Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis Supplemental Information

(1)

Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis

Supplemental Information

(2)

Supplementary Table 1 Details of support received from the pharmaceutical industry by contributors

Name

Year of paymen

t Company

Payment recipient

Payment in euros (or value of benefit in kind)

Purpose

Kevin W Southern - - - - -

Carlo Castellani

2020 Vertex Me personally >1000<5000

Advisory board fees 2020 Vertex Me personally >1000<5000

Other consultancy 2020 Vertex Me personally >1000<5000

Speaker fees

Elise Lammertyn - - - - -

Alan Smyth 2022-

2024

Vertex My institution Total project value: 313k

Investigator Sponsored Study Award 2020-

2022

Investigator Sponsored Study Award 2018-

2020

Investigator Sponsored Study Award Donald VanDevanter 2021 Splisense Me personally >1000<5000 Advisory

board fees Silke van Koningsbruggen-

Rietschel

- - - - -

Jürg Barben - - - - -

Amanda Bevan - - - - -

Edwin Brokaar

Speaker fees

Speaker fees (educationa l activity – expert in online Q&A session CF- caregivers in Belgium on the start

(3)

of CFTR- modulators )

Sarah Collins

Speaker fees

Gary J Connett - - - - -

Thomas W. V. Daniels

Speaker fees Jane Davies

2020

Proteostasi

s My institution >200<500

Advisory board fees

2020 Vertex My institution >1000<5000

Clinical trial

investigator fees

Advisory board fees

2020

Other (please specify

below) Me personally >1000<5000

Advisory board fees 2020 Vertex Me personally

>5000<10,00 0

Other consultancy 2021 Vertex My institution

>5000<10,00 0

Advisory board fees

2021 Vertex My institution

>5000<10,00 0

Clinical trial

investigator fees

Advisory board fees 2021 Vertex Me personally

>5000<10,00 0

Speaker fees 2021 Abbvie Me personally >500<1000

Speaker fees

Clinical trial

investigator fees

Clinical trial

investigator fees

Advisory board fees

(4)

2022

Other (please specify

below) My institution >1000<5000

Advisory board fees

2022 Vertex My institution

>5000<10,00 0

Clinical trial

investigator fees

2022 Vertex Me personally

>5000<10,00 0

Advisory board fees

Dimitri Declercq - - - - -

Silvia Gartner

Advisory board fees Andrea Gramegna ₂₀₂₁ _Vertex Me personally >1000<5000 Speaker fees

Naomi Hamilton - - - - -

Jenny Hauser

Speaker fees Nataliya Kashirskaya

2020 Sanofi Me personally >200<500

Speaker fees 2021 Sanofi Me personally >200<500

Speaker fees

Laurence Kessler - - - - -

Jacqueline Lowdon - - - - -

Halyna Makukh - - - - -

Clémence Martin

2022 Vertex Me personally >1000<5000 Advisory board fees Lisa Morrison

Speaker fees

Dilip Nazareth - - - - -

Jacquelien Noordhoek - - - - -

Ciaran O'Neill - - - - -

Elizabeth Owen

Speaker fees

Helen Oxley 2021 Vertex Me personally >200<500 Speaker

fees

Karen S Raraigh - - - - -

Caroline Raynal - - - - -

Karen Robinson - - - - -

Jobst Roehmel

Speaker fees 2020 Vertex Me personally >1000<5000

Speaker fees

Carsten Schwarz - - - - -

Isabelle Sermet 2019 Vertex My institution 100,000 Investigator Sponsored

(5)

Study Award 2020 Vertex My institution 325,000 Investigator

Results from the 65 respondents of the Delphi consultation are shown below, as well as edits that were made to the statements following the consultation. Additions are shown in bold font (like this) and deletions are shown in strikethrough font (like this).

In the table below:

 Statement 14, on the theme of exercise was removed due to comments and a lack of supporting evidence.

 Statement 19, on the theme of adherence, was removed because it was repetitive with Statement 12.

1 For individuals with clinical features consistent with CF, disease-causing variants of the CFTR gene are those characterised as “CF-causing” or “varying clinical consequences”

by an established and validated program (for example, CFTR2 or CFTR-France).

