408 Form

Pharmacy Medical Policy
Drugs for Cystic Fibrosis Table of Contents
• Policy: Commercial • Information Pertaining to All Policies • Endnotes
• Policy: Medicare • References • Forms • Policy History

Policy Number: 408 BCBSA Reference Number: None Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

Note: All requests for outpatient retail pharmacy for indications listed and not listed on the medical policy guidelines may be submitted to BCBSMA Clinical Pharmacy Operations by completing the Prior Authorization Form on the last page of this document. Physicians may also call BCBSMA Pharmacy Operations department at (800)366-7778 to request a prior authorization/formulary exception verbally. Physicians may also submit requests for retail pharmacy exceptions via the web using Express PAth which can be found on the BCBSMA provider website or directly on the web at https://provider.express-path.com. Patients must have pharmacy benefits under their subscriber certificates.

Prior Authorization Information ☒ Prior Authorization ☐ Step Therapy ☐ Quality Care Dosing

Pharmacy Operations: Tel: 1-800-366-7778 Fax: 1-800-583-6289 Policy last updated 4/2025 Pharmacy (Rx) or Medical (MED) benefit coverage ☒ Rx ☐ MED To request for coverage: Physicians may call, fax, or mail the attached form (Formulary Exception/Prior Authorization form) to the address below.
Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043

Individual Consideration: Policy for requests that do not meet clinical criteria of this policy, see section labeled Individual Consideration
Policy applies to Commercial Members:
• Managed Care (HMO and POS),
• PPO and Indemnity • MEDEX with Rx plan • Managed Major Medical with Custom BCBSMA Formulary • Comprehensive Managed Major Medical with Custom BCBSMA Formulary • Managed Blue for Seniors with Custom BCBSMA Formulary

Please refer to the chart below for the formulary and step status of the medications affected by this policy.

Drug Formulary Information Standard Formulary Status Alyftrek™ (vanzacaftor / tezacaftor / deutivacaftor) PA Required Kalydeco ™ (ivacaftor) PA Required Orkambi ™ (lumacaftor / ivacaftor) PA Required Symdeko ™ (tezacaftor / ivacaftor) PA Required Trikafta ™ (elexacaftor / tezacaftor / ivacaftor) PA Required

We may cover Alyftrek ™ (vanzacaftor / tezacaftor / deutivacaftor) for the treatment of cystic fibrosis when all of the following criteria are met: • Age 6 years of age or older, AND • Concurrent use of Symdeko ™ or Kalydeco ™ or Orkambi ™ or Trikafta™ must be discontinued, AND • Documentation for at least one F508del mutation in the CFTR gene as confirmed by an FDA- cleared cystic fibrosis mutation test OR • Documentation of one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to vanzacaftor / tezacaftor / deutivacaftor based on in vitro data and/or clinical evidence as noted in table 1 below:

• Table 1 lists CFTR mutations responsive to ALYFTREK based on clinical response, and/or in vitro data in FRT or HBE cells, or based on extrapolation of efficacy

