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The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis

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Background Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences. Results CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data. Conclusions Regulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients’ eligibility and access: FDA’s approach was more mechanistic/biology-driven while the EMA’s one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.
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Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
https://doi.org/10.1186/s13023-022-02350-5
RESEARCH
The impact ofFDA andEMA regulatory
decision-making process ontheaccess toCFTR
modulators forthetreatment ofcystic brosis
Enrico Costa1* , Silvia Girotti2, Francesca Pauro3, Hubert G. M. Leufkens4 and Marco Cipolli3
Abstract
Background: Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance
regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this
analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up
the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public
health implications associated with differences.
Results: CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del
homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and
expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators
were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but
in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the
pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of
results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted
non-clinical evidence considering a recovery of the CFTR function 10% based on chloride transport, a reliable indi-
cator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to
expand the label of CFTR modulators without confirmatory clinical data.
Conclusions: Regulators played an important role in fostering the development and approval of CFTR modulators.
However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators,
which extended beyond semantics affecting patients’ eligibility and access: FDA’s approach was more mechanis-
tic/biology-driven while the EMA’s one was more oriented by clinical evidence. This might refer to the connection
between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical
data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical
commitment of ensuring larger access to all potential eligible patients (including those harboring very rare muta-
tions) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.
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Background
Cystic fibrosis (CF) is an autosomal recessive disease
caused by mutations in the cystic fibrosis transmem-
brane conductance regulator (CFTR) gene affecting the
functional expression of the CFTR protein, an ion chan-
nel that regulates the transport of chloride and bicar-
bonate at the cell surface [1]. Since the discovery of the
Open Access
*Correspondence: e.costa@uu.nl
1 WHO Collaborating Centre for Pharmaceutical Policy and Regulations,
Utrecht University, Utrecht, The Netherlands
Full list of author information is available at the end of the article
Page 2 of 14
Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
CFTR gene in 1989 [2], more than 2000 mutations have
been described, with different prevalence and sever-
ity of phenotype. Conventionally, mutations have been
grouped into six classes: mutations introducing prema-
ture termination codons (i.e. frameshift, splicing, or non-
sense mutations) (class I); misfolding mutations (class II);
mutations hindering the regulation of the CFTR channel,
also known as gating mutations (class III). ese classes
are usually associated with greater phenotypic sever-
ity and worse prognosis. On the other hand, mutations
that entail milder clinical symptoms and better progno-
sis: mutations altering channel conductance (Class IV);
mutations reducing the efficiency of CFTR production by
affecting splicing (Class V), and mutations reducing the
stability of mature CFTR at the cell membrane (Class VI)
[35].
Early diagnosis and advances in symptomatic thera-
peutics aimed at dealing with major clinical com-
plications—such as chronic airway infections and
pancreatic insufficiency due to an abnormally thick and
sticky mucus—have substantially improved the life-
expectancy of CF patients [6].
However, better understanding of molecular and cellu-
lar pathology of CF paved the way for the development of
a new class of drugs—called CFTR modulators—target-
ing the CFTR function directly [5]. As new agents were
developed targeting different genotypes, limitations in
the traditional class I–VI CF mutations system became
evident and a new more drug-driven approach was devel-
oped and adopted by regulators for labelling therapeu-
tic indications [1, 7, 8]. According to the US and the EU
orphan legislations, CF is a rare disease and therefore
drugs developed for its treatment are potentially eligi-
ble for Orphan Drug Designation (ODD), a special sta-
tus that provides regulatory and financial incentives to
sponsors to encourage drug development in unmet medi-
cal needs and non-profitable areas. Moreover, the US
Food and Drug Administration (FDA) and the European
Medicines Agency (EMA) have established similar pro-
grammes to expedite the review and approval of medi-
cines to treat serious and unmet medical need conditions
such as CF. e aim of this study is to compare FDA and
EMA approaches in the evaluation and approval of CFTR
modulators and to identify possible clinical and public
health implications associated with differences.
Methods
Data source andanalysis
Qualitative and quantitative data regarding regulatory
decisions (i.e. orphan drug designations, expedited pro-
grams, and approvals) by FDA and EMA on CFTR mod-
ulator medicinal products were retrieved from publicly
accessible documents of the Register of FDA Approved
Medicines [9] and from the register of medicinal prod-
ucts for human use authorized by the EU under the cen-
tralised procedure [10]. Data on evidence supporting
regulatory decisions were further searched on the full
prescribing information of FDA, the European public
assessment report (EPAR) of EMA, clinicaltrials.gov, and
published articles. Proofs were categorized into clinical
and invitro studies. Data from clinical studies included:
phase and design of the study, eligible population
(age and genotype), sample size, primary endpoint(s),
outcome(s), and duration of the study/follow-up. Addi-
tionally, information on epidemiology and in vitro
responsiveness of mutations to CFTR modulators were
retrieved from CFTR2 database [11]—a website that pro-
vides information for patients, researchers, and the gen-
eral public about specific variants in what is commonly
referred to as the CF gene—and from the FDA and the
EMA website, sponsor protocols, and scientific literature
as appropriate. All data were updated as of January 30,
2022. Comparative analyses on orphan designations, and
expedited programs granted by FDA and EMA were car-
ried out, as well as those on decisions regarding eligible
population (age and genotype), timing of decisions, and
evidence (clinical studies vs invitro studies) supporting
approvals and variations of indications.
