Cystic fibrosis:

Cystic Fibrosis  is a chronic,
debilitating genetic condition that
affects the respiratory and digestive
systems of approximately 70,000
people worldwide. Chronic respiratory
tract infection with P. aeruginosa
contributes to the decline in pulmonary
function, which is often associated with
morbidity and mortality among CF
Cystic fibrosis causes thick, sticky
mucus to build up and clog patients'
respiratory tracts, causing what can be
life-threatening infections. Persistent
coughing is a common symptom.

New drugs now in development also
are spreading hope that one day
they'll be able to correct the root cause
of cystic fibrosis -- flaws in the CF
genes inherited from each parent.
Four drugs targeting the fundamental
cause of CF made by Vertex
Pharmaceuticals, Pharmaxis,  and PTC
Therapeutics are in phase 3 clinical
trials. In total, there are 30 drugs in the
pipeline targeting various aspects of
the disease.

In January 2012 Vertex
Pharmaceuticals received a very early
U.S. approval for its cystic fibrosis drug

Kalydeco is the first and only drug to
repair an underlying genetic cause of
cystic fibrosis in people rather than
merely treating the symptoms of the
disease. Kalydeco, however, is only
effective in about 4% of the estimated
30,000 cystic fibrosis patients with a
specific protein mutation known as

The U.S. Food and Drug
Administration granted approval well
ahead of an expected decision on April

The company said Kalydeco will begin
shipping immediately at an annual
price of $294,000. Vertex can justify
charging such a high price for the drug
because it will be used to treat a very
small number of patients.

Approximately 2,400 cystic fibrosis
patients in the U.S and Europe carry
the G551D mutation. Approximately
400 of these patients are under the
age of 6 and cannot be treated with
Kalydeco today. About 40% of the
patients have government-run
insurance which mandates price
discounts ranging of around 20%, said

Kalydeco is already under review in
Europe with an approval decision
expected in the third quarter of 2012.

Kalydeco was approved based on data
from two phase III studies in which
cystic fibrosis patients with the G551D
mutation showed significant and
sustained improvements in lung
function after treatment.

Vertex is studying Kalydeco in
combination with another drug known
as VX809, hoping to demonstrate
similar improvements in lung function
in patients with more prevalent cystic
fibrosis mutations. Data from one such
study is expected mid-year.

In trials the drug showed an
improvement in forced expiratory
volume of 10.6% in those on the drug
through 24 weeks and 10.5% through
48 weeks.

It also showed improvement in other
measures, including weight gain, fewer
respiratory symptoms and reduction of
salt in sweat, a symptom of the
disease. Patients on the drug were
55% less likely to experience a
pulmonary exacerbation, or worsening
of the disease that requires antibiotics,
the company said.

In the Discover trial, which Vertex said
was designed to provide additional
safety data on the drug, 140 patients
were enrolled that had two copies of a
mutation called delta F508, a segment
that includes about half of U.S. cystic
fibrosis patients.

Kalydeco might face competition from
only one other drug – ataluren.
Ataluren, which is currently in late-
stage development, is being
developed by PTC Therapeutics Inc.
as a treatment for CF. PTC
Therapeutics is developing ataluren in
collaboration with Sanofi-Aventis.

University of Michigan scientists have
developed a fine droplet water/oil
emulsion, designed to be inhaled, that
seems to be capable of destroying all
sorts of pulmonary pathogens that
commonly occur in patients with cystic
fibrosis. Because the emulsion works
by disrupting the outer membranes of
bacteria, it is believed that bacterial
resistance to this potential therapy
cannot develop over time.

Nanoemulsions developed at Baker’s
institute consist of soybean oil, water,
alcohol and surfactants forced by high-
stress mechanical extrusion into
droplets less than 400 nanometers in
size. These emulsions have already
proved to be non-toxic, potent killers of
bacteria such as Streptococcus
pneumoniae, H. influenzae and
gonorrhea, of viruses such as herpes
simplex and influenza A, and of several
fungi. Nanoemulsion treatments for
cold sores and toenail fungus are in
Phase 3 clinical trials. They have a
product that looks like it could be
safely administered to the lungs of
people with cystic fibrosis.

