘orphan drugs’ include tax credits for the
costs of research, annual grant funding to offset the cost of
qualified clinical testing expenses, assistance in clinical research study design and a waiver of the Prescription Drug
User Fee Act fillings fee of $1 m per application. More importantly, such drugs have a 7-year period of exclusive marketing post approval irrespective of the lifetime of the patent
(38,39). In the European Union (EU), this figure rises to 10
years in some instances (39). In addition to these benefits, it
usually takes ,5 years to go from phase 2 clinical trials to
market as opposed to 6 – 8 years for traditional drug approval.
From phase 2 trials onwards, orphan drugs also have a much
higher chance of approval, with an 82% success rate as
opposed to 35% for traditional drugs (40).
In opposition to the falloff in approval of drugs for common
conditions by the FDA, there has been an acceleration in the
rate of orphan drug approvals. 2008 was a record year, with
the FDA’s Office of Orphan Drug Development designating
165 products for orphan diseases. As of May 2009, the FDA
had designated 2002 drugs for orphan indications, 338 of
which have been granted marketing approval (41).
Ivacaftor is among a group of orphan drug therapies with
similar price points. Eculizimab, a treatment for paroxysmal
nocturnal hemoglobinuria, a condition affecting 8000
people in the USA, costs $409 500 per patient per year. Galsulfase, a treatment for Maroteaux– Lamy syndrome, which
affects an estimated 50– 300 people in the USA, costs
$365 000 per patient per year (5). As opposed to ivacaftor,
these drugs are biological therapies and account for 60%
of the orphan drug market (41). Although targeted at small
populations, biologics carry with them a potential incremental
cost structure. Many of these therapies target pediatric populations and the drug cost is weight based. As these children live
longer, the annual cost of therapy would be expected to
increase concordantly. The figure of $365 000 per year for galsulfase is calculated based on an average weight and accordingly, treatment of a child of ,5 years of age would be far
less expensive. However, if this same child were to reach 20
years of age, the annual cost could possibly be in the range
of $1 million per year (42).
The cost of biologics is usually a weight-based calculation;
the cost of production of a pill, however, is not. Several nonbiologic therapies have been approved for use by the FDA, but
in terms of cost, ivacaftor is by far and away the most costly to
date. Being an ‘orphan drug’ one expects an elevated price
point, but this particular compound is almost twice the cost
of other non-biologic ‘orphan drugs’ (Table 1). Although the
price point of such non-biologic therapies is estimated based
on the cost of development coupled with the smaller market
potential, two main points remain. First, many of these
begin as orphan drugs but are developed for more expanded
indications or off label use thereby increasing their potential
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Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
market size considerably. Secondly, one of the original barriers to entering the orphan drug market was the potentially
small return on such products, but with global orphan drug
sales reaching $84.9 billion in 2009; they are certainly beginning to generate ‘blockbuster’ size revenue streams (40).
EFFORTS TO REDUCE COSTS
A significant advantage of precision therapy trials is that clinically significant and statistical differences can be demonstrated using much smaller populations of subjects over
shorter periods; the phase 3 trial of ivacaftor included 161 subjects over only 48 weeks (7). It would appear that significant
drug development costs savings could be accrued from the
advantages of such scaled down trials. If current pricing of
orphan drugs was felt to be unsustainable, the prices of such
drugs might be controlled, as is the case in countries outside
of the USA. The addition of a ‘clawback’ provision that
exists in the EU version of the Orphan Drug Act may be
included in the US law; this provision permits a reduction in
the statutory exclusivity period if the orphan drug becomes
sufficiently profitable within the protected time (38). The
adoption of such strategies, however, may lead to pharmaceutical and biotech companies developing fewer therapies for
such devastating and, to date, often neglected diseases.
CONCLUSION
The approval of ivacaftor has signaled a new chapter in the
treatment of the underlying protein defect in CF. Although it
represents a major step forward in terms of disease management, it must be realized that it remains a symptomatic treatment option rather than a cure. Furthermore, this progress in a
DNA-guided treatment has been coupled with a heavy economic burden. This is representative of several other orphan
drugs in terms of the yearly costs. This trend begs the question
of what portends for new DNA-guided treatments, while on
the one hand representing scientific breakthroughs, but on
the other the potential of profoundly exacerbating an already
stressed health care economic landscape. Traditional therapies
have generally been associated with an acceptable threshold of
cost of $35 000– $50 000 per quality-adjusted life year (43).
Clearly, the new CF treatment and other orphan drugs cited
here are at a cost well beyond the previously accepted thresholds. Much more effort in formal assessment of cost and
benefit, along with health care policy, will be necessary. Furthermore, the potential for the life science industry for doing
everything possible to contain costs has certainly not been apparent to date. Perhaps, a new model will ultimately surface,
but until that time the benefit and cost realities seen to date
leave us with a sobering impression of an unacceptably expensive, yet precise form of medicine.
Conflict of Interest statement. E.J.T. and A.A. declares
no conflict of interest. P.B. has received unrestricted educational research grants from A Menarini Inc. and Daiichi
Sankyo Inc.
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