Classication oftheCFTR mutations
Based on the pattern adopted by regulators, muta-
tions have been categorized as follows: F508del, either
as homozygous or heterozygous genotype; Gating, as
already provided by Class III definition; Conduction, as
already provided by Class IV definition; ‘Residual Func-
tion (RF)’; Minimal Function (MF); Other, which includes
all the mutations not belonging to the above-mentioned
categories (see Additional file 1). Acknowledgement of
RF and MF mutations hinges upon predicted residual/
minimal function of CFTR protein in keeping with pop-
ulation-level phenotypic data and in vitro response to
CFTR modulators (IVA and TEZ). MF mutations show
a severe phenotype—in fact, they lead to the complete
absence of CFTR protein production or function—and
do not respond invitro to either IVA or TEZ, or TEZ/
IVA [12, 13]; by contrast, RF mutations have a mild
phenotype and respond to the above-mentioned CFTR
modulators [14, 15]. Clinical severity has been defined
as average sweat chloride (Sweat test—ST) 86mmol/L,
and prevalence of pancreatic insufficiency (PI) 50%
[13], while invitro response to CFTR modulators as an
increase in percent normal chloride transport of 10
percentage points to transfected Fischer Rat yroid
(FRT) cells expressing the CFTR form produced by the
mutation [16]. In this study invitro response data was
obtained from assays performed on various cell models,
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Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
i.e. FRT, CF Bronchial Epithelial (CFBE) and Human
Nasal Epithelial (HNE) cell lines.
Published data on the invitro response to CFTR mod-
ulators were searched on Pubmed as follows: < name of
the mutation > AND < C FTR modulators > or < ivac aftor
OR ivacaftor tezacaftor > . When clinical phenotype
and in vitro response to CFTR modulators could not
be matched to classify the mutation, it was categorized
as Other. Two researchers performed the analysis and
conflicts were solved through discussion with a third
reviewer.
Results
Four products—developed and marketed by the same
company—have been licensed in both the US and the
EU: ivacaftor—IVA (Kalydeco®), a potentiator of CFTR
function that increases the opening probability of the
CFTR channel; lumacaftor/ivacaftor—LUM/IVA (Ork-
ambi®), tezacaftor/ivacaftor—TEZ/IVA (Symdeko® in
the US, Symkevi® in the EU), and elexacaftor/tezacaftor/
ivacaftor—ELX/TEZ/IVA (Trikafta® in the US, Kaf-
trio® in the EU), as fixed combinations of potentiators
and correctors that address the trafficking through the
CFTR protein. All products were first licensed in the
US: IVA 5.8 months before the EU approval; LUM/
IVA 4.7months; TEZ/IVA 8.7 months; ELX/TEZ/IVA
10.2months. In respect of their different pathways, aims
and year of launch, expedited programs were extensively
adopted by FDA and EMA to foster the reviewing and
licensing of CFTR modulators. While all CFTR modula-
tors have been licensed in the US as orphan drugs, in the
EU, the EMAs Committee for Orphan Medicinal Prod-
ucts (COMP) did not recognize the results from the piv-
otal studies of LUM/IVA (despite statistically significant)
as clinically relevant and did not confirm the orphan sta-
tus at the time of marketing authorization (MA). LUM/
IVA therefore missed the 10-year market exclusivity
benefit [17]. In the US, expedited programs were imple-
mented long before the development of CFTR modula-
tors, while in the EU IVA and LUM/IVA were developed
before PRIority MEdicines (PRIME) scheme came into
force.
Anyway, neither in the US nor in the EU, CFTR mod-
ulators were considered eligible for earlier approval, as
they were not granted accelerated approval by FDA and
conditional marketing authorization by EMA respec-
tively (see Additional file2).
Expansion ofindications
CFTR modulators have been developed towards address-
ing three main genetic domains: (1) F508del homozy-
gous (F508del/F508del), (2) F508del heterozygous, and
(3) genotypes not carrying F508del mutation. In keeping
with their own functions and level of responsiveness to
CFTR modulators, non-F508del mutations have been
clustered in subgroups such as Gating, MF, RF and Other.
A few conduction mutations have been described in
medical literature, but the only one explicitly reported in
approved therapeutic indications was R117H, as it exhib-
its a gating defect that was partially corrected by IVA.
Over the past 10 years, therapeutic indications have
expanded from a limited set to a wider array of muta-
tions, and from individuals aged 12 years to paedi-
atric population (Figs. 1 and 2). Whenever based on
clinical data, FDA and EMA decisions were the same,
except for the time delay and the eligible age for IVA of
patients carrying the R117H mutation (FDA 12 years;
EMA 18 years) at the time of licensing [18, 19] and
those 12years carrying F508del/RF genotype, in which
an absolute mean change of + 4.7 (+ 3.7, + 5.8) f rom
baseline in ppFEV1 at average of week 4 and 8 led to the
approval in the US but not in the EU (VX14-661-108).
Differences, on the other hand, have occurred in those
cases where FDA adopted non-clinical evidence for its
decision-making process (Table1). To date, 183 out of
2106 (8.7%) described CF mutations [20] are explicitly eli-
gible for CFTR modulators: 97 for IVA as monotherapy,
154 in combination with TEZ/IVA and 178 with ELX/
TEZ/IVA; only 1 for LUM/IVA (F508del, as homozygote).
Clinical evidence
CFTR modulators have been licensed on the basis of
results from phase III double-blind RCTs, whereas exten-
sions of indications relied either on RCTs or on open-
label single-group studies. Two studies regarding ELX/
TEZ/IVA in patients 12years F508del/F508del (VX17-
445-03) and 12 years F508del/RF or F508del/Gating
(VX18-445-04), provided an active comparator. ree
studies—all regarding extensions of indication for IVA in
patients 2–5years and < 24months patients harbouring
Gating mutations, and LUM/IVA in patients 2–5years
F508del/F508del—were open-label single group CTs.
e main primary endpoint adopted has been the abso-
lute mean change from baseline in ppFEV1; however, in
populations aged 6–11 years the lung clearance index
(LCI2.5) was acknowledged as a more a sensitive meas-
ure of ventilation inhomogeneity, since it is able to detect
early peripheral airway damage in CF patients with a
greater sensitivity than spirometry. e two Agencies
made consistent decisions on refusals, which regarded
a phase II RCT (VX08-770-104) aimed at extending the
indications of IVA to patients 12years F508del/F508del
and a phase III RCT (VX14-661-107) for the extension of
TEZ/IVA to patients 12years old F508del/MF, with an
absolute mean change respectively of + 1.7 from baseline
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Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
in ppFEV1 through week 16, and + 1.2 through week 12
(Table2).
