Gene Therapy Appeal

Research updates

Atypical Cystic Fibrosis

Clinical care

ISSN 1476-3710S E P – D E C 2 0 1 1

TO DAY

The primary purpose of CF Today is toprovide for its readers a reliable source ofmedical, research and other informationrelevant to Cystic Fibrosis and to play asupportive role for CF families. Opinionsexpressed in articles do not necessarilyexpress the official policy of the CysticFibrosis Trust. The editor reserves the rightto edit and otherwise alter articles or letterssubmitted to the magazine for publication.

Some pictures used in this publication maybe posed by models or taken from libraryimages.

Medical information included in this publication isnot intended to replace any advice you may receivefrom your doctor or CF multidisciplinary team andit is important that you seek medical advicewhenever considering a change of treatment regimen.

Cystic Fibrosis Trust11 London Road, Bromley, Kent BR1 1BY.Tel: 020 8464 7211 Fax: 020 8313 0472www.cftrust.org.uk

CF Today is designed and published by theCystic Fibrosis Trust registered as a charityin England and Wales (1079049) and inScotland (SC040196). A company limited byguarantee registered in England and Walesnumber 3880213. Registered office 11London Road, Bromley, Kent BR1 1BY.

Editor: Jacqueline Ali

All communications should be sent toEditor, CF Today, Cystic Fibrosis Trust, 11 London Road, Bromley, Kent BR1 1BYor email cftoday@cftrust.org.uk

©Cystic Fibrosis Trust 2011ISSN 1476-3710

Cover photo: Patient demonstratingnebulisation of gene therapy product, RoyalBrompton Hospital, LondonPhotographer: Keith Gilbert

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ContentsNews 4

Gene Therapy Appeal 6

Ask the expert 8

Research updates 10

Atypical Cystic Fibrosis 12

Clinical care 14

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Edito

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Welcome to this autumn edition of CF Today.

Thank you for all you did to make CF Week sosuccessful in May this year. We were delighted withall the new activity, generating much-needed fundsand raising the profile and public understanding ofCystic Fibrosis.

In this edition you will find updates on our campaignto protect frontline CF services from cuts, anddevelopments in the treatment of CF with smallmolecule drugs. These and other developments arevery important for our vision of significantly longerlife expectancy and better quality of life for peopleliving with CF today and their families.

You will also find an update on progress towards theworld’s first major clinical trial for a potential genetherapy treatment in the lungs of people living withCystic Fibrosis. You will be aware that it was over tenyears ago that the Cystic Fibrosis Trust first broughttogether the leading UK CF gene therapy researchersto form the Gene Therapy Consortium (GTC) andexplore whether gene therapy could be a significantnew treatment in Cystic Fibrosis.

Over the past ten years the team has developed andrefined the gene therapy product, conductedtoxicology studies, completed single dose pilotstudies in some patients, and refined the dosage forthe full clinical trial. The science, the patients, the trialprotocol and the team are all now in place for thisphase 2 clinical trial.

The work to date has cost substantially more thanwas first envisaged and at the time of writing we stilldo not have anything like the full £6million poundsrequired to undertake this clinical study. To me thisfeels like mile 24 of the London Marathon; we havecome so far, but until we get to the finish line wehaven’t achieved what we initially set out to do.

The CF Trust and itssupporters are thereforecurrently engaged in aHerculean effort to raise thefull £6million pounds thatthe GTC needs before theend of this year. Without thefunds in place this trial cannotproceed and without the trialwe will not know the answerto the question posed adecade ago, namely whether gene therapy can be asignificant treatment in Cystic Fibrosis.

Beyond this phase 2 trial there will still need to be aphase 3 trial, the costs of which could well be greaterthan the entire £30million already invested in thiswork, and therefore well beyond the CF Trust’scapacity to fund. The GTC is therefore working tofind a pharmaceutical company to take the genetherapy product into the next stages of testing.

None of that will be possible though without thephase 2 clinical trial happening. Thank you for thehuge amount that you are doing to get the trialfunded and for your generosity. Even at this late stageplease do let us know of contacts or organisationsthat could help with this enormous challenge.

Thank you for all you are doing in so many differentways to support the Trust’s critical work. And kindregards from us all.

Matthew ReedChief Executive

C F T O DAY • S E P – D E C 2 0 1 1 3

Matthew Reed

“A Herculean effort is underwayto raise the £6million needed for the

gene therapy trial.”

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Cystic Fibrosis Trust Chairman Dr Jim Littlewood hasrecently added the latest chapter to his online history ofCystic Fibrosis. This extensive work details the historyof Cystic Fibrosis and the development of and advancesin CF care and treatment since the first description of“fibrocystic disease of the pancreas” by Dorothy HAndersen in the 1930s. This fascinating and detailedaccount now includes the last decade 2000–2010. TheHistory of Cystic Fibrosis can be found atwww.cfmedicine.com/history.

The Cystic FibrosisTrust-backed EuropeanCystic Fibrosis ClinicalTrials Network (CTN)has admitted two newUK centres. The RoyalBrompton and Belfastwill join Birmingham,Leeds and Nottinghamto intensify clinicalresearch in CysticFibrosis and to bringnew medicines to theclinic as quickly aspossible. The CTNworks with the UST h e r a p e u t i c sDevelopment Network,European patient organisations and industry to facilitateclinical trials in Cystic Fibrosis developments withinEurope.

For further information about the Clinical Trials Network,see CF Today Apr–Aug 2011.

New clinical trials centres

announced

A detailed history of CF

Pre-pregnancy genetic testing

gains approval

We are delighted to announcethat NHS Blood andTransplant will be a newcharity partner of the CysticFibrosis Trust for 2011–13 after securing 239 of the staff votes.

Cystic Fibrosis Trust Chief Executive Matthew Reed said: “We areabsolutely delighted that NHS Blood and Transplant have chosen usas their charity for the next two years and look forward to working inpartnership with them.” Staff members have already started to getinvolved in events, recycling and payroll giving and are committed tosome great fundraising challenges ahead.

In April this year, the Government’sgenetic advisory group approved theprinciple of genetic testing forcouples before they conceive, in orderto identify any genetic mutations theymay have which could result ingenetic diseases in their children.

