Details here on the fda clinical trials page--annoying new yahoo format won't allow links, but this is key inclusion data:
Clinical evidence of residual CFTR function based on any 1 of the following: 1)Clinically documented residual exocrine pancreatic function, 2)Sweat chloride value ≤80 mmol/L at screening, or 3) Age of diagnosis ≥12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing
My take is that this is a pretty big "catch all"--it isn't just for the mutations listed but any that are in the classes listed. And that the results will be good because the inclusion criteria is in a sense cherry-picking based on late diagnosis, pancreas function, etc. because those folks will have a high residual CFTR function. Not sure how the labeling would be--would it be "classes of mutations?" That would be my guess, without the other 3 parameters. This could be up to 20% of the population. Interesting to see if anyone asks about this tomorrow.
From what Ian Smith said at the UBS conference, this is an "N of 1" study, as described in the CF slide presentation that's been posted here a couple of times. I think the idea is that each patient serves as their own control. They take pills for some period of time, say a year. And the pills alternate between placebo and kalydeco, maybe 3 months at a time. (I'm guessing at the details) If patients have improved measurements while on Kalydeco relative to placebo periods, you have proof of efficacy on that mutation. Then maybe Vertex gets labeling approval for that mutation. I don't know if literally one patient would be enough to get approval, but I think this is the general idea for getting approval for rare mutations.
Vertex indicated in one of the recent (last couple weeks) conference, that it recently announced an n of 1 study. And a week before that presentation a new Phase 2 study for Kalydeco was announced. The inclusion criteria was:
"Clinical evidence of residual CFTR function based on any 1 of the following: 1)Clinically documented residual exocrine pancreatic function, 2)Sweat chloride value ≤80 mmol/L at screening, or 3) Age of diagnosis ≥12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing."
This is very broad and seems to be able to pick up anyone with residual CFTR function.
I've tried posting many times over the last several days and it "takes" but then doesn't show up??? Any thoughts?
Wanted to alert folks to Vertex' press release on CF Conference presentations available at vrtx webpage and linking there to presentation. Particularly interested in poster 20 and what it means to the future of correctors for CFers and Vertex.
The work shown in Abstract #30 was definitely done at Vertex. But the compound VRT-534 was obtained through the CFF. They found that this particular form is more potent than its chemical isomers(mirror images of VRT-534). The authors think that the compound is a useful tool rather than a drug candidate itself. But it is clear that Van Goor et al. are up to something in the line of correctors beyond VX-809 and 661. See below.
TITLE: IDENTIFICATION AND CHARACTERIZATION OF CFTR CORRECTOR VRT-534 (C-18)
AUTHORS (LAST NAME, FIRST NAME): Grootenhuis, Peter 1; Hadida, Sabine 1; Miller, Mark
1; Zhou, Jinglan 1; Van Goor, Fredrick 1
INSTITUTIONS (ALL): 1. Vertex Pharmaceuticals Incorporated, San Diego, CA, United States.
ABSTRACT BODY: VRT-534 (C-18) is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector made available through the CF Foundation for research purposes. We describe some in vitro characteristics of C-18 and the effect of its chiral centers on activity. Extensive medicinal chemistry and SAR analyses on VRT-768, an initial corrector hit, led to several distinct chemical scaffolds, one of which led to VRT-534. The two chiral centers of C-18 allow for four discrete stereoisomers. We studied the corrector activity of the various stereoisomers by monitoring chloride transport in Ussing chamber studies using cultured primary human bronchial epithelial cells derived from patients with cystic fibrosis who are homozygous for the F508del-CFTR mutation. The chiral center in the benzylic position was found to display a profound effect on the potency. Thus, C-18 (S,R-configuration) was more potent (EC50=0.5 μM) than VRT-535 (R,R-configuration) which had an EC50=2.7 μM. Interestingly, the maximal efficacy of these diastereoisomers was similar. Changing the R-configuration of the hydroxypyrrolidine to S led to 3-fold decrease in potency. To our knowledge, this is the first instance of a clear stereochemical preference for a CFTR corrector; this supports a specific interaction with the putative target. The in vitro potency and efficacy of C-18 render it a useful tool for research into CFTR correction.
Sponsored by Vertex Pharmaceuticals Incorporated.