Table 1: List of CFTR Gene Mutations Responsive to ALYFTREK

Based on Clinical Data*

A455E
G551D
L1077P†
R352Q
S549N
V754M

D1152H
G85E†
L206W
R75Q
S549R
W1098C†

F508del†
H1054D
M1101K†
S1159F
S945L
W1282R

G1244E
I336K
R1066H
S1251N
V562I
Y563N†

Based on in vitro Data‡

1507_1515del9 E116Q
G424S
I556V
P140S
R334L
T1053I
2183A→G
E193K
G463V
I601F
P205S
R334Q
T1086I
3141del9
E292K
G480C
I618T
P499A
R347H
T1246I
3195del6
E403D
G480S
I807M
P5L
R347L
T1299I
3199del6
E474K
G551A
I980K
P574H
R347P
T338I
546insCTA
E56K
G551S
K1060T
P67L
R352W
T351I
A1006E
E588V
G576A
K162E
P750L
R516G
T604I
A1067P
E60K
G576A;R668C §
K464E
P99L
R516S
V1153E
A1067T
E822K
G622D
L1011S
Q1100P
R553Q
V1240G
A107G
E92K
G628R
L102R
Q1291R
R555G
V1293G
A120T
F1016S
G91R
L1065P
Q1313K
R560S
V201M
A234D
F1052V
G970D
L1324P
Q237E
R560T
V232D
A309D
F1074L
G970S
L1335P
Q237H
R668C
V392G
A349V
F1099L
H1085P
L137P
Q359R
R709Q
V456A
A46D
F1107L
H1085R
L1480P
Q372H
R74Q
V456F
A554E
F191V
H1375P
L15P
Q452P
R74W
V520F
A559T
F200I
H139R
L165S
Q493R
R74W;D1270N §
V603F
A559V
F311del
H199R
L320V
Q552P
R74W;V201M§ W361R
A561E
F311L
H199Y
L333F
Q98R
R74W;V201M; D 1270N§
Y1014C

A613T
F508C
H609R
L333H
R1048G
R75L
Y1032C
A62P
F508C;S1251N §
H620P
L346P
R1066C
R751L
Y109N
A72D
F575Y
H620Q
L441P
R1066L
R792G
Y161D
C491R
F587I
H939R
L453S
R1066M
R933G
Y161S
D110E
G1047R
H939R;H949L L619S
R1070Q
S1045Y
Y301C
D110H
G1061R
I1027T
L967S
R1070W
S108F
Y569C
D1270N
G1069R
I105N
L997F
R1162L
S1118F
Y913C
D1445N
G1123R
I1139V
M1101R
R117C
S1159P

D192G
G1247R
I1234Vdel6aa M1137V
R117C;G576A; R 668C
S1235R

D443Y
G1249R
I125T
M150K
R117G
S1255P

D443Y;G576A; R 668C§
G126D
I1269N
M152V
R117H
S13F

D513G
G1349D
I331N
M265R
R117L
S341P

D565G
G149R
I1366N
M952I
R117P
S364P

D579G
G178E
I1398S
M952T
R1283M
S492F

D614G
G178R
I148N
N1088D
R1283S
S549I

D836Y
G194R
I148T
N1303I
R170H
S589N

D924N
G194V
I175V
N1303K‡
R258G
S737F

D979V
G27E
I502T
N186K
R297Q
S912L

D993Y
G27R
I506L
N187K
R31C
S977F

E116K
G314E
I506T
N418S
R31L
T1036N

Based on Extrapolation¶
1341G→A
2789+2insA
3041-15T→G
3849+10kbC→ T
3850-3T→G
5T;TG13
711+3A→ G
1898+3A→G
2789+5G→A
3272-26A→G
3849+4A→G
4005+2T→C
621+3A→G
E831X
2752-26A→G
296+28A→G
3600G→A
3849+40A→G
5T;TG12

• Clinical data is obtained from Trials 1 and 2.
  † This mutation is also predicted to be responsive by FRT assay with ALYFTREK.
  ‡ The N1303K mutation is predicted to be responsive only by HBE assay. All other mutations predicted to be responsive with in vitro data are supported by FRT assay.
  § Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.
  ¶ Efficacy is extrapolated to certain non-canonical splice mutations because clinical trials in all mutations in this subgroup are infeasible and these mutations are not amenable to interrogation by FRT system.

  We may cover Kalydeco ™ (ivacaftor) for the treatment of cystic fibrosis when all of the following criteria are met1: • Age 4 months of age or older AND • Concurrent use of Alyftrek ™ or Symdeko™ or Trikafta ™ or Orkambi™ must be discontinued. AND • Documentation of a mutation of the CFTR gene as confirmed by an FDA- cleared cystic fibrosis mutation test. In Table 2 below.