Non‑clinical evidence
FDA has accepted invitro studies for extending indica-
tions. Non-clinical endpoints taken into account include:
a) the total ionic current (IT) due to the cell surface chan-
nel density; b) gating activity and conductance applied
to FRT cells harbouring the mutation under study; c) the
open channel probability (PO), representing the time
interval when a single CFTR protein channel is open
and transports ions; d) CFTR maturation, which relies
on Western blotting techniques and monitors the cellu-
lar trafficking of CFTR to the apical surface. A recovery
of the CFTR function 10% based on chloride transport
has been considered reliable to lead to milder clinical
manifestations of CF, i.e. a lower incidence of pancre-
atic insufficiency, and a more moderate lung function
decline and lower sweat chloride levels, compared to
patients with minimal CFTR chloride transport [21]. In
2017, after a previous rejection in 2016 [22], based on
data from invitro cell-based assays and on results from
a previously exploratory phase IIa study, FDA granted 23
RF mutations as eligible for IVA [23, 24]. On the contrary,
26 MF mutations—not meeting the chloride transport
threshold—were not approved [25]. As a post-marketing
commitment, the Sponsor was required to conduct a
3-year single arm, observational study to further under-
stand the clinical response to IVA in different subgroups
of CF patients with CFTR mutations deemed responsive
to IVA based on invitro evidence [26]. Moreover, upon
the same type of assays, mutation T338I—which had
previously been refused—was approved for IVA (Fig.1),
TEZ/IVA and ELX/TEZ/IVA (Fig. 2) [27]. Overall, 82
mutations have been approved for IVA on the basis of
invitro assays. Following on the granting of RF muta-
tions for IVA, invitro assays were applied to other CFTR
modulators.
TEZ/IVA was first licensed in the US on the basis of
clinical evidence from invitro studies. FRT assays were
conducted on genotypes carrying IVA-responsive muta-
tions (already approved in 2017) and F508del. TEZ/IVA
showed a similar—rather than an increased—chloride
transport level in comparison with IVA. However, any
correlations of clinical benefit over IVA remained unclear.
Subsequently, one of the two pivotal CTs—the crossover
3-treatment EXPAND study—confirmed the correlation
of invitro response to clinical efficacy of TEZ/IVA for 16
RF mutations. After the extension to patients 6 years,
FDA approved an additional set of mutations through
this pathway: in 2020, 127 additional mutations were
granted eligibility for TEZ/IVA—quite surprisingly, 6 of
Fig. 1 Chronogram of the marketing authorization and the extension of indications of IVA in the US and in the EU. Five extensions of common
indications FDA-EMA have been granted by the FDA 5.2 months (1.3–8.1) before the EMA’s approval
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Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
Fig. 2 Chronogram of the marketing authorization and the extension of indications of LUM/IVA (a), TEZ/IVA (b) and ELX/TEZ/IVA (c) in the US and
in the EU. Extensions of common indications FDA-EMA have been granted first by the FDA: LUM/IVA, 2 extensions in common, median 10.5 months
(5.4–15.6); TEZ/IVA, 1 extension in common, 17.4 months before
Page 6 of 14
Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
these mutations (MF) were approved despite not being
responsive invitro—and 177 for ELX/TEZ/IVA (Fig.2).
Discussion
CFTR modulators have been a groundbreaking and
unprecedent achievement for CF. ese small-molecules
were first discovered through high-throughput screening
(HTS) with medicinal chemistry interventions driven by
predictive invitro assays, and then brought into CTs. All
CFTR modulators were first launched on the US market,
which is the most remunerative pharmaceutical market
in the world [28]. However, this might also refer to the
fact that the sponsor is a US-based company and the ini-
tial development of CFTR modulators was supported by
the US CF Foundation (CFF), thus, exerting some sort
of pressure on the company’s marketing strategy and
policy [29]. Differences were also found in regulatory
approaches, partly due to the legal background of the two
systems, partly related to scientific principles, culture of
weighing benefits and risks, and dealing with the subse-
quent Health Technology Assessment (HTA) evaluations
[30]. For example, COMP’s decision on confirmation of
the ODD for LUM/IVA at the time of MA steered Mem-
ber States’ assessment on value-based pricing and reim-
bursement: HTA organizations emphasized that a < 4%
change in FEV1 was not a relevant clinical outcome, since
its correlation to pulmonary exacerbations (PEX) or to
other clinically relevant outcomes remains unclear [31].
