OA19045A - Administration of deuterated CFTR potentiators. - Google Patents

Abstract

Disclosed is a method of treating in a subject of treating diseases and conditions that are beneficially treated by administering a CFTR potentiator The method comprises administering to the subjet an amount in the range of about 50 mg to about 200 mg once a day of Compound (I) or (II) or pharmaceutically acceptable salts thereof. This invention also provides compositions comprising Compound (I) or (II) and the use of such compositions in methods.

Description

ADMINISTRA TION OF DEUTERA TED CFTR POTENTIA TORS

Related Applications

This application claims the benefît of and priority to U.S. Provisional Patent Application No. 62/221,531, filed September 21, 2015; U.S. Provisional Patent Application No. 62/238,511, filed October 7, 2015; and U.S. Provisional Patent Application No. 62/348,855, filed June 10, 2016. The contents ofthe foregoing applications are incorporated herein by reference in their entirety.

B_ack_grou|)d _of ]_nventi_<)n ........................................

Many current medicines suffer from poor absorption, distribution, metabolism and/or excrétion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive métabolites.

Another ADME limitation that affects many medicines is the formation of toxic or hinlnoic.nlly réactivé métabolites. As a resuit, some patients receiving the drug may expérience toxicities, or the safe dosing of such drugs may be limited such that patients...... _ receive a suboptimal amount of the active agent, fri certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable métabolites is intrinsic to the metabolism of the compound.

In some select cases, a metabolic inhibitor will be co-administered with a drug that isj cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to;

treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an[ inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for| their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997,;

41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy tor decreasing drug clearance, me inmbitton oîaCYF enzyme s activity can atrect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-medîated metabolism of a drug or to reduce the formation of undesirable métabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug effîcacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on the rate of metabolism hâve been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Eoster-^VB, Adv Drug-ReSr-ÎflS^ÎA^MO (“Foster”); Kushner,— -DJ-et-al—Can-J-Rhysiol-RharmacoL-W-9V-79-88;-Eishei-,-MB-et-aL-Curr-Opin-Drug-DisGov----Devel, 2006, 9:101-09 (“Fisher”)). The results hâve been variable and unpredictable. For some compounds deutération caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher atp. 101).

The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one détermine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem., 1991, 34, 2871-76). Many drugs hâve multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deutération necessary to see an effect on metabolism, if any, will be different for each drug.

This invention relates to novel dérivatives of ivacaftor, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions Llidt aie bcncficially treatod by administering a CFTR (cystic fibrnsis “transmembrane conductance rcgulator) potentiator. ........ ..........

Ivacaftor, also known as VX-770 and by the chemical name, N-(2,4-di-tert-butyl-5hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide, acts as a CFTR potentiator. Results from phase III trials of ivacaftor in patients with cystic fibrosis carrying at least one copy of the G551D-CFTR mutation demonstrated marked levels of improvement in lung fonction and other key indicators of the disease including sweat chloride levels, likelihood of pulmonary exacerbations and body weight. Ivacaftor was approved by the FDA in 2012 for the treatment of cystic fibrosis in patients who hâve the G551D-CFTR mutation. In 2014, ivacaftor was approved for treating cystic fibrosis in patients who hâve one of eight additional mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D) in the CFTR gene. In 2015, ivacaftor was approved for treating cystic fibrosis in patients who hâve one of 10 mutations in the CFTR gene (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R andR117H). Ivacaftor was granted fast track désignation and orphan drug désignation by the FDA in 2006 and 2007, respectively, and is marketed under the tradename Kalydeco®. Ivacaftor is also approved in combination with VX-809 (also known as lumacaftor, a CFTR corrector) for the oral treatment of cystic fibrosis patients who carry the more common AF508-CFTKmutation; the combination is marketed under the tradename Orkambi®.

Despite the bénéficiai activities of ivacaftor, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

Summary of Invention

It has now been found that deuterated analogs of ivacaftor (including Compound (I), also referred to as CTP-656, D9-ivacaftor or Compound 106, and Compound (II), also referred to as Compound 105 or D18-ivacaftor) hâve an enhanced metabolic profile when administered to a subject, as compared to ivacaftor. In particular, the parent to métabolite ratio of Compound (I) is greater than the profile found for ivacaftor. Compound (I) is represented by the following structural formula:

:

cd₃ d₃

H (I), r,_r β pharmacpni-irally acceptable sait thereof. Compound ΠΙ) is represented by the following

-------straetur-al-formula:----------------------------------------------------------

or a pharmaceutically acceptable sait thereof.

The enhanced pharmacokinetic profile for Compound (I) relative to ivacaftor suggests that Compound (I) can be efficacious at doses in the range of about 50 to about 200 mg once a day. Based on these discoveries, novel dosing regimens using Compound (I) or (II), or a pharmaceutically acceptable sait thereof, for treating a condition mediated by CFTR in a subject are disclosed herein.

A first embodiment of the invention is a method for treating conditions that can be treated by compounds that potentiate the activity of CFTR. The method comprises administering to a subject an amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, once a day, wherein the amount of Compound (I) or (II), or a________ pharmaceutically acceptafoësanii^ëôClsnrÎherangeTifÎaboubSO-m-glo-aboutTQO-mgr-forexample, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. In particular, the subject is a human. In one aspect of this embodiment, the subject is a human 6 years of âge or older. Preferably, Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered orally at any of the foregoing dosages. In certain embodiments, the Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered orally at any of the foregoing dosages in a pharmaceutical formulation which is a tablet, including any tablet formulation disclosed herein, or a bioequivalent tablet formulation, or a granule. In certain aspects of this embodiment, the compound is Compound (I). In other aspects of this embodiment, the compound is Compound (II).

In an alternative first embodiment, the method comprises administering to a subject an amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, once a day, wherein the amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is in the range of about 25 mg to about 75 mg, for example, about 25 mg, about 37.5 mg, about 50 mg, about 62.5 mg, or about 75 mg, wherein the subject is a human 2 to less than 6 years of âge and less than 14 kg; or alLemalively, is a human 2 Lo less than 6 yeais uf âge and 14 kg or greater/Tnônëâspect, tiïë~dose forthFhuman2tôTëssTlïæT6~ÿears of âge andTess thâri T4 kg is 25 mg. In one aspect, the dose for the human 2 to less than 6 years of âge and greater than 14 kg is 37.5 mg. Preferably, Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered orally at any of the foregoing dosages. Preferably, the Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered orally at any of the foregoing dosages in a pharmaceutical formulation which is a granule. In certain aspects of this embodiment, the compound is Compound (I). In other aspects of this embodiment, the compound is Compound (II).

