Abstract
Overall impression
The 24th North American Cystic Fibrosis (CF) Conference was held in Baltimore, Maryland. The meeting did not have the heightened level of excitement of the past couple of years, but there was an air of anticipation relating to the number of ongoing trials of new therapies. In addition, novel therapies are emerging rapidly and it is clear that CF teams will need to reflect carefully on how these fit into their management strategies.
DECLARATIONS
None declared
None
Not applicable
KWS
KWS is the sole contributor
The three plenary sessions are available on the CFF website:
Pipeline; airway surface modulation – A review by Eric Sorscher (University of Alabama) of the molecular defect in CF and how abnormality of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene impacts on pathophysiology. Potential therapeutic pathways were covered. The clear and illustrative animations in this talk make it a particularly useful teaching aid for those who are new to the field;
Animal models – An excellent summary by David Stoltz (University of Iowa) of the advances in understanding that have resulted from work on animal models, in particular the CF Pig (discussed below);
Transforming CF healthcare: Partnerships for life – Bruce Marshall (from the CF Foundation) and others discuss quality improvement initiatives, in particular in the context of recent changes in US Healthcare.
In preparing this review, I have considered: (1) work that has implications for my current practice; (2) innovations in care; (3) the progress of new therapies; and (4) work that increases our understanding of this condition.
Implications for current practice
Newborn screening (NBS) was the subject of a number of good presentations with new and established programmes presenting their results (abstract numbers [#] 472, 478, 481, 482, 483, 488, 489, 493, 494). 1 The expansion of NBS for CF has been impressive in both North America (NA) and Europe. The UK NBS protocol employs a fairly limited DNA panel, which is at odds with most reports at this conference. However, the downside of more extensive DNA testing is the recognition of CFTR gene changes with uncertain clinical relevance. In the US, these infants are being described as having CFTR-Related Metabolic Syndrome (CRMS) and there was quite a lot of discussion and concern about the long-term implications of this diagnosis. The other unique element of the UK protocol is the repeating of a second IRT measurement when only one CFTR mutation is recognized on the first sample. This reduces the number of infants referred for clinical assessment and sweat testing. It was apparent that the rates of referral for the UK protocol are less than other programmes, including those employing novel tests, such as Pancreatitis Associated Protein (PAP). In summary, there was no clear evidence from data presented that the UK protocol is performing less well than others, but we will need to assess this carefully over the next few years.
Separate European and North American guidelines on the management of CF infants following NBS were published this year.2,3 These guidelines were discussed and, despite being generated through different methodologies, it is reassuring that they resulted in a similar number of statements. On the whole the statements were consistent; however two areas of disparity were apparent:
Anti-staphylococcal prophylaxis – The NA guidelines clearly state that anti-staphylococcal prophylaxis is not recommended, which is at odds with the European guidelines. It was clear from this conference that isolation of Staphylococcus aureus (SA) from respiratory cultures is common in patients from the US (for example, 60% of children in the EPIC Pseudomonas eradication study had SA isolated at baseline). There is an urgent need for a large randomized clinical trial to answer the question as to whether anti-staphylococcal prophylaxis is safe and clinically efficacious;
Respiratory Syncytial Virus (RSV) Prophylaxis – The NA guidelines are equivocal about passive RSV immunization with palivizumab, which is not recommended by the European guidelines. Some good basic science demonstrating the impact of the CF defect on the airway's ability to expel RSV suggests that RSV infection may be an important early event in the establishment of CF lung disease (#147). In contrast a Cochrane systematic review (#313) could not find any evidence from clinical trials to demonstrate reduction in hospitalization or other evidence of benefit from passive immunization with palivizumab. Again this is an area that requires more investigation, as passive immunization is widely used in the US, less so in Europe.
Another sizeable problem in the US is colonization (infection) with Methicillin Resistant SA (MRSA). The extent of this problem possibly reflects high levels of MRSA in the US community (#317). Results of large epidemiological study, STAR-CF (#374), will help to increase knowledge of this pathogen and we look forward to STAR-TOO, an RCT (not yet funded), which plans to examine treatment for MRSA (treat or observe).