Development strategy forCFTR modulators
e clinical development of CFTR modulators expanded
from the monotherapy of the potentiator IVA in a
selected group of Gating mutations[32, 33], to the last
combination ELX/TEZ/IVA [21] targeting the CFTR
function in patients carrying at least one F508del muta-
tion [34, 35]. e overarching approach adopted for stud-
ying CFTR modulators in clinical stage was short-term
double-blind RCTs followed by open label long-term
safety studies [36, 37]. Meanwhile, investigations moved
towards the paediatric population, providing extrapo-
lated data from older population as well as assessing
pharmacokinetics, safety and tolerability [38, 39]. Efficacy
has been found heterogeneous across different CFTR
Table 1 Eligible populations and genotypes for the treatments with the currently approved CFTR modulators
(The complete list of each single eligible mutation is reported in Figs.1 and 2) Denitions: () = eligible; (–) = not eligible; *based on clinical evidence; **based only on
invitro data
IVA ivacaftor ( VX-770), LUM lumacaftor (VX-809), TEZ tezacaftor (VX-661), ELX elexacaftor ( VX-445), RF residual function CFTR mutation, MF minimal function CFTR
mutation
IVA 4months (and 5kg) LUM/
IVA 2years TEZ/IVA 6years ELX/TEZ/IVA 6years
FDA EMA FDA EMA FDA EMA FDA EMA
F508del F508del ✓ ✓
Gating F508del Any Gating muta-
tion responsive to
IVA* or **
Any Gating muta-
tion responsive
to IVA*
Any Gating muta-
tion responsive to
TEZ/IVA**
✓ ✓
Non-F508del Any Gating muta-
tion responsive to
ELX/TEZ/IVA**
Conduction F508del R117H or any
Conduction muta-
tion responsive to
IVA**
R117H Any Conduction
mutation respon-
sive to TEZ/IVA**
✓ ✓
Non-F508del Any Conduction
mutation respon-
sive to ELX/TEZ/
IVA**
RF F508del Any RF mutation
responsive to IVA*
or **
Any RF mutation
responsive to TEZ/
IVA* or **
Any RF mutation
responsive to
TEZ/IVA*
✓ ✓
Non-F508del Any RF mutation
responsive to
ELX/TEZ/IVA**
MF F508del Any MF mutation
responsive to
IVA**
Any MF mutation
responsive to TEZ/
IVA**
✓ ✓
Non-F508del Any MF mutation
responsive to
ELX/TEZ/IVA**
Other F508del Any Other muta-
tion responsive to
IVA**
Any Other muta-
tion responsive to
TEZ/IVA**
✓ ✓
Non-F508del Any Other muta-
tion responsive to
ELX/TEZ/IVA**
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Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
Table 2 Clinical trials supporting regulatory decisions for the Marketing Authorization and the extensions of indication of CFTR modulators
FDA EMA Phase Study Control Study Population Treatment Duration Primary Endpoint Primary Outcome Ref
IVA—Kalydeco
1 31/01/12 23/07/12 III VX08-770-102
(NCT00909532) STRIVE Placebo (parallel) 12 years—G551D
Sample size: 161 48 weeks Absolute mean
change from baseline
in ppFEV1 through
wk 24
LS mean absolute
change IVA vs placebo
(95% CI): + 10.6
(+ 8.6, + 12.6)
[36]
2 III VX08-770-103
(NCT00909727) ENVI-
SION
Placebo (parallel) 6 to 11 years—G551D
Sample size: 52 48 weeks Absolute mean
change from baseline
in ppFEV1 through
wk 24
LS mean absolute
change IVA vs placebo
(95% CI): + 12.5
(+ 6.6, + 18.3)
[57]
3 Not approved Not approved II VX08-770-104
(NCT00953706) DIS-
COVER
Placebo (parallel) 12 years—F508del/
F508del Sample size:
140
16 weeks Aabsolute mean
change from baseline
in ppFEV1 through
wk 16
LS mean absolute
change IVA vs placebo
(95% CI): + 1.7
(‑0.6, + 4.1)
[58]
4 21/02/14 28/07/14 III VX12-770-111
(NCT01614470) KON-
NECTION
Part A: Placebo
(crossover) Part B:
open-label
6 years—non-
G551D gating muta-
tion (*) Sample size: 39
(Part A: 39 Part B: 36)
24 weeks Part A: 8 wk
Part B: 16 wk extension (A) absolute change
from baseline in
ppFEV1 through wk 8
(A) LS mean differ-
ence IVA vs placebo
(95% CI): + 10.7
(+ 7.3, + 14.1)
[32]
(B) Absolute change
from baseline in
ppFEV1 through wk 24
(B) LS mean absolute
change IVA vs placebo
(95% CI): + 13.5
(‑6.9, + 36.5)
5 29/12/14 16/11/15
09/06/20 III VX11-770-110
(NCT01614457) KON-
DUCT
Placebo (parallel) 6 years—R117H,
non-gating mutation
Sample size: 69
24 weeks Absolute change from
baseline in ppFEV1
through wk 24
LS mean differ-
ence IVA vs placebo
(95% CI): + 2.11
(‑1.13, + 5.35)
[33]
6 17/03/15 16/11/15 III VX11-770-108
(NCT01705145) KIWI Open-label 2 to 5 years—gating
mutation (G551D, *)
Sample size: 34 (Part A:
9 Part B: 33)
Part A: 4 days Part B:
24 weeks (A) pharmacokinetic
(A, B) safety: number of
participants with AEs,
SAEs and related AEs
(A) safety: 8 subj
had AEs (88.9%), no
SAEs, 4 subj (44.4%)
had related AEs (B)
safety: 33 subj had AEs
(97.1%), 6 subj (17.6%)
had SAEs, 11 subj had
related AEs (32.4%)
[59]
7 31/07/17 Not approved III VX14-661108
(NCT02392234)
EXPAND
Placebo (crossover) 12 years—F508del/
RF Sample size: 244 8 weeks crossover Absolute change from
baseline in ppFEV1 at
average of wk 4 and 8
LS mean difference
IVA vs placebo (95%
CI): + 4.7 (+ 3.7, + 5.8)
[14]
Page 8 of 14
Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
Table 2 (continued)
FDA EMA Phase Study Control Study Population Treatment Duration Primary Endpoint Primary Outcome Ref
8 15/08/18 22/11/18 III VX15-770-124
(NCT02725567)
ARRIVAL
Open-label < 24 months—gating
