Described herein is a genetic modifier of cystic fibrosis (CF), which may serve as a predictor of the efficacy of a CFTR-directed therapy. SNPs rs7512462 or rs2869027 in non-coding regions of SLC26A9 are shown to correlate with CF lung disease severity in patients having CFTR mutations that leave protein at the cell surface, e.g. gating mutations such as G551D. It is also shown that patient response to Ivacaftor correlates with SLC26A9 genotype. Given the biology of SLC26A9, risk alleles of SLC26A9 should correlate with reduced SLC26A9. SLC26A9 activity (marked by e.g. genotype or expression level) is therefore a predictor of treatment efficacy for any CFTR-directed therapeutic, such as Ivacaftor or Lumacaftor. Associated methods of selecting and treating patients are described, along with related kits, uses, and drug discovery platforms.

Described herein is a genetic modifier of cystic fibrosis (CF), which may serve as a predictor of the efficacy of a CFTR-directed therapy. SNPs rs7512462 or rs2869027 in non-coding regions of SLC26A9 are shown to correlate with CF lung disease severity in patients having CFTR mutations that leave protein at the cell surface, e.g. gating mutations such as G551D. It is also shown that patient response to Ivacaftor correlates with SLC26A9 genotype. Given the biology of SLC26A9, risk alleles of SLC26A9 should correlate with reduced SLC26A9. SLC26A9 activity (marked by e.g. genotype or expression level) is therefore a predictor of treatment efficacy for any CFTR-directed therapeutic, such as Ivacaftor or Lumacaftor. Associated methods of selecting and treating patients are described, along with related kits, uses, and drug discovery platforms.

The present invention provides pharmaceutical combinations comprising (a) a compound of formula (I) wherein R represents phenyl or pyridinyl; wherein phenyl is optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy, hydroxyl, amino, lower alkylamino, lower dialkylamino, acetylamino, halogen and nitro; and wherein pyridinyl is optionally substituted by amino or halogen; R1 represents hydrogen or cyano-lower alkyl; and wherein the prefix lower denotes a radical having up to and including a maximum of 4 carbon atoms; or a pharmaceutically acceptable derivative thereof; and (b) a CD40 agonist.

##STR00001##

The present invention provides pharmaceutical combinations comprising (a) a compound of formula (I) wherein R represents phenyl or pyridinyl; wherein phenyl is optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy, hydroxyl, amino, lower alkylamino, lower dialkylamino, acetylamino, halogen and nitro; and wherein pyridinyl is optionally substituted by amino or halogen; R1 represents hydrogen or cyano-lower alkyl; and wherein the prefix lower denotes a radical having up to and including a maximum of 4 carbon atoms; or a pharmaceutically acceptable derivative thereof; and (b) a CD40 agonist.

##STR00001##

The present invention provides pharmaceutical combinations comprising (a) a compound of formula (I) wherein R represents phenyl or pyridinyl; wherein phenyl is optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy, hydroxyl, amino, lower alkylamino, lower dialkylamino, acetylamino, halogen and nitro; and wherein pyridinyl is optionally substituted by amino or halogen; R1 represents hydrogen or cyano-lower alkyl; and wherein the prefix lower denotes a radical having up to and including a maximum of 4 carbon atoms; or a pharmaceutically acceptable derivative thereof; and (b) a CD40 agonist.

##STR00001##

The present disclosure relates to methods of treating cancer in a patient using a combination of an inhibitor of an immune checkpoint protein and an indole compound or its phosphate derivative.

The present disclosure relates to methods of treating cancer in a patient using a combination of an inhibitor of an immune checkpoint protein and an indole compound or its phosphate derivative.

The present disclosure relates to methods of treating cancer in a patient using a combination of an inhibitor of an immune checkpoint protein and an indole compound or its phosphate derivative.

Methods for treating obstructive hypertrophic cardiomyopathy are described herein. The treatment methods include the administration of a cardiac myosin inhibitor (CK-3773274, also referred to as CK-274 or aficamten) and may include titrating an administrated daily dose based on one or more components of an echocardiogram. The daily dose may be increased, maintained, decreased, or terminated, based on the echocardiogram.

Methods for treating obstructive hypertrophic cardiomyopathy are described herein. The treatment methods include the administration of a cardiac myosin inhibitor (CK-3773274, also referred to as CK-274 or aficamten) and may include titrating an administrated daily dose based on one or more components of an echocardiogram. The daily dose may be increased, maintained, decreased, or terminated, based on the echocardiogram.