A second embodiment is Compound (I) or (II), or a pharmaceutically acceptable sait thereof, for treating conditions that can be treated by compounds that potentiate the activity of CFTR. The compound may be administered at the dosing regimens disclosed herein. In certain aspects of this embodiment, the compound is Compound (I). In other aspects of this embodiment, the compound is Compound (II).

A third embodiment of the invention is the use of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for treating conditions that can fie treated-b.y-CQ.mp.o.unds-tha.Lpo.tËnt.iate-tb.e-ac.ti-Yi.ty Q.LCKrR· The ___compo.undjuayAe_adminis.tere±aLthe_d.QsingXÊgimensÆsxdo^LedJierein,_e.,g^_ari_amQuntjn____ the range of 50 mg to 200 mg, once per day. In certain aspects of this embodiment, the compound is Compound (I). In other aspects of this embodiment, the compound is Compound (II).

A fourth embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and about 50 mg to about 200 mg of Compound (I) or (II), or a pharmaceutically acceptable sait thereof. Specifically, the pharmaceutical composition comprises about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of Compound (I) or (II), or a pharmaceutically acceptable sait thereof. More specifically, for example, the pharmaceutîcal composition comprises 75,100, or 150 mg of Compound I to be admînistered once per day. In a particular embodiment, the pharmaceutîcal composition comprises 100 - 150 mg of Compound I to be admînistered once per day. In a particular embodiment, the pharmaceutîcal composition comprises 100 mg of Compound I to be admînistered once per day. In a particular aspect, the pharmaceutîcal composition is a tablet. An alternative fourth embodiment is a pharmaceutîcal composition comprising a phaiinaueulicdlly acceptable carrier or diluent and about 25 mg to about 75 mg of Cnmpnund ’(I)“ôr“(II), or a pharmaceüticâllÿracceptable-saltthereof—Specifically. the pharmaceutîcal.........................

composition comprises about 25 mg, about 37.5 mg, about 50 mg, about 62.5 mg, or about 75 mg of Compound (I) or (II), or a pharmaceutically acceptable sait thereof. In a particular aspect, the pharmaceutîcal composition is a granule. In certain aspects of this embodiment, the compound is Compound (I). In other aspects of this embodiment, the compound is

Compound (II).

Additional embodiments of the invention are described hereinbelow.

Brief Description of the Drawings

Figure 1A depicts the mean plasma concentration (ng/mL) for CTP-656 and ivacaftor in the single ascending dose study.

Figure IB depicts the mean plasma concentration (ng/mL) for CTP-656 and ivacaftor in the single ascending dose study.

Figure 2 depicts the mean plasma concentration (ng/mL) for CTP-656 and ivacaftor following a 150 mg oral dose.

Figure 3 depicts the parent verses métabolite pharmacokinetic profile for (a) CTP-656 and (b) Ivacaftor (Kalydeco) following a 150 mg oral dose.

Figure 4A depicts the peak current potentiated by sequential additions of test articles.

Figure 4B depicts the AUC of potentiator response.

Figure 4C depicts the AI_Sc of potentiator response for ivacaftor, CTP-656, and D18-ivacaftor. Figure 5 is a schematic of the single ascending dose study.

Figure 6 is a scheme of the métabolites of ivacaftor and CTP-656.

Figure 7A is a schematic ofthe crossover study for D9-ivacaftor and D18-ivacaftor. Figure 7B depicts the mean plasma concentration (ng/mL) for D9-ivacaftor and DI 8ivacaftor following a 25 mg oral dose.

Figure 8 shows a schematic of the design of a multiple-ascending dose trial for CTP-656 (D9ivacaftor). Part A: single dose pharmacokinetic comparison (with crossover) of 150 mg CTP656 (2x 75 mg tablets) versus 150 mg ivacaftor. Part B: assessment of three doses of CTP656 (75 mg, 150 mg, and 225 mg or placebo, dosed once daily for seven days.

Figure 9 is a graph showing the plasma concentration of CTP-656 and ivacaftor after a single dose of CTP-656 or ivacaftor.

Figure 10 is a graph showing the plasma concentration of CTP-656 and métabolites (left panel) and a graph showing the plasma concentration of ivacaftor and métabolites (right panel) allei a single dose of CTP-656 or ivacaftor.

Figure n”isà grapOhowing the plasma concentration of’CTPë556 and metâbôlitësâftëf ............

multiple dosing (once per day for seven days) of CTP-656.

Detailed Description of the Invention

This invention in one embodiment relates to methods of use of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, involving certain dosing regimens and certain pharmaceutical compositions comprising Compound (I) or (Π), or a pharmaceutically acceptable sait thereof. The pharmaceutical compositions and dosing regimens are useful for treating conditions mediated by CFTR (cystic fibrosis transmembrane conductance regulator). In particular, Compound (I) or (II), or a pharmaceutically acceptable sait thereof and the pharmaceutical compositions and methods are useful for treating conditions that can be treated by compounds that potentiate the activity of CFTR.

In one embodiment, the invention provides a method for treating conditions that can be treated by compounds that potentiate the activity of CFTR. The method comprises administering to a subject an amount of Compound (I) or (II), or a pharmaceutically acceptabl.e salLtherenf in the ranges^o£50 mg tn 2Π0 mg once a day. Tn another embodiment, ____the invention provides a method of treating a condition that is mediated by CFTR in a__ subject, the method comprising administering to the subject a composition comprising a Compound I:

or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier, wherein the amount of the compound administered is in the range of 50 mg/day to 200 mg/day and the composition is administered once per day. Specifically, in the above embodiments, for example, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg of Compound I can be administered once per day. More specifically, for example, 75, 100, or 150 mg of Compound I can be administered once per day. In a particular embodiment, 100 150 mg of Compound I can be administered once per day. In a particular embodiment, 100 mg of Compound I can be administered once per day. In particular embodiments, (lie subjecL is a j_iuman ^lïëmâfivëlÿ/the method comprises administëring to a subject an amount of ...................

