SNPMiner Trials by Shray Alag

NCT00511368 (37) NCT00460382 (36) NCT04504071 (35) NCT03783286 (33) NCT04172597 (32) NCT02404233 (29) NCT00959894 (28) NCT00706147 (28) NCT00121017 (28) NCT01685801 (27) NCT04513626 (26) NCT01736761 (26) NCT04495348 (24) NCT02673398 (23) NCT02499978 (22) NCT01605084 (21) NCT04254705 (21) NCT02069834 (21) NCT00939770 (18) NCT01792570 (18) NCT01199939 (18) NCT00356616 (18) NCT02728258 (17) NCT02707601 (17) NCT02770508 (16) NCT00711009 (16) NCT00630864 (16) NCT00491556 (15) NCT04085315 (15) NCT02616029 (15) NCT00830804 (15) NCT04681820 (15) NCT01170962 (14) NCT00984152 (14) NCT03953898 (14) NCT00727597 (14) NCT03212274 (14) NCT01369199 (13) NCT00337467 (13) NCT00098293 (13) NCT01368497 (13) NCT02159599 (13) NCT00424814 (12) NCT04432454 (12) NCT02527096 (12) NCT01849003 (12) NCT03781063 (12) NCT03683524 (11) NCT01614457 (11) NCT00460746 (11) NCT00993148 (11) NCT03061331 (11) NCT02494882 (11) NCT03068312 (11) NCT04453436 (11) NCT01521338 (10) NCT02725567 (10) NCT01614470 (10) NCT01423812 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NCT02554591 (5) NCT01501604 (5) NCT02716116 (5) NCT01136460 (5) NCT00187655 (5) NCT00350272 (5) NCT00837135 (5) NCT03202862 (5) NCT01707199 (5) NCT03839342 (5) NCT01323010 (4) NCT02248324 (4) NCT01698905 (4) NCT01737359 (4) NCT01306045 (4) NCT02804100 (4) NCT01456676 (4) NCT00588172 (4) NCT03434418 (4) NCT03593993 (4) NCT01804140 (4) NCT02882308 (4) NCT03497767 (4) NCT04106024 (4) NCT02716311 (4) NCT04405674 (4) NCT03599518 (4) NCT01675778 (4) NCT01604122 (4) NCT01297777 (4) NCT04519970 (4) NCT00705679 (4) NCT04147351 (4) NCT04129502 (4) NCT03976856 (4) NCT02335944 (4) NCT04625647 (4) NCT03948763 (4) NCT03255083 (4) NCT04002830 (4) NCT02635815 (4) NCT03066206 (4) NCT01331642 (4) NCT00557245 (4) NCT01922583 (4) NCT02893332 (4) NCT03592888 (4) NCT02257424 (4) NCT03874858 (4) NCT00017732 (4) NCT00187720 (4) NCT02593539 (4) NCT01185587 (4) NCT04439292 (4) NCT03884348 (4) NCT01309243 (4) NCT03209063 (4) NCT04160546 (4) NCT03292302 (4) NCT02418234 (4) NCT02535338 (3) NCT02192697 (3) NCT03410043 (3) NCT03845296 (3) NCT02914990 (3) NCT02113813 (3) NCT01532011 (3) NCT04340388 (3) NCT00962533 (3) NCT03856411 (3) NCT04049266 (3) NCT02973763 (3) NCT02926092 (3) NCT00271973 (3) NCT04256941 (3) NCT03812809 (3) NCT02954523 (3) NCT01784068 (3) NCT03446417 (3) NCT02841579 (3) NCT02025114 (3) NCT01288521 (3) NCT01385683 (3) NCT02279004 (3) NCT00998582 (3) NCT03111901 (3) NCT01352715 (3) NCT01619774 (3) NCT01045369 (3) NCT02246998 (3) NCT03969823 (3) NCT00895596 (3) NCT02398929 (3) NCT00724711 (3) NCT04029350 (3) NCT03737994 (3) NCT01443806 (3) NCT02629822 (3) NCT03463525 (3) NCT00710112 (3) NCT03623750 (3) NCT04283955 (3) NCT02743923 (3) NCT01016106 (3) NCT01259089 (3) NCT03971474 (3) NCT02917993 (3) NCT02368990 (3) NCT00279110 (3) NCT02485652 (3) NCT00312169 (3) NCT04541407 (3) NCT02769286 (3) NCT00747487 (3) NCT04267913 (3) NCT01429597 (3) NCT04023617 (3) NCT03790228 (3) NCT01759888 (3) NCT04429152 (3) NCT01810718 (3) NCT02725632 (3) NCT01090011 (3) NCT04544111 (3) NCT02926768 (3) NCT02981108 (3) NCT02459743 (3) NCT00654823 (3) NCT01037127 (3) NCT04439305 (3) NCT01028222 (3) NCT01542411 (3) NCT01031446 (3) NCT02726269 (3) NCT01892644 (3) NCT03260491 (3) NCT01802632 (3) NCT02720094 (3) NCT02630186 (3) NCT01627132 (3) NCT02690675 (3) NCT01013506 (3) NCT04252339 (3) NCT02496663 (3) NCT03386955 (3) NCT03394118 (3) NCT04212702 (3) NCT01754025 (3) NCT01160276 (3) NCT00121979 (3) NCT03228277 (3) NCT04351555 (3) NCT01243346 (3) NCT04510415 (3) NCT02796274 (3) NCT02774005 (3) NCT02064491 (3) NCT04233021 (3) NCT03799601 (3) NCT00260260 (3) NCT02094261 (3) NCT04245085 (3) NCT03058094 (3) NCT01282151 (3) NCT02520778 (3) NCT03161808 (3) NCT04181060 (3) NCT01342679 (3) NCT01443273 (3) NCT01593254 (3) NCT04433481 (3) NCT02529995 (3) NCT03502850 (3) NCT02771314 (3) NCT03823807 (3) NCT03270527 (3) NCT02688881 (3) NCT01005602 (3) NCT02442349 (3) NCT02684591 (2) NCT02282267 (2) NCT03381430 (2) NCT02178397 (2) NCT03608215 (2) NCT02603107 (2) NCT03370770 (2) NCT03322696 (2) NCT03333343 (2) NCT00525473 (2) NCT03127449 (2) NCT01781026 (2) NCT02503722 (2) NCT00975871 (2) NCT03964233 (2) NCT03388099 (2) NCT02317016 (2) NCT03845270 (2) NCT03519958 (2) NCT03918304 (2) NCT02151721 (2) NCT02777658 (2) NCT01016444 (2) NCT02971501 (2) NCT03101254 (2) NCT03178617 (2) NCT01774721 (2) NCT03574753 (2) NCT01357655 (2) NCT01766713 (2) NCT02097225 (2) NCT00658164 (2) NCT03622593 (2) NCT02571036 (2) NCT00969137 (2) NCT00834665 (2) NCT02026011 (2) NCT03622580 (2) NCT03543683 (2) NCT01143493 (2) NCT03671538 (2) NCT04028778 (2) NCT00324961 (2) NCT01915576 (2) NCT02157883 (2) NCT01387022 (2) NCT03864042 (2) NCT03235245 (2) NCT03469960 (2) NCT02795884 (2) NCT04687241 (2) NCT00005541 (2) NCT01242813 (2) NCT03960645 (2) NCT00643058 (2) NCT03443336 (2) NCT02992860 (2) NCT02281760 (2) NCT02201602 (2) NCT04310007 (2) NCT04309019 (2) NCT03720665 (2) NCT00909532 (2) NCT00411944 (2) NCT01604681 (2) NCT01245062 (2) NCT00270231 (2) NCT03256136 (2) NCT03973918 (2) NCT00302692 (2) NCT00125281 (2) NCT02163733 (2) NCT02110407 (2) NCT00475176 (2) NCT03196882 (2) NCT01572818 (2) NCT02556333 (2) NCT04268550 (2) NCT02433717 (2) NCT03428126 (2) NCT01153763 (2) NCT02609776 (2) NCT01420211 (2) NCT03556176 (2) NCT03872440 (2) NCT01405079 (2) NCT03382795 (2) NCT02991950 (2) NCT00013598 (2) NCT03455764 (2) NCT02422628 (2) NCT03831932 (2) NCT03766490 (2) NCT02580474 (2) NCT00499577 (2) NCT02444884 (2) NCT01775943 (2) NCT03544814 (2) NCT01310036 (2) NCT01027663 (2) NCT01928160 (2) NCT01244438 (2) NCT00007150 (2) NCT04462081 (2) NCT02297425 (2) NCT02086071 (2) NCT01050400 (2) NCT03060590 (2) NCT01819428 (2) NCT02709668 (2) NCT02411448 (2) NCT03878719 (2) NCT04622072 (2) NCT04479306 (2) NCT03377023 (2) NCT01378026 (2) NCT03239145 (2) NCT04511533 (2) NCT00226551 (2) NCT02191891 (2) NCT04586270 (2) NCT04669535 (2) NCT04545710 (2) NCT02120222 (2) NCT02738593 (2) NCT00831272 (2) NCT04469543 (2) NCT00573495 (2) NCT04158544 (2) NCT00904150 (2) NCT02110056 (2) NCT02856893 (2) NCT02110043 (2) NCT02182986 (2) NCT04179890 (2) NCT00063232 (2) NCT02197234 (2) NCT03121235 (2) NCT01532089 (2) NCT03887169 (2) NCT02268864 (2) NCT01963845 (2) NCT00866736 (2) NCT03991013 (2) NCT02500927 (2) NCT04657991 (2) NCT02228382 (2) NCT02689570 (2) NCT01513785 (2) NCT02463435 (2) NCT03351361 (2) NCT04527549 (2) NCT03424759 (2) NCT02197247 (2) NCT02321046 (2) NCT04272034 (2) NCT04646824 (2) NCT04027647 (2) NCT02364609 (2) NCT02759835 (2) NCT04349865 (2) NCT00068159 (2) NCT00418015 (2) NCT04310397 (2) NCT03088176 (2) NCT03867175 (2) NCT00339209 (2) NCT00011258 (2) NCT01288430 (2) NCT01616199 (2) NCT03603262 (2) NCT03071705 (2) NCT00969930 (2) NCT00772408 (2) NCT02743468 (2) NCT00277342 (2) NCT04248829 (2) NCT01767454 (2) NCT00933127 (2) NCT03317873 (2) NCT03392246 (2) NCT01909453 (2) NCT03523104 (2) NCT00085917 (2) NCT02507921 (2) NCT03781752 (2) NCT03828422 (2) NCT02193282 (2) NCT03195452 (2) NCT04657289 (2) NCT02294487 (2) NCT01325441 (2) NCT02511106 (2) NCT02997501 (2) NCT04184921 (2) NCT00625092 (2) NCT01657786 (2) NCT01415011 (2) NCT02629523 (2) NCT01718847 (2) NCT02818023 (2) NCT00577707 (2) NCT01943422 (2) NCT00116636 (2) NCT04429542 (2) NCT01841463 (2) NCT03865511 (2) NCT03205267 (2) NCT01218477 (2) NCT02881320 (2) NCT01897480 (2) NCT02810990 (2) NCT04189757 (2) NCT01951001 (2) NCT04254939 (2) NCT03207867 (2) NCT00780949 (2) NCT03355768 (2) NCT00817089 (2) NCT02143466 (2) NCT04499053 (2) NCT01907776 (2) NCT00909727 (2) NCT01562028 (2) NCT03737253 (2) NCT00441974 (2) NCT02155465 (2) NCT04586335 (2) NCT00661999 (2) NCT02705339 (2) NCT04006340 (2) NCT04553887 (2) NCT04645225 (2) NCT03852290 (2) NCT02183922 (2) NCT03970239 (2) NCT00294372 (2) NCT03250676 (2) NCT03792074 (2) NCT00671892 (2) NCT00689182 (2) NCT00106379 (2) NCT01947023 (2) NCT00509652 (2) NCT03683251 (2) NCT02039986 (2) NCT03515837 (2) NCT04081688 (2) NCT03190005 (2) NCT01584648 (2) NCT02292654 (2) NCT03992456 (2) NCT03133546 (2) NCT01485809 (2) NCT01266967 (2) NCT04644315 (2) NCT02909712 (2) NCT00062764 (2) NCT01776684 (2) NCT03042221 (2) NCT01940809 (2) NCT04675008 (2) NCT01161537 (2) NCT01154816 (2) NCT01175759 (2) NCT01199731 (2) NCT02788058 (2) NCT03130452 (2) NCT04687423 (2) NCT01772732 (2) NCT02631447 (2) NCT02525692 (2) NCT02526537 (2) NCT03513666 (2) NCT02027961 (2) NCT03106779 (2) NCT04106544 (2) NCT04258943 (2) NCT00165984 (2) NCT00977470 (2) NCT02092974 (2) NCT03975231 (2) NCT03586453 (2) NCT01998295 (2) NCT02021305 (2) NCT03135197 (2) NCT00432016 (2) NCT04636437 (2) NCT03004625 (2) NCT03851445 (2) NCT04031898 (2) NCT04201418 (2) NCT01911507 (2) NCT03539224 (2) NCT01978236 (2) NCT00866177 (2) NCT00320879 (2) NCT00044304 (2) NCT01999179 (2) NCT00977730 (2) NCT02491775 (2) NCT00212147 (2) NCT02040064 (2) NCT00489385 (2) NCT01713023 (2) NCT04122729 (2) NCT03994393 (2) NCT02438722 (2) NCT02762448 (2) NCT00071903 (2) NCT00626223 (2) NCT01193829 (2) NCT03239340 (2) NCT02991274 (2) NCT02811354 (2) NCT03416530 (2) NCT02522988 (2) 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NCT03678506 (1) NCT02146365 (1) NCT04310943 (1) NCT02619955 (1) NCT02934139 (1) NCT00400387 (1) NCT00375219 (1) NCT00149305 (1) NCT03520946 (1) NCT02787447 (1) NCT04501614 (1) NCT03166631 (1) NCT04213313 (1) NCT02078531 (1) NCT02349048 (1) NCT02981784 (1) NCT04636593 (1) NCT01647711 (1) NCT03231722 (1) NCT03576937 (1) NCT04412070 (1) NCT00554866 (1) NCT03151161 (1) NCT01817166 (1) NCT02220855 (1) NCT02512627 (1) NCT04591197 (1) NCT03402048 (1) NCT04500704 (1) NCT02323724 (1) NCT01166126 (1) NCT03029858 (1) NCT04317599 (1) NCT00300573 (1) NCT00809211 (1) NCT01393730 (1) NCT02318368 (1) NCT02228369 (1) NCT04500717 (1) NCT01074398 (1) NCT03134131 (1) NCT02455167 (1) NCT01004497 (1) NCT02073279 (1) NCT02117817 (1) NCT00323687 (1) NCT01605981 (1) NCT01371955 (1) NCT04147767 (1) NCT04144257 (1) NCT03490123 (1) NCT04423185 (1) NCT02625337 (1) NCT03567629 (1) NCT03360929 (1) NCT00109278 (1) NCT04108156 (1) NCT02132598 (1) NCT00542451 (1) NCT01587573 (1) NCT00868465 (1) NCT01494402 (1) 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SNPMiner SNPMiner Trials (Home Page)