A concern was the report (#298) from the large clinic in Copenhagen of their patients infected with Achromobacter xylosoxidans (previously known as Alcaligenes). They have a significant number of patients with chronic Achromobacter infection and comparison with age matched cohorts with chronic Burkholderia infection suggests a similar rate of respiratory decline (faster than Pseudomonas aeruginosa). It is seems this resistant gram-negative bacteria requires more active treatment than many of us have appreciated.
Innovations in care
Both guidelines on the management of NBS infants recommend breastfeeding, however this recommendation is strengthened by the findings of the Wisconsin NBS study. Breastfeeding (even for less than a month) is associated with fewer Pseudomonas aeruginosa (PA) infections compared to formula-fed infants (#411);
A prospective seven-year study of physical activity (measured by the Habitual Activity Estimation Scale) demonstrated a slower decline in respiratory function in those children who undertook more activity (#451), even when other confounding variables are taken into account. Again these data provide us with more evidence to support our attempts to keep children with CF active;
The appropriate method for screening patients for glucose intolerance and CF-related diabetes (CFRD) is debated. The Adult team at the Brompton London developed revised criteria for CFRD screening and have validated this in a prospective study (#590). Such a strategy needs to be explored in paediatric practice;
A retrospective review of patients with pancreatic sufficiency suggested that low dose pancreatic enzyme replacement therapy improved weight gain and reduced abdominal symptoms (#557). This interesting finding warrants further examination in a clinical trial.
The progress of new therapies
Antibiotics
Aztreonam for inhalation (AZLI). Phase 3 studies are now completed comparing AZLI to Tobramycin Solution for Inhalation (TSI). The results suggest that AZLI has a positive impact on respiratory function and the respiratory component of the CF Quality of Life Measure (CF-QR), greater than TSI, although these results may reflect the fact that the majority of patients had been exposed to TSI before enrolment (#305). Hopefully this drug will soon be available for clinics pending licensing. AZLI will be licensed for prescription on a month on month off basis similar to TSI. It seems that this will be the regimen that US physicians advocate for suppressive PA therapy in CF. The significant improvements compared to TSI in this study may reflect the fact that the majority had been prescribed TSI prior to enrolment. Still the lack of improvement in FEV1 was notable and there may be an argument for rotating antibiotics when considering strategies for long-term PA suppressve therapy;
Liposomal amikacin (ArikaceTM). Phase 2 studies and an open label extension (predominately in Serbia) have demonstrated clinically relevant improvements in respiratory end-points (#227, 243). This is the first liposome packaged antibiotic to be delivered by aerosol and some concerns were raised in meetings about deposition in the lungs, although preliminary safety data suggest this is not a major issue. It is difficult at the moment to assess where this therapy will sit in the CF armamentarium, but the early results are promising, the once daily dosing schedule makes it attractive to patients and it will certainly have a role in the treatment of Mycobacterium abscessus;
Levofloxacin for inhalation (AeroquinTM). Again phase 2 studies for this antibiotic have demonstrated impressive results (155 patients, #232). This agent may have a role in more resistant infections, but some have wondered why develop an aerosolized version of a drug class that is well absorbed when taken orally;
Tobramycin inhalation powder (TIP). The EAGER study comparing TIP to TSI was presented at the conference (#235, 245). This study enrolled 517 patients and showed equivalence. Hopefully this preparation will soon be available for our patients, as the EAGER study clearly showed that this was the preferred intervention for patients;
Fosfomycin/Tobramycin for inhalation (FTI). A phase 2 US study enrolling 135 patients demonstrated positive results for this new combination (#233, 234, 334). Fosfomycin is a pyruvate analogue and the combination with Tobramycin is felt to be synergistic. Together they provide a broad spectrum of activity against gram negative (including PA), gram positive (including MRSA) and anaerobic bacteria. In the US population where SA and MRSA co-infection is common, this may be important;
Intravenous Gallium Nitrate (GaniteTM). Pseudomonas requires a good supply of iron to flourish. In this phase 1 safety study six patients were given intravenous Gallium in an attempt to mop up iron supplies (#273). On the whole the infusion was well tolerated (one patient had a headache) and good levels of Gallium were detected in airway secretions, but not in the blood;
Anti-pseudomonal IgY. The team in Uppsala, Sweden have been working on this for many years and it was good to learn that they now plan to move to a phase 3 study. IgY is extracted from the egg yolk of hens inoculated with PA. Patients will use the IgY solution as a gargle at night-time, with the aim of reducing PA infection of the airway. This will be a placebo-controlled multicentre RCT in Europe.