The Human Genetics Commission(HGC) recommended that genetictesting be made available to all thatwant it, stating that ‘there are nospecific social, ethical or legalprinciples that would makepreconception genetic testing withinthe framework of a populationscreening programme unacceptable.’

Currently only those pre-disposed to developing genetic conditions, forexample those with a family history or from high-risk ethnic groups,are offered genetic testing on the NHS. In Cystic Fibrosis testing isoffered to close relatives and partners of people with Cystic Fibrosis.Individuals or couples without a family history of CF can also undergocarrier testing but this is carried out privately.

The HGC report, entitled Increasing options, informing choice, states thatindividuals should be supported in making informed choices about thereproductive options available to them, and that if antenatal carrierscreening is offered for a genetic condition then preconceptionscreening should also be offered where possible. Testing wouldfacilitate wider patient choice and improved access to informationsupporting reproductive decision-making, it says.

The Commission developed the guidance following a request from theUK National Screening Committee, which will now decide whether therecommendations should be introduced and if so, how they would beimplemented.

Further informationHuman Genetics Commission www.hgc.gov.uk

The Family Cascade Screening Programme for Cystic Fibrosis. CFTrust factsheet. Available fromwww.cftrust.org.uk/aboutcf/publications.

Genetic testing involves screening

DNA molecules for genetic disorders

The Clinical Trials Network aims

to speed up the development of

new CF treatments

New charity partnership

Despite assurances from the Coalition Government thatthere will not be cuts to frontline NHS services, the CFTrust has uncovered a worrying trend of cutbacks acrossthe country, putting CF services under threat.

Many specialist staff are being used to cover vacant postson general wards, while others are seeing their workingtime reduced altogether. Posts are also being downgradedand, in some areas, maternity leave is not being covered,adding to pressure on other staff.

The CF Trust has launched a campaign to stop these cuts,calling on MPs to put pressure on the Government tocomply with the agreed Standards of Care and staffinglevels.

Cystic Fibrosis Trust Chief Executive Matthew Reed said:“We have seen fantastic improvements in quality andlength of life for people with CF, but those improvementsare at significant risk if these cuts are allowed to take hold.Specialist staff are filling the gaps where they can, but wecannot rely on hope and goodwill to maintain quality ofcare.”

The Trust is asking all its supporters to contact their MPto ask them to sign parliamentary petition EDM 2033 andhelp reverse this worrying trend. More information can befound at www.cftrust.org.uk/aboutus/what_we_do/campaigns/nhscuts.

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The Cystic Fibrosis Trust was delighted to be awarded the Institute ofFundraising national award for ‘Best use of Legacy Fundraising’ at theprestigious annual ceremony in London in July. Beating off stiffcompetition from other national charities including RNIB, the Rosie’sLasting Legacy campaign was commended for being the most innovativelegacy programme in the last 12 months. Congratulations to ourmarketing team and thank you to all who have helped make this campaignsuch a success. You can read more about legacy giving on page 15 – wouldyou consider leaving a lasting legacy to the Cystic Fibrosis Trust?

We were delighted to learnin June that Rosie Barnes,former chief executive ofthe Cystic Fibrosis Trust,had been awarded anOBE for services tohealthcare in the Queen'sBirthday Honours List.Many congratulationsfrom all at the Trust Rosie!You can read our tributeto Rosie in CF TodaySep–Dec 2010.

OBE for Rosie Do your bit to safeguard CF care

Parents Conference

19 November 2011

The Cystic Fibrosis Trust Parents Conference will betaking place on Saturday 19 November. The aim of theday is to provide an update on some of the key andemerging areas in Cystic Fibrosis research, treatment andcare, and on the activities of the Cystic Fibrosis Trust.

Invites were posted over the summer to parents and carerson our database. If you have not received an invite andwould like to attend, please emailparentsconf@cftrust.org.uk or telephone 020 8290 7915.Further details can be found on our websitewww.cftrust.org.uk/aboutus/what_we_do/conferences.

Sarah Wheeler (left) and Sue Whitehead (right) from the CF Trust

Marketing Department celebrate the award with Stephen George, Chair

of Remember a Charity

Rosie Barnes OBE

Award for CF Trust legacy campaign

People with CF should make sure they get their annual flu jab eachautumn. The seasonal flu vaccine is offered free of charge to at-riskgroups to protect them from catching flu and developing seriouscomplications. To find out more contact your GP or CF Centre, visitwww.nhs.co.uk or call NHS Direct on 0845 46 47.

Seasonal flu jab

Obviously £6million is a huge amount forour supporters to raise, and as such, it ishoped that the majority of the funds forthe trial will be secured from majordonors, trusts and corporate donors. TheCystic Fibrosis Trust is exploring allavenues both in the UK and abroad inorder to make this happen.

However the continuing support of theCF community is also invaluable, whetherthrough personal donations, fundraisingactivities or raising awareness. Yoursupport has helped build momentum forthe Appeal and demonstrated to potentialmajor donors just how important thisresearch is to so many people.

Thank you for all you have done andcontinue to do to contribute to the GeneTherapy Appeal – your support really ismaking a real difference. There are nowjust a few weeks left during which we willhave a final, big push on this Appeal. Ifyou are able to help in any way or wouldlike to make a donation, please see detailsoverleaf for some ways in which youcould contribute.

The clinical trial phasesThe multi-dose clinical trial planned forspring 2012 is the culmination of tenyears of research into CF gene therapycarried out by the UK CF Gene TherapyConsortium – research made possible bythe efforts of our supporters.

So far, a pilot study has been carried outin small numbers of patients given asingle dose of the gene therapy product.This showed that the product is safe, andhelped determine the optimal dose for themulti-dose trial. In parallel around 200patients have also been recruited in to therun-in study, in order to assess a newrange of sophisticated and sensitive testswhich will be used to measure the effectof gene therapy, and to decide whichpatients would be best suited to gothrough to the multi-dose clinical trial.

