FDA Expands CFTR Modulator Labels, Covering ~95% of US Cystic Fibrosis Patients

The US Food and Drug Administration (FDA) has approved label expansions for a pair of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator regimens, vanzacaftor/tezacaftor/ivacaftor (ALYFTREK) and elexacaftor/tezacaftor/ivacaftor (TRIKAFTA), broadening eligibility to an estimated 95% of people with CF in the United States, according to an announcement from Vertex Pharmaceuticals on April 1, 2026.¹

The expanded indications now encompass any CFTR gene variant resulting in production of CFTR protein, in addition to variants previously identified as clinically or in vitro responsive. Vanzacaftor/tezacaftor/ivacaftor is now indicated for patients aged 6 years and older, while elexacaftor/tezacaftor/ivacaftor’s indication extends to patients aged 2 years and older.¹ The breadth of the new labeling language marks a shift from variant-specific enumeration toward a functional, mechanism-based eligibility criterion.

“This groundbreaking approval represents more than 20 years of innovation in CF, including testing over 600 variants in our laboratory, demonstrating clinical effects in large clinical trials, and studying younger people with CF so they can be treated as early as possible,” said Carmen Bozic, MD, executive vice president of Global Medicines Development and Medical Affairs and chief medical officer at Vertex.

The label expansions were supported by clinical and/or in vitro data evaluating response across 564 CFTR variants for vanzacaftor/tezacaftor/ivacaftor and 521 variants for elexacaftor/tezacaftor/ivacaftor, according to the company's announcement. The regulatory filing was backed by an accumulated dataset incorporating laboratory assay data and clinical evidence generated across multiple studies.

CF Disease Burden and Treatment Landscape

CF is an autosomal recessive disease caused by pathogenic variants in the CFTR gene, affecting more than 97,000 people across the US, Europe, Australia, and Canada.¹ The disease causes progressive multiorgan dysfunction with a median age of death historically reported in the fourth decade of life.¹ Prior to the development of CFTR modulators, treatment was directed at managing downstream consequences of dysfunctional chloride transport rather than the underlying molecular defect.

CFTR modulators represent a class of small molecules that potentiate or correct aberrant CFTR protein function. Ivacaftor (a CFTR potentiator) was the first approved agent in this class and subsequent combination regimens incorporating correctors, such as tezacaftor, elexacaftor, vanzacaftor, expanded eligible populations by addressing the more common F508del mutation and related variants.

Elexacaftor/tezacaftor/ivacaftor received initial FDA approval in 2019 and has since undergone multiple label expansions down to younger age groups. Vanzacaftor/tezacaftor/ivacaftor, a next-generation triple combination incorporating vanzacaftor and deutivacaftor, represents a more recent addition to the approved regimen portfolio.

Mechanism of Action

Vanzacaftor/tezacaftor/ivacaftor combines vanzacaftor and tezacaftor (CFTR correctors that facilitate proper protein folding and trafficking to the cell surface) with ivacaftor (a CFTR potentiator that increases channel open probability). Elexacaftor/tezacaftor/ivacaftor similarly combines elexacaftor and tezacaftor as a dual-corrector backbone with ivacaftor as the potentiator.

The expanded labeling reflects evidence these mechanisms may confer benefit across a broader range of protein-producing variants, regardless of the specific location of the variant within the CFTR protein, according to the announcement.¹

“With this label expansion, any variant that results in production of CFTR protein is now included in the ALYFTREK and TRIKAFTA labels, validating that these medicines can restore CFTR function and provide clinical benefit to patients regardless of where in the CFTR protein a variant is located,” Bozic added.

Safety Profile and Monitoring Requirements

Both agents carry boxed warnings for drug-induced liver injury (DILI). Postmarketing reports have associated elexacaftor/tezacaftor/ivacaftor with cases of liver failure leading to transplantation and death in patients with and without preexisting liver disease; hepatic injury has been reported as early as 1 month after initiation and as late as 15 months. For vanzacaftor/tezacaftor/ivacaftor, transaminase elevations have been observed, though the prescribing information does not yet carry reports of fatal hepatic outcomes specific to that agent.¹

Current labeling recommends liver function testing prior to initiation, monthly for the first 6 months, every 3 months through month 18, and at least annually thereafter. Both agents are contraindicated in severe hepatic impairment and are not recommended in moderate hepatic impairment.¹

Additional postmarketing safety signals include hypersensitivity reactions, intracranial hypertension, neuropsychiatric events, and non-congenital lens opacities in pediatric patients. Strong or moderate CYP3A inducers are not recommended for coadministration and dose reduction is required with moderate or strong CYP3A inhibitors.¹

REFERENCES

1. Vertex Pharmaceuticals Incorporated. Vertex announces US FDA approval for label extensions of ALYFTREK® and TRIKAFTA®, expanding availability of these medicines to ~95% of all people with CF in the United States. BusinessWire. April 1, 2026. Accessed April 1, 2026. https://www.businesswire.com/news/home/20260401690804/en/Vertex-Announces-US-FDA-Approval-for-Label-Extensions-of-ALYFTREK-and-TRIKAFTA-Expanding-Availability-of-These-Medicines-to-95-of-All-People-With-CF-in-the-United-States

2. Vertex Pharmaceuticals. FDA Approves TRIKAFTATM (elexacaftor/tezacaftor/ivacaftor and ivacaftor) to Treat the Underlying Cause of Cystic Fibrosis in People Ages 12 and Older Who Have at Least One F508del Mutation | Vertex Pharmaceuticals. Vertex Pharmaceuticals. Published October 21, 2019. Accessed April 1, 2026. https://investors.vrtx.com/news-releases/news-release-details/fda-approves-trikafta-elexacaftortezacaftorivacaftor-and

3. Vertex Pharmaceuticals. Vertex Announces US FDA Approval of ALYFTREKTM, a Once-Daily Next-in-Class CFTR Modulator for the Treatment of Cystic Fibrosis | Vertex Pharmaceuticals. Vertex Pharmaceuticals. Published December 20, 2024. Accessed April 1, 2026. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-alyftrektm-once-daily-next