(Laurie Barclay, MD, September 2004)

Cystic fibrosis (CF) is a chronic, progressive, and often fatal genetic disease affecting the mucus glands in the respiratory and digestive systems, as well as the sweat glands and the reproductive system.

According to the CF Foundation, CF affects approximately 30,000 Americans, with about 1,000 new cases of CF diagnosed each year. It occurs in one of every 3,900 total live births or one of every 3,200 live Caucasian births, with diagnosis by age three in more than 80% of patients. However, nearly 10% of newly diagnosed cases are age 18 or older. Although CF affects all races and ethnic groups, it is most common in whites of northern European ancestry.

More than 10 million Americans, or about 1 in every 20, are asymptomatic carriers of a defective, autosomal recessive CF gene. This gene leads to production of abnormally thick, sticky secretions that clog the airways, causing life-threatening respiratory infections; and obstruct pancreatic flow, preventing digestive enzymes from reaching the intestines to help break down and absorb food.

Because there are more than 1,000 mutations of the CF gene, symptoms vary among affected individuals. These may include sweat high in salt content, persistent and productive cough, wheezing or shortness of breath, increased appetite but poor weight gain and malnutrition, and greasy, bulky stools. Loss of excessive amounts of salt in the sweat can cause electrolyte imbalance and cardiac arrhythmias or shock. Other medical problems may include sinusitis, nasal polyps, pneumothorax, hemoptysis, cor pulmonale, abdominal pain and discomfort, intestinal gas, rectal prolapse, liver disease, pancreatitis, and gallstones.

CF was once always fatal in childhood, with lung disease the usual cause of death. Thanks to advances in treatment over the past two decades, median survival is now 33.4 years, and nearly 40% of the CF population is age 18 and older. Adults with the disease may develop CF-related diabetes, osteoporosis, and sterility in men or premature labor or stillbirth in women.

Diagnosis is typically made with the sweat test, which confirms a high salt level, or with the immunoreactive trypsinogen test in newborns. Other useful tests may include genetic analysis, chest x-rays, pulmonary function tests, sputum cultures, and stool examinations.

Treatment varies with the stage of the disease and with the affected organs, but usually includes vigorous daily chest physical therapy and exercise to clear mucus from the lungs, and a well-balanced, high-calorie diet low in fat and high in protein. Supplemental pancreatic enzymes and vitamins A, D, E, and K are often helpful. However, high doses of pancreatic enzyme supplements were recently shown to be associated with development of colonic strictures in a few patients. Lung medications used to improve breathing, such as bronchodilators, mucolytics, and decongestants, are often inhaled in an aerosolized solution.

Recent advances approved by the Food and Drug Administration (FDA) include aerosolized tobramycin solution to treat lung infections; Pulmozyme, a mucus-thinning drug to reduce respiratory infections and improve lung function; azithromycin, an antibiotic effective against chronic pulmonary infection with Pseudomonas aeruginosa; and ciprofloxacin, an oral anti-Pseudomonas antibiotic. A small, hand-held "flutter" device helps clear the airways and loosen mucus without conventional chest therapy. To reduce mucus stickiness, a naturally occurring enzyme called DNAse cuts long DNA molecules released from dead white blood cells into shorter fragments.

Although gene therapy for CF is not yet feasible, ongoing research may hold promise for the future. The CF gene, which was identified in 1989, produces a transmembrane conductance regulator (CFTR) protein regulating movement of chloride ions through cell membranes in the lungs, pancreas, colon, and genitourinary tract. Depending on the specific CFTR mutation, the manifestations and severity of CF may vary, as well as the approach to treatment.

In the laboratory, investigators have been able to use a virus or liposome as a vector to carry the normal gene into cells cultured from the nasal passages of patients with CF, thereby correcting the abnormality in chloride transport. Giving CF patients the normal gene in nose drops using an adenovirus vector has reversed the chloride defect in small regions in the nasal passages themselves. Unanswered questions about gene therapy include optimal packaging of the normal gene, delivery into the lungs and other target organs, adverse effects such as inflammation, and long-term results.