Following the completion of the run-instudy, the multi-dose trial is now ready tocommence next spring. This is a phase 2clinical trial, in which over 100 people atthe Consortium sites in London andEdinburgh will be given either the gene

therapy product or a placebo, once amonth for a year. For safety reasons, thestarting times will be staggered so somepatients will begin the trial later thanothers; therefore the trial will take around18 months to complete. The results willthen be analysed to see if patients showimprovements in their lung function andother measurements over this time period.

If the trial is successful and the resultsconfirm that the product is an effectivetreatment for CF in the lungs, the aim isto then find a pharmaceutical company totake the product into a phase 3 clinicaltrial involving larger numbers of patientsand likely on an international scale, togather more information about theeffectiveness of the treatment and anyside effects. Phase 3 trials usually markthe final stage of clinical testing, and thepurpose is to gather enough data about atreatment to request marketing approval,manufacture the product, and make itavailable to patients. However sometimesregulatory bodies may request furtherstudies are conducted if they are notconvinced of the benefit to patients.

Gene Therapy Appeal

At the time of going to press, progress on our Gene Therapy Appeal – to raise the £6million needed for

the clinical trial planned for spring 2012 – was very encouraging. By early August, over £200,000 (excluding

gift aid) had been donated by our community supporters alone.

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The gene therapy product

C F T O DAY • S E P – D E C 2 0 1 1

Further updates on the gene therapy appealcan be viewed by clicking ‘latest genetherapy news’ on our home pagewww.cftrust.org.uk.

What is the gene therapy product? The gene therapy product that will be givento patients in the multi-dose trial is amixture of two main components:

DNA – which contains the correct versionof the CF gene

A vector (gene transfer agent) – whichhelps deliver the gene to the correctlocation in the cell.

The gene transfer agent or vector iscomposed of a lipid (fat), which has apositive charge. This binds with the DNA,which is negatively charged, so that themolecules are tightly bound together anddon’t disintegrate when the product isnebulised. Upon nebulisation, the productis taken up by cells in the respiratory tract,where the correct copy of the gene shouldstart to express itself.

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C F T O DAY • S E P – D E C 2 0 1 1Oli and Nush are on hand to help

schools raise £600 in 6 weeks

Ways you can helpDonateVisit www.virginmoneygiving.com/cysticfibrosisgenetherapy-1 to donate online.

Donate via JustTextGiving: text GENE06 £5 to 70070 to donate £5 orGENE06 £10 to donate £10 to the Appeal.

Spread the wordWhy not Tell 6 people about our campaign? Help raise awareness of thisimportant work and encourage friends, families, colleagues or anyone elseto donate!

Organise or take part in a fundraising eventHow about organizing a coffee morning, jumble sale or fun day to raisefunds for the appeal and have a great fun day in the process? We canprovide lots of support to help you – visit www.cftrust.org.uk/help/howtoorganiseanevent.

On our website, you can also find out about some of the fantastic andfun events you can take part in to raise funds. Runs, walks, bounces,bakes – there’s something for everyone. Visit www.cftrust.org.uk/help.

Could your company help?Would your company consider supporting our campaign? Perhaps byholding a non-uniform day, cake sale or by making a donation? Visitwww.cftrust.org.uk/help/fundraising-at-work or emailcorporate@cftrust.org.uk for more info.

Could your child’s school help?We’ve enlisted Oli and Nush, stars of Getting Nosey about CF – toencourage schools to support our Appeal (see below).

As part of the Gene Therapy Appeal, wehave developed a postcard based on ourGetting Nosey about CF DVD, for anyschools that may be interested in helping toraise funds for the Gene Therapy Appeal.

If we could encourage just over 9,000schools (one school for every personliving with CF in the UK) to take partin our '£600 in 6 weeks' challenge – wecould raise the £6million needed forthe trial!

If you or your child or a friend or relativewith school-aged children could take thepostcard into school during the first weekof autumn term and encourage the schoolto take up the challenge, we would bedelighted to support them with theirfundraising. We can provide a lesson planand presentation, colouring in sheets,fundraising ideas, Big Cake Bake packs orjust some posters and balloons!

Postcards are enclosed in the currentedition of Inspired! If you don’t receiveInspired! you can order a postcard bycontacting the events team.

For more information call our eventsteam on 0300 373 1100, emailevents@cftrust.org.uk or visit ourwebsite ww.cftrust.org.uk/oliandnush.Please get in touch and let us help yourchildren’s school to raise £600 in 6weeks – all towards our £6millionAppeal.

Could your school raise £600 in 6 weeks

Ask

the e

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8 C F T O DAY • S E P – D E C 2 0 1 1

Ask the expert

Treatments for specific mutations

Q A relative with CF has the

mutation F508del with

711+1G>T. I was wondering if there is

any research being undertaken to help

combat this mutation.

A One of the new approaches in drugdevelopment is to try to treat the

disease at the protein level and differentdrugs must be developed to rectify thespecific defects caused by differentmutations. To this end, VertexPharmaceuticals is developing a drug calledVX-809, which is designed specifically tocorrect the fault caused by F508del. TheF508del mutation gives rise to a proteinthat does not even get to the cell membrane(where it is required) and so cannotpossibly work. VX-809 allows the“chaperone” machinery in the cell to movethe F508del CF protein to the cellmembrane where it has some activity, eventhough it is still a defective protein.

In my opinion, VX-809 does show somepromise although it might not get tomarket in its present form (see research updateon page 10).

The other mutation in this patient,711+1G>T, is what is called a splicingmutation, and results in a piece of theprotein missing. At present, there are nodrugs in the pipeline for this kind of defect,although the research being undertaken atthe DNA level is very active.

For information on VX-809, visitwww.vrtx.com/current-projects/drug-candidates/VX-809.html.

Acquisition of Aspergillus

Q My daughter has CF and my

partner has Aspergillosis (but not

CF) and is concerned about contact with

my daughter. My partner has asked a

consultant, who has assured us that this

is not an issue as Aspergillus cannot be

passed from person to person and is

generally found in the environment.

Having done an extensive Google search

on the subject myself, it would appear

that there is no evidence for person to

person transfer.

Can you confirm that it is ok for my

partner to have normal contact with my

daughter?

A We have no evidence of person-to-person spread for Aspergillus.

Acquisition is most likely to occur from anyone of the multiplicity of environmentalsources. There is no reason to preventnormal contact between your partner andyour child with Cystic Fibrosis.