% consensus 91.5%

Agree 54

Disagree 5

Cannot answer 6

2 Individuals under consideration for CFTR modulator therapy should have molecular diagnostic testing of the CFTR gene that includes, at minimum, the most frequent variants known to be CF-causing in their population of origin. Further analysis may include exonic regions, intron-exon junctions, and presence of copy number variants, in the case of incomplete genotype after initial molecular testing.

(8)

% consensus 91.7%

Agree 55

Disagree 5

Cannot answer 5

3 CFTR gene variants should be considered of uncertain clinical significance in the absence of epidemiological or laboratory evidence. These variants should undergo further evaluation to determine their pathogenic or benign status and potential responsiveness to VST.

% consensus 98.4%

Agree 60

Disagree 1

Cannot answer 4

4 PwCF aged six years and older, with one or two F508del variants, should have daily treatment with triple modulator therapy (elexacaftor-tezacaftor-ivacaftor).

% consensus 88.7%

Agree 55

Disagree 7

Cannot answer 6

5 PwCF and at least one responsive non-F508del variants should be considered for mono (ivacaftor), dual (tezacaftor-ivacaftor) or triple CFTR modulator therapy (elexacaftor-tezacaftor-ivacaftor).

% consensus 86.4%

Agree 51

Disagree 8

Cannot answer 6

6 Children with CF with eligible CFTR gene variants should be offered treatment with ivacaftor from 4 months of age.

% consensus 90.4%

Agree 47

Disagree 5

Cannot answer, skipped 12, 1

7 Children with CF who are homozygous for the F508del variant, aged 2-5 years, should be offered treatment with dual modulator therapy (lumacaftor-ivacaftor).

% consensus 87.7%

Agree 50

Disagree 7

Cannot answer 8

8 Parent/carers of pre-school children with CF should be aware of the efficacy data and safety profile of VST before treatment start.

% consensus 90.3%

Agree 56

Disagree 6

Cannot answer 3

9 Before initiating treatment, pwCF and their families should have a detailed discussion with the CF team, outlining the impact of taking CFTR modulator therapy, backed up with written information .

% consensus 89.2%

Agree 58

Disagree 7

Cannot answer 0

10 Before starting CFTR modulator therapy, a detailed drug history should be obtained and cross checked with prescribing information about potential drug interactions.

% consensus 100.0%

Agree 64

(9)

Disagree 0

Cannot answer 1

11 PwCF should be followed up at least three monthly every 3 months after starting CFTR modulator therapy to monitor progress and screen for side effects.

% consensus 85.7%

Agree 54

Disagree 9

Cannot answer 2

12 CF teams should monitor adherence to CFTR modulator therapy, for example, by using pharmacy prescribing dispensing data.

% consensus 90.3%

Agree 56

Disagree 6

Cannot answer 3

13 Before commencing and once established on a VST, pwCF, in partnership with the physiotherapy team, may need to adapt and optimise their airway clearance technique and sinus treatments.

% consensus 87.9%

Agree 51

Disagree 7

Cannot answer 7

14 Consider alternative approaches to airway clearance (for example supplementary exercise) following the initiation of VST.

% consensus 83.6%

Agree 46

Disagree 9

15 For pwCF starting a VST, the management of CFRD should be reviewed and adapted on an individual basis, considering clinical and nutritional status

% consensus 95.2%

Agree 59

Disagree 3

16 PwCF on VST should continue to receive regular monitoring of nutritional status and dietary intake, according to changing energy requirements.

% consensus 96.9%

Agree 63

Disagree 2

Cannot answer 0

17 Frequency of support of nutritional assessment should be individualised, depending on age, clinical status and CFTR modulator therapy.

% consensus 100.0%

Agree 64

Disagree 0

Cannot answer 1

18 CF teams should be familiar with the wide-ranging psychological impact of VST and prepare, advise and support pwCF and their caregivers as required, involving the CF psychologist when indicated.

