Cystic Fibrosis Foundation - Drug Development Pipeline

Drug Development Pipeline

The Cystic Fibrosis Foundation has built a dynamic "pipeline" for the development of more new potential CF therapies than ever before. To treat a complex disease like cystic fibrosis (CF), therapies must target problems in the airways and the digestive system.

In the cystic fibrosis drug development pipeline, there also are promising new therapies designed to rectify the cause of CF—a faulty gene and/or its faulty protein product.

Below is a "snapshot" of those potential CF therapies that are currently in development as of April 1, 2009.

	RESEARCH	PRE-	PHASE	PHASE	PHASE	TO
		CLINICAL	1	2	3	PATIENTS

Gene Therapy

CFTR Modulation

Restore Airway Surface Liquid

Cystic Fibrosis Foundation Drug Development Pipeline


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Clinical Trial Descriptions

GENE THERAPY

Because a faulty gene causes cystic fibrosis (CF), adding normal copies of the gene to cells could correct these cells and ultimately cure the disease. This approach is exploring ways to introduce normal copies of the gene into CF airways.

Compacted DNA (PLASmin™): Copernicus Therapeutics, supported by a CFFT TDA and the TDN. Using compacted DNA (non-viral) to introduce normal copies of the gene into CF airways. A Phase 1a trial demonstrated chloride current changes in the noses of CF patients, but no evidence of gene expression. The gene therapy product is being reformulated prior to additional clinical trials in an attempt to improve the amount and duration of gene expression.

CFTR MODULATION

These therapies are designed to correct the function of the defective CFTR protein made by the CF gene, allowing chloride and sodium (salt) to move properly in and out of cells lining the lungs and other organs.

Ataluren (formerly known as PTC124): PTC Therapeutics – A novel, small molecule compound, that promotes the read-through of premature truncation codons in the CFTR mRNA. It has been demonstrated to be safe, orally available and well tolerated in a Phase 1 single-dose trial in healthy volunteers. A Phase 2 trial in CF patients conducted in the United States and Israel demonstrated safety and encouraging biological results. A Phase 2b trial is scheduled to begin in Spring 2009.
VX-770: Vertex Pharmaceuticals, supported by CFFT. VX-770 is a "potentiator" that may act upon the CFTR protein and help to open the chloride channel in CF cells. Phase 1 dosing has been completed in healthy volunteers and CF patients. A Phase 2 trial in CF patients with at least one copy of the G551D mutation in their CF gene demonstrated improvements in biological measures of CFTR function (nasal potential difference and sweat chloride) and clinical measures of pulmonary health (FEV₁). Two Phase 3 studies (one for pediatric and one for adolescent/adult patients) are scheduled to begin in Spring 2009.
VX-809: Vertex Pharmaceuticals, supported by CFFT. VX-809 is a “corrector” that helps move defective CFTR protein to the proper place in the airway cell membrane and improve its function as a chloride channel. A Phase 2a trial is scheduled to begin in Spring 2009.

RESTORE AIRWAY SURFACE LIQUID

In cystic fibrosis, changes in salt transport within cells dehydrate mucus, causing it to become thick and sticky. This approach targets proteins other than CFTR to improve the movement of salt in and out of cells, allowing mucus to be more hydrated and, therefore, cleared more easily.

Hypertonic Saline: A CFFT-funded Phase 3 trial in Australia had beneficial effects on pulmonary health in CF patients. Follow-on studies are determining if younger patients would benefit from this inhaled therapy.
Denufosol: Inspire Pharmaceuticals, supported by a CFFT TDA and the TDN. Correct the ion transport defect in CF. In June 2008, Inspire announced top-line results from TIGER-1, its first Phase 3 trial with denufosol for CF. The trial demonstrated statistical significance for its primary endpoint of change in FEV₁ from baseline compared to placebo. Inspire is currently enrolling patients in TIGER-2, the second pivotal Phase 3 trial with denufosol.
Bronchitol: Pharmaxis – A Phase 3 trial of Bronchitol (an inhaled dry powder mannitol) has begun in the United States and in Canada. Theoretically, mannitol should help rehydrate CF secretions, improving airway clearance. Trials in Australia and Europe support this hypothesis.
SPI-8811: Sucampo Pharmaceuticals and the TDN. Oral agent believed to bypass transport defect of chloride ions. Initial Phase 2a trial evaluating safety and efficacy. Thirty patients recruited.
Moli 1901: Lantibio, supported by a CFFT TDA and the TDN. Thought to affect the ion transport defect in CF patients. Phase 1 trial demonstrated safety. Placebo-controlled, multi-dose, dose-ranging Phase 2 trial in Europe demonstrated positive changes in pulmonary function with highest dose.
Gilead GS9411: As a follow-on compound from Parion 552 that was used to demonstrate proof of concept, GS9411 has entered a Phase 1 CF clinical trial. It acts by blocking sodium absorption.

MUCUS ALTERATION

These studies are evaluating drugs for their effectiveness in preventing, thinning and clearing thick mucus from the airways.

Pulmozyme^®: Genentech, approved in 1993 and currently being used by more than 18,000 patients in the United States. Clinical trials were conducted in the CFF’s care center network.

ANTI-INFLAMMATORY

The drugs in this category are being studied for their ability to reduce inflammation in CF lungs, which should help decrease chronic damage to lung tissue.