Compound (I) or (II), or a pharmaceutically acceptable sait thereof, once a day, wherein the amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is in the range of 25 mg to 75 mg, for example, 25 mg, 37.5 mg, 50 mg, 62.5 mg, or 75 mg, wherein the subject is a human 2 to less than 6 years of age and less than 14 kg; or altematively, is a human 2 to less than 6 years of age and 14 kg or greater. In one aspect, the dose for the human 2 to less than 6 years of age and less than 14 kg is 25 mg. In one aspect, the dose for the human 2 to less than 6 years of age and greater than 14 kg is 37.5 mg.

Conditions treatable by the methods disclosed herein include cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabètes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, MeUiiomaJjlÿcaiiQsisXIlijJ^eJ-rlIei^dilary-empliysemajZkmgeni^ ............O.steagenesis±n.p.eiie.cta,Jiem.ditary_hÿpofihriiiQgenemia,_ACTjdÊfLciency,_Diab.et.es___________ insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, PerlizaeusMerzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophie latéral sclerosis, Progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonie dystrophy, as well as Spongiform encéphalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease, Sjogren's disease, and a bile duct disorder or a kidney ion channel disorder, including, but not limited to, Bartter’s syndrome and Dent’s disease.

In a spécifie embodiment, the condition is cystic fibrosis in a subject such as a human patient in need thereof. In another spécifie embodiment, the condition is chronic obstructive pulmonary disease in a subject such as a human patient in need thereof. In certain embodiments, the subject is a humafi patient having the G551D-CFTR mutation. In certain embodiments, the subject is a human patient having one of the following mutations in the CFTR gene: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D. In certain emboaiments, tne subject is a human patient having one ot the rollowmg mutations m ........... “the CFTR gëüëïG55ÏDTG1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, .............. S549R and RI 17H. In another example of the foregoing embodiments, the compound is administered orally once a day.

In the foregoing embodiments, the compound is administered optionally in combination with a second agent. In certain embodiments, the subject is a human patient having the AF508-CFTR mutation. Examples of second agents include CFTR correctors, such as lumacaftor (VX-809) or tezacaftor (VX-661). In some embodiments wherein Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered optionally in combination with a second agent, the amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered once daily at 50 mg to 200 mg each time, for example, 50 mg, at 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. Altematively, wherein Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered optionally in combination with a second agent, the amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is administered once daily at 25 mg to 75 mg each ---------time, for example, 25 mg, 37.5 mg, 50 m-g^-ôXXmg, or 75 mg,---------------------------------.......E£fecti-ve-doses-w-ill-als0-var-y,-as-recogn.i.zed-by-those-ski.lled-i.n-the-art,-dependi.ng-Qn-the diseases treated, the severity of the disease, the route of administration, the sex, âge and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.

For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy régime using just that agent. Preferabiy, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art.

See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage ofthe second therapeutic agent and/or Compound (I) or (II), or a pharmaceuticaîly acceptable sait thereof, to be reduced from that required in a monotherapy. This has Lhc advdiitagc of minimizing toxic side effects of either the second therapeutic agent WCornp(nÎndTIjLTr(lIjror^pharmaceutically-acceptablc-salt-thetëof^syner-gistiG...............

improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound préparation or formulation.

In another embodiment, any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof one or more second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with ivacaftor. The choice of second therapeutic agent is also dépendent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising Compound (I) or (II), or a pharmaceuticaîly acceptable sait thereof, and a second therapeutic agent.

In particular, the combination thérapies of this invention include co-administering a Compound (I) or (II), or a pharmaceuticaîly acceptable sait thereof, or a pharmaceuticaîly acceptable sait thereof and a second therapeutic agent such as VX-809 (lumacaftor) or VX661 (tezacaftor), to a subject in need thereof for treatment. In certain embodiments, the subject. is a human patient having the AF508-CFTR mutation (in particular, a human patient homozygous for the F508del mutation).

The terni “co-administered” as used herein means that the second therapeutic agent may be administered together with Compound (I) or (II), or a pharmaceuticaîly acceptable sait thereof, as part of a single dosage form (such as a composition of this invention comprising a compound ofthe invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Altematively, the additional agent may be administered prior to, consecutively with, or following the administration of Compound (I) or (II), or a pharmaceuticaîly acceptable sait thereof. fri such combination therapy treatment, both Compound (I) or (II), or a pharmaceuticaîly acceptable sait thereof, and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both Compound (I) or (II), or a pharmaceutically acceptable sait thereof, and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or Compound (I) or (II), or a pharmaceutically acceptable sait thereof, to said subject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications reterenced herein, as well as in Wells et al., eds., Pharmaco therapy Handbuok, 2nd Edition, ................. Appleton ândTânge, Stamford,Tonn. (2000)TPDR PharmacopoeiaTTarascon Pocket Phannacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan’s purview to déterminé the second therapeutic agent’s optimal effective-amount range.

In one embodiment of the invention, the effective amount of the second therapeutic agent is less than its effective amount would be where Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, alone or together with one or more of the abovedescribed second therapeutic agents in the manufacture of a médicament, either as a single composition or as separate dosage forms, for treatment or prévention in a subject of a disease, disorder or symptom set forth above. Another aspect of the invention is Compound (I) or ---------------(-n.)^_r-^haÎn^eeutieally-^cceptab.le-sdtitheÎeQf^fa.r use in th£-tr.e.atm.eiiLQ£.pi.eveiition in a— .............................subjeGt-0-f-a-disease^disorder-o.r-symptom-thereoTd.elineatedJierein,---------------------------In one embodiment, any atom not designated as deuterium is present at its natural isotopic abundance in Compound (I) or (II), or a pharmaceutically acceptable sait thereof.

The synthesis of Compound (I) or (II), or a pharmaceutically acceptable sait thereof may be readily achieved by the methods described U.S. Patent No. 8,865,902, the teachings of which are incorporated herein by reference. In particular, Example 3 of U.S. Patent No. 8,865,902 describes a synthesis of Compound (I) and Example 4 describes a synthesis of Compound (II).

Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

The invention also provides pharmaceutical compositions comprising an effective amount of Compound (I) or (II), or a pharmaceutically acceptable sait thereof; and a pharmaceutically acceptable carrier. The carrier(s) are “acceptable” in the sense of being compatible with the other ingrédients of the formulation and, in the case of a pharmaceutically acceptable carrier, not dclctcrious to the récipient thereof in an amount used ....... inthe médicament; ...... ”

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aiuminum stéarate, lecithin, sérum proteins, such as human sérum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloïdal silica, magnésium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of the présent invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Rôle of Lipid PYHpients in Modifying Oral and Parentéral Drug Delivery: Basic Principles and Biological Z .............. F.xnmples.” Kishor M. Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.

The pharmaceutical compositions ofthe invention include those suitable for oral administration. Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, granules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such préparative methods include the step of bringing into association with the molécule to be administered ingrédients such as the carrier that constitutes one or more accessory ingrédients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingrédients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In certain embodiments, the compound is administered orally. Compositions ofthe present invention suiLable fui oial administration may be presented ns discrète units such as ^^dï^]liâchëts/ôrISblëtrëâclrcôntarmng“a“predetermined-amount-of-the-aGtiwe-in.gr-edient;.......

a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid émulsion; a water-in-oil liquid émulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In a spécifie embodiment, the compound is administered orally as a tablet. Alternatively, the compound is administered orally as a granule.

In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubrîcating agents, such as magnésium stéarate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried comstarch. When aqueous suspensions are administered orally, the active ingrédient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. In another embodiment, the composition is in the form of a tablet. In certain embodiments, exemplary formulations for the tablet are disclosed in US. Patent No. 8,754,224, the teachings of which are herein incorporatcd by reference.

_______________Tn _? particular embodiment. the tablet contains 150 mg of Compound (I) or (II), or a pharmaceutically acceptable sait thereof, and thêTollEWing inactive ingredi^^luidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnésium stéarate, microcrystalline cellulose, and sodium lauryl sulfate. In certain embodiments, the tablet film coat contains camauba wax, FD&C Blue #2, PEG 3350, polyvïnyl alcohol, talc, and titanium dioxide. In certain embodiments, the tablet is printed with a printing ink; the printing ink may contain ammonium hydroxide, iron oxide black, propylene glycol, and shellac. In another particular embodiment, the tablet contains 75 mg of Compound I (CTP-656, D9-ivacaftor), together with the following inactive ingrédients: microcrystalline cellulose, lactose monohydrate, colloïdal silicon dioxide, croscarmellose sodium, magnésium stéarate, and sodium lauryl sulfate. Multiple tablets may be administered to provide a suitable once-daily dose (e.g., two 75 mg tablets administered together for a 150 mg once-daily dose). In another particular embodiment, the tablet comprises granules compressed with extra-granular material; the granules comprise about 17.1 percent (by weight of the tablet) of an amorphous dispersion of Compound I (wherein the amorphous dispersion comprises about 80% substantially amorphous Compound I by weight of the dispersion, hypromellose acetate succinate (HPMCAS) (about 19.5 percent by weight of the dispersion) and sodium laurel sulfate (about 0.5 percent by weight of the dispersion)), a compression aid such as microcrystalline cellulose (e.g., Avicel PHI01) (about 39.0 percent by weight of the tablet), a diluent/filler such as lactose monohydrate 316 (about 38.9 percent by weight of the tablet) a surfactant such as sodium lauryl sulfate (SLS) (about 0.50 percent by weight of the tablet), a disintegrant such as croscarmellose sodium (e.g., Ac-di-sol) (about 1.50 percent by weight of the tablet) and a lubricant such as Hyqual magnésium stéarate (about 0.20 percent by weight of the tablet), and the extracellular matrix comprises a disintegrant such as croscarmellose sodium (e.g., Ac-di-sol) (about 1.50 percent by weight of the tablet), a glidant such as colloïdal silicon dioxide (about 0.50 percent by weight ofthe tablet) and additional lubricant such as magnésium stéarate (e.g., Hyqual (about 0.80 percent by weight of the tablet). Thus, in one embodiment, the invention provides a pharmaceutical composition comprising about 17.1 wt % of a solid dispersion by weight of the composition, wherein the dispersion comprises about 80 wt % of substantially amorphous Compound I (CTP-656) by weight of the dispersion, about 19.5 wt % of hypromellose acetate succinate (HPMCAS) by weight of the dispersion, and about 0.5 wt % SLS by weight of the dispersion; about 39.0 wt % of microcrystalline cellulose by weight of the composition; about 38.9 wt % of lactose monohydrate by weight of the composition; about 3 wt % of sodium

------er-osea-meHos^-by weight of the composition; about 0.5 wt % ol-S-LS-b-y weight of the---------------Gomposition^-about-OT5-wt-%-oLGolloidal-silÎG0n-di©x-ide-b-y-wei-ghLo.f-the-co.mposi.tioii^aiid--about 0.8 wt % of magnésium stéarate by weight of the composition. In certain embodiments, the tablet comprises 75 mg of Compound I (CTP-656). In other embodiments, the tablet comprises 100 mg of Compound I (CTP-656). In still other embodiments, the tablet comprises 150 mg of Compound I (CTP-656).

In another particular embodiment, the granule is enclosed in a unit-dose packet containing 25 mg, 50 mg or 75 mg of Compound (I) or (II), or a pharmaceutically acceptable sait thereof. Each unit-dose packet of Compound (I) or (II) oral granules contains 25 mg of Compound (I) or (II), 50 mg of Compound (I) or (II) or 75 mg of Compound (I) or (II) and the following inactive ingrédients: colloïdal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnésium stéarate, mannitol, sucralose, and sodium lauryl sulfate. In another embodiment, the composition is in the form of a granule. In certain embodiments, exemplary formulations for the granule are disclosed in US. Patent No. 8,883,206, the teachings of which are herein incorporated by reference. In another embodiment, a composition of this invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to hâve or that demonstrates advantageous properties when adniiiiisleied with a compound having the same mechanism of action as ivacaftor

.....................Prëfëfâblÿ_; ^_thëreiyond“tfrerapeutic“agent-is an-agent-useful-in-the-treatment-oTa-variet-y-of conditions, including cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabètes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congénital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabètes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophie latéral sclerosis, Progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonie dystrophy, as well as Spongiform ______________encéphalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler................'.......... Scheinker syndrome, COPD, dry-eye disease, Sjôgrmï'sTiisëase, andTrbîlëftüct~dtsorder or a kidney ion channel disorder, including, but not limited to, Bartter’s syndrome and Dent s disease.

