In November, Vertex submitted an application to the European Medicines Agency EMA to extend the use of Kaftrio to people with specific mutations beyond F508del, aged 2 years and older. Until now, Kaftrio had only been approved and reimbursed for people with at least one F508del mutation, but this extension would also make people with specific rare mutations eligible. This is a first in Europe.

Which mutations are involved?

About 200 mutations are involved, which can be roughly classified into four major groups:

  1. People with an N1303K mutation. In Europe, this is the third most common mutation.
  2. 5 specific non-canonical splicing mutations: 711+3A→G, 2789+5G→A, 3272‑26A→G, 3849+10kbC→T, and E831X. These splicing mutations are abnormalities in the CFTR gene that result in either lower amounts of protein or a slightly altered (and therefore ineffective) CFTR protein. As a result, there is a significant reduction in the amount of CFTR protein that reaches the cell surface.
  3. The 18 mutations tested in a clinical trial conducted by Vertex last year: 2789+5G→A, 3272 26A→G, 3849+10kbC→T, P5L, R117C, L206W, V232D, T338I, R347H, A455E, S945L, L997F, R1066H, D1152H, G85E, R347P, L1077P, M1101K. The results of this study have not yet been published. Vertex did reveal that the lung function of the study participants increased by an average of 9.2% thanks to Kaftrio. This is slightly less than average in people with at least one F508del mutation, but certainly significant. More results are expected early next year.
  4. 178 mutations that have already been approved in the United States:
1.             3141del9

2.             546insCTA

3.             A1067T

4.             A455E

5.             A46D

6.             A349V

7.             A1006E

8.             A120T

9.             A234D

10.          A554E

11.          D110E

12.          D110H

13.          D1152H

14.          D1270N

15.          D579G

16.          D443Y

17.          D924N

18.          D192G

19.          D979V

20.          D614G

21.          D836Y

22.          D443Y;G576A;R668C

23.          E193K

24.          E56K

25.          E474K

26.          E116K

27.          E60K

28.          E588V

29.          E92K

30.          E403D

31.          E822K

32.          F508del

33.          F1052V

34.          F1074L

35.          F311L

36.          F575Y

37.          F1099L

38.          F508C

39.          F311del

40.          F191V

41.          F1016S

42.          F508C;S1251N

43.          G1069R

44.          G1244E

45.          G1349D

46.          G178R

47.          G551D

48.          G551S

49.          G85E

50.          G1061R

51.          G480C

52.          G27R

53.          G463V

54.          G628R

55.          G622D

56.          G126D

57.          G970D

58.          G194R

59.          G314E

60.          G194V

61.          G576A

62.          G1249R

63.          G178E

64.          G576A;R668C

65.          H139R

66.          H1085R

67.          H1085P

68.          H939R

69.          H1375P

70.          H1054D

71.          H199Y

72.          I502T

73.          I618T

74.          I175V

75.          I1366N

76.          I601F

77.          I980K

78.          I1269N

79.          I1027T

80.          I148T

81.          I336K

82.          I807M

83.          I1139V

84.          K1060T

85.          L206W

86.          L1077P

87.          L165S

88.          L1335P

89.          L967S

90.          L320V

91.          L346P

92.          L1324P

93.          L997F

94.          L15P

95.          L453S

96.          L1480P

97.          M1101K

98.          M265R

99.          M152V

100.        M952I


101.        M952T

102.        P67L

103.        P5L

104.        P205S

105.        P574H

106.        Q98R

107.        Q1291R

108.        Q237E

109.        Q237H

110.        Q359R

111.        R1070Q

112.        R1070W

113.        R117C

114.        R117H

115.        R347H

116.        R352Q

117.        R74W

118.        R347P

119.        R117G

120.        R170H

121.        R334L

122.        R117L

123.        R31L

124.        R933G

125.        R352W

126.        R117P

127.        R258G

128.        R751L

129.        R347L

130.        R1283S

131.        R1162L

132.        R553Q

133.        R792G

134.        R1066H

135.        R668C

136.        R334Q

137.        R1283M

138.        R75Q

139.        R74Q

140.        R74W;V201M;D1270N

141.        R74W;D1270N

142.        R74W;V201M

143.        S1251N

144.        S1255P

145.        S549N

146.        S549R

147.        S945L

148.        S977F

149.        S13F

150.        S1159F


151.        S912L

152.        S1159P

153.        S589N

154.        S341P

155.        S492F

156.        S737F

157.        S364P

158.        T1053I

159.        T1036N

160.        T338I

161.        V456A

162.        V456F

163.        V201M

164.        V562I

165.        V1153E

166.        V1240G

167.        V1293G

168.        V754M

169.        V232D

170.        W361R

171.        W1098C

172.        W1282R

173.        Y563N

174.        Y161D

175.        Y109N

176.        Y1014C

177.        Y161S

178.        Y1032C


An approval could allow Kaftrio to be prescribed to an additional 2,800 people across Europe, according to the manufacturer.

When can we expect a decision?

EMA declared the dossier admissible at the end of November, meaning that they would be able to start their assessment. This procedure at European level normally takes 6 to 9 months. However, in many countries, an approval by EMA does not necessarily mean that there is access for those eligible, as reimbursement discussions take place on a national level.

We should also remain very cautious. This is the first time such a broad dossier has been submitted to EMA. Moreover, not all evidence comes from clinical studies, but also from lab tests, for example. It remains to be seen whether EMA considers this evidence sufficient. It could also be that EMA gives a partially positive opinion.

So will there be Kaftrio for everyone?

No. We know from studies around Europe that there are still a number of mutations that do respond well to Kaftrio, but are most likely not included in this application. And then there are the stop mutations, resulting in a complete absence of CFTR protein. As modulators do not work in this case, there is no point in seeking approval for these mutations.

Philip Watt, President of CFE stated

‘This is a really welcome first step for those people with CF that currently do not get access to Kaftrio because of their rare CFTR mutation is currently not approved by the EMA. It will take some months now for the Vertex dossier to be considered by the EMA and all being well, sanctioned by the European Commission and national governments. In welcoming this crucial first step – it’s also important to emphasise that some people will never benefit (or may not tolerate) a CFTR modulator – so there is still need for new and innovative therapies beyond Kafrio. The potential of mRNA and gene editing are examples of innovative therapies being researched at present- with still no definitive research outcomes from either and more research needed.’

What will CF Europe do now?

Of course we remain in close contact with Vertex concerning the status of this application. We will also carefully monitor EMA’s decision-making process. This is possibly the first time that a decision on granting marketing authorisation would be based partly on data not directly originating from a clinical trial. This could be an important precedent for future innovative therapies, and not only for people with CF, but for the whole rare disease community.

This article is based on a press release from Vertex Pharmaceuticals.