  Table 2 (Kalydeco Mutations) 711+3A→G F311del I148T R75Q S589N 2789+5G→A F311L I175V R117C S737F 3272-26A→G F508C I807M R117G S945L 3849+10kbC→T F508C;S1251N † I1027T R117H S977F A120T F1052V I1139V R117L S1159F

A234D F1074L K1060T R117P S1159P A349V G178E L206W R170H S1251N A455E G178R L320V R347H S1255P A1067T G194R L967S R347L T338I D110E G314E L997F R352Q T1053I D110H G551D L1480P R553Q V232D D192G G551S M152V R668C V562I D579G G576A M952I R792G V754M D924N G970D M952T R933G V1293G D1152H G1069R P67L R1070Q W1282R D1270N G1244E Q237E R1070W Y1014C E56K G1249R Q237H R1162L Y1032C E193K G1349D Q359R R1283M E822K H939R Q1291R S549N E831X H1375P R74W S549R *Clinical data exist for these mutations. †Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.

We may cover Orkambi ™ (lumacaftor and ivacaftor) for the treatment of cystic fibrosis when all of the following criteria are met: • Age 1 years of age or older AND • Documentation of TWO copies of the F508del mutation in the CFTR gene as confirmed by an FDA- cleared cystic fibrosis mutation test AND • Concurrent use of Alyftrek ™ or Symdeko™ or Trikafta ™ or Kalydeco™ must be discontinued.

We may cover Symdeko ™ (tezacaftor and ivacaftor) for the treatment of cystic fibrosis when all of the following criteria are met: • Age 6 years of age or older, AND • Documentation of Homozygous for the F508del mutation in the CFTR gene as confirmed by an FDA- cleared cystic fibrosis mutation test OR • Documentation of one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence as noted in table 3 below:

AND • Concurrent use of Kalydeco ™ or Orkambi ™ or Alyftrek ™ or Trikafta ™ must be discontinued.

Table 3: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to SYMDEKO 546insCTA E92K G576A L346P R117G S589N 711+3A→G E116K G576A;R668C † L967S R117H S737F 2789+5G→A E193K G622D L997F R117L S912L 3272-26A→G E403D G970D L1324P R117P S945L

3849+10kbC→T E588V G1069R L1335P R170H S977F A120T E822K G1244E L1480P R258G S1159F A234D E831X G1249R M152V R334L S1159P A349V F191V G1349D M265R R334Q S1251N A455E F311del H939R M952I R347H S1255P A554E F311L H1054D M952T R347L T338I A1006E F508C H1375P P5L R347P T1036N A1067T F508C;S1251N † I148T P67L R352Q T1053I A120T E822K G1244E L1480P R258G S1159F A234D E831X G1249R M152V R334L S1159P A349V F191V G1349D M265R R334Q S1251N A455E F311del H939R M952I R347H S1255P A554E F311L H1054D M952T R347L T338I A1006E F508C H1375P P5L R347P T1036N A1067T F508C;S1251N † I148T P67L R352Q T1053I D110E F508del ‡ I175V P205S R352W V201M D110H F575Y I336K Q98R R553Q V232D D192G F1016S I601F Q237E R668C V562I D443Y F1052V I618T Q237H R751L V754M D443Y;G576A;R668C † F1074L I807M Q359R R792G V1153E D579G F1099L I980K Q1291R R933G V1240G D614G G126D I1027T R31L R1066H V1293G D836Y G178E I1139V R74Q R1070Q W1282R D924N G178R I1269N R74W R1070W Y109N D979V G194R I1366N R74W;D1270N † R1162L Y161S D1152H G194V K1060T R74W;V201M † R1283M Y1014C D1270N G314E L15P R74W;V201M;D1270N † R1283S Y1032C E56K G551D L206W R75Q S549N E60K G551S L320V R117C S549R

We may cover Trikafta ™ (elexacaftor, tezacaftor and ivacaftor) for the treatment of cystic fibrosis when all of the following criteria are met1: • Age 2 years of age or older, AND • Concurrent use of Symdeko ™ or Kalydeco ™ or Orkambi ™ or Alyftrek ™ must be discontinued, AND • Documentation for at least one F508del mutation in the CFTR gene as confirmed by an FDA- cleared cystic fibrosis mutation test in table 4below.