In a spécifie embodiment, the second therapeutic agent is an agent useful in the treatment of cystic fibrosis. In certain embodiments, the second therapeutic agent is an agent useful in the treatment of cystic fibrosis in a human patient having the G551D-CFTR mutation. In certain embodiments, the second therapeutic agent is an agent useful in the treatment of cystic fibrosis in a human patient having any of the following mutations in the CFTR gene: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D. In certain embodiments, the second therapeutic agent is an agent usefol m the treatment of cystic fibrosis in a human patient having any of the following mutations in the CFTR gene:

G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R and R117H.

In one embodiment, the second therapeutic agent is VX-809 (lumacaftor) or VX-661 (tezacaftor). In certain embodiments, the subject is a human patient having the AF508-CFTR mutation (in particular, a human patient homozygous for the F508del mutation).

In another embodiment, the invention provides separate dosage forms of Compoundi (I) or (II), or a pharmaceutically acceptable sait thereof, and one or more of any of the abovedescribed second Lheiapeulic agents, wherein Compound (I) or (II), or a pharmacenticfilly= âccëptâblFsâirtlïërëôf,âhd^_sëcônd“Îh^ap“eutic^_agent“are-associated-with-one-aiiother-^The .......-— term “associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or sîmultaneously).

In the pharmaceutical compositions of the invention, Compound (I) or (II), or a pharmaceutically acceptable sait thereof, is présent in an effective amount. As used herein, the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.

The invention also provides a product that includes a) a pharmaceutical composition comprising Compound I or II, or a sait thereof, in an amount in the range of 50 mg to 200 mg; and b) prescribing information for administering Compound I or II, or a sait thereof. The prescribing information includes instructions to administer 50 mg to 200 mg of Compound I or II, or a sait thereof, once per day to a subject in need of such treatment, e.g., a subject suffering from or susceptible to a condition that is mediated by CFTR, such as cystic fibrosis.

_____________Tfap interrplationship of dosages for animais and humans (based on milligrams per___________________ rneter sqi.mred of body surface) is described in FreireiclictaVCancer Ch^nôtherrReprl-9Ù6, .............—~

50: 219. Body surface area may be approximately determined from height and weight of the subject. See, e.g, Scientifïc Tables, Geigy Pharmaceuticals, Ardsley, N.Y, 1970, 537.

Définitions

The term “treat” means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g, a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interfères with the normal fonction of a cell, tissue, or organ. ’ «

!

i

It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a préparation of ivacaftor will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15; Garnies, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

In Compound (I) or (II) any atom not spcuifiually dcsignatcd as a particular isotope+s= meant to repfësëht any stablëTsôÎôpe onfiâTâtoïn. ünlëss’ôthswtse statedywhema^Osition.......

is designated specifically as “H” or “hydrogen”, the position is understood to hâve hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium”, the position is understood to hâve deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium).

The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

In other embodiments, a compound of this invention (i.e., Compound I or Compound II) has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3

------0241^%-dculsrixn^^ ---------------------------------------------------The term “isotopologue” refers to a species in which the chemical structure differs from Compound (I) or (II) only in the isotopic composition thereof.

The term “compound,” when referring to a compound of this invention, refers to a collection of molécules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molécules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will dépend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the cfficicncy of incorporation of deuterium in the various synthesis steps used to prépare the compound.

The invention also provides salts of Compound (I) or (II). A sait of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition sait.

The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergie response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable sait” means any non-toxic sait that, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound of this invention. A “pharmaceutically acceptable counterion” is an ionic portion of a sait that is not toxic when released from the sait upon administration to a récipient.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts .monoh-ydrogenphosphate,-dihydrogenphosphate,-met aphosphate,-pyrophosphate,-chloride,--bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malcate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, βhydroxybutyrate, glycolate, maleate, tartrate, methanesulfonatc, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with minerai acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

The term “stable compounds,” as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

ne term bioéquivalent, as used herein, means a drug product snowing me absence of a significant différence in the rate and extent to which the active ingrédient or active moiety in a pharmaceutical équivalent to the drug product becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study, wherein “significant différence” means that the 90% Confidence Intervals (CI) of the test drug product must fit between 80%-125% of the reference drug product (see Online Training Seminar: “The FDA Process for Approving Generic Drugs”; www.fda.gov/Training/For HealthProfessionals/ucm090320.htm). The Food and Drug Administration (FDA) has issued guidelines regarding bioequivalent drug products including spécifie recommendations on the tolerable variation of inactive ingrédients in a drug product that would likely render it a pharmaceutically équivalent form. See, for example, the FDA's Guidance for Industry: Submission of Summary Bioequivalence Data for AND A s from May 2011, the entire contents of which are incorporât ed herein.

“D” and “d” both refer to deuterium. “Stereoisomer” refers to both enantiomers and diastereomers. “Tert” and “t-” each refer to tertiary. “US” refers to the United States of America.

-atoms-w-ith-a-GOirespondi-ng-number-of-deuter-i-um-atomsT·

Examples

Example 1. Phase 1 Single Ascending Dose (SAD) clinical trial

Ten healthy male and female volunteers were enrolled in a single ascending dose study of 3 doses of CTP-656 (75,150 and 300 mg), with a cross-over comparison of 150 mg CTP-656 and 150 mg Kalydeco® (the trade naine of ivacaftor) (Figure 5). Doses of CTP-656 were administered as an aqueous suspension, and Kalydeco was administered as a tablet. Ail doses of CTP-656 and Kalydeco were administered within 30 minutes after the start of a high-fat containing breakfast. There was a 7 day washout between doses. The objective of the study was to compare the pharmacokinetics of single ascending doses (75,150, and 300 mg) of CTP-656, to compare the pharmacokinetics of a single dose of 150 mg CTP-656 and 150 mg Kalydeco and to assess the safety and tolerability of CTP-656.

Overall, CTP-656 administered as single doses at doses 75 mg, 150 mg and 300 mg (following a high-fat meal) was generally well tolerated in healthy male and female subjects. Kalydeco® tablets, administered as a single oral dose of 150 mg (following a high-fat meal) were also generally well tolerated in healthy male and female subjects.

There were no clinically signifîcant différences in safety assessinenLs between CTP7)56/75 mg, Γ5Ό mg or 3Tr0Tng)~and”Kâlÿdëcô®^_(T5O mg) andlïcTapparent dose-relâtëdTfënds’.......

in subjects following CTP-656.