Bugs in dishwashers

Q I saw on the news recently that

dishwashers could harbour bugs

that are potentially dangerous to people

with Cystic Fibrosis. Is this something to

be concerned about?

A You may have seen some articles inthe press regarding fungi in

dishwashers. Virtually any moist surfacewill harbour germs and most bugsincluding Pseudomonas aeruginosa are found in

environmental sites including washingmachines, dishwashers, damp dishclothsetc. However although these sites harbourbacteria that does not inevitably mean theyall present a serious risk of infection tosomeone with Cystic Fibrosis. In additionthe fungi described in the news story –Exophiala dermatitidis – is considered to bea harmless coloniser of the airways ofpeople with CF and there is no evidence tosuggest it is pathogenic (harmful) in the CFlung. Life for CF families has to be abalance between unnecessary risk ofinfection and quality of life.

We would advise that people with CF andtheir families always use their dishwasher atthe highest possible temperature to ensureeradication of as many organisms aspossible, and also maintain and clean theirdishwasher regularly in accordance with themanufacturer’s advice.

Our experts for this issue were:

Dr Jim Littlewood, Chairman, CysticFibrosis Trust

Members of the UK CF MicrobiologyConsortium

You can view an archive of past Ask the Expert questions at

www.cftrust.org.uk/aboutcf/asktheexpert.

Please note if you have any queries or concerns about any aspect of Cystic

Fibrosis you should contact your CF team in the first instance.

Aspergillus is a fungus (or mould) that is

very common in the environment

Submit your question to asktheexpert@cftrust.org.uk

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Using dishwashers at as high a temperature

as possible helps eradicate micro-organisms

Ask the Expert is the Cystic Fibrosis Trust’s expert advice service for people with Cystic Fibrosis and their

families. Questions are answered by a panel of clinicians who specialise in different areas. Although your query

and the response may appear on the Cystic Fibrosis Trust website or in this magazine, your name and personal

details will always remain confidential and will not be published.

Confe

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C F T O DAY • S E P – D E C 2 0 1 1 9

European Cystic Fibrosis Society Conference –from the patient perspective

I was asked to give a patient perspective on involvement in clinicaltrials, as part of the ECFS Clinical Trials Network (CTN) trainingday, at the European CF Society Conference (Hamburg, 8–14 June).My two-day trip, funded by the ECFS CTN, gave me a veryinteresting insight into my first ECFS Conference.

Delegates (mainly clinicians, scientists and other allied healthprofessionals) descended on Hamburg in their hundreds, comingfrom all countries across Europe and some from beyond the EU.The presentations I attended, including ‘Clinical Trials in YoungChildren with CF’, and ‘Maximising the Value of Registry Data inEurope’ were very informative and created interesting discussionpoints. At the tender age of 44, the ‘CF Ageing Group Meeting’also seemed an obvious meeting for me to join, where there wasdiscussion on a questionnaire for the ageing CF population acrossthe UK and Europe and how registry data could be used to givean overall picture of this patient group’s clinical status over the years– i.e. how were they when they were younger and how are theytoday as ageing adults with Cystic Fibrosis.

My presentation, ‘Clinical Trials – the CF Patient Perspective’, wasbased not solely on my experience of clinical trials, but also on thatof others with CF who responded to my questions on the CFTrust’s Adult Forum (www.cftrust.org.uk/forum) and ExpertPatient Adviser Facebook page (www.facebook.com/epacftrust).

Some well-considered, detailed responses (thank you!) provided aninteresting perspective for the audience of about 70 delegates, themajority of whom were either already part of the European CFCTN or aspiring to become a CTN site.

Fellow CF patients from the CF Trust’s forums gave me their viewon clinical trials in which they’d already been involved. It wasreassuring to hear UK CF patients’ opinions on factors which eitherencouraged or discouraged them from being involved in clinical

trials, along with their advice on how clinical trial centres shouldpresent and conduct trials. Following my presentation, in tandemwith a presentation from the Scientific Director of Vaincre LaMucoviscidose (French CF patient organisation) on the importanceof the ECFS CTN for people with CF, we heard the perceptionson clinical trials of the pharmaceutical industry, followed by a USperspective on maintaining quality standards in clinical trials. Arepresentative from the European Medicines Agency gave apresentation on training in regulatory requirements at clinical trialcentres in Europe. Delegates then broke off into groups to discussaspects of running clinical trials at a ECFS CTN site.

I spent some of the evening looking at products and literature onthe pharmaceutical stands, represented by many of the key nameswe all recognise. The hearty German food and muggy conditionsduring my short time in Hamburg gave both my digestive enzymesand lungs a good work out!

Further informationEuropean Clinical Trials Network. CF Today. Apr–Aug 2011. Seealso www.ecfs.eu/ctn.

www.cftrust.org.uk/research/clinicaltrials

CF News NetworkYou can keep up to date with the latest developments in CysticFibrosis research worldwide including CF conference highlights bysubscribing to CF News Network (CFNN). This independent CFnews portal contains a handy round-up of some of the key researchnews from across the globe, with expert comment by CF clinicians.Visit www.cfnewsnetwork.com to register for your free monthly e-newsletters.

Cystic Fibrosis Trust Expert Patient Adviser Dominic Kavanagh was asked to speak at the recent ECFS

Conference in Hamburg on the patient perspective of taking part in clinical trials. As Dom explains, the

experience was both rewarding and thought-provoking.

EPA Dominic discusses clinical trials from the patient perspective

Regulatory requirements at clinical trial centres was one of the

conference hot topics

Vertex Latest

C F T O DAY • S E P – D E C 2 0 1 1

In the last CF Today we reported that VX-770, a CF drugin development by Vertex Pharmaceuticals and aimed atthose with the G551D mutation aged six and older, hadshown promising results in a phase 3 clinical trial. In Junethis year, further data presented at the European CFConference in Hamburg showed that the reported 10%improvement in lung function was able to be sustainedover a period of 48 weeks, indicating that the beneficialeffects of the treatment are also long-lasting.