CenterWatch has identified a pipeline of 17 drugs in various phases of development for CF, including antimicrobials, agents decreasing mucus stickiness, drugs targeting the abnormal chloride transport protein, and gene therapy.

Inspire Pharmaceuticals has completed Phase II development of INS 37217 Respiratory, a second-generation P2Y (2) agonist administered by standard jet nebulizer. In a double-blind, randomized comparison trial in 90 patients with CF at 14 clinical centers in the U.S, INS37217 Respiratory given three times daily for 28 days was well-tolerated and had a statistically significant benefit in lung function compared with placebo (P = .006 for FEV1; P = .007 for FEF25-75%; and P = .022 for FVC). The improvement in FEF25-75% may be most significant because decline in small airway function, as reflected in FEF25-75%, is the earliest manifestation of CF-related lung disease.

All three doses of INS37217 Respiratory, up to 60mg, were well-tolerated, and 93% of enrolled patients completed the study. Cough was the most common adverse event, affecting 46% of subjects overall without significant differences between groups, including placebo. Inspire plans to develop INS37217 Respiratory as an early intervention therapy, and has received Orphan Drug Status and Fast Track designations from the FDA for use of this product in CF.

Targeted Genetics is in Phase IIb development of a CF gene therapy product known as tgAAV-CF, which uses an adeno-associated virus (AAV) vector to deliver a copy of the CFTR gene to affected cells. This is the world's first clinically studied application of AAV gene delivery technology, according to Targeted Genetics. In several clinical trials, tgAAVCF was delivered to target cells in the nasal sinuses, persisted for up to 90 days following a single administration, and was associated with a decrease in the inflammatory protein IL-8 and an increase in a physiologic measurement of chloride channel function.

In adults with mild to moderate CF lung disease, an aerosol formulation of tgAAVCF was widely distributed throughout the lung, based on a Phase I dose-escalation study. The product was well-tolerated, with a good safety profile, gene transfer at all doses evaluated, and at the highest dose, persistence of the vector for up to 90 days. In a Phase II, double-blind, repeat dosing study, 36 individuals received drug or placebo and were evaluated with lung function tests, high-resolution imaging, and analysis of sputum samples for levels of cytokines and pathogenic bacteria.

Based on review by an independent data and safety monitoring committee, age of enrollment in the study was lowered from 18 years of age to 15 and then to 12 years of age. The hope is that tgAAVCF may be more effective long-term if given before extensive lung damage develops. Adverse events and laboratory parameters have been similar for placebo- and tgAAVCF-treated patients. Overall lung function as measured by FEV1 was evaluated at days 30, 60 and 90, and it was improved at day 30 for tgAAVCF versus placebo (P = .04). After 14 days, levels of IL-8, an inflammatory cytokine, were lower in tgAAVCF-treated patients than in the placebo group. All patients tested showed excellent gene transfer measured by DNA-PCR on cells obtained during bronchoscopy. AAV-neutralizing antibody response occurred both systemically and locally.

In July of 2003, Targeted Genetics and the CF Foundation began a Phase IIb, multicenter, double-blind, placebo-controlled clinical trial of tgAAVCF in 100 patients 12 years of age and older with mild to moderate CF. Based on scheduled interim analysis in June 2004, an independent data monitoring committee recommended continuation of the study as planned.

Corus 1020, an aztreonam antibiotic reformulated for inhalation, is in Phase II development by Corus Pharma. This antibiotic has a broad spectrum of activity, including Pseudomonas aeruginosa, but it is currently FDA approved only for intravenous use. In March 2002, the FDA granted orphan drug status to Corus 1020. For faster delivery of Corus 1020, Corus has collaborated with PARI GmbH for use of the eFlow technology. Delivery time with eFlow is 3-4 minutes, compared with 15-20 minutes per dose for current jet nebulizers.

