An open label N of 1 study to evaluate the safety and efficacy of long-term treatment with Ivacaftor in combination with ATALUREN (PTC124) in Subjects with Nonsense Mutation Cystic Fibrosis

PI: Steven Rowe MD, MSPH

Institution: University of Alabama at Birmingham

MDBR Statistics

Institutions Awarded

47

Countries Awarded

11

# of Awards

106

Total Amount

$6,405,314

Specific Aims 1 and 2: Determine the clinical efficacy and effect on CFTR activity of combining ataluren and ivacaftor to a stable CF medical regimen that includes ivacaftor in CF patient(s) homozygous for nonsense mutations, with at least one being W1282X CFTR.

Progress: We completed two separate clinical studies, each involving a subject homozygous for nonsense mutations, and treated with the combination of ivacaftor and ataluren. Each study was slightly different due to constraints regarding access to the investigational agents. The first subject (W1282X/W1282X) received 6 months of ivacaftor and ataluren together after being on stable ivacaftor prior to the study. Throughout the study, the addition of ataluren was well tolerated when added to ivacaftor and there were no concerns regarding the safety of the regimen. CFTR activity, as measured by NPD, improved with addition of ataluren whereas sweat chloride increased slightly. Neither lung function nor symptom score by CFQ-R did not change with addition of ataluren, but there was a significant increase in BMI.

The second patient (W1282/G542X; completed during the no-cost extension) was on a stable dose of ataluren, and then had ivacaftor intermittently added to the regimen, in 3 two week cycles separated by 2-4 week washout periods. Throughout the study, the addition of ivacaftor was well tolerated when added to ataluren and there were no concerns regarding the safety of the regimen. As in the first subject, CFTR activity, as measured by NPD, improved with addition of ataluren whereas sweat chloride increased slightly. Spirometry improved with the addition of ivacaftor, and CFQ-R also improved, whereas BMI did not change, likely due to the short treatment period. Our conclusions is that ivacaftor may be efficacious for the W1282X mutation, particularly when combined with the readthrough agent ataluren, warranting further work combining translational readthrough agents with W1282X potentiators, including ivacaftor.

Specific Aim 3: Corroborate clinical trial findings with primary HNE cells derived from the same W1282X homozygous subject(s).

We published a manuscript in the Journal of Cystic Fibrosis (Mutyam et al. Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation. J Cyst Fibros 2017;16:24-29) demonstrating activity of ivacaftor in vitro. We have tested and continue to test the effect of additional agents using primary HNE cells from the reference subject. To date, CFTR activity in these cells has been assessed after treatment with the optimal dose of available readthrough agents (geniticin (G418), ataluren, gentamicin, and escin) or corrector molecules (lumacaftor (VX-809). In addition, several combination approaches of readthrough agents or ivacaftor with corrector molecules have been evaluated. None of these approaches as yet has elicited a significant improvement in CFTR activity over ivacaftor alone, and is likely related to low mRNA levels, as confirmed by RT-PCR.

Strategies to augment mRNA levels may be needed to realize improvements in CFTR-dependent ion transport.