% consensus 96.9%

Agree 62

Disagree 2

Cannot answer 1

19 CF teams must assess adherence to VST at every appointment to optimise health outcomes.

(10)

% consensus 89.2%

Agree 58

Disagree 7

Cannot answer 0

20 Symptoms of depression and anxiety must should be assessed pre-VST and no later than 3 months after starting.

% consensus 84.2%

Agree 48

Disagree 9

Cannot answer 8

21 Prior to initiating VST in women with CF, contraception and fertility should be reassessed, and appropriate counselling provided.

% consensus 98.4%

Agree 61

Disagree 1

22 The decision to use VST during pregnancy should weigh the risk to maternal health in the event of withholding therapy and the lack of data regarding safety to the foetus.

% consensus 94.9%

Agree 56

Disagree 3

Cannot answer 6

23 Women treated with VST planning to breastfeed should be informed regarding the lack of data on safety during breastfeeding.

% consensus 98.4%

Agree 61

Disagree 1

Cannot answer 3

24 All pwCF with non-responsive CFTR gene variants should continue to receive high- quality CF-specialist multi-disciplinary care at a specialist or accredited CF centre.

% consensus 96.9%

Agree 63

Disagree 2

Cannot answer 0

25 It is important that pwCF and non-responsive CFTR gene variants are informed of clinical trials and supported to participate in trials.

% consensus 96.9%

Agree 63

Disagree 2

Cannot answer 0

26 PwCF and CFTR gene variant(s) with unclear response to modulator therapy should be offered referral to a centre with capacity for in vitro ex vivo testing of CFTR response, to potentially establish an individualised treatment plan, including with modulator

therapies.

% consensus 85.5%

Agree 53

Disagree 9

27 For pwCF after solid organ transplant, VST should be considered for eligible patients after discussion of the potential risks and benefits between the patient, the CF team, and the transplant team.

% consensus 94.9%

Agree 56

Disagree 3

(11)

Cannot answer 6

28 For patients with a diagnosis of CFTR-related disorder, there is no evidence to support the use of VST outside of clinical trials.

% consensus 92.2%

Agree 47

Disagree 4

Cannot answer 14

29 For infants with an unclear diagnosis following newborn screening for CF (CRMS/CFSPID), the use of VST is not indicated.

% consensus 100.0%

Agree 49

Disagree 0

Cannot answer 16

30 For new high-cost CF therapies, a robust health technology assessment should evaluate the impact on pwCF and society.

% consensus 88.3%

Agree 53

Disagree 7

Cannot answer 5

31 The CF community should advocate globally for equitable access to new therapies with proven efficacy for all pwCF.

% consensus 100.0%

Agree 65

Disagree 0

Cannot answer 0

32 Evidence used to inform reimbursement decisions using public money should be transparent and available to the public.

% consensus 100.0%

Agree 65

Disagree 0

Cannot answer 0

(12)

Supplementary Table 4 CFTR gene variants and currently licensed VST

A comprehensive list of CFTR gene variants (Human Genome Variation Society [HGVS] and legacy names) with indication as to current eligibility for mono (ivacaftor [IVA]), dual (tezacaftor-ivacaftor [TEZ-IVA]) or triple therapy (elexacaftor-tezacaftor-ivacaftor [ELX-TEZ-IVA]).

Eligibility is determined by US product label information (licence), as accessible on US patient information website for these three agents (1

^st

May 2022).

Please note that some of these variants have been classified as non-CF causing (marked

^a

), several exonic variants are known or suspected to result in a major splicing defect (marked

^b

) and others are variants of unknown significance (VUS) by either CFTR2 or CFTR-France (marked

^c

).

As outlined in the text of this paper a clear diagnosis of CF is a pre-requisite to prescription of one of these CFTR modulator therapies.