The product has been licensed to
Nanobio Corporation.

Gilead Sciences  said its inhalable
antibiotic for cystic fibrosis beat a rival
drug in a head-to-head clinical trial.
The Gilead treatment, Cayston  
(aztreonam lysine), was compared with
Novartis' inhalable antibiotic,
tobramycin (Tobi), in 273 patients,
most of whom had already gotten three
cycles of the Novartis drug in the year
before they entered the study.
Researchers found that the Gilead
treatment offered an 8.35 percent
improvement on FEV1 scores, a
measurement of how forcefully patients
can blow air out of their lungs in one
Cayston was approved by the U.S.
Food and Drug Administration in
February 2010 and by the Australian
Therapeutic Goods Administration in
January 2010.

Lilly is buying Alnara Pharmaceuticals
in order to get a foothold in the
enzyme replacement therapy market.
The acquired firm’s lead product
liprotamase is an oral, nonporcine
pancreatic enzyme replacement
therapy (PERT), which is currently
under FDA review for the treatment of
exocrine pancreatic insufficiency.

Commented Bryce Carmine, executive
vp of Lilly and president of Lilly
BioMedicines:“Alnara has been very
successful in the development of
liprotamase, as indicated by its recent
submission to FDA, and we look
forward to partnering with Alnara’
experts during the regulatory review

Liprotamase comprises the digestive
enzymes lipase, protease, and
amylase, and is produced using
recombinant technology. It has been
formulated so patients need only take
1–2 small capsules per meal or snack.

The firm’s process development and
production partner for liprotamase is
Lonza, which has provided the
microbial fermentation, process
optimization, technical, and regulatory
support for generating the product.
Lonza is manufacturing Liprotamase at
its FDA-registered facility in the Czech

The development of liprotamase over
the last 12 months has been carried
out by Alnara in collaboration with
Cystic Fibrosis Foundation
Therapeutics, the nonprofit drug
discovery and development affiliate of
the Cystic Fibrosis Foundation. The
product was acquired by Alnara from
the Cystic Fibrosis Foundation  in
2009, which earlier the same year had
taken the product over from Altus

The clinical development program for
liprotamase included some 500
patients with exocrine pancreatic
insufficiency due to cystic fibrosis,
chronic pancreatitis or
pancreatectomy. Alnara claims the
Phase II and Phase III clinical trials
represent the largest body of
prospective clinical data for any
pancreatic enzyme.

In tests, the drug Zolinza, which was
developed to treat blood cell cancers,
reversed almost a third of the harm
done to cells by Cystic Fibrosis.
Zolinza (Vorinostat)  is manufactured
by Patheon, Inc., for Merck & Co.

Ataluren (formerly called PTC124) also
holds promise in treating more than
2,400 different genetic disorders
caused by socalled nonsense
mutations, among them Cystic Fibrosis.
It is made by PTC Therapeutics.

The three-month data from a Phase 2
study showed in July 2011 that
treatment of adults with nonsense
mutation cystic fibrosis (nmCF) with
PTC Therapeutics Inc.'s ataluren
resulted in improvements in chloride
channel activity, CF-related cough,
and positive trends in lung function.

Ataluren, a protein restoration therapy,
is designed to overcome the nonsense
mutation and enable the production of
a full-length, functional CFTR protein.
A genetic test can determine if a
patient's disease is caused by a
nonsense mutation.

"The results suggest that ataluren
promotes the production of full-length,
functional cystic fibrosis
transmembrane conductance regulator
(CFTR) protein and addresses the
underlying cause of the disorder,"
states Michael Wilschanski, director of
pediatric gastroenterology, Hadassah
University Hospital in Jerusalem.

In nmCF, an interruption in the genetic
code—known as a nonsense
mutation—prematurely halts the
synthesis of CFTR, causing the protein
to be short and non-functioning.
Nonsense mutations are categorized
as Class I mutations that result in little
or no production of the CFTR protein.
CF patients with Class I mutations
typically experience more severe
disease symptoms than those with
lower-risk genotypes, including a
greater than two-fold increased risk of
death, a higher probability of end-
stage lung disease, and a higher
prevalence of pancreatic insufficiency.