Table 4: List of CFTR Gene Mutations Responsive to TRIKAFTA Mutations responsive to TRIKAFTA based on clinical data* 2789+5G→A D1152H† L206W† R1066H† S945L† 3272-26A→G F508del† L997F† R117C† T338I† 3849+10kbC→T G85E† M1101K† R347H† V232D† A455E† L1077P† P5L† R347P† Mutations responsive to TRIKAFTA based on in vitro data‡ N1303K F200I I1139V P574H S1045Y 1507_1515del9 F311del I125T P67L S108F 2183A→G F311L I1269N P750L S1118F 3141del9 F508C I1366N Q1291R S1159F 546insCTA F508C;S1251N I148N Q1313K S1159P A1006E F575Y I148T Q237E S1235R A1067P F587I I175V Q237H S1251N A1067T G1047R I331N Q359R S1255P A107G G1061R I336K Q372H S13F A120T G1069R I502T Q493R S341P A234D G1123R I506L Q552P S364P A309D G1244E I556V Q98R S492F A349V G1247R I601F R1048G S549I A46D G1249R I618T R1070Q S549N A554E G126D I807M R1070W S549R A62P G1349D I980K R1162L S589N

C491R G178E K1060T R117C;G576A;R668C S737F D110E G178R K162E R117G S912L D110H G194R K464E R117H S977F D1270N G194V L1011S R117L T1036N D1445N G27E L1324P R117P T1053I D192G G27R L1335P R1283M T1086I D443Y G314E L137P R1283S T1246I D443Y;G576A;R668C G424S L1480P R170H T1299I D565G G463V L15P R258G T351I D579G G480C L165S R297Q V1153E D614G G480S L320V R31C V1240G D836Y G551A L333F R31L V1293G D924N G551D L333H R334L V201M D979V G551S L346P R334Q V392G D993Y G576A L441P R347L V456A E116K G576A;R668C L453S R352Q V456F E116Q G622D L619S R352W V562I E193K G628R L967S R516S V603F E292K G970D M1137V R553Q V754M E403D G970S M150K R555G W1098C E474K H1054D M152V R668C W1282R E56K H1085P M265R R709Q W361R E588V H1085R M952I R74Q Y1014C E60K H1375P M952T R74W Y1032C E822K H139R N1088D R74W;D1270N Y109N E92K H199Y N1303I R74W;V201M Y161D F1016S H620P N186K R74W;V201M;D1270N Y161S F1052V H620Q N187K R751L Y301C F1074L H939R N418S R75L Y563N F1099L H939R;H949L P140S R75Q

F1107L I1027T P205S R792G F191V I105N P499A R933G

Mutations responsive to TRIKAFTA based on extrapolation from Trial 5§ 4005+2T→C 2789+2insA 3849+40A→G 5T;TG13 1341G→A 296+28A→G 3849+4A→G 621+3A→G 1898+3A→G 3041-15T→G 3850-3T→G 711+3A→G 2752-26A→G 3600G→A 5T;TG12 E831X

• Clinical data obtained from Trials 1, 2, and 5. † This mutation is also predicted to be responsive by FRT assay. ‡ The N1303K mutation is predicted to be responsive by HBE assay. All other mutations predicted to be responsive with in vitro data are supported by FRT assay.

  § Efficacy is extrapolated from Trial 5 to non-canonical splice mutations because clinical trials in all mutations of this subgroup are infeasible and these mutations are not amenable to interrogation by FRT system.

  We do not cover the above drugs for other conditions not listed above.

