New Therapies Begin To Fill CF Pipeline

BY BRUCE JANCIN
Elsevier Global Medical News

SAN DIEGO — The drug development pipeline for cystic fibrosis is chock full of promising agents that address a wide range of key aspects of the disease.

A few of these products have already been approved in the European Union and Canada, and are now under review by the Food and Drug Administration. Others are in phase III trials, Dr. Paula J. Anderson, FCCP, said at the annual meeting of the American College of Chest Physicians.

“It’s really a very exciting time to be a researcher in the area of cystic fibrosis. These new treatments will contribute to the life expectancy in cystic fibrosis and may have applications in other diseases, like non-CF bronchiectasis and perhaps other genetic diseases,” noted Dr. Anderson, professor of medicine and director of the adult cystic fibrosis program at the University of Arkansas, Little Rock.

Here are some of the most promising of the emerging therapies:

Modifiers of the CF transmembrane conductance regulator (CFTR). These agents constitute the most exciting advance in CF in 15 years, in Dr. Anderson’s view, because they address the central underlying disease deficit. The CFTR is essentially a chloride channel sitting in the membrane of cells in the airway, gastrointestinal tract, and sweat glands. Defects in the CFTR result in distorted chloride and sodium flux, with resultant thick, viscous, dysfunctional secretions.

Ataluren (PTC Therapeutics Inc.) overcomes class I nonsense step mutations in the CFTR gene so the CFTR protein can be properly translated and delivered to the airway epithelium. Phase II studies showed that ataluren, which is an oral agent, resulted in improvement in sweat chloride and nasal potential difference. It is now in a definitive, 48-week, phase III clinical trial whose primary end point is change in forced expiratory volume in 1 second (FEV₁). Only about 10% of CF patients have the type of class I mutation for which ataluren will be effective, but in these patients, it is likely to bring major benefits.

VX-809 (Vertex Pharmaceuticals Inc.) is a CFTR corrector that works on class II mutations, such as F408del. “This is huge, because we have so many patients with that mutation,” Dr. Anderson observed. VX-809 allows the CFTR protein to be released from the endoplasmic reticulum and move to the apical membrane. It is now in phase II studies.

VX-770 (Vertex) is a CFTR potentiator rather than a corrector. It opens chloride channels and overcomes class III mutations. The drug is now in phase III clinical trials. In a phase II study, it resulted in improved sweat chloride and FEV₁ in patients with the relatively uncommon G551D mutation.

Airway surface liquid enhancers. Denufosol (Inspire Pharmaceuticals Inc.) is the agent furthest along in this category. It improves viscous airway liquids by working through the P2Y receptor to increase chloride secretion. In phase II studies, denufosol improved FEV₁. The drug, which is inhaled three times daily, is now nearing completion of phase III trials.

Osmotic therapy. This type of treatment is designed to improve mucociliary clearance and decrease CF exacerbations. Hypertonic saline aerosol 7% is an agent approved for this purpose that is already widely used in adults and older children; first-ever trials in infants are ongoing.

Inhaled mannitol (Bronchitol, Pharmaxis Ltd.) is a novel, inhaled dry powder. This medication is in phase III CF trials, and also is under study for the treatment of non-CF bronchiectasis.

Anti-inflammatory agents. These drugs are the holy grail of CF therapy, according to Dr. Anderson. The inflammation of CF is neutrophilic and has a large number of mediators.

Numerous agents are in phase I and II studies, including simvastatin, inhaled glutathione, pioglitazone, sildenafil, oral N-acetylcysteine, docosahexaenoic acid, too early to tell whether any of them will be beneficial.

“Right now, high-dose ibuprofen is the only recommended therapy, and it’s not in widespread use, mainly because of toxicities and dosing issues,” Dr. Anderson said.

The median life expectancy of patients with CF now stands at 37 years. Audience member Dr. Daniel Schidlow, professor of pediatrics at Drexel University, Philadelphia, predicted that “a really good anti-inflammatory drug for CF would probably prolong our patients” lives by another 20 years.

“That’s the silver bullet in 2010: a corticosteroid-like drug in its efficacy, but without the side effects,“ added Dr. Schidlow, who is also physician-in-chief at St. Christopher’s Hospital for Children, Philadelphia.

Inhaled antimicrobials. Here the pipeline is particularly plentiful. And that’s good news, as at present the sole approved agent for use in CF in the United States is inhaled tobramycin solution (TOBI).

Inhaled aztreonam lysine (Cayston, Gilead Sciences Inc.) is probably closest to hitting the U.S. market. It is already approved in the EU and Canada, and is now under review at the FDA. In published studies, Cayston improved FEV₁, bacterial density, and quality of life scores. It is administered three times daily.

Colistimethate sodium (Colobreathe, Forest Laboratories Inc.) is under review in the EU, having completed phase III trials. Tobramycin inhaled powder (Novartis) is a once- or twice-daily drug that has also completed phase III trials.

Liposomal amikacin (Arikace, Transave Inc.) has completed phase II studies. Its once-daily dosing is a strong plus. This agent appears to penetrate biofilms, which would be a boon in pseudomonal infections. Inhaled levofloxacin (Aeroquin, Mpex Pharmaceuticals Inc.) also has finished phase II testing.

Inhaled fosfomycin/tobramycin (Gilead) is a twice-daily agent with broad-spectrum coverage that is in ongoing phase II studies. Ciprofloxacin also is undergoing phase II trials.

Many of the investigational agents are delivered by the novel eFlow nebulizer (PARI Pharma GmbH), a batterypowered, portable device that can give a dose of medication in about 3 minutes.

“I’m hoping that in the future we won’t have to throw IV antibiotics in a nebulizer and use them [off label] without any advanced testing of the effects in the lungs or dosing,“ Dr. Anderson said.

Gene therapy. It’s not dead, but it has proved much more difficult than imagined. Indeed, the only clinical trial of gene therapy for CF going on anywhere is a 3-year, 100-patient U.K. study that is testing the viability of a plasmid DNA formulation.

There is a sense within much of the research community that modulation of the CFTR mght be a more effective way of addressing the underlying disease defect than is gene transfer, Dr. Anderson said. Agents such as ataluren and VX-809 are among the earliest viable examples of pharmacogenetics, in which specific drugs are designed to address different types of mutations.

It’s worth noting, however, that nearly 1,500 mutations have been identified so far in the CF gene since it was first described in 1989.

Dr. Anderson disclosed that she serves on the advisory board of Bayer Healthcare Pharmaceuticals and has received grants to conduct research on behalf of Bayer, Gilead Sciences Inc., Inspire Pharmaceuticals Inc., and the Cystic Fibrosis Foundation.

Dr. Philip Marcus, MPH, FCCP, comments: Cystic fibrosis, an illness well understood mechanistically, has remained difficult to treat. We have been able to extend the life of those with the disease into early adulthood, primarily by the use of better antibiotics and mucus clearing agents. This report shows that there is greater hope for the future. Of course, agents developed for use in the CF population will extend into other populations and increase the profitability for drug development.