The T_max for CTP-656 was similar between each of the treatments, with the apparent terminal haif-life of 14-17 hours. The apparent terminal half-life of 150 mg of Kalydeco® (11.18 hours) was shorter than for CTP-656.

For CTP-656, the relationship between dose and exposure was found to be approximately linear using log-log régression analysis, with the increase in exposure being greater than dose proportional across dose levels (75 mg, 150 mg and 300 mg) (Figures la and 1b).

A summary of the pharmacokinetic properties of CTP-656 and Kalydeco is presented in the chart below:

Dosed Drug	CTP-656 75 mg	CTP-656 150 mg	Kalydeco 150 mg	CTP-656 300 mg
PK Parameter	Mean (CV%)
T max	5.00	5.00	5.00	5.00 /c nn 1 η
(hr)*1	(5.00-12.OU)	(5.00-10.00)	(3.00-12.00)	· xJ xz .L xz > xJkJ J
C max (ng/mL)	838 (22)	2,212 (26)	1,101 (46)	4,968 (23)
c V24hr (ng/mL)	270 (36)	712 (40)	169 (38)	1,540 (39)
AUC 0-mf (ng*hr/mL)	16,581 (31)	44,916 (36)	12,925 (32)	105,179 (34)

T1/2 (hr)	14.1 (17)	15.0 (21)	11.2 (16)	17.3 (14)
CL/F (L/hr)	4.9 (29)	3.8 (44)	13.3 (49)	3.2 (36)

^a Médian (Range)For 150 mg of CTP-656, C_max was approximately 2-fold, AUCo-inf was approximately 3.5-fold, and C₂4hr was 4.2-fold that of Kalydeco® tablets. The CL/F (clearance over bioavailability, a measure of the clearance of an orally-dosed drug) for CTP656 was approximately 30% thaï of Kalydeco® (Figure 2).

A comparison of the pharmacokinetic properties of CTP-656 and Kalydeco for the

150 dose is presented in the chart below:

Dosed Drug	CTP-656 (n=9)	Kalydeco (n=9)	Ratio of CTP-656 to Kalydeco
PK Parameter	Mean (CV%)
T max (hr)	a 5.0-10.0	a 3.0-10.0	—
^12hr (ng/mL)	1306.7 (27)	412.8 (33)	3.2
c 24111(ng/mL)	712.2 (40)	168.9 (38)	4.2
AUCn 0-24hr (ng*hr/mL)	27289.0 (29)	9876.4 (33)	2.8
C max (ng/mL)	2212.2 (26)	1101.0 (46)	2.0
T.„	15.00	11.18
(hr)	(21)	(16)	1.3

^arange

Therefore, based on the enhanced PK profile for CTP-656 relative to Kalydeco®,

CTP-656 has potential to show efficacy at doses in the range of 50-200 mg QD (once daily).

Example 2. Parent vs. Métabolite Pharmacokinetic Profile

As shown in Figure 3, deutération dramatically impacts the metabolism of the deuterated ivacaftor analog CTP-656 compared to ivacaftor after a single dose. Ivacaftor, CTP-656, and their métabolites are shown in Figure 6. There is a significant réduction in the production of the métabolites D8-M1 and D6-M6 from CTP-656 relative to the production of the métabolites Ml and M6 from ivacaftor. Thus, the parent-to-Ml ratio of AUCo-24hr for CTP656/D8-M1 is 2,0, compared to 0,58 for the ratio of ivacaftor to Ml, The parent-to-Ml ratio of Cmax and C₂4hr for CTP-656/D8-M1 are 2.1 and 2.2, respectively, compared to 0.54 and 0.55, respectively, for ivacaftor/Ml. Further, the parent-to-M6 ratio of AUCq.₂41u· for CTP656/D6-M6 is 4.0, compared to 1.5 for the ratio of ivacaftor to M6. The parent-to-M6 ratio of C_max and C₂4hr for CTP-656/D6-M6 are 4.3 and 2.5 respectively, compared to 1.4 and 0.97, respectively, for ivacaftor/M6. As seen in Figure 3 (a), CTP-656 is the most abundant species in plasma ai ail times measured, in comrasi io ivacaftor (b), where ihe Ml métabolite prédominâtes after 2 hours, and the levefôf the M6 métabolite reaches the lëvëTôf ivacaftor after about 8 hours. As a resuit, the most pharmacologically-active species (i.e., the parent) is the most abundant species for CTP-656, but not for ivacaftor.

CTP-656 PK Parameters: Parent/Metabolite Ratios
		c ^max	c ^24hr
CTP-656/D8-M1	2.0	2.1	2.2
CTP-656/D6-M6	4.0	4.3	2.5
Ivacaftor PK Parameters: Parent/Metabolite Ratios
	AUCn 0-24hr	c ^max	C241U-
Ivacaftor/Ml	0.58	0.54	0.55
Ivacaftor/M6	1.5	1.4	0.97

In summary, CTP-656 demonstrated a superior pharmacokinetic profile compared to Kalydeco, the current standard of care for treatment of cystic fibrosis patients. Results of the Phase 1 trial also showed that CTP-656 was well-tolerated and its safety profile was -Gompar-able-to-Kal-ydeGO^-In-the-Rhase-l-Gross-over-Gompar-i-son-ofGTP-656-and-Kal-ydeG05— CTP-656 demonstrated a superior pharmacokinetic profile compared to Kalydeco including a reduced rate of clearance, longer half-life, substantially increased exposure and greater plasma levels at 24 hours. An analysis of métabolites in plasma also showed that the overall exposure profile of CTP-656 differed from that of Kalydeco in that the majority of plasma exposure in the case of CTP-656 was due to parent drug, whereas with Kalydeco the majority of plasma exposure was due to a less-active métabolite and an approximately équivalent amount of an inactive métabolite was also observed. It is believed that the longer half-life and lower métabolite levels measured for CTP-656 offer a dosing advantage to the patient.