Vertex is now planning to submit applications forapproval of VX-770 as a CF treatment in the UnitedStates, Canada and Europe including a MarketingAuthorization Application in the European Union in the

second half of 2011. Ifapproved, VX-770 could belicensed as a treatment in theUK as early as next year.

Interim data from a secondVertex clinical trial, investigatinga combination of VX-770 withanother drug, VX-809, werealso released in June. This phase2 study is investigating whetherthe combination of drugs iseffective in those with theF508del mutation. However the

data were not as encouraging as hoped; results for one keymeasure – a reduction in sweat chloride (see box) – werelower than expected. Vertex intends to initiate the secondpart of this study in the fourth quarter of 2011.

The ‘small molecule’ approach

VX-770 and VX-809 are known as ‘small molecule’ drugs.These drugs have a low molecular weight and are usuallyeasily absorbed into the body. Importantly for patients,this means they can be taken orally as a small tablet (inthe trials, one tablet was administered twice daily).

Vertex’s small molecule drugs are designed to target theroot cause of Cystic Fibrosis – the Cystic FibrosisTransmembrane Conductance Regulator (CFTR) protein– which is either missing or doesn’t work properly insomeone with CF depending on which mutation theyhave. CFTR is responsible for regulating the flow ofchloride across the cell surface to help hydrate and clearmucus from the airways. Theoretically therefore correctingthe action of this protein would allow sodium andchloride to move properly in and out of cells and prevent

the mucus build up which causes the damaging symptomsto the lungs and digestive system seen in Cystic Fibrosis.

As the two drugs in development by Vertex – VX-770 andVX-809 – are aimed at two different CF mutations, theyhave two different modes of action.

VX-770, which is targeted at the G551D mutation, is aCFTR potentiator. In those with the G551D mutation(around 4–5% of the UK CF population) CFTR isproduced but doesn’t follow instructions from the cell toallow chloride ions out. VX-770 potentiates the function ofCFTR, i.e. increases the time it is open, helping it tobehave normally once it reaches the cell surface.

VX-809, which is targeted at the F508del mutation, is aCFTR corrector. In those with the F508del mutation(over 90% of the UK CF population) the CFTR proteindoes not reach the cell surface in normal amounts. VX-809 corrects the production of CFTR, helping it to reachthe cell surface where it is then able to function.

Further developments on the Vertex treatments will beposted on the CF Trust homepage www.cftrust.org.uk.

Further information

Vertex Pharmaceuticals www.vrtx.com

For more information about mutation classes in CF seeCF Today Winter 2008/9.

Data were also released in June from a phase 2 trial ofanother CF treatment targeting the basic defect.

PTC Therapeutics’ Ataluren (formerly called PTC 124) iseffective against a certain class of mutation known as‘nonsense’ mutations (normally ending in X, for exampleG542X), which prematurely halt the synthesis of CFTR,causing it to be too short and therefore not functionproperly. Around 10% of people with CF have at least oneof these Class 1 mutations, and the therapy could also beapplied to other genetic diseases involving nonsensemutations, such as Duchenne Muscular Dystrophy.

Data from the phase 2 trial showed that CF patients whotook the drug (which is also an oral preparation) threetimes daily, had improved function of the CFTR protein(measured with an electrical test in the nose) and adecrease in the frequency of cough. Ataluren was alsoassociated with improved lung function.

It is now being evaluated in a phase 3 clinical trial inEurope and North America.

Further information

PTC Therapeutics www.ptcbio.com

Ataluren advances

The Vertex drugs will likely betaken as a single tablet twice daily

The significance of sweat chloride

Raised sweat chloride levels are a diagnostic measure ofCF, resulting from defective CFTR activity in cells in thesweat duct. People with CF typically have sweat chloridelevels in excess of 60 mmol/L, while values in people whodo not have CF are less than 40 mmol/L. Reduction insweat chloride is considered to be a marker of improvedCFTR function.

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How CF Trust grants can boost longer-term research

Plans are in place for the phase 2 gene therapy trial tocommence in spring 2012, subject to the required fundingbeing secured. You can read about the gene therapy appealon page 6.

An inhaled treatment to reduce mucus build up in thelungs of people with CF and other respiratory conditionshas been put on hold after queries were raised about theeffectiveness of the treatment.

In clinical trials, treatment with Bronchitol improved lungfunction in children and adults by 8%. However although

the treatment is licensed for use in Australia wheremanufacturer Pharmaxis is based, the Committee forMedicinal Products for Human Use (CHMP) rejected thecompany’s application to market Bronchitol in Europe,citing concerns that while the drug seemed to work wellin adult patients the results in younger patients were lessconsistent.

At the time of going to press, Pharmaxis had justsubmitted a formal request to the CHMP to re-examinetheir marketing application. And although Bronchitol maynot be suitable for everyone with Cystic Fibrosis, many CFexperts in Europe are supporting the re-examination. DrDiana Bilton, Consultant Physician at the Royal BromptonHospital in London, said: “We need to extend thetreatment options and choice for people with CF and hopeto see this treatment be made available.”

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Gene therapy

Bronchitol on hold

Readers of CF Today will be accustomed to seeing newsabout grants awarded by the Cystic Fibrosis Trust to fundresearch projects, which usually provide funding for twoto three years of research. What you might not appreciateis how sometimes this is just the start of a process leadingto much longer-term support for Cystic Fibrosis research.

In the past, I have been fortunate enough to receive grantsfrom the CF Trust for research into the microbiology ofCF infections; part of a long and fruitful collaborationwith Dr Martin Walshaw and colleagues at the Adult CFUnit in the Liverpool Heart and Chest Hospital. Inparticular, the CF Trust, alone or jointly with the BigLottery Fund, has supported our research into theLiverpool EpidemicStrain (LES) ofPseudomonas aeruginosa,which is a particularlyproblematic strain ofP s e u d o m o n a s .Support from the Trustenabled two PhD studentsto complete degrees in CF research: Dr Catherine Smart(2002–2005) and Dr Jo Fothergill (2005–2008). Perhapsmore importantly though, because of the success of ourCF Trust-funded research, we were able to obtain furtherfunding from a number of other sources.

