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in this sectionChina poised to enter global vaccine market p471

JAK inhibitors set to challenge biologics in RA p467

Cytokines

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First cystic fibrosis drug advances towards approvalThe first disease-modifying therapy for cys-tic fibrosis could reach the market next year, following the publication of highly promising data from two phase 3 trials in recent months. Although the drug in question, ivacaftor (VX-770), will address just a small percentage of the cystic fibrosis population initially, it marks the beginning of a new era of small-molecule drugs that could profoundly change the course of therapy for the vast majority of individuals with the disease (Table 1). “Addressing the disease upstream has the potential to impact things that we know about and perhaps even things that we do not know about,” says Preston Campbell, executive vice president for medical affairs of the Cystic Fibrosis Foundation (CFF). The majority of individuals with cystic fibrosis will have to wait several more years before disease-modifying drugs become available, however, as efforts to address the most common mutation in cystic fibrosis remain at an early stage.

Cystic fibrosis is possibly the most vis-ible reminder of the failure—so far at least —to convert advances in understanding the molecular underpinnings of genetic disease into clinically useful therapies. The condition is caused by mutations in a gene encoding a chloride-selective ATP-binding cassette trans-porter called cystic fibrosis transmembrane conductance regulator (CFTR). Defects in this CFTR protein affect the transport of chloride and other ions across the cell membrane, lead-ing to the accumulation of thick, sticky mucus in the lung, and giving rise to persistent lung infections. Other complications include malnu-trition and poor weight gain due to pancreatic insufficiency, electrolyte imbalances and male infertility due to blockage of the vas deferens. Diabetes, osteoporosis and liver disease are also associated with the condition.

CFTR was cloned and sequenced more than 20 years ago (Science 245, 1066–1073, 1989), but efforts arising out of this work, involving both drug- and gene-therapy–based approaches, failed to make much headway. Drug discovery attempts, based on a variety of CFTR chan-nel modulators or ‘potentiators’, including flavonoids, sulfonamides, phenylglycines and benzimidazolones, foundered due to poor potency or excessive toxicity (Pharmacol. Ther.

125, 219–229, 2010). Experimental gene thera-pies have been stymied repeatedly by a lack of suitable vectors and poor efficacy.

Currently available regimens for cystic fibro-sis simply manage symptoms. Antibiotics are used to fight lung infections; anti-inflammato-ries to prevent damage to lung tissue (although for safety reasons their use is limited); pancreatic enzymes to correct pancreatic insufficiency and improve nutritional status; and DNase enzymes to help reduce mucus viscosity. (Physical ther-apy, nutritional therapy and lung transplant remain important options as well.) Improved management of the condition over the past five decades has steadily increased life expectancy, but median survival is still an all-too-short 37 years. Respiratory failure due to lung disease is the most common cause of death.

Vertex Pharmaceuticals, of Cambridge, Massachusetts, was first into the clinic with an oral CFTR potentiator, ivacaftor, which acts by increasing the gating activity of an activated, though malfunctioning, CFTR channel. The company gained a platform to screen for com-pounds that modulate CFTR activity through its $592-million, stock-based acquisition of

San Diego–based Aurora Biosciences a decade ago (Nat. Biotechnol. 19, 496, 2001). Through that deal, it also inherited an alliance with the CFF, of Bethesda, Maryland, which has contin-ued to help fund the development of its cystic fibrosis pipeline.

Vertex now plans to file for approval for ivacaftor in the US and Europe during the sec-ond half of 2011. The drug, which is initially in development for patients carrying at least one copy of a CFTR mutation called G551D, successfully completed two phase 3 trials, STRIVE, which recruited 161 patients aged 12 and upward, and ENVISION, which recruited 52 patients aged 6–11 years. In each placebo-controlled study, the drug reached the primary endpoint of an absolute improvement in lung function from baseline, as measured by forced expiratory volume in one second (FEV1), after 24 weeks of treatment. In STRIVE, those in the drug treatment group had a mean improve-ment over baseline of 10.6% versus those in the placebo group. This effect was maintained at 48 weeks, when the mean improvement was 10.5%. In ENVISION, those in the drug treat-ment group had a mean 12.5% improvement

A two-year-old child is treated for cystic fibrosis at Via Christi Regional Medical Center-St. Francis Campus, in Wichita, Kansas. Improved management has steadily increased life expectancy for people with cystic fibrosis, but median survival is still 37 years.

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Drug discovery and the public purse p469

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466 volume 29 number 6 june 2011 nature biotechnology

over baseline versus those in the placebo group after 24 weeks. As Nature Biotechnology went to press, release of the 48-week data from that study was imminent.

“I think everyone involved in these stud-ies was optimistic, but I think they were very pleasantly surprised by the magnitude of the improvement in FEV1,” says Bruce Stanton, professor of microbiology and immunology at Dartmouth Medical School, in Hanover, New Hampshire. Lung function declines gradually in cystic fibrosis, at a rate of about 1–2% per year, he says.

“The improvement seen in lung function—a relative improvement of 16 to 17%, absolute improvement of 10.5%—really translates, at minimum, to five or more years [of survival],” says Campbell. But the real question, he adds, is what the impact will be on the rate of decline of lung function. “If you can just change it from 2% to 1%, you add decades to the lives of cystic fibrosis patients,” he says.