Example 3- Measurement of CTP-656 and Ivacaftor activity

Chloride transport of G551D-CFTR overexpressed in Fischer Rat Thyroid cells was measured in an Ussing chamber apparatus. The short circuit current (Isc) was monitored after basolateral permeabilization with 100 μΜ amphotericin and activation of CFTR by 10 μΜ forskolin. Testing was performed in the presence of a chloride gradient at 35°C. Test articles were applied in an additive and sequential manner to epithelia at 0.0008 μΜ, 0.004 μΜ, 0.02 μΜ, and 0.1 μΜ along with 0.5 μΕ, 2.0 μΕ, 0.5 μΕ, and 2.5 μΕ additions of the DMSO vehicle. Values are the means of responses from each test concentration applied to six epithelia. (Figme4A)

......Chlofidéfransport ofhomozygous F508dël-CFTR human broncKiâT^itKëliârcëll ............ monolayers (patient code CFFT027G) was measured in an Using chamber apparatus. The short circuit current (Isc) was monitored after blockade of sodium current through the épithélial sodium channel (ENaC) with 30 μΜ amiloride and activation of CFTR by 10 μΜ forskolin. Symmetric physiologie saline solutions at 27°C were used for température correction of F508del-CFTR. Test articles were applied in an additive and sequential manner to epithelia at 0.0008 μΜ, 0.004 μΜ, 0.02 μΜ, and 0.1 μΜ along with 0.5 μΕ, 2.0 μΕ, 0.5 μΕ, and 2.5 μΕ additions of the DMSO vehicle. Values are the means of responses from each test concentration applied to six epithelia. (Figure 4B and Figure 4C).

Therefore, D9-, D18-ivacaftor and ivacaftor provided équivalent in vitro CFTR potentiation.

Example 4- Human Crossover Study for D9-ivacaftor and D18-ivacaftor Six healthy volunteers were enrolled in a cross-over comparison of 25 mg D9-ivacaftor (CTP-656) and 25 mg D18-ivacaftor (Figure 7A). The objective of the study was to compare the pharmacokinetics of a single dose of 25 mg D9-ivacaftor and 25 mg D18-ivacaftor. Doses

AlLdosesrofJT9J.Ya_caftorXClTP_r6.5_6Xand_D18-i.vacaftor_v,Ler_e_administered_to_fastod_subje.cts_____ (three subjects per group). There was a 7 day washout between doses.

A comparison of the pharmacokinetic properties of D9-ivacaftor and D18-ivacaftor is presented in the chart below:

Dosed Drug	D9-ivacaftor	D18-ivacaftor
PK Parameter	Mean (CV%)

	T max (hr)a	3.0 (2.0-4.0)	2.5 (2.0-5.0)
C max (ng/mL)	270 (24)	233 (18)
r ^24hr (ng/mL)	52.6 (28)	42.3 (16)
AUC„. f O-inf /ng*hr/mr.i	3,812 (26)	3,196 (T 5)

—Medi-an-(-Range)

It was found that D9-ivacaftor showed a superior PK profile compared to D18ivacaftor (Figure 7B).

Example 5- Préparation of tablet form

CTP-656 (D9-ivacaftor) (17.1% by weight of an 80% amorphous dispersion) was blended with micro crystalline cellulose (Avicel PHI 01) (39.00 percent by weight), lactose monohydrate 316 (38.9 percent by weight) sodium lauryl sulfate (0.50 percent by weight), croscarmellose sodium (Ac-di-sol) (1.50 percent by weight) and Hyqual magnésium stéarate (0.20 percent by weight) in a bottle blender. The blend was compacted and milled to form granules, which are sieved through #20 and #80 mesh sieves. The granules and remaining fines are blended with additional croscarmellose sodium (Ac-di-sol) (1.50 percent by weight), colloïdal silicon dioxide (0.50 percent by weight) and additional Hyqual magnésium stéarate (0.80 percent by weight), and the final blend compressed into tablets using a rotary press. Each tablet contains 75 mg CTP-656 (D9-ivacaftor).

Example 6- Human Crossover Study for D9-ivacaftor and ivacaftor

Healthy volunteers were enrolled in a cross-over comparison of 150 mg D9-ivacaftor (CTPfî;56“)“ândT“5O mg ivacaftaT(lCalydëco)ÇFigure 8Tlcft panel)rTlïFô1yëctîvëôfÎhë^füdy was tô“ compare the safety, tolerability, and pharmacokinetics of a single dose of 150 mg D9ivacaftor and 150 mg ivacaftor. Doses of D9-ivacaftor (CTP-656) and ivacaftor were administered as tablets (the D9-ivacaftor was administered as two 75 mg tablets). Ail doses of D9-ivacaftor (CTP-656) and D18-ivacaftor were administered to fed subjects (high fat breakfast) (four subjects per sequence). There was a 7 day washoui between doses. Blood samples were taken at intervals.

The results are shown in Figures 9 and 10. It was found that CTP-656 had approximately 3-fold enhanced C₂4h,· and AUCo_₂4hr compared to ivacaftor (Figure 9). Oral

19045 clearance of CTP-656 was about one-third that of ivacaftor. The half-life of CTP-656 was about 15 hours, which is about 40% greater than the half-life of ivacaftor (about 11 hours). Further, the ratio of CTP-656 to métabolites D-Ml and D-M6 (see Figure 6) was higher than the ratio of ivacaftor to the métabolites Ml and M6 (Figure 10). Example 7- Human Multiple Ascending Dose Study for D9-ivacaftor Healthy volunteers were enrolled in a multiple-ascending dose study of D9-ivacaftor (CTP656) (Figure 8, right panel). The objective of the study was to compare the safety, tolerability, and pharmacokinetics of D9-ivacaftor at three doses for seven days, compared to
piaceoo. uoses oi L/y-ivacanor anu piaceoo were aumimsiereu. as laoieis (me uy- ivacaftor was administered as one, two or three 75 mg tablets, for doses of 75 mg, 150 mg, of 225 mg). Ail doses of D9-ivacaftor (CTP-656) were administered to fed subjects (high fat breakfast) (8 subjects per sequence received CTP-656, two subjects per sequence received placebo). There was a 7 day washout between doses. Blood samples were taken at intervals and the plasma concentration of CTP-656. The results are shown in Figure 11. It was found that steady state plasma levels of CTP-656 were reached after about three days of dosing. CTP-656 showed a doseproportional increase in exposure with repeated dosing for the 150 mg dose relative to the 75 mg dose. The 225 mg dose group showed higher than dose-proportional exposure. The ratio of CTP-656 to métabolites D-Ml and D-M6 in plasma was greater than one, The CTP-656 and D-Ml accumulation ratio was about 1-6 to 1.8 for key exposure parameters C24hr and AUCo_24hi·· No serious adverse events were reported; the majority of adverse events reported were mild in severity. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative ex amples, make and utilize the rnmpannd<5 c£the present În ventÎan and practice tbe c.la.imed methods; Tt qhnnld be
............................under.sto.o.d-thaLthe-fbr.e.g()ing-discussion_and_examples_merel.y_pr.cscnt_a_dc.tailcd_description............................. of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and équivalents can be made without departing from the spirit and scope of the invention.