More recently, in collaboration with others at theUniversity of Liverpool (Dr Mike Brockhurst and DrSteve Paterson), we were awarded approximately £500,000in two separate grants from the Wellcome Trust, for aproject lasting from 2009 until 2015. A further £150,000was obtained from the Dr Hadwen Trust (2008–2012).Perhaps most significantly, when Liverpool was awardeda grant to establish the National Institute of HealthResearch’s only Biomedical Research Centre on MicrobialDisease (approximately £20 million, 2008–2012), one ofthe 15 projects being undertaken (led by myself and DrWalshaw) was focused on various aspects of epidemic

strains of P. aeruginosa in CF, and hasenabled Dr Fothergill to continueworking in CF research. The purposeof the Biomedical Research Centre(www.liverpoolbrc.org) is to facilitateprojects that could translate intobenefits for patients, and the projectscover a range of infections. It wasimportant that we secured a place forCF infections amongst the portfolioof projects, and we wouldn’t havebeen able to do this without theprevious support of the CF Trust.The work carried out has led to the development of better

diagnostic tests and aclearer understanding ofthe LES.

Without the initial workfunded by the CF Trust,

we would not have beenin a position to obtain this

additional funding, and I’m sure that others involved inCF research have similar stories. Hence, be assured, thatwhen you see the CF Trust list theresearch that it supports, this by nomeans represents the depth ofCF-related research currentlytaking place in the UK, much ofwhich was enabled by initial CFTrust grants.

Further details of CF microbiologyresearch in the UK can be foundon the website of the UK CFMicrobiology Consortiumwww.cfmicrobiology.org.uk.

Craig Winstanley, Reader in Microbiology, Institute of Infection andGlobal Health, University of Liverpool

Craig Winstanley, University of Liverpool

Agar plates are used to testfor bacterial resistance to

antibiotics

“Because of the success of our CFTrust-funded research, we were able to

obtain further funding from a number ofother sources.”

C F T O DAY • S E P – D E C 2 0 1 1

What is atypical Cystic Fibrosis?

Atypical Cystic Fibrosis is the name used when a personhas signs and symptoms that are consistent with CF butdoes not fulfill the strict rules that are used to make adiagnosis of Cystic Fibrosis. In most cases, this is becausethe amount of salt in the sweat is not high enough to makea diagnosis of Cystic Fibrosis.

As people with CF have a high concentration of salt intheir sweat, the sweat test (where sweat is collected and thesalt concentration measured) has been and remains animportant part of making a CF diagnosis. This saltconcentration is determined by the chloride value, whichin people without CF is rarely above 30. A chloride valueover 60 is considered consistent with CF, and many peoplewith standard (sometimes called classical) CF have a muchhigher value. A chloride value between 40 and 60 in aperson with signs and symptoms consistent with CF isoften given the name atypical CF.

Is the term ‘atypical CF’ universally accepted?

Atypical CF is a controversial name and some feel that itshouldn’t be used, i.e., that you either have CF or youdon’t. In North America, recent consensus guidelines onmaking a diagnosis of CF do not support the use ofatypical CF, although in reality many physicians in the USdo use the term. Atypical CF is more widely used inEurope.

How does atypical CF happen?

Nearly 2,000 different gene abnormalities (ormutations) have been recognised on the CFgene; it is not surprising therefore that some ofthese abnormalities are associated with lesssevere disease. These gene abnormalities donot completely stop the CF gene from workingand it is able to do some of its job, controlling saltmovement across cells.

Is being diagnosed with atypical CF a good or a bad

thing?

Being diagnosed with atypical CF can completely changea person’s life, as it ends a long journey of uncertainty.Once a person with atypical CF starts to receiveappropriate care, they may report a tremendousimprovement in their well-being.

Studies have shown that, as a group, people with atypicalCF enjoy better condition than people with classical CysticFibrosis. For example, most patients with atypical CF donot need to take pancreatic enzymes with their meals.However, although the overall outlook is better, individualswith atypical CF can experience quite severe disease, inparticular lung infection, and it important that they aremonitored carefully. It is also important that CF teamsappropriately segregate people with atypical CF to ensurethat they are not exposed to bugs that can infect theirairways. If good segregation policies are not in place, itcould be argued that attending a standard CF clinic placessomeone with atypical CF at increased risk, which mayoutweigh the benefit of attending a CF clinic.

At what age can a person be diagnosed with atypical CF?

On the whole, people with atypical CF are diagnosed laterthan those with classical Cystic Fibrosis. Sometimes thiscan be in their adult life. The diagnosis of a lifelongcondition can be upsetting for older children and adultsand CF teams need to be empathetic to the needs of thesepatients.

Does the newborn screening programme identify

infants with atypical CF?

The recent national programme to screen newborninfants for Cystic Fibrosis has been a tremendous success,however one of the results of this programme has beenthe identification of a small number of infants with anunclear diagnosis. In Europe, this is called an equivocaldiagnosis of Cystic Fibrosis. These children are well andit is difficult to predict how they will progress over time.In North America, infants with an unclear diagnosis afternewborn screening (NBS) have been given the termCFTR-related metabolic syndrome (CRMS). By using this

term the families are able to access the US medical system.This term has not been adopted in Europe and we willcontinue to monitor the progress of these children withan equivocal diagnosis following newborn screeningcarefully in clinics. With both newborn screening and theincreased recognition of atypical CF by physicians lookingafter adult patients, it is likely that the number of patientswith this diagnosis will increase over the next five to tenyears.

Atypical Cystic Fibrosis

‘Atypical CF’ is a form of Cystic Fibrosis thought to affect approximately 2% of all those with

CF and is often characterized by less severe symptoms than seen in so-called ‘classical CF’.

However as Dr Kevin Southern at the University of Liverpool explains, atypical CF is not always

easy to diagnose, with many patients receiving a diagnosis later in life.

“In atypical CF, the CF gene is stillable to do some of its work.”

“It is likely that diagnoses ofatypical CF will increase over the next five

to ten years.”

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Should patients with atypical CF carry out normal CF

treatment regimens?