Non-antibiotic therapies
VX770 (#280). This is the most exciting of the compounds to come from high throughput screening (HTS), albeit limited in its action to patients with the G551D mutation. It was not surprising to learn that two large phase 3 studies of this compound (ENVISION and STRIVE) have completed recruitment and we anticipate results will be available next year;
VX809 (#224). This compound, recognized through HTS, corrects the trafficking defect associated with the ΔF508 mutation. The results of this phase 2 study demonstrated significant reduction in sweat chloride, but not to the extent seen with VX770. A planned study (DISCOVER) will explore a combination of VX809 (to correct the ΔF508 defect) and VX770 (to potentiate the function of that protein once it reaches the cell membrane). As ΔF508 accounts for most cases of CF, if this combination strategy works, these orally available drugs will have a profound impact on CF care;
Denufosol (#253, 254, 256). This agent is delivered topically to the lungs and stimulates chloride transport through non-CFTR pathways. Phase 2 and early phase 3 trials were selectively presented (subgroup analysis). It seems that benefits in respiratory outcomes are not considerable (particularly when compared to the (1) antibiotic studies described above), however an appealing aspect of this agent is the safety profile, which appears excellent (including some very high dose animal studies presented here). Consideration may be given to early intervention studies in this case;
Mannitol (BronchitolTM). The results of two phase 3 studies were presented (NA study, #225 and the open label arm of the European study, #286). Combined data from these similar studies provides some good evidence of benefit in respiratory function and one anticipates that this agent will be available for clinical use soon. The delivery of this dry powder at the dose of 400 mg twice a day, requires 20 capsules to be taken. It will be interesting to see how our patients take to this new therapy. Pending licensing issues, this compound should be available in the next year;
AtalurenTM (#266). This compound (PTC-124) was also discovered through HTS and causes read-through of stop-codon mutations (such as G542X), potentially correcting that molecular defect. Phase 2 studies suggested adequate effi-cacytomove to aphase 3 study. Recruitment for that study will be complete before the end of 2010 and results presented next year.
Do we understand CF better?
The main highlight of this conference was the progress with the CF pig from the team in Iowa. This animal model, generated through targeted gene manipulation using cloning technology (first used on Dolly the sheep), will be extremely valuable in increasing our understanding of CF and testing new therapies. To date, the pigs born with CF have not survived longer than a few days because of severe bowel obstruction (analogous to meconium ileus). In some animals, surgical correction has prolonged survival, enabling study of lung disease. The University of Iowa team are now working towards producing a CF pig model that expresses CFTR in the gut. A similar selective transgenic mouse was produced that enabled better survival, facilitating study of the airway pathology. The group hope this pig will be available in the New Year.
In the meantime, the poor survival of the CF pig has focused research on early events with some interesting findings summarized below:
The CF pig trachea has abnormal anatomy at birth with dysplastic smooth muscle and cartilage rings. Similar findings have now been found in infants with CF (#142);
The male CF pig has absence of the vas deferens from birth (#203);
The CF pig does not have evidence of airway inflammation before infection (#204). Subsequent infection is with characteristic CF pathogens (but also Bordetella Bronchiseptica, a common airway pathogen in animals (kennel cough), also reported in patients with CF);
CF pigs have reduced IGF-1 levels in the brain at birth suggesting a fundamental CFTR-related problem with growth (#593). Similar studies in mice found correction of this defect when CFTR was selectively expressed in the brain.
Finally it was good to hear results from CFTR-II, the project established in Baltimore to better define phenotypes of unclear mutations. Physicians are encouraged to submit genotype data and clinical details of patients with atypical presentation. The team then manufacture these mutations in cell lines, in which they can measure CFTR-mediated chloride transport. Early results from these studies suggest a relationship with sweat chloride that can be modelled (#182). These results will enable us to better understand unusual CF genotypes and provide clearer information for families. As NBS results in the recognition of such infants this will be an important advance.
In summary, the 24th NACFC provided much food for thought. It is clear that new therapies are being evaluated at a pace that many of us did not feel possible and it is a credit to all involved that so much has been achieved so quickly. CF teams will need to reflect carefully on the implications for their practice.
Footnotes
Acknowledgements
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