HGVS name Legacy name IVA TEZ-IVA ELX-TEZ-IVA

c.2657+5G>A 2789+5G>A Y Y N

c.3011_3019delCTATAGCAG 3141del9 or 3143del9 N N Y

c.3140-26A>G 3272-26A>G Y Y N

c.3718-2477C>T 3849+10kbC>T Y Y N

c.413_415dup 546insCTA or L138ins N Y Y

c.579+3A>G 711+3A>G Y Y N

c.3017C>A A1006E N Y Y

c.3199G>A A1067T^c Y Y Y

c.358G>A A120T Y Y Y

c.701C>A A234D^c Y Y Y

c.1046C>T A349V^c Y Y Y

c.137C>A A46D N N Y

c.1364C>A A455E Y Y Y

(13)

c.1661C>A A554E^c N Y Y

c.330C>A D110E Y Y Y

c.328G>C D110H Y Y Y

c.3454G>C D1152H Y Y Y

c.3808G>A D1270N^a Y Y Y

c.575A>G D192G Y Y Y

c.1327G>T D443Y N Y Y

c.[1327G>T;1727G>C;2002C>T] D443Y;G576A;R668C^a N Y Y

c.1736A>G D579G Y Y Y

c.1841A>G D614G N Y Y

c.2506G>T D836Y^a N Y Y

c.2770G>A D924N^c Y Y Y

c.2936A>T D979V N Y Y

c.346G>A E116K N Y Y

c.577G>A E193K Y Y Y

c.1209G>C E403D^b N Y Y

c.1420G>A E474K N N Y

c.166G>A E56K Y Y Y

c.1763A>T E588V N Y Y

c.178G>A E60K N Y Y

c.2464G>A E822K^c Y Y Y

(14)

c.2491G>T E831X Y Y N

c.274G>A E92K N Y Y

c.3047T>C F1016S N Y Y

c.3154T>G F1052V Y Y Y

c.3222T>A or c.3220T>C F1074L Y Y Y

c.3297C>A F1099L N Y Y

c.571T>G F191V N Y Y

c.935_937del F311del or F312del Y Y Y

c.933C>G or c.933C>A F311L Y Y Y

c.1523T>G F508C^a Y Y Y

c.[1523T>G;3752G>A] F508C;S1251N Y Y Y

c.1521_1523delCTT F508del N Y Y

c.1724T>A F575Y N Y Y

c.3181G>C G1061R N N Y

c.3205G>A G1069R Y Y Y

c.3731G>A G1244E Y Y Y

c.3745G>A G1249R Y Y Y

c.377G>A G126D N Y Y

c.4046G>A G1349D Y Y Y

c.533G>A G178E^c Y Y Y

c.532G>A G178R Y Y Y

(15)

c.580G>A G194R Y Y Y

c.581G>T G194V N Y Y

c.79G>A G27R N N Y

c.941G>A G314E Y Y Y

c.1388G>T G463V^c N N Y

c.1438G>T G480C^c N N Y

c.1652G>A G551D Y Y Y

c.1651G>A G551S Y Y Y

c.1727G>C G576A^a Y Y Y

c.[1727G>C;2002C>T] G576A;R668C^a N Y Y

c.1865G>A G622D N Y Y

c.1882G>A or c.1882G>C G628R N N Y

c.254G>A G85E N N Y

c.2909G>A G970D Y Y Y

c.3160C>G H1054D N Y Y

c.3254A>C H1085P^c N N Y

c.3254A>G H1085R N N Y

c.4124A>C H1375P Y Y Y

c.416A>G H139R N N Y

c.595C>T H199Y N N Y

c.2816A>G H939R^b Y Y Y

(16)

c.3080T>C I1027T^a Y Y Y

c.3415A>G I1139V Y Y Y

c.3806T>A I1269N N Y Y

c.4097T>A I1366N N Y Y

c.443T>C I148T^a Y Y Y

c.523A>G I175V^b Y Y Y

c.1007T>A I336K N Y Y

c.1505T>C I502T N N Y

c.1801A>T I601F N Y Y

c.1853T>C I618T N Y Y

c.2421A>G I807M^a Y Y Y

c.2939T>A I980K N Y Y

c.3179A>C K1060T^c Y Y Y

c.3230T>C L1077P N N Y

c.3971T>C L1324P N Y Y

c.4004T>C L1335P N Y Y

c.4439T>C L1480P Y Y Y

c.44T>C L15P N Y Y

c.494T>C L165S N N Y

c.617T>G L206W Y Y Y

c.958T>G L320V^a Y Y Y

(17)