The basic principles of CF care – maintaining excellent weight,keeping the airways free of infection and encouraging a healthyand active lifestyle – apply to patients with atypical Cystic Fibrosis.It is important that CF teams have systems in place to achievethese goals; however, it may be that someone with atypical CFwho has excellent weight and health does not need to be seen asfrequently as someone with classical Cystic Fibrosis. If that isthe case they (or their carers) must have a clear idea of signs orsymptoms that they should be aware of and they should be ableto contact the CF team easily for advice.

In summary

Some people have signs and symptoms consistent with CF butdo not fulfill the strict rules to make a diagnosis of CysticFibrosis. Many physicians use the term atypical CF to describethese people. A diagnosis of atypical CF can help someone accessappropriate care and this can have a tremendous impact on theirwell-being. On the whole, people with atypical Cystic Fibrosishave less severe condition than people with classical CF, howeverindividuals can be significantly affected and CF teams must haveappropriate systems in place to provide these people with themonitoring and care they require.

Dr Kevin W Southern, Reader and Honorary Consultant in PaediatricRespiratory Medicine, University of Liverpool

“The consultant couldn’t really say what thefuture held.”Elaine Mallion, who turns 50 this month, was diagnosed with atypical CFin her thirties.

I'd been seeking an explanation for a fairly persistent, clear-the-throat sort of cough, without any joy. At least my husband alwaysknew where to find me in a supermarket! Then in 1993 when Iwas 31, I had a chest infection, which took about six weeks toshake off. After various referrals, I was diagnosed as havingatypical Cystic Fibrosis. As mine is apparently a rare mutation theconsultant couldn’t really say what the future held, as there wereso few statistics on this form of Cystic Fibrosis. “You’ll probablybe much the same for five years or so, after that we don’t really know…”

I’d been living with the cough since childhood. When I was about16, I was referred to an ENT consultant who thought it may besomething to do with my sinuses. When I left home and startedto talk to GPs myself, I was referred for acupuncture and allergy

tests (some intolerance to dairy products was identified) andI was prescribed inhalers and nasal sprays for possibleasthma and allergic rhinitis.

I think, after all those years, it was a relief to know there wassome actual reason for my cough. But CF? That was a bitof a shock. All I knew about Cystic Fibrosis at that stage isthat people were generally lucky if they survived into theirthirties. There was no history of it in my family. My husbandand I had just reached the stage where we were thinking ofhaving children. After the diagnosis, we decided not to starta family, mainly because we really didn’t know what theprognosis was and how having children would affect myhealth. Seventeen years on, I wonder if it was the rightdecision (hindsight is a wonderful thing).

Once I’d had the diagnosis I decided to take steps to makesure I kept my lungs fit. As one of my friends once said: “It’sgood that you’ve got something that encourages you to go to the gym!”I also enjoy cycling.

Given that I’ve gotCF, I actually feelincredibly lucky. Thismonth, I’ll becelebrating my 50thbirthday. So far(touch wood), onlymy lungs seem tohave been affectedand even then, they’refine most of the time.I take oral antibioticsand do some dailyphysio with theFlutter device. Ofcourse there are somedifficulties, such astrying to get a decentprice for travelinsurance andsometimes GPs seemto find it hard to appreciate there are different forms ofCystic Fibrosis. I have also recently stopped working fulltime, as having been employed in a rather stressful position,I felt it was important to put my health first – I am currentlydoing voluntary work whilst exploring other options. Butoverall, I feel that I live my life much as any ‘normal’ personand hope to keep on doing so for some time to come!

Elaine Mallion

“Once a person with atypical CFstarts to receive appropriate care, they

may report a tremendous improvement intheir well-being.”

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The project to improve and streamline thepeer review process for CF services isprogressing well and has now completed itsinitial consultation period. We have had anexcellent response from patients, parentsand clinicians who have completedquestionnaires or taken part in events andteleconferences.

Our team of Expert Patient Advisers(EPAs) have been central to canvassingopinions, and EPA for the South WestSophie Lewis and I have compiled a reportwhich will appear on the CF Trust websitein due course. A big thank you to all of youwho got in touch to share your ideas, andcontribute to this important piece of work.The next phase of the project will be

starting this autumn with two pilot peerreviews, testing out a new process andhandbook which will contain everything weneed to know in order to deliver anefficient and effective service review. It willhave information for staff in the NHS,managers, commissioners, parents/patientsand our staff here at the CF Trust who willcontinue to facilitate the reviews.

Future reviews will be focused around therevised Standards of Care 2011 (an updatedversion of the widely-used CF TrustStandards originally produced in 2001),

which are currently being developed byleading CF clinical experts from allprofessions across the UK.

Since the Cystic Fibrosis Trust firstimplemented the process of peer review in2006, and having now completed the firstround of reviews for all CF specialistservices, peer review continues to be seenas a vital tool in assessing services againstthe UK Standards of Care by NHSmanagers and CF clinical teams. Up untilthe end of 2009 peer review had helped tolever an additional £18million of NHSfunding for CF care that would not haveotherwise been forthcoming. It is clearlyimportant, given the current economicclimate and the continual squeezing ofNHS budgets, that we continue this processto ensure that all people living with CF inthe UK have fair and equal access to thevery best possible quality of treatment andcare.

Alicia Ridoult, Clinical Care and CommissioningManager, Cystic Fibrosis Trust

In July, the Cystic Fibrosis Trust publisheda revised version of its physiotherapyconsensus document, entitled Standards ofCare and Good Clinical Practice for thePhysiotherapy Management of Cystic Fibrosis.

The document, which provides detailedguidance on issues such as airway clearancetechniques, exercise and inhalation therapy,was produced by a working group ofspecialist CF physiotherapists from acrossthe UK.

Penny Agent, Specialist CF Physiotherapistat the Royal Brompton Hospital in Londonand chair of the working group said: “Thiscomprehensive document of good clinicalpractice will be a useful tool to allphysiotherapists and other clinicians

involved in the delivery ofcare to people with CF,and as well ashighlighting expertpractice it is intended toe n c o u r a g ephysiotherapists to localguidance tailored totheir individual needs.”

Cystic Fibrosis Trust consensus documentsprovide detailed guidance about key issuesin Cystic Fibrosis for those involved in CFcare, treatment and research. Eachdocument is produced by a specialistworking group and feedback sought fromthe wider CF clinical community and otherexperts, and by CF patients and parents inorder to reach a consensus on best practicein the areas covered. Our consensus

documents can be downloaded atwww.cftrust.org.uk/aboutcf/publications or printed copies ordered bycontacting the CF Trust.