  Other Information Blue Cross Blue Shield of Massachusetts (BCBSMA*) members (other than Medex®; Blue MedicareRx, Medicare Advantage plans that include prescription drug coverage) will be required to fill their prescriptions for the above medications at one of the providers in our retail specialty pharmacy network, see link below:

  Link to Specialty Pharmacy List
  Individual Consideration All our medical policies are written for the majority of people with a given condition. Each policy is based on medical science. For many of our medical policies, each individual’s unique clinical circumstances may be considered in light of current scientific literature. Physicians may send relevant clinical information for individual patients for consideration to:

  Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043
  Tel: 1-800-366-7778 Fax: 1-800-583-6289

  Policy History
  Date Action 6/2025 Updated to add Alyftrek 5/2023 Updated additional mutations for Trikafta
  7/2023 Updated Age for Trikafta. 11/2022 Updated new age for Orkambi ™ for homozygous F508del mutation criteria. 7/2021 Updated to include age update for Trikafta ™ 2/2021 Updated to add New eligible mutations to the policy. 10/2020 Updated to include new age edit for Kalydeco ™. 2/2020 Updated to add Trikafta™ to the policy. 8/2019 Updated to include new age range for Symdeko ™. 9/2018 Updated to include new age range for Orkambi ™ & Kalydeco ™.

6/2018 Updated to include Symdeko™ and to add Specialty Pharmacy Link. 10/2017 Updated to change Walgreens Specialty Name. 7/2017 Updated to include additional genes and add AllCare to Specialty pharmacy list. 6/2017 Updated address for Pharmacy Operations. 11/2016 Updated to include new age indication for Orkambi ™. 4/2016 Updated to include Orkambi™ & add Walgreens Specialty. 4/2015 Updated for new FDA approved ages. 2/2015 Updated new gene types which were FDA approved. 4/2014 Updated new gene types which were FDA approved. 2/2014 Removal of Curascript from Specialty Pharmacy section. 1/2014 Updated to remove Blue Value. 1/2013 New Policy, effective 1/1/2013. References

1. Kalydeco ™ [package insert]. Cambridge, MA: Vertex Pharmaceuticals, Inc.: 2012.
2. Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. Jan 30 2012.
3. Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. Nov 18 2010;363(21):1991-2003.
4. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. Nov 3 2011;365(18):1663-1672.
5. Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in Subjects with Cystic Fibrosis who are Homozygous for the F508del-CFTR Mutation. Chest. Mar 1 2012.
6. Sanders DB, Farrell PM. Transformative mutation specific pharmacotherapy for cystic fibrosis. BMJ. 2012;344:e79.
7. Aherns R, Rodriguez S, Yen K, Davies JC. VX-770 in subjects 6 to 11 years with cystic fibrosis and the G551D-CFTR mutation. Pediatric Pulmonology. 2011;46:283.
8. Orkambi ™ [package insert]. Cambridge, MA: Vertex Pharmaceuticals, Inc.: July 2015.
9. Symdeko ™ [package insert]. Cambridge, MA: Vertex Pharmaceuticals, Inc.: Feb 2018.
10. Trikafta ™ [package insert]. Cambridge, MA: Vertex Pharmaceuticals, Inc.: Oct 2019. Alyftrek ™ [package insert]. Cambridge, MA: Vertex Pharmaceuticals, Inc.: Jan 2025. Endnotes

11. Based on BCBSA Technology Evaluation Center Specialty Pharmacy Combined Capacity (SPCC) Report #3-2012 Ivacaftor (Kalydeco™), reviewed March 2012.

    To request prior authorization using the Massachusetts Standard Form for Medication Prior Authorization Requests (eForm), click the link below: http://www.bluecrossma.org/medical-policies/sites/g/files/csphws2091/files/acquiadam- assets/023%20E%20Form%20medication%20prior%20auth%20instruction%20prn.pdf