After Phase I studies in CF showed that Corus 1020 was well-tolerated without serious adverse effects, 138 patients were enrolled in a U.S. multicenter Phase II study, with the support of the CF Foundation Therapeutics Development Network. This randomized, blinded, placebo-controlled study is designed to evaluate efficacy, safety and tolerability.

Genaera is in Phase II development of Lomucin (talniflumate, MSI-1995), a orally administered mucoregulator that blocks hCLCA1-dependent overproduction of mucus by cells in the respiratory epithelium. In a Phase IV trial in chronic asthma, this drug was well tolerated with no serious adverse events. A Phase II clinical trial in 60 patients with CF is a double-blind, placebo- controlled, randomized study of preliminary safety and efficacy.

Actimmune, or interferon gamma-1b, is an immune system stimulant in Phase II testing by InterMune, which is already marketing this drug in the U.S. for chronic granulomatous disease (CGD) and severe, malignant osteopetrosis. By stimulating macrophages, interferon gamma-1b enhances killing and removal of infectious organisms including bacteria and fungi. This drug may also help regulate fibroblast activity and thereby prevent excessive scarring.

Molichem Medicines is in Phase II testing of MOLI 1901/duramycin, and it has obtained Orphan Drug Designation in Europe for CF treatment. By binding to cellular membranes and causing elevations in intracellular calcium, this drug targets the specific, functional abnormality caused by the CF mutation, in hopes of restoring normal lung cleansing mechanisms and preventing premature death.

Another ion transport modulator is SPI-8811, in Phase II testing by Sucampo Pharmaceuticals in collaboration with the CF Foundation. This drug activates the ClC-2 chloride channel, which is different from the CFTR channel. In theory, this alternate means to transport chloride ions across cell membranes could help bypass the basic defect of CF and render the mucus more watery and less sticky, and the destructive symptoms of CF could be prevented.

Alphagen is a form of gene therapy in Phase I development by - geneRx+/Aradigm. This alpha-1-antitrypsin (AAT) gene is contained in a plasmid vector formulated with a cationic lipid, designed to be administered via inhalation of aerosolized product. Although Alphagen was created to treat AAT deficiency and chronic obstructive pulmonary disease caused by relative local deficiency of AAT in the lungs, it could theoretically also be useful in CF. It has been shown to be safe and effective in animals, and AAT-deficient patients given this formulation express the AAT gene in respiratory epithelium for at least one week and have evidence of reduced inflammation. A nasal instillation study is underway in patients with CF.

TOBI, or tobramycin, is a broad spectrum aminoglycoside antibiotic which is FDA-approved. Chiron is now in Phase I testing of a new aerosol formulation shown to significantly reduce Pseudomonas infections in patients with CF. Because the inhaled drug directly reaches the infected lung tissue, this formulation reduces the required dose and the potential for toxicity, and it is also easier and less expensive to administer than intravenous injection.

Demegen has obtained pre-investigational new drug status and Orphan Drug designation for P113D, a novel, synthetic antimicrobial peptide derived from histatins found in human saliva. This drug is designed for delivery via inhalation to treat and prevent lung infections in CF patients, and it has demonstrated a high level of in vitro activity against P. aeruginosa and a variety of other Gram-negative and -positive bacteria, including drug-resistant patient isolates. P113D binds to the cell surface and increases the permeability of both the outer and inner membranes of Gram-negative bacteria, killing them within seconds. Because of its unique mechanism of action, it should not increase drug resistance to typical antibiotics. Toxicology and clinical testing suggests that P113D is safe and well tolerated.

Great strides have been made in the past two decades in improving survival and quality of life in CF, and the future appear to hold even greater promise. Identifying the genetic defect responsible for CF has opened new avenues to reduce the debilitating effects of CF, prolong lives, and even to find a cure for this deadly disease. Knowledge of the molecular processes involved in CF has allowed development of new treatments already in the pipeline. Although research on gene therapy for CF is still in its infancy, this approach may ultimately offer the best hope of curing CF rather than merely alleviating its symptoms.