The annual UK Cystic Fibrosis PatientRegistry Report for 2009 was published onthe Cystic Fibrosis Trust website in Marchthis year. For the first time, data for eachCF Centre and Clinic was identifiable,meaning that it is now possible to comparethe clinical outcomes for the service thatyou attend with other services in the UK.We do feel that the current report formatis rather heavy going in terms of theamount of statistical data with only briefexplanations of some of the findings;therefore we are currently reviewing howthe report may be presented in future,perhaps producing more than one versionto account for the different audiences. Ifyou have viewed the report we hope thatyou found it useful and interesting and,indeed, we would value any feedback.

The 2010 Registry Report is due to bepublished on our website by the end of thisyear. We are really pleased to see acontinuing increase in the number ofpatients registered on the database, as wellas an increase in the number of patients forwhom there is full data, based on clinicalinformation from their Annual Review.This information is very important in

“Up until the end of 2009peer review had helped to lever an

additional £18million of NHSfunding for CF care that would nothave otherwise been forthcoming.”

Peer reviews help CF Centres and Clinics

improve the care they are able to offer patients

A new CF Trust consensus document will

help improve CF physiotherapy services

across the UK

New CF Trust publication

provides support for

physiotherapistsUK Cystic Fibrosis Registry

update

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Peer review of CF services

– where are we now?

Legacy givin

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Leaving a legacy: Are you worth more

than you think?

In January 2011 we published an article in CF Today to answersome of your questions about making and changing wills. Whileyou plan for the future, obtaining professional advice and havingyour will carefully drafted can also help with Inheritance Taxplanning. You may not be aware that donations made to charityare tax exempt and free of Inheritance Tax and can thereforehelp to reduce your tax bill.

Inheritance Tax – how it might affect you

Inheritance Tax is paid on an estate when somebody dies. It's alsosometimes payable on trusts or gifts made during someone’slifetime. Many estates don’t have to pay Inheritance Tax becausethey're valued at less than the threshold set by HM Revenue &Customs – currently £325,000 for individuals and £650,000 formarried couples. This may seem like a large sum of money, butif you include your home, you may find your savings andpossessions add up to more than that. Inheritance Tax is chargedat 40% on the amount over the threshold.

Changes on the way

“I want to make giving 10% of your legacy to charity the new norm in ourcountry,” the Chancellor George Osborne announced in his Marchbudget. The Government will reduce the rate of Inheritance Taxby 4% in cases where at least 10 % of the total value of an estateis donated to charity. This is due to come into effect on 6 April2012. The Treasury has launched a consultation about the reliefand how it will be implemented and we will keep you updatedwhen more details are available.

Why legacy income is so important

Last year we received just under £1million in legacy income.

This amount could enable the Cystic Fibrosis Trust to provideinformation, advice and support to people affected by Cystic

Fibrosis for an entire year. This includes our publications, grantssuch as pre-payment certificates for prescription charges andtravel expenses for transplant assessments, and the costs ofrunning our helpline.

This amount could almost cover our clinical care programme fora year, which aims to ensure the clinical care for people with CFis as good as it can be, wherever they live in the UK. This includesour programme of peer reviewing CF clinics (see page 14) andactively supporting clinicians around the UK and their teams toprovide the best possible care.

Legacy income enables us to continue with our vital work,helping to improve the quality and length of life for people withCystic Fibrosis. To find out more about leaving a gift in your willto the CF Trust, please contact Sue Whitehead, Legacy MarketingManager at swhitehead@cftrust.org.uk or 020 8290 8051.

“Donations made to charity aretax exempt and free of Inheritance Taxand can therefore help to reduce your

tax bill.”

Legacy income helps us to improve the lives of people with living

with CF

helping us to understand how patients are doing over a period of time in terms oftheir clinical outcomes. The clinical dataalso helps researchers to develop new andimproved treatments, and it now ensuresthat CF services are funded in accordance

with the level oftreatment and carerequired for eachindividual patient.

We hope that like us youwill be encouraged by the increasing qualityand quantity of data supplied by eachservice, and provided by individuals, and bythe openness that we achieved in being ableto identify every service with the aim of

driving up standards of care across thewhole of the UK.

Jo Osmond, Director of Clinical Care andCommissioning, Cystic Fibrosis Trust.

The 2009 Registry Report can be viewed at:www.cftrust.org.uk/research/applydata..

If you would like to comment on the report,please email publications@cftrust.org.uk.

“Data from the CF Registryhelps researchers develop new and

improved CF treatments.”

Clin

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Founded in 1964, the Cystic Fibrosis Trust is the UK's onlynational charity dealing with all aspects of Cystic Fibrosis.

Our objectives are to:

•Fund medical and scientific research to develop a cure and provide effective treatments for Cystic Fibrosis.

•Ensure appropriate clinical care for those with Cystic Fibrosis.

•Provide information, advice, support and, where appropriate, financial assistance to anyone affected by

Cystic Fibrosis.

Cystic Fibrosis Trust

11 London Road, Bromley, Kent BR1 1BY

Tel: 020 8464 7211 Fax: 020 8313 0472

www.cftrust.org.uk

You can view CF Today online and download our extensive range of

factsheets and booklets providing further information about Cystic Fibrosis at

www.cftrust.org.uk/aboutcf/publications

Cystic Fibrosis Trust

HelplinesOur Support Service has three Helplines offering the following services:

Our Helplines operate from 9am – 5pm weekdays. An answer machine is availableduring busy periods and outside these hours.

You can also access our website www.cftrust.org.uk to find out more about CF TrustHelplines and to download various forms and factsheets relating to these services.

For a confidential service thatenables anyone to obtaininformation, advice and supporton any aspect of Cystic Fibrosis –

For information and advice aboutbenefits and how to apply forthem –

For information and advice onhow to access small grants fromthe Cystic Fibrosis Trust andother organisations –

Benefits Advice

0300 373 1010

Welfare Grants

0300 373 1020

CF Helpline

0300 373 1000