Ibuprofen: A four-year CFF-supported high dose ibuprofen trial completed in 1990 demonstrated less lung function decline in the treatment group than the control group. This effect was greatest in 5-13 year-olds.
Oral N-acetylcysteine: BioAdvantex – An antioxidant, oral N-acetylcysteine replenishes glutathione levels in neutrophils. Placebo-controlled 12-week study at Stanford Univ. demonstrated decreases in inflammatory cells in lung and positive indications of changes in pulmonary function.
DHA: Univ. of Massachusetts, CFFT-supported as clinical research grant. Pilot study to examine effect of infant formula fortified with DHA on pathogenesis of CF in 120 newly diagnosed patients at 16 centers began in 2003.
Sildenafil (Revatio): Based upon prior work by researchers at the University of New Mexico, clinicians there are examining whether sildenafil can lower markers of airway inflammation and measures of airway infection in CF patients, as well as alter the patient's perception of their own well being.
Inhaled Glutathione: A Phase 1 trial of inhaled glutathione has been completed in Germany and a Phase 2b trial is now in progress.
Pioglitazone, Hydroxychloroquine: These approved therapies (approved for non-CF indications) are being evaluated in exploratory Phase 1 trials in CF to determine if they are tolerated and if anti-inflammatory effects are seen.
Simvastatin (Zocor™): A HMG-CoA reductase inhibitor that increases nitric oxide (NO) production in cultured CF epithelial cells. Investigators are evaluating, in a CFFT-funded trial, whether simvastatin increases exhaled NO production in CF patients, synthesis of pro-inflammatory cytokines and whether measures of inflammation in the upper respiratory tract correlate with those from the lower respiratory tract.
HE-3286: Hollis-Eden Pharmaceuticals, supported by a CFFT TDA. An oral immune-regulating hormone which has replaced HE2000.

ANTI-INFECTIVE

The compounds in this category are being evaluated for their effectiveness in fighting acute and chronic lung infections by destroying infection-causing bacteria that enter into the airways and colonize.

TOBI^®: Novartis Pharmaceuticals – This CFF/Children’s Hospital, Seattle-developed aerosol antibiotic was licensed to Chiron and received FDA approval in 1997. Currently being used by more than 15,000 patients worldwide. Benefit at first sign(s) of Pseudomonas infection is being evaluated.
Azithromycin: Pfizer – A large-scale, CFFT-conceived and supported, TDN-coordinated trial completed in 2002. In patients with chronic Pseudomonas aeruginosa, this oral antibiotic improved lung function and weight gain, and decreased hospitalization rate. Two follow up studies are in progress.
AZLI: Gilead Sciences, supported by a CFFT TDA and conducted in the TDN. Multiple Phase 3 trials of the aerosolized form of aztreonam, a widely used IV antibiotic in CF, have been completed and the FDA has reviewed all the data. Data from another clinical trial will be required but further discussions with the FDA are necessary to determine if ongoing trials will suffice.
TIP (TOBI Inhaled Powder): Novartis Pharmaceuticals is developing TOBI as a powder to enable a faster, more convenient dosing regimen. Dosing of TIP will take a fraction of the time of liquid TOBI. A Phase 3 trial has completed enrollment.
Arikace^TM: Transave – A liposomal formulation of the antibiotic amikacin. Animal model studies have shown it to decrease the Pseudomonas aeruginosa burden in the lung. A Phase 1/2 trial in Europe has completed enrollment. A Phase 2 trial began in the TDN in 2007.
BAY Q3939: Bayer Schering Pharma is developing an inhaled version of their antibiotic ciprofloxacin for treatment of airway infections. A small Phase 2 study in Germany is underway. A U.S. multicenter Phast 2 trial is currently enrolling patients.
MP-376: MP-376 is a new formulation of levofloxacin being developed by Mpex Pharmaceuticals for aerosol administration to CF patients for management of chronic pulmonary infections due to Pseudomonas aeruginosa and other bacteria. A U.S. multicenter Phase 2 trial is currently enrolling patients.
KB001: Kalobios Pharmaceuticals has initiated a Phase 1 clinical trial to test the safety of their antibody approach for treatment of Pseudomonas aeruginosa lung infections.
GS 9310/11: Gilead Sciences inhaled combination antibiotic (fosfomycin and tobramycin) has completed Phase 1 testing in Australia. A U.S. multicenter Phase 2 trial is currently enrolling patients.

TRANSPLANTATION

One potential drug is being evaluated for its ability to reduce the chance of organ rejection, which is common after transplantation.

Inhaled Cyclosporine: APT Pharmaceuticals – Inhaled formulation of cyclosporine was tested in a randomized placebo controlled trial at the Univ. of Pittsburgh. The group treated with inhaled cyclosporine showed a significant decrease in number of deaths and the development of chronic rejection. An additional clinical trial has been requested by the FDA before this drug is approved for clinical use.

NUTRITION

Specially formulated supplements in this category include vitamins, as well as enzymes that increase both fat and vitamin absorption, allowing better nutrition for people with CF, who can become malnourished as a result of thick mucus clogging the pancreas.

AquADEKs: Yasoo Health – Oral antioxidant vitamin formulation specifically for CF patients. A Phase 1 trial has been completed. A clinical trial to assess the safety and ability of this formulation to increase blood levels of antioxidants, normalize plasma levels of fat-soluble vitamins, improve pulmonary function and improve growth parameters began in 2007. AquADEKs is available to patients.
Pancrelipase Enzyme Products: The FDA has required pancreatic enzyme products to be reformulated and undergo clinical testing in order to receive FDA approval. Companies completing this process include: Axcan Scandipharm (Ultrase), DCI (PANCRECARB), Eurand (Zentase), McNeil (Pancrease MT) and Solvay (Creon).
Liprotomase (formerly Trizytek): Altus Pharmaceuticals, supported by a CFFT TDA, conducted in the TDN. Non-porcine pancreatic enzyme replacement. Phase 1 studies have not identified safety concerns. A Phase 2 trial has been completed, demonstrating safety and efficacy and a Phase 3 trial also has ended. Work to complete requirements for FDA submission is ongoing.

Updated 04/01/09