Report for Clinical Trial NCT02724527

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of N91115 for Efficacy and Safety in Patients With CF Heterozygous for F508del-CFTR + Gating Mutation Being Treated With Ivacaftor

Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R).

NCT02724527 Cystic Fibrosis
MeSH:Cystic Fibrosis Fibrosis

2 Interventions

Name: Cavosonstat

Description: CFTR modulator that stabilizes CFTR
Type: Drug
Group Labels: 1

Cavosonstat (N91115) 400 mg

Name: Placebo

Description: Matched Placebo capsule
Type: Drug
Group Labels: 1

Placebo


Primary Outcomes

Description: Forced Expiratory Volume (FEV) absolute measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) is calculated using the Hankinson method.

Measure: The absolute change in ppFEV1 in the N91115 treated group

Time: Baseline, week 4 and 8 assessments

Secondary Outcomes

Description: Forced Expiratory Volume relative measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) is calculated using the Hankinson method.

Measure: The relative change from study baseline within the active treatment group in ppFEV1 values

Time: Baseline, week 4 and 8 assessments

Description: Sweat chloride concentration measured by pilocarpine iontophoresis, a standard clinical laboratory technique. Sweat collection accomplished with the Wescor Macroduct System.

Measure: Absolute change from study baseline within the active treatment group in sweat chloride

Time: Baseline, week 4 and 8 assessments

Description: Patient questionnaires will compare baseline scores on their respiratory symptoms to weeks 4 and 8

Measure: Changes in the respiratory domain of the Cystic Fibrosis Questionnaire - Revised, (CFQ-R)

Time: Baseline, week 4 and 8 assessments

Description: Patient questionnaires will compare baseline global impression of changes in health from baseline to weeks 4 and 8

Measure: Absolute change from baseline within the active treatment group in Patient Global Impression of Change

Time: Baseline, week 4 and 8 assessments

Description: Assessments of clinical laboratory values, electrocardiogram (ECG), pulmonary exacerbations, and vital signs

Measure: Safety as determined by adverse events assessment

Time: Baseline to 8 weeks treatment with a 28-day follow up period

Description: Plasma collection for assessment of N91115 and ivacaftor Cmax

Measure: Pharmacokinetic Assessment of Maximum Plasma Concentration [Cmax] for N91115 & ivacaftor

Time: Weeks 1, 4 and 8

Description: Plasma collection for assessment of N91115 and ivacaftor AUC

Measure: Pharmacokinetic Assessment of area under the plasma concentration verse time curve [AUC] for N91115 & ivacaftor

Time: Weeks 1, 4 and 8

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There are 9 SNPs

SNPs


1 G1244E

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E ---


2 G1349D

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D ---


3 G178R

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R ---


4 G551D

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D ---


5 G551S

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S ---


6 S1251N

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N ---


7 S1255P

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---


8 S549N

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N ---


9 S549R

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R ---



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