NACF 2017. P247. Efficacy and Safety of Tezacaftor/Ivacaftor in Patients Aged ≥12 Years with CF Homozygous for F508del-CFTR: A Randomized Placebo-Controlled Phase 3 Trial

 J. Taylor-Cousar, et al.

Results:

509 pts received ≥1 dose of tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (n=251) or placebo (PBO) (n=258). Baseline (BL) characteristics were well balanced between groups. There was a significant treatment effect favouring TEZ/IVA in absolute change in ppFEV1 (4.0 percentage points; 95% CI 3.1, 4.8; P<0.0001); a similar effect was seen in pts with ppFEV1 <40 at BL (TEZ/IVA [n=23] vs PBO [n=24]: 3.5 percentage points; 95% CI 1.0, 6.1; P=0.0070). Treatment differences for relative change in ppFEV1 and pulmonary exacerbations (Pex) (event rate, 0.64 vs 0.99; P=0.0054 [negative binomial regression]) met statistical significance while the comparison for change in BMI did not. Effects favouring TEZ/ IVA in CFQ-R and sweat chloride were nominally significant. In pts who had treatment-emergent adverse events (AEs), the majority were mild (TEZ/IVA 45.4% vs PBO 38.4%) or moderate (TEZ/IVA 36.3% vs PBO 45.3%); the most common were infective PEx (TEZ/IVA 29.9% vs PBO 37.2%), cough (26.3% vs 32.6%), headache (17.5% vs 14.3%), nasopharyngitis (16.7% vs 15.1%), and sputum increased (14.3% vs 16.3%). Predefined respiratory events occurred in 13.1% of pts in the TEZ/IVA arm and 15.9% in the PBO arm. Discontinuations due to AEs occurred in 2.8% (TEZ/IVA) and 3.1% (PBO) of pts; none were due to respiratory events. Serious AEs were reported in 12.4% (TEZ/IVA) and 18.2% (PBO) of pts, and no deaths were reported.

Conclusions:

Significant improvements in ppFEV1, PEx rate, CFQ-R score (nominal), and sweat chloride (nominal) were observed with 24 wks of TEZ/IVA vs PBO. Treatment was well tolerated with few discontinuations due to AEs. Incidence of respiratory events was similar between PBO and TEZ/IVA, and none resulted in treatment discontinuation. These study results support the safety and efficacy of TEZ/IVA in pts with CF homozygous for F508del-CFTR.

NACF 2017. P273. Efficacy and Safety of Tezacaftor/Ivacaftor and Ivacaftor in Patients Aged ≥12 Years with CF Heterozygous for F508del and a Residual Function Mutation: A Randomized, Double blind, Placebo-Controlled, Crossover Phase 3 Study

 S. Rowe, et al.

Results:

Pts received tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (TEZ/ IVA) (n=161), IVA monotherapy (n=156), or placebo (PBO) (n=161). Study baseline characteristics were balanced between groups (mean [SD] ages (y), 35.6 [13.5], 36.3 [15.2], and 32.6 [13.9] and mean [SD] baseline ppFEV1, 61.8 [14.9], 62.8 [14.6], and 62.1 [14.0] percentage points for TEZ/IVA, IVA, and PBO). Significant treatment effects were observed for TEZ/IVA and IVA in absolute ppFEV1 and CFQ-R respiratory domain score vs PBO. In addition, the treatment difference of absolute ppFEV1 between TEZ/IVA and IVA was statistically significant in favour of TEZ/ IVA. The majority of adverse events (AEs) were mild (TEZ/IVA 35.8%; IVA 35.0%; PBO 38.9%) or moderate (34.0%; 32.5%; 33.3%). The most common AEs (>10%) were infective pulmonary exacerbation of CF, cough, headache, and haemoptysis. No increase in respiration abnormal with TEZ/IVA was observed. No treatment discontinuations due to AEs were reported in the TEZ/IVA group vs 1.3% IVA and 0.6% PBO. Serious AEs were reported (TEZ/IVA 4.9%; IVA 6.4%; PBO 8.6%). No deaths occurred during the study.

Conclusions:

Significant improvements in ppFEV1 and CFQ-R respiratory domain were seen with TEZ/IVA and IVA treatment vs PBO. Significant improvement in ppFEV1 was also seen with TEZ/IVA vs IVA. Treatments were well tolerated with no (TEZ/IVA) or few (IVA) discontinuations due to AEs. These findings support safety and efficacy of TEZ/IVA and IVA in pts with CF heterozygous for F508del and a second mutation resulting in CFTR residual function.

CARE™ FACULTY PERSPECTIVE:

The two studies on tezacaftor-ivacaftor show that this combination therapy improves lung function (FEV1) and reduces exacerbation rate in CF patients with the most common genotype (Phe508del/ Phe508del) similar to lumacaftor-ivacaftor (OrkambiTM) but with better tolerability, and also improves lung function in patients with a residual function mutation, to a similar degree as ivacaftor monotherapy. Whether the combination of improved FEV1 and reduced exacerbation rate will result in greater treatment effects over time is unclear at this point though conceivable, as exacerbations contribute to a more rapid pulmonary function decline. Results from the open-label extension studies in which the majority of the study subjects were enrolled, may help clarify this in the near future.

While these studies demonstrate that CFTR modulating therapies have beneficial effects on some aspects of the disease, the clinical benefit of the current combination therapies for CF patients with the most common CFTR genotype (Phe508del/ Phe508del) falls within the range of established symptomatic therapies such as nebulized inhaled hypertonic saline or recombinant human DNAse. There is still an unmet need for truly effective new therapies to be developed for all individuals with CF. The complete study results on tezacaftor-ivacaftor combination therapy were recently published in the New England Journal of Medicine (Taylor-Cousar JL, et al., and Rowe SM, et al., N Engl J Med. 2017 Nov 3. [Epub ahead of print]), with an accompanying Editorial (Grasemann H, N Engl J Med. 2017 Nov 3. [Epub ahead of print]).

Whether new CFTR targeting combination therapies that are in the drug development pipeline, will ultimately result in clinically meaningful improvement of lung function and clinical status needs to be seen. Preliminary results presented by Dr. E. Tullis from Toronto suggest that the addition of a second corrector to corrector/potentiator combination regimens can result in improved efficacy of CFTR modulator therapy.