c.1037T>C L346P N Y Y

c.1358T>C L453S N N Y

c.2900T>C L967S Y Y Y

c.2991G>C L997F^a Y Y Y

c.3302T>A M1101K N N Y

c.454A>G M152V^b Y Y Y

c.794T>G M265R N Y Y

c.2856G>C M952I Y Y Y

c.2855T>C M952T^c Y Y Y

c.613C>T P205S N Y Y

c.1721C>A P574H N N Y

c.14C>T P5L N Y Y

c.200C>T P67L Y Y Y

c.3872A>G Q1291R Y Y Y

c.709C>G Q237E Y Y Y

c.711G>C Q237H^c Y Y Y

c.1076A>G Q359R Y Y Y

c.293A>G Q98R N Y Y

c.3197G>A R1066H N Y Y

c.3209G>A R1070Q Y Y Y

c.3208C>T R1070W Y Y Y

(18)

c.3485G>T R1162L^a Y Y Y

c.349C>T R117C Y Y Y

c.349C>G R117G Y Y Y

c.350G>A R117H Y Y Y

c.350G>T R117L Y Y Y

c.350G>C R117P Y Y Y

c.3848G>T R1283M Y Y Y

c.3849G>C or c.3849G>T R1283S^c N Y Y

c.509G>A R170H^a Y Y Y

c.772A>G R258G N Y Y

c.92G>T R31L^c N Y Y

c.1001G>T R334L N Y Y

c.1001G>A R334Q N Y Y

c.1040G>A R347H Y Y Y

c.1040G>T R347L Y Y Y

c.1040G>C R347P N Y Y

c.1055G>A R352Q Y Y Y

c.1054C>T R352W N Y Y

c.1658G>A R553Q^c Y Y Y

c.2002C>T R668C^a Y Y Y

c.221G>A R74Q^c N Y Y

(19)

c.220C>T R74W^a Y Y Y

c.[220C>T;3808G>A] R74W;D1270N^a N Y Y

c.[220C>T;601G>A] R74W;V201M^a N Y Y

c.[220C>T;601G>A;3808G>A] R74W;V201M;D1270N^a N Y Y

c.2252G>T R751L^c N Y Y

c.224G>A R75Q^a Y Y Y

c.2374C>G R792G^c Y Y Y

c.2797A>G R933G Y Y Y

c.3476C>T S1159F Y Y Y

c.3475T>C S1159P Y Y Y

c.3752G>A S1251N Y Y Y

c.3763T>C S1255P Y Y Y

c.38C>T S13F N N Y

c.1021T>C S341P N N Y

c.1090T>C S364P^c N N Y

c.1475C>T S492F N N Y

c.1646G>A S549N Y Y Y

c.1645A>C or c.1647T>G S549R Y Y Y

c.1766G>A S589N^b,c Y Y Y

c.2210C>T S737F^b,c Y Y Y

c.2735C>T S912L^c N Y Y

(20)

c.2834C>T S945L Y Y Y

c.2930C>T S977F Y Y Y

c.3107C>A T1036N N Y Y

c.3158C>T T1053I^a Y Y Y

c.1013C>T T338I Y Y Y

c.3458T>A V1153E N Y Y

c.3719T>G V1240G N Y Y

c.3878T>G V1293G^c Y Y Y

c.601G>A V201M N Y Y

c.695T>A V232D Y Y Y

c.1367T>C V456A N N Y

c.1366G>T V456F^c N N Y

c.1684G>A V562I^a Y Y Y

c.2260G>A V754M^a Y Y Y

c.3294G>C W1098C N N Y

c.3844T>C W1282R^c Y Y Y

c.1081T>C W361R N N Y

c.1081T>A W361R^c N N Y

c.3041A>G Y1014C^c Y Y Y

c.3095A>G Y1032C Y Y Y

c.325T>A Y109N^c N Y Y

(21)

c.481T>G Y161D N N Y

c.482A>C Y161S^c N Y Y

a

classified as non-CF causing (i.e., causing a CFTR-RD or non-disease causing) by either CFTR2 or CFTR-France

b

exonic variants that are known or suspected to result in a major splicing defect

c

Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis Supplemental Information