mutation (G551D, *)
or R117H Sample size:
Part A (Cohort 1): 7 Part
B (Cohort 5): 19
Part A: 4 days Part B:
24 weeks (A) pharmacokinetic
(A, B) safety: number of
participants with AEs,
SAEs and related AEs
(A) safety: 3 subj had
AEs (42.9%), no SAEs,
no related AEs (B)
safety: 18 subj had AEs
(94.7%), 2 subj (10.5%)
had SAEs, 7 subj
(36.8%) had related
AEs
[60]
29/04/19 09/12/19 Open-label < 24 months—gating
mutation (G551D, *)
or R117H Sample size:
Part A (Cohort 2): 6 Part
B (Cohort 6): 11
(A) safety: 4 subj had
AEs (66.7%), no SAEs
(B) safety: 10 subj had
AEs (90.9%), 3 subj
(27.3%) had SAEs,
2 subj (18.2%) had
related AEs
[61]
24/09/20 03/11/20 Open-label < 24 months—gating
mutation (G551D, *)
or R117H Sample size:
Part A (Cohort 3): 6 Part
B (Cohort 7): 6
(A) safety: 3 subj had
AEs (50.0%), 1 subj
(16.7%) had SAEs, no
related AEs (B) safety: 6
subj had AEs (100%), 1
subj (16.7%) had SAEs,
no related AEs
[61]
LUM/IVA—Orkambi
9 02/07/15 19/11/15 III VX12-809-103
(NCT01807923) TRAF-
FIC
Placebo (parallel) 12 years—F508del/
F508del Sample size:
549
24 weeks Absolute change from
baseline in ppFEV1
through wk 24
LS mean difference
LUM/IVA vs placebo
(pooled analysis) (95%
CI): + 3.3 (+ 2.3, + 4.3)
for LUM 600 mg + 2.8
(+ 1.8, + 3.8) for LUM
400 mg
[62]
10 VX12-809-104
(NCT01807949)
TRANSPORT
Placebo (parallel) 12 years—F508del/
F508del Sample size:
559
24 weeks
11 28/09/16 08/01/18 III VX14-809-109
(NCT02514473) Placebo (parallel) 6 to 11 years—
F508del/F508del
Sample size: 204
24 weeks Absolute change in
LCI2.5 through wk 24 LS mean LUM/IVA vs
placebo (95% CI): 1.1
( 1.4, 0.8)
[39]
12 07/08/18 15/01/19 III VX15-809-115
(NCT02797132) Open-label 2 to 5 years—F508del/
F508del Sample size:
62 (Part A: 12 Part
B: 60)
Part A: 15 days Part B:
24 weeks (A) pharmacokinetic
(A, B) safety: number
of participants with
AEs and/SAEs
(B) safety: 59 subj had
AEs (98%), 4 subj (7%)
had SAEs
[63]
Page 9 of 14
Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
Table 2 (continued)
FDA EMA Phase Study Control Study Population Treatment Duration Primary Endpoint Primary Outcome Ref
TEZ/IVA—Symdeko (Symkevi)
13 12/02/18 31/10/18 III VX14-661-106
(NCT02347657)
EVOLVE
Placebo (parallel) 12 years—F508del/
F508del Sample size:
504
24 weeks Absolute change from
baseline in ppFEV1
through wk 24
LS mean difference
TEZ/IVA vs placebo
(95% CI): + 4.0
(+ 3.1, + 4.8)
[64]
7 III VX14-661-108
(NCT02392234)
EXPAND
Placebo (crossover) 12 years—F508del/
RF Sample size: 244 8 weeks Absolute change from
baseline in ppFEV1 at
average of wk 4 and 8
LS mean difference
TEZ/IVA vs placebo
(95% CI): + 6.8
(+ 5.7, + 7.8)
[14]
14 21/06/19 25/11/20 III VX16-661-115
(NCT03559062) Placebo (parallel) 6 to 11 years—
F508del/RF + F508del/
F508del Sample size:
67
8 weeks Absolute change in
LCI2.5 through wk 8 LS mean TEZ/
IVA vs placebo
(95% CI): 0.51
(‑0.74, 0.29)
[65]
15 Not approved Not approved III VX14-661-107
(NCT02516410) Placebo (parallel) 12 years—F508del/
MF Sample size: 168 12 weeks Absolute change from
baseline in ppFEV1
through wk 12
LS mean difference
TEZ/IVA vs placebo
(95% CI): + 1.2
(‑0.3, + 2.6)
[12]
ELX/TEZ/IVA—Trikafta (Kaftrio)
16 21/10/19 21/08/20 III VX17-445-102
(NCT03525444) Placebo (parallel) 12 years—F508del/
MF Sample size: 403 24 weeks Absolute change in
ppFEV1 from baseline
at wk 4
LS Mean difference
ELX/TEZ/IVA vs control
(95% CI): + 13.8
(+ 12.1, + 15.4)
[34]
17 III VX17-445-103
(NCT03525548) Active (parallel) 12 years—F508del/
F508del Sample size:
107
4 weeks Absolute change in
ppFEV1 from baseline
at wk 4
LS Mean difference
ELX/TEZ/IVA vs
control (95% CI): + 10
(+ 7.4, + 12.6)
[66]
18 N/A 26/04/21 III VX18-445-104
(NCT04058353) Active (parallel) 12 years—F508del/
RF + F508del/Gating
Sample size: 258
8 weeks Absolute change in
ppFEV1 from baseline
at wk 8
LS Mean difference
ELX/TEZ/IVA vs
control (95% CI): + 3.7
(+ 2.8, + 4.6)
[35]
19 08/06/21 07/01/22 III VX18-445-106
(NCT03691779) Open-label 6 to 11 years—
F508del/
MF + F508del/F508del
Sample size: 66 (Part A:
16 Part B: 66)
Part A: 15 days Part B:
24 weeks (A) pharmacokynetic
(A, B) safety: number
of participants with
TEAEs and SAEs
(A) safety: 12 subj had
AEs (75%), no SAEs (B)
safety: 65 subj had AEs
(98.5%), 1 subj (1.5%)
had SAEs
[67]
Bold style has been used only to highlight the results of the studies
Denitions: * = G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P or G1349D; RF = residual function CFTR mutation according to the clinical trial list [14]; MF minimal function CFTR mutation according to the
clinical trial list [68], IVA ivacaftor ( VX-770), LUM lumacaftor (VX-809), TEZ tezacaftor (VX-661), ELX elexacaftor ( VX-445), RCT R andomized Controlled Trial; SID = once daily, BID twice daily, ppFEV1 percentage of predicted
forced expiratory volume in 1s, LCI2.5 Lung Clearance Index 2.5: its decrease indicates improvement in lung function; AEs Adverse Events, SAEs Serious Adverse Events, LS Means Least Squares Means, CI condence interval
Page 10 of 14
Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
modulators and targeted population, but—remarkably—
FDA and EMA adopted the same decisions for both
approvals or refusals.
