Therapeutic Focus – Cystic fibrosis market looking for breath of fresh air


With the thumbs up from an FDA advisory committee last week for Gilead’s aztreonam, the rather staid world of cystic fibrosis treatments could finally get a new therapy, to help in the battle in this hard to treat disease. The last approved drug in field was Novartis’ TOBI in 1998.

But as an analysis from EP Vantage shows, while aztreonam, also known as Cayston, will be a new treatment, it like the majority of drugs approved for use in the disorder helps to alleviate the symptoms of CF rather than modify the disease. As the table below shows many marketed drugs are either pancreatic enzymes that help keep patients’ weight up by aiding them to fight against illness, or like Cayston an antibiotic used to treat the lung infections associated with CF.

Marketed Cystic fibrosis (CF) products Annual Sales WW ($m)
Product Company Pharmacological Class Indication Summary 2008 2010 2012 2014 Launch WW
Creon Solvay Pancreatic enzyme product (PEP) Pancreatic insufficiency [Marketed]; Cystic fibrosis (CF) [Marketed] 319 411 528 637 31/12/1992
Pulmozyme Roche Expectorant Cystic fibrosis (CF) [Marketed] 459 525 562 590 07/01/1994
TOBI Novartis Aminoglycoside Cystic fibrosis (CF) [Marketed] 295 327 333 241 31/01/1998
Zenpep Eurand Pancreatic enzyme product (PEP) Pancreatic insufficiency [Marketed]; Cystic fibrosis (CF) [Marketed] - 81 141 181 30/09/2009
Ultrase Axcan Pharma Pancreatic enzyme product (PEP) Pancreatic insufficiency [Marketed]; Cystic fibrosis (CF) [Marketed] 59 82 100 117 -
Cayston Gilead Sciences Antibiotic Cystic fibrosis (CF) [Approved]; Bronchitis, chronic [Phase II] - 18 105 204 31/12/2009

One of the reasons why there has been a heavy focus on antibiotics is because one of the leading causes of decreasing lung function in CF patients is the lung infections that patients frequently get. Novartis’s TOBI is an inhaled antibiotic medication, which fights Pseudomonas aeruginosa infections and is the only drug approved in the US for this specific use.

If it is approved Cayston should be warmly welcomed because like many infections the bacteria develop resistance to antibiotics, and Cayston, which works against gram-negative bacteria, should provide doctors with an alternative and valuable treatment option. The drug, while not one of Gilead Sciences’ bigger products, is still forecast to have respectable sales of $268m by 2014.

The drug, however, has not been without its problems and in September 2008 received a complete response letter from the FDA (Surprise rejection of Gilead's Aztreonam leaves hole in new treatments for cystic fibrosis, September 17, 2008). In March, European regulators also declined to give it a positive recommendation claiming that there was insufficient evidence of either long-term benefits with repeated doses, the regulator also asked about the risk of bacterial resistance with long-term use (European rejection of Cayston opens door for others, March 20, 2009). It is now thought that additional trials will be required to get approval in Europe.

On the horizon

Of the products that could eventually have a real impact on the disease and modify symptoms, one of the most advanced is Vertex Pharmaceuticals’ VX-770. The drug which entered phase III trials in May is an ion transport modulator that facilitates transport of chloride ions across cell membranes by a different process from that which is defective in CF patients.

It is hoped that VX-770’s ability to activate chlorine transport should reduce the thickness of mucus in CF patients’ lungs and increase their ability to clear it in the lungs, pancreas and liver. Phase III results are expected in mid-2010 and will be watched closely (Vertex drug could breath life into cystic fibrosis market, April 1, 2008).

However, the drug is not at this point expected to be a blockbuster. It is only targeted at patients who have the G551D mutation in the gene that causes cystic fibrosis, a small group who only make up 5% of the people who suffer from the disorder.

Vertex also has another disease modifying drug in development, VX809, an oral cystic fibrosis transmembrane conductance regulator (CFTR) corrector drug which is in phase IIa studies.

Of the other drugs that could tackle the underlying causes of the disease is Genyzme’s Ataluren. The drug targets a genetic mutation, called a nonsense mutation, which prevents cells from generating full length proteins. In CF patients the nonsense mutation prematurely halts the synthesis of the CFTR protein, a chloride channel necessary for normal function of the lung, pancreas, liver, and other organs. Ataluren overrides this premature stop signal, allowing fully functioning proteins to be created.

A phase III trial in cystic fibrosis was started last September, to see if Ataluren can improve lung function. Considering that patients with CF caused by a nonsense mutation have a very severe form of the disease, even limited benefit could well be viewed as a success in this patient group.

The drug is also in a phase II trial in Duchenne muscular dystrophy, which can also be caused by a nonsense mutation (Therapeutic focus - Promising therapies emerging for muscular dystrophy, October 21, 2009). But like VX-770 the patient population is a subset of the wider CF population.

Inspire Pharmaceuticals last month announced completion of patient enrolment in its second phase III trial for its drug INS37217 Respiratory (denufosol tetrasodium). The drug works by treating the underlying ion channel defect in CF, increasing airway hydration and chloride secretion and inhibiting sodium absorption, as well upping the beat frequency of the ciliary in the lungs. Top line results from the 48 week Tiger-2 trial are expected in the first quarter of 2011 and could be the trigger for the group to sign up a non-US partner for the drug, which is forecast to have sales of $95m by 2014.

Sucampo Pharmaceuticals’ SPI-8811 also works on ion transport modulation, increasing the movement of chloride ions across cell membranes, reducing the thickness of mucus and allowing easier clearance from the lungs. The drug is currently in phase II trials, but there has been little news on its progress. SP-8811 is also not listed in, indicating that it could have been mothballed by the company.

So while the FDA panel’s recommendation for Cayston is a positive, it looks as if there is still a very long way to go until the majority of CF suffers have an effective treatment to combat the underlying cause of their disease.

Cystic fibrosis pipeline Annual Sales WW ($m)
Product Pharmacological Class Company 2010 2012 2014
Filed Bronchitol Respiratory agent Pharmaxis - 4 30
Phase III Tobramycin inhalation powder Aminoglycoside Novartis
VX-770 CFTR modulator Vertex Pharmaceuticals 12 27
Zithromax Macrolide Pfizer 362 299 252
INS37217 Respiratory P2Y2 receptor agonist Inspire Pharmaceuticals 68 166
Ataluren Transcription modulator Genzyme/PTC Therapeutics
Phase II Aerosolized AAT Alpha-1-antitrypsin Kamada/PARI Pharma
Arikace Aminoglycoside Transave/PARI Pharma
GS 9310/11 Antibiotic Gilead Sciences
KB001 Anti-Pseudomonas MAb KaloBios Pharmaceuticals
SPI-8811 Calcium channel activator (prostone) Sucampo Pharmaceuticals
VX-809 Cystic fibrosis agent Vertex Pharmaceuticals
VR496 Cystic fibrosis agent Vectura
Aerolytic Cystic fibrosis agent Aerovance
Anti-Pseudomonas IgY Cystic fibrosis agent IMMUNSYSTEM
Zavesca Glucosyltransferase inhibitor Actelion 50 53 30
Depelestat (DX-890) Neutrophil elastase inhibitor Debiopharm
Cipro Inhale Quinolone Bayer
Liposomal Ciprofloxacin Quinolone Tekmira Pharmaceuticals
Aeroquin Quinolone Mpex Pharmaceuticals

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