CFTR gene mutations approved for each type of CFTR modulator therapy

CFTR gene mutations approved for each type of CFTR modulator therapy

546insCTA	E403D	G628R	L346P	R117H	S912L
711+3A>G	E474K	G970D	L453S	R117L	S945L
2789+5G>A	E588V	G1061R	L967S	R117P	S977F
3141del9	E822K	G1069R	L997F	R170H	S1159F
3272-26A>G	E831X	G1244E	L1077P	R258G	S1159P
3849+10kbC>T	F191V	G1249R	L1324P	R334L	S1251N
A46D	F311del	G1349D	L1335P	R334Q	S1255P
A120T	F311L	H139R	L1480P	R347H	T338I
A234D	F508C	H199Y	M152V	R347L	T1036N
A349V	F508C;S1251N	H939R	M265R	R347P	T1053I
A455E	F508del*	H1054D	M952I	R352Q	V201M
A554E	F575Y	H1085P	M952T	R352W	V232D
A1006E	F1016S	H1085R	M1101K	R553Q	V456A
A1067T	F1052V	H1375P	P5L	R668C	V456F
D110E	F1074L	I148T	P67L	R751L	V562I
D110H	F1099L	I175V	P205S	R792G	V754M
D192G	G27R	I336K	P574H	R933G	V1153E
D443Y	G85E	I502T	Q98R	R1066H	V1240G
D443Y;G576A;R668C	G126D	I601F	Q237E	R1070Q	V1293G
D579G	G178E	I618T	Q237H	R1070W	W361R
D614G	G178R	I807M	Q359R	R1162L	W1098C
D836Y	G194R	I980K	Q1291R	R1283M	W1282R
D924N	G194V	I1027T	R31L	R1283S	Y109N
D979V	G314E	I1139V	R74Q	S13F	Y161D
D1152H	G463V	I1269N	R74W	S341P	Y161S
D1270N	G480C	I1366N	R74W;D1270N	S364P	Y563N
E56K	G551D	K1060T	R74W;V201M	S492F	Y1014C
E60K	G551S	L15P	R74W;V201M;D1270N	S549N	Y1032C
E92K	G576A	L165S	R75Q	S549R
E116K	G576A;R668C	L206W	R117C	S589N
E193K	G622D	L320V	R117G	S737F

Color key:
Approved for ELX-TEZ-IVA, TEZ-IVA, and IVA
Approved for ELX-TEZ-IVA and TEZ-IVA
Approved for ELX-TEZ-IVA only
Approved for IVA and TEZ-IVA but not ELX-TEZ-IVA^¶

A patient is eligible for ELX-TEZ-IVA if they have 1 or more of the above mutations (except for the 5 mutations noted), with any disease-causing mutation at the other allele. In general, if a patient has a genotype that is eligible for more than 1 therapy, we suggest starting on the maximal therapy available for their age group (ie, triple therapy > dual therapy > monotherapy). As of May 2023, IVA is approved in the United States for children ≥1 month old, ELX-TEZ-IVA for ≥2 years, and TEZ-IVA for ≥6 years.

CFTR: cystic fibrosis transmembrane conductance regulator; ELX-TEZ-IVA (ETI): elexacaftor-tezacaftor-ivacaftor; TEZ-IVA: tezacaftor-ivacaftor; IVA: ivacaftor, LUM-IVA: lumacaftor-ivacaftor.

* F508del is the most common CFTR gene mutation in most populations. Drug eligibility considerations are:

F508del heterozygotes – To be eligible for ELX-TEZ-IVA, only 1 copy of F508del is required. To be eligible for TEZ-IVA, patients must have 2 copies of a responsive mutation (eg, F508del with any other responsive mutation on the other allele).
F508del homozygotes – Patients who are homozygotes for F508del are eligible for several drug combinations. We recommend triple therapy (ETI) rather than dual therapy (TEZ-IVA or LUM-IVA) as soon as they reach an eligible age for ETI (≥2 years). We suggest LUM-IVA for children ages 1 to <2 years.

¶ ELX-TEZ-IVA has not been approved for use in these 5 "splice site" mutations, because the assay used as a predictor of efficacy is not valid for this type of mutation. Clinical studies of ELX-TEZ-IVA have not included sufficient numbers of patients with these rare mutations to assess efficacy in this population. However, the demonstrated efficacy of IVA and TEZ-IVA for patients with these mutations suggests that ELX-TEZ-IVA would also be effective.

Data from:

KALYDECO® (ivacaftor) Tablets and Oral Granules. Vertex Pharmaceuticals Incorporated. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207925s016lbl.pdf (Accessed on May 9 2023).
SYMDEKO® (tezacaftor/ivacaftor; ivacaftor) Tablets. Vertex Pharmaceuticals Incorporated. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210491s007lbl.pdf (Accessed on December 20, 2020).
TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor; ivacaftor) Tablets and Oral Granules. Vertex Pharmaceuticals Incorporated. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217660s000lbl.pdf (Accessed on April 29, 2023).

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CFTR gene mutations approved for each type of CFTR modulator therapy