Results from IVA targeting G551D mutation [36] were
considered the benchmark for the development of fol-
lowing CFTR modulators: accordingly, LUM/IVA and
TEZ/IVA showed a modest clinical benefit, while ELX/
TEZ/IVA was recognized as the standard of care for gen-
otypes carrying at least one F508del mutation, namely
the most frequent allelic variant in CF: with slight geo-
graphical differences, current CFTR modulators could
target on average 70–80% of CF patients [40, 41]. By way
of contrast, 20–30% of patients are not yet eligible for
treatments, and this percentage includes: a) rare muta-
tions neither enrolled in CTs nor studied, and therefore
not licensed by regulators; b) mutations whose biological
features prevent the use of CFTR modulators, i.e. prema-
ture stop mutations producing truncated unstable mRNA
and a lack of full-length CFTR proteins, so that the use of
CFTR modulators would be not plausible.
Predictable models
e extrapolation of data from preclinical models to
expand the clinical use of CFTR modulators has been
the major difference found between FDA and EMA [42].
As ion transport properties of primary human CF res-
piratory epithelial cells can be preserved in cell cultures,
non-clinical studies have been used as proof-of-concept
to demonstrate the preliminary efficacy of CFTR modu-
lators [43].
Testing modulators on a variety of laboratory or
patient-derived cells (eratyping) has the potential
of characterizing complex CFTR variants, of assessing
modulator responsiveness of rare/unique CFTR muta-
tions, and even of providing an optimization in the
modulator therapy regimen through modulator respon-
siveness comparison. Patient-derived model systems
may avoid the challenges of varying responses to CFTR
modulators within the same genotype among different
patients (for the purpose of a personalized therapy) and
can support the selection of suitable “likely responders
to drug” subgroups to be enrolled in CTs through the
characterization of unclassified CFTR variants by the
response to modulators [44]. For example, a strong cor-
relation between invitro data and clinical outcomes has
been observed with IVA in patients carrying F508del
mutation: < 10% recovery of CFTR was subsequently con-
firmed as a non-statistically significant increase for FEV1.
Although stringent criteria must be met before consider-
ing the use of invitro data alone to expand a drug indica-
tion—such as a good understanding of the disease and a
solid comprehension of the drug’s mechanism of action
[45]—not all situations have confirmed such correlation:
LUM/IVA showed a very promising 25.1% recovery of
CFTR functionality in F508del genotypes but a modest
increment in FEV1 [46]. ese discrepancies have raised
doubts on the validity of preclinical models and their use
for regulatory approvals. In the EU, preclinical data were
accepted for granting initial ODD, a stage where non-
clinical studies were considered reliable for anticipating
clinical effects of new products. By contrast, at the time
of MA only confirmed clinical data were acknowledged.
Implications forpatients andhealthcare systems
Differences between FDA and EMA in the way of review-
ing and licensing medicines lay on procedures and rel-
evant clinical decisions. In oncology, for example, the
Agency that provided a positive opinion was found to
be more restrictive in terms of wording indications com-
pared with the Agency that first granted approval [47].
In the case of CF, differences extend beyond semantics,
procedures and timing of approval, but affect patients’
eligibility. In the US, extensions of indication based on
invitro data have addressed patients carrying mutations
not included in CTs because of their rarity [48]. Since
then, new and alternative predictable models have been
implemented. Recent advances in adult stem cell biol-
ogy have produced the development of organoids using a
variety of tissue sources such as intestine, respiratory epi-
thelium and kidney [48]. When no approved treatments
are available for rare mutations, and large scale CTs are
therefore not feasible, n-of-1 trials have been proposed to
contribute to the totality of evidence for expanding drug
indications. However, this approach has some methodo-
logical strengths and weaknesses to be carefully consid-
ered before supporting expansion of access to expensive
medicines [49].
A stepwise model tomerge drug‑regulation andHTA
As regulators have to manage the challenge of uncer-
tainty in the benefit/harm assessment, systems of per-
sonalized therapy might progressively support regulatory
decisions and subsequent HTA evaluations. An increased
coordination between these two levels may promote a
new and more flexible model that could fall under the
tag of ‘payment at results’ agreements. e introduction
of Next-Generation Sequencing in clinical practice has
opened new perspective for precision and personalized
medicines. In oncology, the need for systematic interpre-
tation of molecular alterations and their translation into
clinical practice has been addressed thorough the imple-
mentation of the so-called ‘Molecular Tumour Boards’:
a panel of experts who analyse tumour genotypes in
order to recommend the most suitable targeted therapy
[50, 51]. A ‘CF Molecular Board’ could be implemented,
with a view to promoting an efficient and timely manner
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Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
access to CFTR modulators to patient carrying muta-
tions not included in CTs. Genotypes might be screened
and when considered eligible for CFTR modulators, they
should be candidate to theratyping tests, the results of
which should be confirmed in clinical setting. Efficient
use is essential for public health funded systems, in par-
ticular in the case of orphan drugs which are tagged at
high nominal price [52]. is approach can meet both the
ethical imperative of taking care of individual patients
and the recognition of a value-based price.