Claims (34)

1. We claim:

   1. A compound represented by the following structural formula:

   H (Compound (I)), or a pharmaceuticaîly acceptable sait thereof, for use in a method of treating a condition that is mediated by CFTR, wherein the mpthnrl rnmprkps admînigterincr 5Π mo tn ΛΠΠ mg nf Cnmpniind (T) nr a pharmacRnticaHy

   -----------aeeeptable-salt-thereof^onGe-per-da-y;---------------
2. 2. The compound for use of claim 1, wherein the method comprises administering 50 mg to

   200 mg of Compound (I) or a pharmaceuticaîly acceptable sait thereof, once per day.
3. 3. The compound for use of claim 1, wherein the condition is cystic fibrosis.
4. 4. The compound for use of claim 1, wherein the method comprises administering 50 mg of Compound (I) or a pharmaceuticaîly acceptable sait thereof, once per day.
5. 5. The compound for use of claim 1, wherein the method comprises administering 75 mg of Compound (I) or a pharmaceuticaîly acceptable sait thereof, once per day.
6. 6. The compound for use of claim 1, wherein the method comprises administering 150 mg of Compound (I) or a pharmaceuticaîly acceptable sait thereof, once per day.
7. 7. The compound for use of claim 1, wherein temëthüdqxjn^rises^dimiristeriïig^S mg σί Compound (I) or a pharmaceuticaîly acceptable sait thereof, once per day.
8. 8. The compound for use of claim 1, wherein the method comprises administering 300 mg of Compound (I) or a pharmaceuticaîly acceptable sait thereof, once per day.
9. 9. The compound for use of claim 1, wherein method comprises administering Compound (I) in combination with one or more additional therapeutic agents.

   I !

   !

   i i

   ΙΟ. The compound for use of claim 9, wherein the one or more additional therapeutic agents comprises an agent useful in the treatment of cystic fibrosis.
10. 11. The compound for use of claim 9, wherein the one or more additional therapeutic agents comprises lumacaftor or tezacaftor.
11. 12. The compound for use of claim 1, wherein Compound (I) is administered orally.
12. 13. The compuinid foi use uf claim 12, wherein Compound (I) is adminisLered in a

    ThâmïâcëütiCârfôrmïnâtiôffwlïicKiFâtâblët? ........
13. 14. The compound for use of claim 12, wherein Compound (I) is administered in a pharmaceutical formulation which is a granule.
14. 15. The compound for use of claim 1, wherein any atom in Compound (I) or a pharmaceutically acceptable sait thereof not designated as deuterium is présent at its naturel isotopic abundance.
15. 16. The compound for use of claim 1, wherein the isotopic enrichment for each designated deuterium atom in Compound (I) or a pharmaceutically acceptable sait thereof is at least 90%.
16. 17. The compound for use of claim 1, wherein the isotopic enrichment for each designated deuterium atom in Compound (I) or a pharmaceutically acceptable sait thereof is at least _
17. 18. The compound for use of claim 1, wherein the isotopic enrichment for each designated deuterium atom in Compound (I) or a pharmaceutically acceptable sait thereof is at least 97%.
18. 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 50 mg to 300 mg of a compound represented by the following structural formula:

    ^H (Compound (I)), or a pharmaceutically acceptable sait thereof.
19. 20. The pharmaceutical composition of claim 19, comprising 50 mg to 200 mg of Compound (I) or a pharmaoenticÎilly acceptable sait thereof.
20. 21. The pharmaceutical composition of claim 19, comprising 50 mg of Compound (I) or a pharmaceutically acceptable sait thereof.
21. 22. The pharmaceutical composition of claim 19, comprising 75 mg of Compound (I) or a pharmaceutically acceptable sait thereof.
22. 23. The pharmaceutical composition of claim 19, comprising 150 mg of Compound (I) or a pharmaceutically acceptable sait thereof.
23. 24. The pharmaceutical composition of claim 19, comprising 225 mg of Compound (I) or a pharmaceutically acceptable sait thereof.
24. 25. The pharmaceutical composition of claim 19, comprising 300 mg of Compound (I) or a pharmaceutically acceptable sait thereof.

    '2'6. Thëpharmaceuficâl composition of claim l’97wherein the composition further comprises one or more additional therapeutic agents.
25. 27. The pharmaceutical composition of claim 19, wherein the one or more additional therapeutic agents comprises an agent useful in the treatment of cystic fibrosis.
26. 28. The pharmaceutical composition of claim 19, wherein the one or more additional therapeutic agents comprises lumacaftor or tezacaftor.
27. 29. The pharmaceutical composition, of claim 19, wherein the pharmaceutical composition is suitable for oral administration.
28. 30. The pharmaceutical composition of claim 29, wherein the composition is a tablet.
29. 31. The pharmaceutical composition of claim 29, wherein the composition is a granule.
30. 32. The pharmaceutical composition of claim 19, wherein any atom in Compound (I) or a pharmaceutically acceptable sait thereof nul designated as deuLeiium is piesenl al its naLuial isotôpic’âb’ïmdmcë.
31. 33. The pharmaceutical composition of claim 19, wherein the isotopic enrichment for each designated deuterium atom in Compound (I) or a pharmaceutically acceptable sait thereof is at least 90%.
32. 34. The pharmaceutical composition of claim 19, wherein the isotopic enrichment for each designated deuterium atom in Compound (I) or a pharmaceutically acceptable sait thereof is at least 95%.
33. 35. The pharmaceutical composition of claim 19, wherein the isotopic enrichment for each designated deuterium atom in Compound (I) or a pharmaceutically acceptable sait thereof is at least 97%.
34. 36. The pharmaceutical composition of claim 19, wherein the composition is administered xmce-a-day,---------------------------------------------------------------------------------