Ivacaftor also demonstrated improvements on several secondary endpoints, includ-ing reductions in pulmonary exacerbations requiring antibiotic treatment, improvements in weight gain and patient-reported outcomes. Whether these effects will convert into sus-tained improvements in mucociliary clearance and elimination of bacterial lung infection remains an open question for now. “Those are studies that need to be done much further down the road,” Stanton says. “It’s still possible these individuals may have to take antibiotics, for example.”

Ivacaftor will initially address about 4% of the 70,000 cystic fibrosis patients in the US and Europe who carry the G551D mutation—par-ticularly prevalent in Celtic populations. “We certainly believe that the other gating mutations will respond like G551D,” says Campbell. “That population may be as high as 15% or more.”

Vertex is also combining the drug with a CFTR ‘corrector’ named lumacaftor (VX-809), which improves the trafficking of misfolded proteins to the cell membrane. This drug addresses patients with the most common cystic fibrosis mutation, ΔF508, which occurs at a fre-quency of about 70% in the global cystic fibro-sis patient population (about 90% of patients have at least one ΔF508 allele and around half are homozygous for the mutation). A phase 2 combination trial—which also includes a lumacaftor monotherapy arm—is under way in homozygous individuals. This effort remains early stage, however. A final decision from the US Food and Drug Administration is “at least four years away or more before we see it being approved,” says Campbell. And one corrector may not be enough to bring CFTR trafficking beyond the desired threshold of about 50% of

stop codons (Nature 447, 87–91, 2007). “You’re increasing the frequency at which readthrough will occur,” Peltz says.

The antibiotic gentamicin also suppresses nonsense mutations, but pilot trials carried out a decade ago indicated that it was not suf-ficiently potent. Ataluren could, potentially, address over 2,400 genetic diseases, Peltz says, and the drug attracted a large partnership deal with Cambridge, Massachusetts–based Genzyme, now owned by Paris-based Sanofi. Its first new drug application, in Duchenne muscular dystrophy, is imminent. Data from the cystic fibrosis trial are expected in the first half of next year.

In all, over 500 cystic fibrosis–causing muta-tions have been identified, many of them extremely rare. The CFF is leading an initiative that has so far led to the creation of cell lines based on the 90 most common mutations, to enable their systematic evaluation. Although individually tailored therapies for each muta-tion would never be feasible, Campbell envis-ages a range of drugs, each of which will cater for a different constellation of mutations. “Cystic fibrosis will ultimately be a poster child for pharmacogenomics,” he predicts.

Cormac Sheridan, Dublin

normal. “To achieve that we may need to cor-rect that defect at two steps along the folding pathway,” says CFF’s Campbell. The CFF has recently invested $100 million—$75 million of which is earmarked for Vertex—to boost dis-covery and development of further corrector molecules.

PTC Therapeutics, of South Plainfield, New Jersey, is addressing a different cohort of indi-viduals with cystic fibrosis—those who harbor a nonsense mutation in their CFTR genes aris-ing from the presence of a premature, in-frame stop codon. These amount to around 10% of the total patient population, although in Israel, due to a founder effect, some 50% of patients have this type of mutation. The company, also a CFF partner, has completed enrollment onto a phase 3 clinical trial of ataluren (formerly PTC124), a small-molecule 1,2,4-oxadiazole that promotes selective readthrough of prema-ture codons during translation. “The cell has evolved a surveillance mechanism that discrim-inates between a normal termination codon and a premature termination codon,” says PTC founder and CEO Stuart Peltz. Ataluren, identi-fied by high-throughput screening, harnesses this process and appears to act by modulating translation termination efficiency at premature

“My goal as CEO is never to inaugurate a new research and development center.” Sanofi CEO Chris Viehbacher comments on the French pharma’s new strategy of co-investing in early-stage biotechs. (Boston Business Journal, 12 April 2011)

“it’s a concern for all our staff…There is no doubt it is difficult finding highly experienced people who do not have conflicts.” Center for Drug Evaluation and Research head Janet Woodcock comments on the difficulties stringent conflict rules present to FDA advisory committee recruitment. (Reuters, 9 May 2011)

“Look at the choice a venture capital fund has: to invest in the next social network that might go public in 12 months, versus a scientific idea where they might get the opportunity to take it to the FDA eight years from now, and then maybe get a letter where they have to do additional clinical trials on top of that.” Barclays’ Drew

Burch on why VCs are ditching biotech and trading on social networking instead. (Reuters, 5 April 2011)

in their words

Table 1 Disease-modifying cystic fibrosis drugs in developmentCompany Molecule Mechanism Status

PTC Therapeutics/Genzyme

Ataluren (3-[5-(2-fluorophenyl)- 1,2,4-oxadiazol-3-yl]benzoic acid)

Promotes selective readthrough of premature stop codons

Phase 3

Vertex

Ivacaftor (VX-770; N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide)

Improves CFTR-mediated ion transport

Phase 3

Lumacaftor (VX-809; (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid)

Increases trafficking of misfolded CFTR protein to cell membrane

Phase 2

VX-661 (undisclosed small molecule) For use in ΔF508 patients. Increases trafficking of misfolded CFTR protein to cell membrane

Phase 2a

aPhase 2 trial scheduled to begin in late 2011.

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