Reviewing pharmaceutical R&D funding forrare diseases
Despite the unquestionable advances in the treatment of
CF and the potential impact of personalized approaches
to target further rare mutations, a significant number of
individuals in the world do not benefit from CFTR mod-
ulators. And there is more to come. New CFTR modu-
lators and new innovative approaches are currently in
development to target patients who have experienced
limited benefits from already approved CFTR modula-
tors and also for targeting non-sense mutations [53].
Orphan legislations and incentive systems have
brought a huge contribution to target unmet medical
needs, also in CF. But it is time now to rethink and set
sustainable policies for the future, by ensuring R&D pro-
grams to meet patients’ needs, as well as equitable access
to the innovations. In the US, new approaches have been
recently implemented on public–private collaboration
to foster the delivery of new gene therapies to patients
affected by ultra-rare diseases [54].
However, also in the EU, one of the four pillars of the
‘Pharmaceutical strategy for Europe’ aims at ensur-
ing access to affordable medicines for patients, and at
addressing unmet medical needs, such as CF [55].
In the area of (ultra)rare diseases, experimenting with
public–private partnerships throughout the life-cycle of a
drug could better address its development towards medi-
cal needs, so mitigating and sharing business risks and
dealing with failures, and most importantly steeringthe
pricing of drugs once they are placed on the market,
in order to improve their affordability and subsequent
access for patients.
Public andglobal health outlook
e epidemiological profile of CF has been changing.
Advances in the management of the disease have increas-
ingly transformed what was considered an exclusive
pediatric disease into an adult disorder. On the other
hand, epidemiological studies have shown that CF extend
beyond the US and the EU boundaries. Given its higher
prevalence among Caucasians, CF has long been con-
sidered an exclusive disease of western countries. How-
ever, data on CFTR mutations have been progressively
reported from Asia, the Middle East, Latin America and
Africa [56]. e incidence of CF in Low-Income Coun-
tries (LICs) is variable and depends on the composition
and origin of the population, and the awareness of the
condition which inevitably leads to its underdiagnosis,
misdiagnosis, and underreporting. However, nowadays
effective medicines are available and their patents are
expiring, which can globally lead to an improvement of
their affordability. Meanwhile, confirmatory results from
clinical use of CFTR modulators on rare mutations might
also contribute to maximizing the cost–benefit profile
of these medicines in LICs. But in Western Countries
several challenges remain, especially for HTA where
comparative CTs and the contribution of Real-World Evi-
dence (RWE) are expected to increasingly contribute to
better define the place in therapy of different treatments
and their value (and hence their accessibility).
Conclusions
Our analysis has brought valuable insights on the regula-
tory decision-making process of FDA and EMA on CFTR
modulators for the treatment of CF, emphasizing the role
of regulators in fostering the development and approval
of these medicines and the streamlined access to a grow-
ing number of patients. Remarkably, FDA took the unu-
sual decision of expanding the use of CFTR modulators
on the basis of data from invitro. By contrast, EMA did
not deem preclinical data sufficient to expand the label of
CFTR modulators without clinical data.
Such differences raise an important question: what
should drive the approval of new drugs or a new indica-
tion? Clinical evidence or biological markers? We pro-
posed a two-step personalized-based model to merge
the ethical commitment of ensuring larger access to all
potential eligible patients (as provided by FDA) with the
one of ensuring access to clinically assessed and effective
medicines (as provided by EMA).
As most of the novel medicines that have been intro-
duced in clinical practice globally are first approved by
FDA and EMA, the two-step approach we have proposed
here—to confirm biological plausibility in clinical prac-
tice within a reimbursement agreement—can provide a
more comprehensive amount of knowledge for an incre-
mental cost-effective use of CFTR modulators worldwide.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s13023- 022- 02350-5.
Additional le1. Algorithm adopted to classify the eligible mutations to
CFTR modulators as approved by FDA and EMA. Complete phenotypic
data comprehends: average sweat chloride (sweat test, ST) (mmol/L) and
pancreatic insufficiency in percentage (PI%). Criteria for severe phenotype
Page 12 of 14
Costaetal. Orphanet Journal of Rare Diseases (2022) 17:188
are ST 86 mmol/L, and PI% 50%. Definitions: * = if mentioned; WT-
CFTR = wild-type CFTR protein; RF = residual function CFTR mutation;
MF = minimal function CFTR mutation. Other: a = Uncomplete/missing
phenotypic data; b = conflicting phenotypic; c = conflicting phenotypic/
responsiveness data.
Additional le2. Framework for fostering the development, review
and approval of medicines for rare and serious life-threatening condi-
tions in the US and in the EU. Definitions: MA = Marketing Authorization,
SMEs = small & medium-sized enterprises. At the time of marketing
authorization LUM/IVA was withdrawn from the Community Register of
designated Orphan Medicinal Products of the EU upon request of the
sponsor [25]. In the EU, the designation to accelerated assessment - which
shortens the review time from 210 to 150 days - was granted to IVA and
LUM/IVA, while the EMA did not agree to the applicant’s request for TEZ/
IVA being considered not of major public health interest [69]. The triple
combination ELX/TEZ/IVA was initially reviewed under EMA’s accelerated
assessment program, but since the applicant requested a 3-month clock
stop during assessment - ultimately reduced to 2 months - the conditions
for accelerated assessment could no longer be met [35].
Acknowledgements
None.
Author contributions
EC: conceived of the study, participated in its design, collected data, per-
formed the analyses interpreted the data, and drafted the manuscript; SG:
participated in the design, collected and interpreted the data and draft the
manuscript; FP: participated in the design, interpreted the genetic data; HL:
participated in the planning of analyses and interpretation of results; LL: con-
ceived of the study, participated in the planning of analyses and interpretation
of results; All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Please contact author for data requests.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
EC: member of the Committee for Orphan Medicinal Products (COMP) at EMA.
The views expressed in this article are the personal views of the author and
may not be understood or quoted as being made on behalf of or reflect-
ing the position of the regulatory agency with which the author is affiliated.
SG: the author declares that she has no competing interests. FP: the author
declares that she has no competing interests. HL: former chair of the Dutch
Medicines Evaluation Board (MEB), former member of several committees
and working parties of the European Medicines Agency (EMA). MC: received
grants from Vertex Ph (ISS), from the Italian Minister of Health (COVID-2020-
12371781) and from Pfizer (ID_61509709). He also served on advisory boards
for Vertex Ph, Chiesi, Viatris, Kither.
Author details
1 WHO Collaborating Centre for Pharmaceutical Policy and Regulations, Utre-
cht University, Utrecht, The Netherlands. 2 Section of Pharmacology, Depart-
ment of Diagnostics and Public Health, University of Verona, Verona, Italy.
3 Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona,
Italy. 4 Emeritus Professor Regulatory Science and Pharmaceutical Policy, Utre-
cht University, Utrecht, The Netherlands.
Received: 10 February 2022 Accepted: 26 April 2022
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... Indeed, this 'highly effective' modulator therapy demonstrated to significantly improve lung function (>10 ppFEV1) in phase III clinical trials not only in PwCF homozygous for F508del [28] but also in those carrying this mutation in one allele and a minimal function mutation (i.e., classes I/II) in trans [29]. Over this period, several label extensions have been approved (most by the US FDA) to uncommon CFTR mutations [13,15,30], and >85% of PwCF in North America, Oceania and various countries in Europe are currently eligible for at least one of these clinically approved modulator therapies. ...
... These include not only CFTR-directed therapeutics but also targeting alternative channels/transporters to compensate for CFTR dysfunction and beyond [10,12,31]. Meanwhile, CF scientific community also continues to develop novel cell models to more efficiently predict clinical efficacy and responsiveness [14, [32][33][34][35], since conventional clinical trial designs are underpowered and impractical for rare CFTR mutations due to the very low number of individuals [30,36,37]. Indeed, it is estimated that for >1000 CFTR variants there are ≤5 PwCF worldwide [12,15,37,38]. ...
... Despite cell lines are unable to predict therapeutic responses in PwCF at an individual level, they have been useful in supporting drug discovery and development for common and rare CF-causing mutations [2]. Indeed, the FDA has licensed label extension of clinically approved CFTR modulators to several additional mutations based on data from FRT cell lines heterologously expressing mutant CFTR cDNA [13,15,30] with subsequent clinical studies confirming the therapeutic benefits for some of these mutations [56,74,75]. Furthermore, a study has paired in vitro measurements of CFTR function in either FRT or CFBE41o -cell lines stably expressing CFTR variants with clinical and genetic data from the CFTR2 database, and demonstrated that there is a strong correlation between CFTR function and sweat Cllevels [76]. ...
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The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations.
... These platforms can predict the individual's response to treatment and characterise the functional defect caused by CFTR mutations. This form of in vitro analysis has been permitted by the US Food and Drug Administration (FDA) to facilitate the approval of therapeutics for rare CFTR mutations in addition to in vitro testing systems using non-primary cells, such as Fisher Rat Thyroid (FRT) cells (21). CFTR-dependent chloride transport assays in patient-derived nasal epithelial cells (22)(23)(24)(25)(26) as well as forskolin-induced swelling assays in intestinal organoids (27-31) have been used in a patientspecific manner to predict modulator efficacy for the patient. ...
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The NIH and FDA’s newly launched 27-member public–private partnership will spend US$76 million addressing the hurdles of AAV-based gene therapies for ultra-rare diseases. The NIH and FDA’s newly launched 27-member public–private partnership will spend US$76 million addressing the hurdles of AAV-based gene therapies for ultra-rare diseases.
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Background Elexacaftor–tezacaftor–ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor–ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. Methods We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del–gating or Phe508del–residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor–ivacaftor, patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor–tezacaftor–ivacaftor group. Results After the run-in period, 132 patients received elexacaftor–tezacaftor–ivacaftor and 126 received active control. Elexacaftor–tezacaftor–ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire–Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor–tezacaftor–ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, −0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor–tezacaftor–ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. Conclusions Elexacaftor–tezacaftor–ivacaftor was efficacious and safe in patients with Phe508del–gating or Phe508del–residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.) VISUAL ABSTRACT Triple Therapy for Cystic Fibrosis
Article
Cystic fibrosis is a monogenic disease considered to affect at least 100 000 people worldwide. Mutations in CFTR, the gene encoding the epithelial ion channel that normally transports chloride and bicarbonate, lead to impaired mucus hydration and clearance. Classical cystic fibrosis is thus characterised by chronic pulmonary infection and inflammation, pancreatic exocrine insufficiency, male infertility, and might include several comorbidities such as cystic fibrosis-related diabetes or cystic fibrosis liver disease. This autosomal recessive disease is diagnosed in many regions following newborn screening, whereas in other regions, diagnosis is based on a group of recognised multiorgan clinical manifestations, raised sweat chloride concentrations, or CFTR mutations. Disease that is less easily diagnosed, and in some cases affecting only one organ, can be seen in the context of gene variants leading to residual protein function. Management strategies, including augmenting mucociliary clearance and aggressively treating infections, have gradually improved life expectancy for people with cystic fibrosis. However, restoration of CFTR function via new small molecule modulator drugs is transforming the disease for many patients. Clinical trial pipelines are actively exploring many other approaches, which will be increasingly needed as survival improves and as the population of adults with cystic fibrosis increases. Here, we present the current understanding of CFTR mutations, protein function, and disease pathophysiology, consider strengths and limitations of current management strategies, and look to the future of multidisciplinary care for those with cystic fibrosis.